Abstract The incidence of non-alcoholic fatty liver (NAFLD) remains high, and many NAFLD patients suffer from severe ischemia-reperfusion injury (IRI). Currently, no practical approach can be used to treat IRI. Puerarin plays a vital role in treating multiple diseases, such as NAFLD, stroke, diabetes, and high blood pressure. However, its role in the IRI of the fatty liver is still unclear. We aimed to explore whether puerarin could protect the fatty liver from IRI. C57BL/6J mice were fed with a high‐fat diet (HFD) followed by ischemia reperfusion injury. We showed that hepatic IRI was more severe in the fatty liver compared with the normal liver, and puerarin could significantly protect the fatty liver against IRI and alleviate oxidative stress. The PI3K-AKT signaling pathway was activated during IRI, while liver steatosis decreased the level of activation. Puerarin significantly protected the fatty liver from IRI by reactivating the PI3K-AKT signaling pathway. However, LY294002, a PI3K-AKT inhibitor, attenuated the protective effect of puerarin. In conclusion, puerarin could significantly protect the fatty liver against IRI by activating the PI3K-AKT signaling pathway. nonalcoholic non alcoholic (NAFLD ischemiareperfusion . (IRI) Currently diseases stroke diabetes pressure However unclear C57BL6J CBLJ C57BL 6J C BL J highfat fat HFD (HFD stress PI3KAKT PIKAKT PI3K AKT PI K activation LY294002 LY inhibitor conclusion (IRI CBL KAKT PIK LY29400 LY2940 LY294 LY29 LY2

Abstract MCH1 is a synthetic macamide that has shown in vitro inhibitory activity on fatty acid amide hydrolase (FAAH), an enzyme responsible for endocannabinoid metabolism. This inhibition can modulate endocannabinoid and dopamine signaling in the nucleus accumbens (NAc), potentially having an antidepressant-like effect. The present study aimed to evaluate the effect of the in vivo administration of MCH1 (3, 10, and 30 mg/kg, ip) in 2-month-old BALB/c male mice (n=97) on forced swimming test (FST), light-dark box (LDB), and open field test (OFT) and on early gene expression changes 2 h after drug injection related to the endocannabinoid system (Cnr1 and Faah) and dopaminergic signaling (Drd1 and Drd2) in the NAc core. We found that the 10 mg/kg MCH1 dose reduced the immobility time compared to the vehicle group in the FST with no effect on anxiety-like behaviors measured in the LDB or OFT. However, a 10 mg/kg MCH1 dose increased locomotor activity in the OFT compared to the vehicle. Moreover, RT-qPCR results showed that the 30 mg/kg MCH1 dose increased Faah gene expression by 2.8-fold, and 10 mg/kg MCH1 increased the Cnr1 gene expression by 4.3-fold compared to the vehicle. No changes were observed in the expression of the Drd1 and Drd2 genes in the NAc at either MCH1 dose. These results indicated that MCH1 might have an antidepressant-like effect without an anxiogenic effect and induces significant changes in endocannabinoid-related genes but not in genes of the dopaminergic signaling system in the NAc of mice. MCH FAAH, FAAH , (FAAH) metabolism NAc, (NAc) antidepressantlike antidepressant like 3, 3 (3 mgkg mg kg ip 2monthold monthold month old BALBc BALB c n=97 n97 n 97 (n=97 FST, (FST) lightdark light dark LDB, (LDB) (OFT Cnr (Cnr Drd (Drd core 1 anxietylike anxiety However Moreover RTqPCR RT qPCR 2.8fold, 28fold fold 2.8 fold, 8 2.8-fold 4.3fold 43fold 4.3 4 endocannabinoidrelated (FAAH (NAc ( n=9 n9 9 (n=9 (FST (LDB 8fold 2.8fold 28 2. 3fold 43 4. n= (n= (n

