ObjectiveTo investigate the effects of the classical Chinese medicine compound prescription Erjingwan on the inflammatory response and apoptosis of skeletal muscle cells in a mouse model of sarcopenia and decipher the mechanism based on the silent information regulator 1 （SIRT1）/nuclear factor erythroid 2-related factor 2 （Nrf2）/heme oxygenase-1 （HO-1） signaling pathway. MethodsForty C57/BL6 male mice were randomized into a control group， a model group， and groups with different doses of Erjingwan （8，16，32 g·kg^-1）. The mouse model of sarcopenia was established by D-gal-induced skeletal muscle senescence. The body weight and grip strength of mice treated with different doses of Erjingwan were examined to evaluate their physiological functions. Hematoxylin-eosin （HE） staining and Masson staining were used to observe the pathological changes and fibrosis in the skeletal muscle of mice. Enzyme-linked immunosorbent assay （ELISA） was adopted to determine the levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in the serum samples of mice， and biochemical tests were conducted to quantify the levels of superoxide dismutase （SOD）， malondialdehyde （MDA）， and glutathione （GSH） in the serum. The protein and mRNA levels of SIRT1， Nrf2， B-cell lymphoma （Bcl-2）， and Bcl-2-associated X protein （Bax） were determined by Western blot and Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）， respectively. ResultsAfter 4 weeks of drug intervention， the model group exhibited significant reductions in body weight and grip strength （P0.01） compared with the control group. Compared with the model group， all doses of Erjingwan increased the body weight in mice at week 8 （P0.01） and grip strength from week 6 （P0.01）. HE staining revealed clear muscle fiber structure in the control group， muscle fiber rupture and atrophy in the model group， and dose-dependent repair of muscle fiber structure in the Erjingwan groups. Masson staining showed minimal collagen fibers and mild fibrosis in the control group， collagen fiber proliferation and severe fibrosis in the model group， and collagen proliferation with dose-dependent inhibition of fibrosis in the Erjingwan groups. ELISA results showed that serum levels of TNF-α and IL-6 were elevated in the model group compared with those in the control group （P0.01）. After intervention， the low-dose Erjingwan group exhibited a decreased TNF-α level （P0.05）， while the medium and high-dose groups showed decreases in both TNF-α and IL-6 levels （P0.01）. Biochemical assays revealed that the model group had decreased SOD and GSH levels （P0.01） and an increased MDA level （P0.01） compared with the control group. The medium and high-dose Erjingwan groups exhibited increases in SOD and GSH levels （P0.01） and decreases in MDA level （P0.01）， compared with the model group. WB and Real-time PCR results showed that compared with the control group， the model group presented down-regulated protein and mRNA levels of SIRT1， Nrf2， HO-1， and Bcl-2 in the muscle tissue （P0.01） and up-regulated protein and mRNA levels of Bax （P0.01）. Compared with the model group， Erjingwan at different doses up-regulated the protein levels of SIRT1， Nrf2， HO-1， and Bcl-2 （P0.01） and down-regulated the protein and mRNA levels of Bax （P0.01） in the muscle tissue. Low-dose Erjingwan elevated the mRNA levels of Nrf2 and HO-1 （P0.05， P0.01）， and medium and high-dose Erjingwan up-regulated the mRNA levels of SIRT1， Nrf2， HO-1， and Bcl-2 （P0.01）. ConclusionErjingwan reduced the content of inflammatory factors in skeletal muscle cells， improved the antioxidant capacity， and attenuated pathological changes and fibrosis in the muscle of the mouse model of sarcopenia by regulating the SIRT1/Nrf2/HO-1 pathway， inflammatory response， and apoptosis network.

