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Diabetes mellitus(DM)is a common metabolic disease,and its hyperglycemia can induce many complications and even threaten human health and life.Ferritinophagy,currently a research focus,has been proven to be related to the occurrence and development of DM and its complications.Ferritinophagy,which is cell-selective,is mediated by nuclear receptor coactivator 4(NCOA4),which degrades ferritin in autophagosomes and releases excessive iron ions so that irons are overloaded and ROS are accumulated.This process contributes to the upstream ferroptosis.This article reviews the mechanism of ferritinophagy and its pathogenesis in DM and its complications,and further analyzes the effects of regulated ferritinophagy on DM and its complications,pro-viding new insight into the prevention and treatment of DM and its complications.
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BACKGROUND:Autophagy and ferroptosis play important roles in the development of chronic kidney disease,but the molecular mechanisms and gene targets related to autophagy and ferroptosis in renal tissue of chronic kidney disease are still unclear. OBJECTIVE:To screen differentially expressed genes in chronic kidney disease-related datasets based on bioinformatics,and to explore potential key biomarkers suitable for screening renal function progression in patients with chronic kidney disease. METHODS:(1)The GSE137570 dataset was obtained from GEO database to screen the differentially expressed genes by Networkanalyst database analysis.Ferroptosis and autophagy related targets were obtained by OMIM,GENECARD,FerrDb and HAMdb databases.The respective data were intersected to obtain autophagy-ferroptosis related differentially expressed genes in chronic kidney disease for parallel enrichment analysis.The STRING website was used to construct the protein-protein interaction network of differentially expressed genes,which was imported into Cytoscape software and analyzed by MCODE and Cytohubba plug-in to screen potential core targets.Enrichment analysis was performed to obtain the functions of these potential core targets.(2)In the in vitro experiment,mouse renal tubular epithelial cells were divided into two groups:the control group received no intervention,while the model group was stimulated with 5 ng/mL transforming growth factor β1 for 24 hours to induce mesenchymal transformation of renal tubular epithelial cells.Flow cytometry was used to measure the levels of reactive oxygen species and changes in mitochondrial membrane potential in the cells.RT-PCR was employed to assess ferroptosis,autophagy-related markers,and the mRNA expression of potential core targets in the cells. RESULTS AND CONCLUSION:After screening the GSE137570 dataset,a total of 480 differentially expressed genes were obtained,including 104 upregulated genes and 376 downregulated genes(log2|(FC)|>1,P<0.05).There were 562 ferroptosis-related targets and 1 266 autophagy-related targets obtained from the OMIM,GENECARD,FerrDb,and HAMdb databases.Intersection of differentially expressed genes with ferroptosis-and autophagy-related targets yielded 15 ferroptosis-related targets and 18 autophagy-related targets,respectively.The enrichment analysis results indicate that ferroptosis-related differentially expressed genes are primarily involved in biological processes such as sulfur amino acid metabolism,neutrophil degranulation,and ferroptosis signaling pathways.Autophagy-related differentially expressed genes are mainly enriched in biological processes such as platelet degranulation,extracellular matrix degradation,and receptor tyrosine kinase signaling.After screened by MCODE and CytoHubba,key genes were identified in the protein-protein interaction network,including CD44,ALB,TIMP1,PLG,CCL2,and DPP4.Immune infiltration analysis results indicate that immune cells such as B cells,CD4+ T cells,NK cells,and monocytes show significant differential expression in renal tissue after chronic kidney disease,and the core targets are also significantly correlated with these immune cells(P<0.05).The results of receiver operator characteristic curve analysis further demonstrate that the pathological progression of chronic kidney disease can be effectively diagnosed by CD44,ALB,TIMP1,PLG,CCL2,and DPP4.Single-cell sequencing results show that,except for PLG,the expression of target genes in the renal tissue of mice in each model group is generally consistent with the results of this experiment.RT-PCR results demonstrate that,for the validation of autophagy and ferroptosis phenotypes,compared with the control group,the model group shows a significant decrease in mRNA expression of LC3B,Nrf2,and SLC7A11(P<0.05),and a significant increase in P62 mRNA expression(P<0.05).Regarding the validation of potential core targets,compared with the control group,the model group exhibits a significant decrease in mRNA expression of ALB and PLG(P<0.05),and a significant increase in TIMP1 and CCL2 mRNA expression(P<0.05).Overall,these findings indicate that,through bioinformatics analysis and experimental validation,CD44,ALB,TIMP1,PLG,and CCL2 are abnormally expressed in the renal tissue of patients with chronic kidney disease,closely correlated with estimated glomerular filtration rate and tubulointerstitial fibrosis,and maybe play a predictive role in the progression of chronic kidney disease.