Abstract The aim of this study was to explore the association between differential percentages of dendritic cell (DC) subsets in peripheral blood and malignancy (grade and lymph node metastasis) of peritoneal adenocarcinoma patients and the frequencies of dendritic cell subsets in the normal controls. The peripheral blood of 30 patients with peritoneal adenocarcinoma and 12 healthy controls were collected for multicolor flow cytometry analysis. Peritoneal adenocarcinoma patients were grouped according to the malignant degree (grade and lymph node metastasis). Percentages of myeloid DCs (mDCs) and its subsets MDC1 and MDC2 in DCs were lower in peripheral blood of patients with peritoneal adenocarcinoma than in normal controls. The percentages of plasmacytoid dendritic cells (pDCs) and CD16+mDCs in DCs were higher than in normal controls. Compared with poor differentiation grade, patients with well/moderate differentiation grade had an increased percentage of CD16+mDCs. Contrary to CD16+mDCs, the percentage of MDC1 was lower in the well/moderate differentiation grade group. In patients with no lymph node metastasis, pDCs and CD16+mDCs levels were higher compared with patients with lymph node metastasis. mDCs and MDC1 levels had opposite results. pDCs were positively correlated with CD16+mDCs in peripheral blood of peritoneal patients, as was mDCs and MDC1. CD16+mDCs were negatively correlated with MDC1. The percentages of pDCs and CD16+mDCs in DCs were positively correlated with CD3+CD8+T cells, and pDCs also positively correlated with CD8+PD-1+T cells. Our results revealed that DCs subsets correlated with peritoneal adenocarcinoma malignancy. Dendritic cells play an independent role in the immune function of peritoneal adenocarcinoma. DC (DC metastasis 3 1 analysis . (mDCs MDC (pDCs CD16mDCs CDmDCs CD16 CD wellmoderate well moderate group CD3CD8T CDCDT CD3 CD8 T CD8+PD1+T CD8PD1T CDPDT CD8+PD 1+T PD CD1 PD1 CD8PD CDPD 1T

Abstract The cure rates for osteosarcoma have remained unchanged in the past three decades, especially for patients with pulmonary metastasis. Thus, a new and effective treatment for metastatic osteosarcoma is urgently needed. Anlotinib has been reported to have antitumor effects on advanced osteosarcoma. However, both the effect of anlotinib on autophagy in osteosarcoma and the mechanism of anlotinib-mediated autophagy in pulmonary metastasis are unclear. The effect of anlotinib treatment on the metastasis of osteosarcoma was investigated by transwell assays, wound healing assays, and animal experiments. Related proteins were detected by western blotting after anlotinib treatment, ATG5 silencing, or ATG5 overexpression. Immunofluorescence staining and transmission electron microscopy were used to detect alterations in autophagy and the cytoskeleton. Anlotinib inhibited the migration and invasion of osteosarcoma cells but promoted autophagy and increased ATG5 expression. Furthermore, the decreases in invasion and migration induced by anlotinib treatment were enhanced by ATG5 silencing. In addition, Y-27632 inhibited cytoskeletal rearrangement, which was rescued by ATG5 overexpression. ATG5 overexpression enhanced epithelial-mesenchymal transition (EMT). Mechanistically, anlotinib-induced autophagy promoted migration and invasion by activating EMT and cytoskeletal rearrangement through ATG5 both in vitro and in vivo. Our results demonstrated that anlotinib can induce protective autophagy in osteosarcoma cells and that inhibition of anlotinib-induced autophagy enhanced the inhibitory effects of anlotinib on osteosarcoma metastasis. Thus, the therapeutic effect of anlotinib treatment can be improved by combination treatment with autophagy inhibitors, which provides a new direction for the treatment of metastatic osteosarcoma. decades Thus needed However anlotinibmediated mediated unclear assays experiments ATG silencing cytoskeleton expression Furthermore addition Y27632 Y 27632 Y-2763 epithelialmesenchymal epithelial mesenchymal EMT. . (EMT) Mechanistically anlotinibinduced vivo inhibitors Y2763 2763 Y-276 (EMT Y276 276 Y-27 Y27 27 Y-2 Y2 2 Y-

