-
ELife Jul 2024The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments can...
The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments can result from saturation of the plasticity mechanism (Nguyen-Vu et al., 2017), or, more generally, from a history-dependent change in the threshold for plasticity. This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-K and H2-D (MHCI KD), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here, we extend this work by testing predictions of the threshold metaplasticity hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the knockout mouse model of Fragile X syndrome (FXS). Mice lacking gene expression in cerebellar Purkinje cells (L7- KO) were selectively impaired on two oculomotor learning tasks in which PF-Purkinje cell LTD has been implicated, with no impairment on LTD-independent oculomotor learning tasks. Consistent with the threshold metaplasticity hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7- KO mice, as previously reported in MHCI KDmice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficits in L7- KO mice. These results support the hypothesis that cerebellar LTD-dependent learning is governed by an experience-dependent sliding threshold for plasticity. An increased threshold for LTD in response to elevated neural activity would tend to oppose firing rate stability, but could serve to stabilize synaptic weights and recently acquired memories. The metaplasticity perspective could inform the development of new clinical approaches for addressing learning impairments in autism and other disorders of the nervous system.
Topics: Animals; Fragile X Syndrome; Mice; Disease Models, Animal; Fragile X Mental Retardation Protein; Mice, Knockout; Purkinje Cells; Neuronal Plasticity; Male; Learning
PubMed: 38953282
DOI: 10.7554/eLife.92543 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Long-term treatment of anemia involving frequent blood transfusions and intravenous iron administration increases the risks of hepatic iron overload and steatosis in the... (Review)
Review
Long-term treatment of anemia involving frequent blood transfusions and intravenous iron administration increases the risks of hepatic iron overload and steatosis in the patients undergoing hemodialysis.Pathological accumulation of iron damages hepatocytes,not only elevating the risks of progressive hepatic fibrosis and cirrhosis but also potentially accelerating the process of hepatic steatosis.Iron overload and steatosis may interact with each other,exacerbating liver damage and ultimately leading to further deterioration of hepatic fibrosis and cirrhosis.MRI characterized by non-invasiveness and high repeatability,enables the simultaneous quantitative assessment of hepatic iron and fat content,providing crucial information for early diagnosis and intervention of liver diseases.In recent years,researchers have achieved significant advances in the application of MRI in the diagnosis and treatment of liver diseases.MRI can accurately reflect the extent of hepatic iron overload and steatosis in patients and predict the risk of liver diseases.This article reviews the latest advances,challenges,and perspectives in the application of MRI in assessing hepatic iron overload and steatosis in the patients undergoing hemodialysis,aiming to offer valuable references for clinical practice.
Topics: Humans; Iron Overload; Magnetic Resonance Imaging; Renal Dialysis; Fatty Liver; Liver
PubMed: 38953270
DOI: 10.3881/j.issn.1000-503X.16066 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024With the continuous development of identification technologies such as mass spectrometry,omics,and antibody technology,post-translational modification (PTM) has... (Review)
Review
With the continuous development of identification technologies such as mass spectrometry,omics,and antibody technology,post-translational modification (PTM) has demonstrated increasing potential in medical research.PTM as a novel chemical modification method provides new perspectives for the research on diseases.Succinylation as a novel modification has aroused the interest of more and more researchers.The available studies about succinylation mainly focus on a desuccinylase named sirtuin 5.This enzyme plays a key role in modification and has been preliminarily explored in cardiovascular studies.This paper summarizes the influencing factors and regulatory roles of succinylation and the links between succinylation and other PTMs and reviews the research progress of PTMs in the cardiovascular field,aiming to deepen the understanding about the role of this modification and give new insights to the research in this field.
Topics: Cardiovascular Diseases; Humans; Lysine; Protein Processing, Post-Translational; Succinic Acid
PubMed: 38953268
DOI: 10.3881/j.issn.1000-503X.15944 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Alzheimer's disease (AD) is a severe threat to human health and one of the three major causes of human death.Double-stranded RNA-dependent protein kinase (PKR) is an... (Review)
Review
Alzheimer's disease (AD) is a severe threat to human health and one of the three major causes of human death.Double-stranded RNA-dependent protein kinase (PKR) is an interferon-induced protein kinase involved in innate immunity.In the occurrence and development of AD,PKR is upregulated and continuously activated.On the one hand,the activation of PKR triggers an integrated stress response in brain cells.On the other hand,it indirectly upregulates the expression of β-site amyloid precursor protein cleaving enzyme 1 and facilitates the accumulation of amyloid-β protein (Aβ),which could activate PKR activator to further activate PKR,thus forming a sustained accumulation cycle of Aβ.In addition,PKR can promote Tau phosphorylation,thereby reducing microtubule stability in nerve cells.Inflammation in brain tissue,neurotoxicity resulted from Aβ accumulation,and disruption of microtubule stability led to the progression of AD and the declines of memory and cognitive function.Therefore,PKR is a key molecule in the development and progression of AD.Effective PKR detection can aid in the diagnosis and prediction of AD progression and provide opportunities for clinical treatment.The inhibitors targeting PKR are expected to control the activity of PKR,thereby controlling the progression of AD.Therefore,PKR could be a target for the development of therapeutic drugs for AD.