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Cognitive decline is one of the main clinical symptoms of neurodegenerative diseases. There is no specific drug treatment, which seriously affects the quality of life and rehabilitation process of these patients. Non-invasive brain stimulation (NIBS) technology such as transcranial magnetic stimulation and transcranial electrical stimulation known as its advantages of non-invasive, painless, and easy to operate, has been used in clinical treatment of cognitive disorders. In particular, it has a good effect on improving cognitive functions such as memory, attention, orientation and language ability. In recent years, the study of cerebellar involvement in learning and memory through brain-cerebellar circuit has attracted much attention, and cerebellum has become a new target for NIBS technology exploration. However, the correlation between cerebellar NIBS and cognitive function regulation is still unclear. This paper aims to provide the evidences of the anatomic and functional basis of cerebellar involvement in cognitive function regulation and cerebellar non-invasive stimulation on cognitive function regulation.
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Objective:To explore the related factors affecting the prognosis of patients with tardive dyskinesia, in order to find the risk factors of poor prognosis.Methods:A retrospective cohort study was implemented to collect the data of 113 patients with tardive dyskinesia from the movement disorders clinic of the Department of Neurology, Peking Union Medical College Hospital by telephone follow-up. The main variables studied included gender, age, educational level, living environment, job, cigarette smoking, alcohol drinking, hypertension, diabetes, medication type, interval from taking medicine to dyskinesia, course of dyskinesia and intervention measures. The data were analyzed by the statistical software SPSS 25.0. The quantitative data analysis was done by normality test and descriptive statistics, and the qualitative data analysis was done by χ 2 test or Fisher exact probability test. The variables with P≤0.01 in univariate analysis were included in multivariate Logistic regression analysis. Results:Among the 113 patients, 16 patients (14.16%) were cured, 27 patients (23.89%) had obvious improvement, 25 patients (22.12%) had slight improvement, 26 patients (23.01%) had no obvious change, 15 patients (13.27%) had slight deterioration, and 4 patients (3.54%) had obvious deterioration. The good prognosis rate was 60.18%, and the poor prognosis rate was 39.82%. In single factor analysis, the related factors for poor prognosis included age>52 years (χ 2=15.07, P<0.001), educational level in secondary schools and below (χ 2=8.58, P=0.003), physical labor (χ 2=4.66, P=0.031), hypertension (χ 2 = 16.38, P<0.001), diabetes mellitus (χ 2=6.06, P=0.011), dyskinesia caused by first-generation antipsychotics, calcium channel blocker or flupentixol/melitracen tablets ( P<0.001), and the duration of dyskinesia more than 2 years (χ 2 =7.05, P=0.008). Multivariate Logistic regression analysis showed that the independent risk factors for poor prognosis of tardive dyskinesia included hypertension ( OR=3.60, 95% CI 1.17-11.05, P=0.025) and dyskinesia caused by first-generation antipsychotics, calcium channel blocker or flupentixol/melitracen tablets ( OR=3.14, 95% CI 1.21-8.16, P=0.019). Conclusions:Most patients with tardive dyskinesia have a good prognosis. Hypertension and dyskinesia caused by first-generation antipsychotics, calcium channel blocker or flupentixol/melitracen tablets are independent risk factors for poor prognosis.