Abstract The aim of this study was to evaluate the association between diabetes and cognitive performance in a nationally representative study in Brazil. We also aimed to investigate the interaction between frailty and diabetes on cognitive performance. A cross-sectional analysis of the Brazilian Longitudinal Study of Aging (ELSI-Brazil) baseline data that included adults aged 50 years and older was conducted. Linear regression models were used to study the association between diabetes and cognitive performance. A total of 8,149 participants were included, and a subgroup analysis was performed in 1,768 with hemoglobin A1c data. Diabetes and hemoglobin A1c levels were not associated with cognitive performance. Interaction of hemoglobin A1c levels with frailty status was found on global cognitive z-score (P-value for interaction=0.038). These results suggested an association between higher hemoglobin A1c levels and lower cognitive performance only in non-frail participants. Additionally, undiagnosed diabetes with higher hemoglobin A1c levels was associated with both poor global cognitive (β=-0.36; 95%CI: -0.62; -0.10, P=0.008) and semantic verbal fluency performance (β=-0.47; 95%CI: -0.73; -0.21, P=0.001). In conclusion, higher hemoglobin A1c levels were associated with lower cognitive performance among non-frail participants. Higher hemoglobin A1c levels without a previous diagnosis of diabetes were also related to poor cognitive performance. Future longitudinal analyses of the ELSI-Brazil study will provide further information on the role of frailty in the association of diabetes and glycemic control with cognitive decline. Brazil crosssectional cross sectional ELSIBrazil ELSI (ELSI-Brazil 5 conducted 8149 8 149 8,14 1768 1 768 1,76 Ac c zscore z score Pvalue P value interaction=0.038. interaction0038 interaction=0.038 . 0 038 interaction=0.038) nonfrail non frail Additionally β=0.36 β036 β β= 0.36 36 (β=-0.36 95%CI 95CI CI 95 0.62 062 62 -0.62 0.10, 010 10 -0.10 P=0.008 P0008 008 β=0.47 β047 0.47 47 (β=-0.47 0.73 073 73 -0.73 0.21, 021 21 -0.21 P=0.001. P0001 P=0.001 001 P=0.001) conclusion decline 814 14 8,1 176 76 1,7 interaction003 interaction=0.03 03 β=0.3 β03 036 0.3 3 (β=-0.3 9 0.6 06 6 -0.6 0.10 01 -0.1 P=0.00 P000 00 β=0.4 β04 047 0.4 4 (β=-0.4 0.7 07 7 -0.7 0.21 02 2 -0.2 81 8, 17 1, interaction00 interaction=0.0 β=0. β0 0. (β=-0. -0. 0.1 P=0.0 P00 04 0.2 interaction0 interaction=0. β=0 (β=-0 -0 P=0. P0 interaction=0 (β=- - P=0 interaction= (β= P= (β