Topics: Alzheimer Disease; Humans; eIF-2 Kinase; Amyloid beta-Peptides; tau Proteins; Phosphorylation; Brain; Amyloid beta-Protein Precursor
PubMed: 38953267
DOI: 10.3881/j.issn.1000-503X.15792 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Primary liver cancer is one of the most common malignant tumors of the digestive system,of which hepatocellular carcinoma (HCC) accounts for more than 90% of the total... (Review)
Review
Primary liver cancer is one of the most common malignant tumors of the digestive system,of which hepatocellular carcinoma (HCC) accounts for more than 90% of the total cases.The patients with early HCC treated by surgical resection generally demonstrate good prognosis.However,due to the insidious onset,HCC in the vast majority of patients has progressed to the mid-to-late stage when being diagnosed.As a result,surgical treatment has unsatisfactory effects,and non-surgical treatment methods generally have severe side effects and low tumor selectivity.Nanoparticles (NP) with small sizes,large specific surface areas,and unique physical and chemical properties have become potential carriers for the delivery of therapeutic agents such as drugs,genes,and cytokines.The nano-delivery systems with NP as the carrier can regulate the metabolism and transformation of drugs,genes,and cytokines from time,space,and dose via functional modification,showing great potential in the treatment of HCC.This paper introduces the current status and advantages of several common nano-delivery systems,including organic nano-carriers,inorganic nano-carriers,and exosomes,in the treatment of HCC.Furthermore,this paper summarizes the mechanisms of NP-based nano-carriers in treating HCC and provides reference for the development of new nano-delivery systems.
Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Drug Delivery Systems; Nanoparticles; Nanotechnology; Drug Carriers
PubMed: 38953262
DOI: 10.3881/j.issn.1000-503X.15669 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Objective To explore the relationship between the expression levels of microRNA-155 (miR-155) and suppressor of cytokine signaling 1 (SOCS1) in the colonic mucosal...
[Correlations Between the Expression of MicroRNA-155 and Suppressor of Cytokine Signaling 1 in Colonic Mucosal Tissue and Disease Severity in Patients With Ulcerative Colitis].
Objective To explore the relationship between the expression levels of microRNA-155 (miR-155) and suppressor of cytokine signaling 1 (SOCS1) in the colonic mucosal tissue of patients with ulcerative colitis (UC) and the severity of the disease.Methods A total of 130 UC patients admitted to the Second Affiliated Hospital of Hebei North University from September 2021 to June 2023 were selected.According to the modified Mayo score system,the patients were assigned into an active stage group (=85) and a remission stage group (=45).According to the modified Truelove and Witts classification criteria,the UC patients at the active stage were assigned into a mild group (=35),a moderate group (=30),and a severe group (=20).A total of 90 healthy individuals who underwent colonoscopy for physical examination or those who had normal colonoscopy results after single polypectomy and excluded other diseases were selected as the control group.The colonic mucosal tissues of UC patients with obvious lesions and the colonic mucosal tissue 20 cm away from the anus of the control group were collected.The levels of miR-155 and SOCS1 mRNA in tissues were determined by fluorescence quantitative PCR,and the expression of SOCS1 protein in tissues was determined by immunohistochemistry.The correlations of the levels of miR-155 and SOCS1 mRNA in the colonic mucosal tissue with the modified Mayo score of UC patients were analyzed.The values of the levels of miR-155 and SOCS1 mRNA in predicting the occurrence of severe illness in the UC patients at the active stage were evaluated.Results Compared with the control group and the remission stage group,the active stage group showed up-regulated expression level of miR-155,down-regulated level of SOCS1 mRNA,and decreased positive rate of SOCS1 protein in the colonic mucosal tissue (all <0.001).The expression level of miR-155 and modified Mayo score in colonic mucosal tissues of UC patients at the active stage increased,while the mRNA level of SOCS1 was down-regulated as the disease evolved from being mild to severe (all <0.001).The modified Mayo score was positively correlated with the miR-155 level and negative correlated with the mRNA level of SOCS1 in colonic mucosal tissues of UC patients (all <0.001).The high miR-155 level (=2.762,95%=1.284-5.944,=0.009),low mRNA level of SOCS1 (=2.617,95%=1.302-5.258,=0.007),and modified Mayo score≥12 points (=3.232,95%=1.450-7.204,=0.004) were all risk factors for severe disease in the UC patients at the active stage.The area under curve of miR-155 combined with SOCS1 mRNA in predicting severe illness in the UC patients at the active stage was 0.920.Conclusions The expression levels of miR-155 and SOCS1 mRNA were correlated with the disease severity in the UC patients at the active stage.The combination of the two indicators demonstrates good performance in predicting the occurrence of severe illness in UC patients at the active stage.