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ObjectiveTo analyze the utilization of outcome indexes and other trial design elements in randomized controlled trials (RCTs) of Chinese medicine for diabetic kidney disease (DKD) and provide a basis for the design of clinical trials and the development of core outcome index sets for Chinese medicine treatment of DKD. MethodSeven medical databases (CNKI, Wanfang Data, VIP, SinoMed, etc.) and two clinical trial registration centers (clinicaltrials.gov and chinadrugtrials.org.cn) were searched for RCTs of Chinese medicine for DKD published in the past 5 years. The included studies were assessed for risk of bias using the Cochrane Handbook for Systematic Reviews of Interventions, and the outcome indexes and other trial design elements were statistically analyzed. ResultNinety-seven RCTs were enrolled, including five trial registration protocols. The overall risk of bias was found to be high in the included studies. Stage Ⅲ DKD (36 studies, 41.38%) and the Qi-Yin deficiency with blood stasis syndrome (16 studies, 26.23%) were the top DKD stage and traditional Chinese medicine (TCM) syndrome, respectively. The treatment duration ranged from 2 weeks to 96 weeks, with 12 weeks being the most common duration (52 studies, 56.52%). A total of 152 outcome indexes were used in 92 RCTs and five registered trials, with a frequency of 1 040 times. These indexes were classified into eight categories: Laboratory tests (blood), laboratory tests (urine), clinical efficacy, TCM syndrome score, quality of life scales, vital signs, other indexes, and other events. The most frequently used outcome indexes were serum creatinine (68 times, 70.10%), clinical response rate (55 times, 56.70%), fasting blood glucose (51 times, 52.58%), blood urea nitrogen (48 times, 49.48%), total cholesterol (47 times, 48.45%), and 24-hour urinary protein excretion (43 times, 44.33%). Safety indexes were used in 56 RCTs and two registered trials, with 53 different indexes and a frequency of 227 times. The most frequently used safety indexes were adverse reactions (49 times, 84.48%), liver function (28 times, 48.28%), complete blood count (24 times, 41.38%), electrocardiogram (17 times, 29.31%), and urinalysis (14 times, 24.14%). Ten RCTs and five registered trials reported primary outcome indexes, and 54 RCTs reported clinical response rates. ConclusionThe current design of outcome indexes in RCTs of Chinese medicine for DKD is not standardized. In the future, efforts should be made to develop core outcome index sets that highlight the characteristics of TCM, improve the quality of clinical research, and enhance the applicability of trial results.
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Objective:To explore the potential mechanism of Fuzheng Jiedu Decoction created by professor Yu Huiping in the treatment of primary immune thrombocytopenia (ITP) in children based on network pharmacology.Methods:The targets of Fuzheng Jiedu Decoction and ITP were retrieved within SymMap database and TCMID database, and all the common genes in the potential targets of the decoction and ITP were retained. The interaction relationship among the targets was obtained in the String database, and cluster analysis was conducted to obtain the core target group of Fuzheng Jiedu Decoction for ITP. In the David database, the potential KEGG Pathway was obtained through enrichment analysis, the Pathway of non-specific diseases was classified and selected, and a network of "Traditional Chinese Medicine - Target - Pathway" was constructed.Results:There are 500 potential targets for Fuzheng Jiedu Decoction to treat ITP. After Cluster analysis of PPI network, a total of 16 gene clusters were obtained, among which Cluster 1 score was 65.663, making it a potential core target group for Fuzheng Jiedu Decoction to treat ITP. The core enriched target group amounts to 114 pathways, and there were four first-level catalogs which includes Human Diseases (50%), Organismal Systems (25%), Environmental Information Processing (17%), and Cellular Processes (8%). Among them, TNF signaling pathway and HIF-1 signaling pathway were highly enriched for non-specific diseases. In the nodes of the network, The Chinese herbs with the highest Degree of aggregation in the network nodes were Agrimoniae herba (Degree=66), Glycyrrhizae radix et rhizoma praeparata cum melle (Degree=64), the target proteins were MAPK3 (Degree=51),MAPK1 (Degree=50),and the pathway was PI3K-Akt signaling pathway (Degree=29). Conclusion:Fuzheng Jiedu Decoction is mainly used to treat children's ITP with Agrimoniae herba and Glycyrrhizae radix et rhizoma praeparata cum melle,and it is related to the regulation of platelet number, adhesion and focusing.