There's limited evidence of the potential benefits of cardiopulmonary and metabolic rehabilitation (CPMR) in patients with heart failure with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF) and coronary artery disease (CAD). The aim of this study was to investigate the impact of CPMR on the myocardial ischemia response (MIR), exercise-induced arrhythmias (EIA), New York Heart Association (NYHA) functional class, heart rate recovery (HRR), Borg CR10 perceived symptoms, and the SF-36 physical and mental health summary scores. A prospective cohort study was conducted with 106 patients undergoing 12 weeks of CPMR who completed two exercise tests pre- and post-CPMR: 1) maximum incremental test (CPX) and 2) submaximal constant load test (SUB). After CPMR, the effects on MIR, EIA, NYHA functional class, and HRR during both tests were analyzed. There was a significant change in NYHA functional classes after CPMR, with 96% of the patients in class I (vs 62% pre-CPMR, P<0.0001), 4% in class II (vs 32%), and none in class III (vs 6%). There was a significant reduction in the frequency of EIA (P<0.05) and MIR (P<0.001) and a significantly improved performance on both CPX and SUB tests (P<0.0001). Lastly, there was significant progress in the recovery metrics like HRR (P<0.0001), the Borg CR10 (P<0.0001), and the SF-36 summary scores (P<0.0001). The CPMR resulted in a significant decrease in EIA, delayed ischemia threshold in CPX and SUB tests, increased functional capacity, and improved quality of life. Theres s (CPMR HFpEF (HFpEF HFmrEF (HFmrEF CAD. CAD . (CAD) , (MIR) exerciseinduced induced (EIA) (NYHA HRR, (HRR) CR CR1 symptoms SF36 SF 36 SF-3 10 1 pre postCPMR post post-CPMR (CPX 2 SUB. (SUB) analyzed 96 vs 62 preCPMR, preCPMR pre-CPMR P<0.0001, P00001 P P<0.0001 0 0001 P<0.0001) 4 32%, 32 32% 32%) 6%. 6 6% 6%) P<0.05 P005 05 (P<0.05 P<0.001 P0001 001 (P<0.001 P<0.0001. (P<0.0001) Lastly capacity life (CAD (MIR (EIA (HRR SF3 3 SF- (SUB 9 P0000 P<0.000 000 P<0.0 P00 (P<0.0 P<0.00 P000 00 (P<0.00 (P<0.0001 P<0. P0 (P<0. (P<0.000 P<0 (P<0 P< (P< (P

Immature hematopoietic progenitors are a constant source for renewal of hemocyte populations and the basic component of the tissue and cell repair apparatus. A unique property of these cells of internalizing extracellular double-stranded DNA has been previously shown. The leukostimulatory effect demonstrated in our pioneering studies was considered to be due to the feature of this cell. In the present research, we have analyzed the effects of DNA genome reconstructor preparation (DNAgr), DNAmix, and human recombinant angiogenin on both hematopoietic stem cells and multipotent progenitors. Treatment with bone marrow cells of experimental mice with these preparations stimulates colony formation by hematopoietic stem cells and proliferation of multipotent descendants. The main lineage responsible for this is the granulocyte-macrophage hematopoietic lineage. Using fluorescent microscopy as well as FACS assay, co-localization of primitive c-Kit- and Sca-1-positive progenitors and the TAMRA-labeled double-stranded DNA has been shown. Human recombinant angiogenin was used as a reference agent. Cells with specific markers were quantified in intact bone marrow and colonies grown in the presence of inducers. Quantitative analysis revealed that a total of 14,000 fragment copies of 500 bp, which is 0.2% of the haploid genome, can be delivered into early progenitors. Extracellular double-stranded DNA fragments stimulated the colony formation in early hematopoietic progenitors from the bone marrow, which assumed their effect on cells in G0. The observed number of Sca1+/c-Kit+ cells in colonies testifies to the possibility of both symmetrical and asymmetrical division of the initial hematopoietic stem cell and its progeny. apparatus doublestranded double stranded shown research DNAgr, DNAgr , (DNAgr) DNAmix descendants granulocytemacrophage granulocyte macrophage assay colocalization co localization cKit c Kit c-Kit Sca1positive Scapositive Sca 1 positive TAMRAlabeled TAMRA labeled agent inducers 14000 14 000 14,00 50 bp 02 0 2 0.2 G0 G Sca1+/cKit+ Sca1cKit ScacKit Sca1+/c Kit+ Sca1 Sca1+/c-Kit progeny (DNAgr 1400 00 14,0 5 0. Sca1+/cKit Sca1c Scac 140 14,