ObjectiveTo investigate the effects of the classical Chinese medicine compound prescription Erjingwan on the inflammatory response and apoptosis of skeletal muscle cells in a mouse model of sarcopenia and decipher the mechanism based on the silent information regulator 1 （SIRT1）/nuclear factor erythroid 2-related factor 2 （Nrf2）/heme oxygenase-1 （HO-1） signaling pathway. MethodsForty C57/BL6 male mice were randomized into a control group， a model group， and groups with different doses of Erjingwan （8，16，32 g·kg^-1）. The mouse model of sarcopenia was established by D-gal-induced skeletal muscle senescence. The body weight and grip strength of mice treated with different doses of Erjingwan were examined to evaluate their physiological functions. Hematoxylin-eosin （HE） staining and Masson staining were used to observe the pathological changes and fibrosis in the skeletal muscle of mice. Enzyme-linked immunosorbent assay （ELISA） was adopted to determine the levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in the serum samples of mice， and biochemical tests were conducted to quantify the levels of superoxide dismutase （SOD）， malondialdehyde （MDA）， and glutathione （GSH） in the serum. The protein and mRNA levels of SIRT1， Nrf2， B-cell lymphoma （Bcl-2）， and Bcl-2-associated X protein （Bax） were determined by Western blot and Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）， respectively. ResultsAfter 4 weeks of drug intervention， the model group exhibited significant reductions in body weight and grip strength （P0.01） compared with the control group. Compared with the model group， all doses of Erjingwan increased the body weight in mice at week 8 （P0.01） and grip strength from week 6 （P0.01）. HE staining revealed clear muscle fiber structure in the control group， muscle fiber rupture and atrophy in the model group， and dose-dependent repair of muscle fiber structure in the Erjingwan groups. Masson staining showed minimal collagen fibers and mild fibrosis in the control group， collagen fiber proliferation and severe fibrosis in the model group， and collagen proliferation with dose-dependent inhibition of fibrosis in the Erjingwan groups. ELISA results showed that serum levels of TNF-α and IL-6 were elevated in the model group compared with those in the control group （P0.01）. After intervention， the low-dose Erjingwan group exhibited a decreased TNF-α level （P0.05）， while the medium and high-dose groups showed decreases in both TNF-α and IL-6 levels （P0.01）. Biochemical assays revealed that the model group had decreased SOD and GSH levels （P0.01） and an increased MDA level （P0.01） compared with the control group. The medium and high-dose Erjingwan groups exhibited increases in SOD and GSH levels （P0.01） and decreases in MDA level （P0.01）， compared with the model group. WB and Real-time PCR results showed that compared with the control group， the model group presented down-regulated protein and mRNA levels of SIRT1， Nrf2， HO-1， and Bcl-2 in the muscle tissue （P0.01） and up-regulated protein and mRNA levels of Bax （P0.01）. Compared with the model group， Erjingwan at different doses up-regulated the protein levels of SIRT1， Nrf2， HO-1， and Bcl-2 （P0.01） and down-regulated the protein and mRNA levels of Bax （P0.01） in the muscle tissue. Low-dose Erjingwan elevated the mRNA levels of Nrf2 and HO-1 （P0.05， P0.01）， and medium and high-dose Erjingwan up-regulated the mRNA levels of SIRT1， Nrf2， HO-1， and Bcl-2 （P0.01）. ConclusionErjingwan reduced the content of inflammatory factors in skeletal muscle cells， improved the antioxidant capacity， and attenuated pathological changes and fibrosis in the muscle of the mouse model of sarcopenia by regulating the SIRT1/Nrf2/HO-1 pathway， inflammatory response， and apoptosis network.