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The ongoing global pandemic of coronavirus disease 2019 (COVID-19) has caused huge number of human deaths. Currently, there are no specific drugs or vaccines available for this virus. The viral polymerase is a promising antiviral target. However, the structure of COVID-19 virus polymerase is yet unknown. Here, we describe the near-atomic resolution structure of its core polymerase complex, consisting of nsp12 catalytic subunit and nsp7-nsp8 cofactors. This structure highly resembles the counterpart of SARS-CoV with conserved motifs for all viral RNA-dependent RNA polymerases, and suggests the mechanism for activation by cofactors. Biochemical studies revealed reduced activity of the core polymerase complex and lower thermostability of individual subunits of COVID-19 virus as compared to that of SARS-CoV. These findings provide important insights into RNA synthesis by coronavirus polymerase and indicate a well adaptation of COVID-19 virus towards humans with relatively lower body temperatures than the natural bat hosts.
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Objective To study the relationship between plasma neurodegenerative protein level and non-motor symptoms(NMS)in PD patients.Methods Eighty-four PD patients served as a PD group and 54age-matched persons undergoing physical examination served as a control group. The NMS of PD patients were assessed according to the HAMD scale.The plasma levels of tau,p-tau181,Aβ-42andα-syn were measured by ELISA and analyzed by Spearman correlation analysis and binary logistic regression analysis respectively.Results The FSS score and plasmaα-syn level were significantly higher while the plasma Aβ-42level was significantly lower in PD group than in control group(3.22±1.68 vs 1.89±1.16,P=0.000;320.00±64.91ng/L vs 277.78±52.75ng/L,P=0.000;267.61±77.75ng/L vs 321.80±49.41ng/L,P=0.001).No significant difference was detected in plasma tau and p-tau181levels between the two groups(P>0.05).The plasmaα-syn level was positively related with the FSS score(r=0.237,P=0.030)and was an influencing factor of FSS(OR=1.019,95%CI:1.006-1.032,P=0.004).Conclusion Plasma neurodegenerative protein level is related with NMS and plasmaα-syn level is a peripheral biomarker for fatigue in PD patients.
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Objective To investigate the changes of microstructure and blood perfusion of thalamus and basal ganglia in patients with untreated depressive disorder using diffusion kurtosis imaging (DKI) and three-dimensional arterial spin labeling (3D ASL) perfusion imaging.Methods Totally 21 untreated patients with depressive disorder (disease group) and 32 healthy volunteers (control group) underwent DKI,3D ASL and routine MR scanning were enrolled.DKI parameters (mean kurtosis [MK],axial kurtosis [Ka],radial kurtosis [Kr],fractional anisotropy [FA],mean diffusivity [MD],axial diffusivity [Da] and radial diffusivity [Dr]) and 3D ASL parameters (cerebral blood flow [CBF]) of bilateral heads of caudate nucleus,thalamus and putamens were measured and compared between the 2 groups.Results Compared with control group,Ka of left caudate head in disease group was significantly higher,while Kr was significantly lower (both P< 0.05).Ka of right putamens in disease group was significantly higher than that in control group (P<0.05).Compared with control group,CBF of left caudate head and bilateral putamens decreased significantly in disease group (all P<0.05).Conclusion Untreated depressed patients show abnormal DKI parameters and blood perfusion in basal ganglia,which indicating that microstructure integrity is impaired and blood perfusion decreases.The abnormalities in basal ganglia microstructure and blood perfusion may serve as one of the neuroimaging features of depressive disorders.