High-altitude hypoxia exposure can lead to phospholipase D-mediated lipid metabolism disorder in spleen tissues and induce ferroptosis. Nonetheless, the key genes underlying hypoxia-induced splenic phospholipase D and the ferroptosis pathway remain unclear. This study aimed to establish a hypoxia animal model. Combined transcriptomic and proteomic analyses showed that 95 predicted target genes (proteins) were significantly differentially expressed under hypoxic conditions. Key genes in phospholipase D and ferroptosis pathways under hypoxic exposure were identified by combining Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis techniques. Gene set enrichment analysis (GSEA) showed that the differential gene sets of the phospholipase D and ferroptosis signaling pathways were upregulated in the high-altitude hypoxia group. The genes in the phospholipase D signalling pathway were verified, and the expression levels of KIT and DGKG were upregulated in spleen tissues under hypoxic exposure. Subsequently, the mRNA and protein expression levels of genes from the exogenous pathway such as TFRC, SLC40A1, SLC7A11, TRP53, and FTH1 and those from the endogenous pathway such as GPX4, HMOX1, and ALOX15 differentials in the ferroptosis signalling pathway were verified, and the results indicated significant differential expression. In summary, exposure to high-altitude hypoxia mediated phospholipid metabolism disturbance through the phospholipase D signalling pathway and further induced ferroptosis, leading to splenic injury. Highaltitude High altitude Dmediated Nonetheless hypoxiainduced unclear model 9 proteins (proteins conditions GO (GO KEGG (KEGG techniques GSEA (GSEA highaltitude high group verified Subsequently TFRC SLC40A1 SLCA SLC A SLC7A11 TRP53 TRP FTH GPX4 GPX HMOX1 HMOX ALOX ALOX1 summary injury SLC40A SLC7A1 TRP5 SLC7A

The present study investigated the reliability and sensitivity of a wearable near-infrared spectroscopy (wNIRS) device in moderate and heavy exercise intensity domains. On three separate days, eleven males performed an incremental test to exhaustion, and in the following visits, four submaximal constant-load bouts (i.e., test and retest) were performed in the moderate-intensity domain (100 and 130 W) and heavy-intensity domain (160 and 190 W). The local tissue oxygen saturation index (SmO2) and pulmonary oxygen uptake (V̇O2) were measured continuously. The absolute SmO2 and V̇O2 values and the change (Δ) from the 3rd to 6th min of exercise were calculated. There was good reliability for SmO2 measurements, as indicated by the high intraclass correlation coefficient analysis (ICC ≥0.84 for all) and low coefficient of variation between the two trials (CV ≤4.1% for all). Steady-state responses were observed for SmO2 and V̇O2 from the 3rd to the 6th min in the two moderate-intensity bouts (P>0.05), whereas SmO2 decreased and V̇O2 increased from the 3rd to the 6th min in the two heavy-intensity bouts (P<0.05). Together, these findings suggested that the SmO2 measured with a wNIRS device is reliable and sensitive to track local metabolic changes provoked by slight increments in exercise intensity. nearinfrared near infrared (wNIRS domains days exhaustion visits constantload constant load i.e., ie i e (i.e. retest moderateintensity 100 (10 13 W heavyintensity 160 (16 19 W. . SmO (SmO2 VO2 VO V O2 O (V̇O2 continuously V̇O Δ (Δ rd th calculated measurements ICC 084 0 84 ≥0.8 all CV 41 4 1 ≤4.1 all. Steadystate Steady state P>0.05, P005 P P>0.05 , 05 (P>0.05) P<0.05. P<0.05 (P<0.05) Together i.e. (i.e 10 (1 16 (SmO (V̇O 08 8 ≥0. ≤4. P00 P>0.0 (P>0.05 P<0.0 (P<0.05 i.e ( ≥0 ≤4 P0 P>0. (P>0.0 P<0. (P<0.0 ≥ ≤ P>0 (P>0. P<0 (P<0. P> (P>0 P< (P<0 (P> (P< (P