BACKGROUND:Differentially expressed RNA-binding proteins in the intervertebral disc plays a key role in intervertebral disc degeneration,and decreased levels of the RNA-binding protein KRT18 are associated with degenerative disc disease,but its specific role in the nucleus pulposus cells has not yet been fully determined. OBJECTIVE:To investigate the interaction of KRT18 with mRNA and long non-coding RNA on nucleus pulposus cells of the intervertebral disc and its mechanism. METHODS:Normal and degenerated nucleus pulposus cells were obtained from nucleus pulposus samples of patients undergoing interbody fusion for lumbar fracture or intervertebral disc degeneration.iRIP-seq,functional enrichment analysis,and DNA microarray analysis were performed to identify the mRNA and long non-coding RNA binding with KRT18.Subsequently,KRT18 was knocked down in nucleus pulposus cells based on the analysis results,and the expression levels of related genes were detected at the protein and RNA levels through protein immunoblotting and qRT-PCR,respectively. RESULTS AND CONCLUSION:Through iRIP-seq analysis,we identified abundant KRT18 binding sites within the GUAAUC and AGCCUC sequences,indicating that KRT18 may be involved in regulating RNA transcription,translation,stability or play a role in cell signaling pathways.It can stably bind to mature mRNA,among which highly expressed genes include CRLF1,IGFBP4,etc.At the same time,the peak genes of long non-coding RNA binding with it include SNHG25,SNHG12,NEAT1,USP32,EIF4A2 and CDH4.Most of these genes are involved in various biological processes such as apoptosis and inflammation,and can mediate related pathways of extracellular matrix metabolism.KRT18 can regulate their stability,transport,translation,splicing and other functions,thus affecting gene expression and cell function.We further verified through experiments the knockdown of KRT18 in nucleus pulposus cells,and found that the level of extracellular matrix metabolism was inhibited and unbalanced,resulting in intervertebral disc degeneration in vitro.This study investigated the regulatory mechanism of KRT18 from the perspective of its binding with mRNA and long non-coding RNA for the first time,and speculated the potential function of KRT18 in the pathogenesis of intervertebral disc degeneration,laying a foundation for future research on the key functions of KRT18.

BACKGROUND: The use of potentially inappropriate medications (PIMs) is a major concern for medication safety as it may entail more harm than potential benefits for older adults. This study aimed to explore the prescribing rate, healthcare utilization, and expenditure of older adults using PIMs in China. METHODS: A cross-sectional analysis was conducted using a national representative database of all medical insurance beneficiaries across China, extracting ambulatory visit records of adults aged 65 years and above between 2015 and 2017. Descriptive analysis was conducted to measure the rate of patients exposed to PIM, prescribing rate of each PIM, average annual outpatient visits per patient, average total medication costs for each visit, average annual cost of PIMs for each patient, and average annual medication costs for each patient. Generalized linear model with logit link function and binomial distribution was used to examine the adjusted associations between PIMs and independent variables. RESULTS: In total, 845,278 (33.2%) participants were identified to be exposed to at least one PIM. Patients aged 75-84 years (38.1%, 969,809/2,545,430) and ≥85 years (37.9%, 964,718/2,545,430) were more likely to be prescribed with PIMs. Beneficiaries of the Urban Employee Basic Medical Insurance (UEBMI) and living in eastern and southern regions were more frequently prescribed with PIMs. Compared with patients without PIM exposure (7.5 visits, drug cost of RMB 1545.0 Yuan), patients with PIM exposure showed higher adjusted average annual number of outpatient visits (10.7 visits, β = 3.228, 95% confidence interval [CI] = 3.196-3.261) and higher annual drug costs (RMB 2461.8 Yuan, Coef. = 916.864, 95% CI = RMB 906.292-927.436 Yuan). CONCLUSIONS The results showed that the use of PIM among older adults was common in China. This study suggests that the use of PIM could be considered as a clear target, pending multidimensional efforts, to promote rational prescribing for older adults.
Humans ; Aged ; Cross-Sectional Studies ; Aged, 80 and over ; Male ; Female ; China ; Inappropriate Prescribing/economics* ; Patient Acceptance of Health Care/statistics & numerical data* ; Potentially Inappropriate Medication List/statistics & numerical data* ; Health Expenditures/statistics & numerical data*