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BACKGROUND:Now experimental and clinical research on suitable bone substitutes for alveolar bone defects after dental implantation is an issue of concern.OBJECTIVE:To study the therapeutic effect of titanium core/bone morphogenetic protein (BMP) composite material on alveolar bone defects after immediate implant placement.METHODS:Twenty-four New Zealand rabbits were randomly assigned into normal group (no intervention),experimental group or control group.Animal models of bone femoral greater trochanter defect were made in the experimental and control groups.Dental implant and titanium core/BMP composite material were implanted in the experimental group,while dental implant and titanium core were implanted in the control group.Percentage of CD4+,CD8+ T lymphocytes,natural killer cell activity and interleukin 2 level were detected at postoperative 4 weeks;bone mineral density and osteogenesis around the implant were detected at postoperative 16 weeks through X-ray and histological examinations.RESULTS AND CONCLUSION:X-ray results showed that the bone mineral density in the experimental group was significantly higher than that in the control group (P < 0.05).Histological results showed that in the experimental group,different degrees of cell lysis around the composite,more bone cells and bone matrices were found,implant-bone osseointegration formed well,and red-dyed mature bone tissues were detective inside the implant.Compared with the experimental group,lower number of bone cells and fibrocytes were found in the control group.Additionally,the percentage of CD4+ and CD8+ T lymphocytes,natural killer cell activity and interleukin 2 level in the experimental group were significantly lower than those in the control group (P < 0.05).To conclude,the titanium core/BMP composite material can effectively repair alveolar bone defects after immediate implant placement to guide the growth of bone cells.
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<p><b>OBJECTIVE</b>To observe the effects of transcutaneous electrical acupoint stimulation (TEAS) on gastric emptying in patients undergoing selective surgery based on velocity of gastric emptying by ultrasonography.</p><p><b>METHODS</b>A total of 75 patients with selective operation of subarachnoid block at lower limb in the afternoon were randomly assigned to a TEAS group, a sham group and a control group, 25 patients in each one. All the patients were provided with semi-fluid diet at 8 a.m. The TEAS group was treated with TEAS 5 min after semi-fluid diets at bilateral Zusanli (ST 36) and Neiguan (PC 6) for 30 min, with frequency of 5 Hz and intensity which was 1 mA lower than the tolerance threshold. The sham group patients were stimulated at the same acupoints with current intensity which was 1 mA lower than the sensory threshold. The control group received no treatment. On the day of operation, and ultrasonography was given at time of empty stomach (T0), immediately after the semi-fluid diets (T1), and every 30 min after diets (T2-T6), respectively, to measure the gastric content and emptying time at semire-clining position and right lateral position.</p><p><b>RESULTS</b>The volume of gastric content in the three groups at T3-T6 was significantly less than that at T1 (all<0.05). The volume of gastric content at T4-T6 at semire-clining position in the TEAS group was significantly less than that in the control group and sham group (all<0.05). The volume of gastric content at T5-T6 at right lateral position in the TEAS group was significantly less than that in the control group and sham group (all<0.05). The gastric emptying time in the TEAS group was significantly less than that in the control group and sham group (both<0.05).</p><p><b>CONCLUSION</b>The gastric emptying velocity could be evaluated by ultrasonography. TEAS could improve the velocity of gastric emptying and reduce the gastric emptying time.</p>
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Objective To investigate whether the combination of maintenance hemodialysis (MHD) with hemoperfusion (HP) could improve the left ventricular structure and function of MHD patients with resistant hypertension. Methods This study was a prospective, randomized, controlled clinical trial. 65 MHD patients with resistant hypertension of our hospital were enrolled and then randomly divided into Group HD+HP and Group HD. The follow-up study was 12 months. The major outcome measures were related to the cardiac structure and function, and the serum inflammatory factors. Results No statistical differences of related factors such as blood pressure and cardiac function was observed in HD group. The serum concentration of inflammatory factors was higher after one-year HD treatment alone. But the serum concentration of inflammatory related factors , blood pressure, cardiac function and related indexes were lower in HD + HP than in Group HD (P < 0.05);HD + HP group had higher ejection fraction (EF) and SV, which demonstrated the improved cardiac function (P < 0.05). Conclusions HD + HP was superior to HD in the treatment in alleviating cardiac after-load and improving the left ventricular structure and function of MHD patients with resistance hypertension.