Glioblastomas are known for their poor clinical prognosis, with recurrent tumors often exhibiting greater invasiveness and faster growth rates compared to primary tumors. To understand the intratumoral changes driving this phenomenon, we employed single-cell sequencing to analyze the differences between two pairs of primary and recurrent glioblastomas. Our findings revealed an upregulation of ferroptosis in endothelial cells within recurrent tumors, identified by the significant overexpression of the NOX4 gene. Further analysis indicated that knocking down NOX4 in endothelial cells reduced the activity of the ferroptosis pathway. Utilizing conditioned media from endothelial cells with lower ferroptosis activity, we observed a decrease in the growth rate of glioblastoma cells. These results highlighted the complex role of ferroptosis within tumors and suggested that targeting ferroptosis in the treatment of glioblastomas requires careful consideration of its effects on endothelial cells, as it may otherwise produce counterproductive outcomes. prognosis phenomenon singlecell single cell NOX gene pathway outcomes

The present study utilized the spared nerve injury (SNI) to create a mouse model of depression to investigate the impact of esketamine on depressive-like behaviors, on the expression of PSD-95 and CRMP2 proteins, and on changes in neuronal dendritic spine plasticity in the prefrontal cortex (PFC). Depressive-like behavioral tests were performed 1 h after esketamine treatment, and the PFC tissues were obtained on the fourth day after completing the behavioral tests. Then, dendritic spine density and morphology in the PFC were measured using Golgi staining, and CRMP2 and PSD-95 proteins were obtained from PFC tissue by western blotting. The results of this study showed that esketamine significantly increased the immobility time in the forced swimming test and tail suspension test. In the open field test, esketamine increased the time spent in the open arms, the time spent in the central area, and the total distance covered. It also increased the protein expression levels of CRMP2 and PSD-95 in addition to the total and mature dendritic spine density of the PFC in SNI-depressed mice. Esketamine can significantly improve depression-like behaviors in SNI-depressed mice and promote an increase in dendritic spine density and maturation in the PFC. These effects may be associated with changes in CRMP2 and PSD-95 expression. SNI (SNI depressivelike depressive like PSD95 PSD 95 PSD-9 CRMP . (PFC) Depressivelike Depressive treatment Then staining blotting arms area covered SNIdepressed depressed depressionlike PSD9 9 PSD- (PFC

Epidemiological surveys show that the incidence of age-related dementia and cognitive impairment is increasing and it has been a heavy burden for society, families, and healthcare systems, making the preservation of cognitive function in an increasingly aging population a major challenge. Exercise is beneficial for brain health, and FDNC5/irisin, a new exercise-induced myokine, is thought to be a beneficial mediator to cognitive function and plays an important role in the crosstalk between skeletal muscle and brain. This review provides a critical assessment of the recent progress in both fundamental and clinical research of FDNC5/irisin in dementia and cognitive impairment-related disorders. Furthermore, we present a novel perspective on the therapeutic effectiveness of FDNC5/irisin in alleviating these conditions. agerelated age related society families systems challenge health FDNC5irisin FDNCirisin FDNC5 irisin FDNC exerciseinduced exercise induced myokine impairmentrelated disorders Furthermore conditions