The existing epilepsy seizure detection algorithms have problems such as overfitting and poor generalization ability due to high reliance on manual labeling of electroencephalogram's data and data imbalance between seizure and interictal periods. An unsupervised learning detection method for epileptic seizure that jointed graph attention network (GAT) and Transformer framework (GAT-T) was proposed. In this method, channel correlations were adaptively learned by GAT encoder. Temporal information was captured by one-dimensional convolution decoder. Combining outputs of the two mentioned above, predicted values for electroencephalogram were generated. The collective anomaly score was calculated and the detection threshold was determined. The results demonstrated that GAT-T achieved the average performance exceeding 90% (or 99%) with a 0.25 s (or 2 s) time segment length, which could effectively detect epileptic seizures. Moreover, the channel association probability matrix was expected to assist clinicians in the initial screening of the epileptogenic zone, and ablation experiments also reflected the significance of each module in GAT-T. This study may assist clinicians in making more accurate diagnostic and therapeutic decisions for epilepsy patients.
Humans ; Electroencephalography/methods* ; Epilepsy/physiopathology* ; Algorithms ; Seizures/physiopathology* ; Neural Networks, Computer ; Signal Processing, Computer-Assisted

Acute kidney injury (AKI) has high morbidity and mortality, but effective clinical drugs and management are lacking. Previous studies have suggested that macrophages play a crucial role in the inflammatory response to AKI and may serve as potential therapeutic targets. Emerging evidence has highlighted the importance of forkhead box protein O1 (FoxO1) in mediating macrophage activation and polarization in various diseases, but the specific mechanisms by which FoxO1 regulates macrophages during AKI remain unclear. The present study aimed to investigate the role of FoxO1 in macrophages in the pathogenesis of AKI. We observed a significant upregulation of FoxO1 in kidney macrophages following ischemia-reperfusion (I/R) injury. Additionally, our findings demonstrated that the administration of FoxO1 inhibitor AS1842856-encapsulated liposome (AS-Lipo), mainly acting on macrophages, effectively mitigated renal injury induced by I/R injury in mice. By generating myeloid-specific FoxO1-knockout mice, we further observed that the deficiency of FoxO1 in myeloid cells protected against I/R injury-induced AKI. Furthermore, our study provided evidence of FoxO1's pivotal role in macrophage chemotaxis, inflammation, and migration. Moreover, the impact of FoxO1 on the regulation of macrophage migration was mediated through RhoA guanine nucleotide exchange factor 1 (ARHGEF1), indicating that ARHGEF1 may serve as a potential intermediary between FoxO1 and the activity of the RhoA pathway. Consequently, our findings propose that FoxO1 plays a crucial role as a mediator and biomarker in the context of AKI. Targeting macrophage FoxO1 pharmacologically could potentially offer a promising therapeutic approach for AKI.

Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function. In the present study we investigated the contribution of megakaryocytic leukemia 1 (MKL1), a transcriptional modulator, to liver regeneration. We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients. Mice with MKL1 deletion exhibited defective regenerative response in the liver. Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription. MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1. Of interest, phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid (PA). PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure. Finally, PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients. In conclusion, our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration. Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.

Objective:To evaluate the efficacy of lumbar cisterna drainage(LCD) in treating paraplegia after thoracic endovascular aortic repair(TEVAR) for acute aortic dissection.Methods:A retrospective descriptive study was used to analyze 4 patients with aortic dissection who developed paraplegia after transthoracic aortic stent graft repair (TEVAR) admitted to Beijing Friendship Hospital Affiliated to Capital Medical University from May 2015 to May 2022. There were 3 males and 1 females, aged between 38 and 65 years old. All patients with paraplegia after TEVAR were treated with LCD. Follow-up was carried out by outpatient and telephone for 12 months. The imaging indicators and clinical efficacy were observed.Results:Two patients were fully recovered before discharge, one patient was completely recovered by about 3 months after surgery, and one patient still had reduced sensation and grade 4 muscle strength at 12 months of follow-up. The CT angiography of all 4 patients did not show any evidence of endoleak, and there was no enlargement of the distal dissecting aneurysm.Conclusion:Lumbar cisterna drainage can alleviate or cure paraplegia caused by spinal cord ischemia after TEVAR for acute aortic dissection.