Topics: Humans; MicroRNAs; Colitis, Ulcerative; Suppressor of Cytokine Signaling 1 Protein; Intestinal Mucosa; Severity of Illness Index; Colon; Female; Male; Middle Aged; Adult
PubMed: 38953257
DOI: 10.3881/j.issn.1000-503X.15863 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Objective To evaluate the value of SOX1 and PAX1 gene methylation detection in the secondary triage of high-grade cervical lesions.Methods Exfoliated cervical cells were...
Objective To evaluate the value of SOX1 and PAX1 gene methylation detection in the secondary triage of high-grade cervical lesions.Methods Exfoliated cervical cells were collected from 122 patients tested positive for human papilloma virus (HPV) and subjected to thin-prep cytologic test (TCT) and SOX1/PAX1 gene methylation tests.Results The HPV test combined with TCT showed the sensitivity of 95.24% and the specificity of 23.75% for detecting cervical intraepithelial neoplasia (CIN) grade 2 and above (CIN2+).After the addition of the SOX1/PAX1 gene methylation detection in secondary triage,the sensitivity for detecting CIN2+ was 83.33%,which had no statistically significant difference from the sensitivity of TCT combined with HPV test (=0.078).However,the specificity reached 77.50%,which was significantly higher than that of HPV test combined with TCT (<0.001).The SOX1/PAX1 gene methylation level in the CIN2+ group was higher than those in the normal cervical tissue and the CIN1 group(<0.001).The cut-off values of SOX1 and PAX1 gene methylation for CIN2+ detection were -11.81 and -11.98,respectively.Conclusion Adding the detection of SOX1/PAX1 gene methylation in secondary triage significantly improves the efficiency and accuracy of CIN2+ detection.
Topics: Humans; Female; Paired Box Transcription Factors; DNA Methylation; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; SOXB1 Transcription Factors; Adult; Middle Aged; Sensitivity and Specificity; Young Adult
PubMed: 38953256
DOI: 10.3881/j.issn.1000-503X.15734 -
[Expression Levels and Regulation of Selenoprotein Genes in Patients With Coronavirus Disease 2019].Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Objective To investigate the expression levels of selenoprotein genes in the patients with coronavirus disease 2019 (COVID-19) and the possible regulatory...
Objective To investigate the expression levels of selenoprotein genes in the patients with coronavirus disease 2019 (COVID-19) and the possible regulatory mechanisms.Methods The dataset GSE177477 was obtained from the Gene Expression Omnibus,consisting of a symptomatic group (=11),an asymptomatic group (=18),and a healthy control group (=18).The dataset was preprocessed to screen the differentially expressed genes (DEG) related to COVID-19,and gene ontology functional annotation and Kyoto encyclopedia of genes and genomes enrichment analysis were performed for the DEGs.The protein-protein interaction network of DEGs was established,and multivariate Logistic regression was employed to analyze the effects of selenoprotein genes on the presence/absence of symptoms in the patients with COVID-19.Results Compared with the healthy control,the symptomatic COVID-19 patients presented up-regulated expression of GPX1,GPX4,GPX6,DIO2,TXNRD1,SELENOF,SELENOK,SELENOS,SELENOT,and SELENOW and down-regulated expression of TXNRD2 and SELENON (all <0.05).The asymptomatic patients showcased up-regulated expression of GPX2,SELENOI,SELENOO,SELENOS,SELENOT,and SELENOW and down-regulated expression of SELP (all <0.05).The results of multivariate Logistic regression analysis showed that the abnormally high expression of GPX1 (=0.067,95%=0.005-0.904,=0.042) and SELENON (=56.663,95%=3.114-856.999,=0.006) was the risk factor for symptomatic COVID-19,and the abnormally high expression of SELP was a risk factor for asymptomatic COVID-19 (=15.000,95%=2.537-88.701,=0.003).Conclusions Selenoprotein genes with differential expression are involved in the regulation of COVID-19 development.The findings provide a new reference for the prevention and treatment of COVID-19.