Objective:To establish the ultra-high performance liquid chromatography (UPLC) fingerprint and high performance liquid chromatography (HPLC) content determination method of Curcumae Radix standard decoction; To predict the quality markers of Curcumae Radix standard decoction combined with network pharmacology.Methods:UPLC method was used to establish the fingerprint of Curcumae Radix standard decoction, and the common peaks were determined. Combined with chemical pattern recognition techniques such as similarity analysis and clustering analysis, Curcumae Radix standard decoction from different producing areas was studied, and curcumol was used as an index to determine the content of 24 batches of Curcumae Radix standard decoction. At the same time, network pharmacology was used to predict potential of curcumol and (1S, 6β)-1β-Methyl-4-(1-methylethylidene)-7β-(3-oxobutyl) bicyclo [4.1.0] heptan-3-one.Results:A total of 24 batches of Curcumae Radix standard decoction from different habitats were compared and analyzed, and 10 common peaks were calibrated. The similarity of 24 batches of samples ranged from 0.982 to 0.999. Clustering analysis and principal component analysis divided them into three categories. Heat map analysis showed that peak 8 (curcumol) and peak 9 ((1S, 6β)-1β-Methyl-4-(1-methylethylidene)-7β-(3-oxobutyl) bicyclo [4.1.0] heptan-3-one) were the main components. The content of curcumol in 24 batches of Curcumae Radix standard decoction was 0.69-1.87 mg/g; curcumol and (1S, 6β)-1β-Methyl-4-(1-methylethylidene)-7β- (3-oxobutyl) bicyclo [4.1.0] heptan-3-one may regulate the neuroactive ligand-receptor interaction signaling pathway, calcium signaling, and excitation by regulating neuroactive ligand-receptor interaction signaling pathway, calcium signaling, and excitation. It was preliminarily predicted that curcumol and (1S, 6β)-1β-Methyl-4-(1-methylethylidene)-7β-(3-oxobutyl) bicyclo [4.1.0] heptan-3-one were potential quality markers of Curcumae Radix.Conclusion:Curcumol and (1S, 6β)-1β-Methyl-4-(1-methylethylidene)-7β-(3-oxobutyl) bicyclo [4.1.0] heptan-3-one are potential quality markers of Curcumae Radix standard decoction, and the established fingerprint can be used for the quality control of Curcumae Radix standard decoction.

Objective:Acoustic neuroma(AN)is a benign tumor that usually affects a patient's hearing and balance function.For the screening and diagnosis of AN,the traditional approach mainly relies on audiological examination and magnetic resonance imaging(MRI),often ignoring the importance of vestibular function assessment in the affected area.As an emerging method of vestibular function detection,video head impulse test(vHIT)has been widely used in clinic,but research on its use in AN diagnosis is relatively limited.This study aims to explore the value of vHIT in the diagnosis of AN,vestibular dysfunction assessment,and postoperative compensation establishment in unilateral AN patients undergoing unilateral AN resection through labyrinthine approach. Methods:This retrospective study was conducted on 27 AN patients who underwent unilateral AN resection via labyrinthine approach from October 2020 to March 2022 in the Department of Otolaryngology-Head and Neck Surgery,the Second Xiangya Hospital,Central South University.vHIT was performed 1 week before surgery to assess vestibular function,pure tone audiometry(PTA)was used to assess hearing level,and ear MRI was used to assess tumor size.Follow-up vHIT was conducted at 1 week,1 month,6 months,and 1 year post-surgery.The correlation of vHIT with hearing and tumor size was analyzed. Results:Preoperative vHIT showed that the posterior semicircular canal on the affected side was the most common semicircular canal with reduced vestibulo-ocular reflex(VOR)gain.There was a correlation between the VOR gain of vHIT on the affected side and the hearing level(r=-0.47,P<0.05)or tumor size(r=-0.54,P<0.01).The results of vHIT on the affected side showed that the hearing level and mean VOR gain of the anterior semicircular canal increased slightly with time,and the amplitude and saccade percentage of the dominant saccades of the 3 semicircular canals increased,while the latency time decreased,with the most obvious changes occurring 1 week post-surgery. Conclusion:vHIT can effectively monitor the changes of vestibular function in AN patients before and after surgery and has application value in assisting the diagnosis of vestibular dysfunction in AN patients.