Topics: Humans; Selenoproteins; COVID-19; SARS-CoV-2; Protein Interaction Maps
PubMed: 38953254
DOI: 10.3881/j.issn.1000-503X.15834 -
Gut and Liver Jul 2024Young Korean men are obligated to serve in the military for 18 to 21 months. We investigated the effects of military service on steatotic liver disease (SLD) and other...
BACKGROUND/AIMS
Young Korean men are obligated to serve in the military for 18 to 21 months. We investigated the effects of military service on steatotic liver disease (SLD) and other metabolic parameters.
METHODS
Pre-enlistment health check-up performed from 2019 to 2022 and in-service health check-up performed from 2020 to 2022 were merged as paired data. SLD was defined as a hepatic steatosis index of 36 or higher. Hypertension (HTN) and hypertriglyceridemia were also included in the analysis.
RESULTS
A total of 503,136 paired cases were included in the analysis. Comparing pre-enlistment and in-service health check-ups, the prevalence of SLD (22.2% vs 17.6%, p<0.001), HTN (7.6% vs 4.3%, p<0.001), and hypertriglyceridemia (8.1% vs 2.9%, p<0.001) decreased during military service. In terms of body mass index, the proportion of underweight (8.2% vs 1.4%, p<0.001) and severely obese (6.1% vs 4.9%, p<0.001) individuals decreased over time. Regarding factors associated with SLD development and resolution, age was positively associated with SLD development (odds ratio, 1.146; p<0.001) and a health check-up interval of <450 days was a protective factor for SLD development (odds ratio, 0.746; p<0.001). Those serving in the marines were less likely to develop SLD, whereas those serving in the navy were more likely to develop SLD. Serving in the army or the navy was negatively associated with SLD resolution, whereas serving in the air force was positively associated with SLD resolution.
CONCLUSIONS
The prevalence of SLD, HTN, and hypertriglyceridemia decreased substantially during Korean military service.
PubMed: 38953118
DOI: 10.5009/gnl240077 -
Frontiers in Pharmacology 2024Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and...
BACKGROUND
Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and animals. Here, we demonstrate the changes in hepatic metabolites and lipids and explain the underlying mechanism of ezetimibe in hepatic steatosis.
METHODS
We fed Otsuka Long-Evans Tokushima Fatty (OLETF) rats a high-fat diet (60 kcal % fat) with or vehicle (control) or ezetimibe (10 mg kg) via stomach gavage for 12 weeks and performed comprehensive metabolomic and lipidomic profiling of liver tissue. We used rat liver tissues, HepG2 hepatoma cell lines, and siRNA to explore the underlying mechanism.
RESULTS
In OLETF rats on a high-fat diet, ezetimibe showed improvements in metabolic parameters and reduction in hepatic fat accumulation. The comprehensive metabolomic and lipidomic profiling revealed significant changes in phospholipids, particularly phosphatidylcholines (PC), and alterations in the fatty acyl-chain composition in hepatic PCs. Further analyses involving gene expression and triglyceride assessments in rat liver tissues, HepG2 hepatoma cell lines, and siRNA experiments unveiled that ezetimibe's mechanism involves the upregulation of key phospholipid biosynthesis genes, CTP:phosphocholine cytidylyltransferase alpha and phosphatidylethanolamine N-methyl-transferase, and the phospholipid remodeling gene lysophosphatidylcholine acyltransferase 3.
CONCLUSION
This study demonstrate that ezetimibe improves metabolic parameters and reduces hepatic fat accumulation by influencing the composition and levels of phospholipids, specifically phosphatidylcholines, and by upregulating genes related to phospholipid biosynthesis and remodeling. These findings provide valuable insights into the molecular pathways through which ezetimibe mitigates hepatic fat accumulation, emphasizing the role of phospholipid metabolism.
PubMed: 38953111
DOI: 10.3389/fphar.2024.1406493