Rivaroxaban is a direct factor Xa inhibitor. Its interindividual variability is large and may be connected to the occurrence of adverse drug reactions or drug inefficacy. Pharmacogenetics studies concentrating on the reasons underlying rivaroxaban's inadequate response could help explain the differences in treatment results and medication safety profiles. Against this background, this study evaluated whether polymorphisms in the gene encoding the ABCG2 transporter modify the pharmacokinetic characteristics of rivaroxaban. A total of 117 healthy volunteers participated in two bioequivalence experiments with a single oral dose of 20 mg rivaroxaban, with one group fasting and the other being fed. Ultra-high-performance liquid chromatography coupled with mass spectrometry was employed to determine the plasma concentrations of rivaroxaban, and the WinNonlin program was used to calculate the pharmacokinetics parameters. In the fasting group, the rivaroxaban pharmacokinetic parameters of Vd (508.27 vs 334.45 vs 275.59 L) and t1/2 (41.04 vs 16.43 vs 15.47 h) were significantly higher in ABCG2 421 A/A genotype carriers than in ABCG2 421 C/C and 421 C/A genotype carriers (P<0.05). The mean values of Cmax (145.81 vs 176.27 vs 190.19 ng/mL), AUC0-t (1193.81 vs 1374.69 vs 1570.77 ng/mL·h), and Cl (11.82 vs 14.50 vs 13.01 mL/h) for these groups were lower, but this difference was not statistically significant (P>0.05). These findings suggested that the ABCG2 421 A/A genotype may impact rivaroxaban parameters after a single dose in healthy subjects. This finding must be validated before it is applied in clinical practice. inhibitor inefficacy rivaroxabans s profiles background ABCG 11 2 fed Ultrahighperformance Ultra high performance 508.27 50827 508 27 (508.2 33445 334 45 334.4 27559 275 59 275.5 L t12 t t1 t1/ 41.04 4104 41 04 (41.0 1643 16 43 16.4 1547 15 47 15.4 h 42 AA CC C CA P<0.05. P005 P P<0.05 . 0 05 (P<0.05) 145.81 14581 145 81 (145.8 17627 176 176.2 19019 190 19 190.1 ng/mL, ngmL ng/mL , ng mL ng/mL) AUC0t AUCt AUC0 AUC 1193.81 119381 1193 (1193.8 137469 1374 69 1374.6 157077 1570 77 1570.7 ng/mL·h, ngmLh ng/mL·h ng/mL·h) 11.82 1182 82 (11.8 1450 14 50 14.5 1301 13 01 13.0 mL/h mLh lower P>0.05. P>0.05 (P>0.05) subjects practice 1 508.2 5082 (508. 3344 33 4 334. 2755 5 275. 41.0 410 (41. 164 16. 154 15. P00 P<0.0 (P<0.05 145.8 1458 8 (145. 1762 17 176. 1901 190. 1193.8 11938 119 (1193. 13746 137 6 1374. 15707 157 7 1570. 11.8 118 (11. 14. 130 13. P>0.0 (P>0.05 508. (508 3 41. (41 P0 P<0. (P<0.0 145. (145 1193. (1193 11. (11 P>0. (P>0.0 (50 (4 P<0 (P<0. (14 (119 (1 P>0 (P>0. (5 ( P< (P<0 P> (P>0 (P< (P> (P

This study explored the association between loneliness and mental health among nurses in China during the COVID-19 pandemic. This cross-sectional study was conducted from March to April 2022. We enrolled 2,811 nurses from a tertiary hospital in China. Demographic characteristics, lifestyle factors, work-related factors, and psychological characteristics were collected from participants via a self-reported questionnaire. Loneliness was measured with the three-item short form of the Revised UCLA Loneliness Scale, and the Patient Health Questionnaire (PHQ-9) and the General Anxiety Disorder (GAD-7) scale were used to measure mental health. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) were determined using binary logistic regression. Among participants in this study, 12.0% (337) experienced loneliness, and 7.8% (219) and 6.7% (189) reported depression and anxiety, respectively. The loneliness scores were categorized into three levels (3, 4-6, and 7-9). For depression, compared with the lowest reference, the ORs and 95% CI across the tertile were 1.31 (0.69-1.84) and 2.53 (1.11-5.76) after adjustment, respectively, and the P-value for trend was 0.045. For anxiety, compared with the lowest reference, the ORs and 95%CI across the tertile were 1.84 (1.28-2.63) and 2.52 (1.57-4.10) after adjustment, respectively; the P-value for trend was 0.004. This study showed that loneliness was significantly associated with poor mental health among nurses during the COVID-19 pandemic. These findings suggested that medical establishments should offer interventions for nurses to prevent mental health problems by targeting this modifiable risk factor. COVID19 COVID 19 COVID-1 pandemic crosssectional cross sectional 2022 2811 2 811 2,81 factors workrelated work related selfreported self questionnaire threeitem item Scale PHQ9 PHQ 9 (PHQ-9 GAD7 GAD 7 (GAD-7 (ORs 95 (CI regression 120 12 0 12.0 337 (337 78 8 7.8 219 (219 67 6 6.7 189 (189 anxiety respectively 3, 3 (3 46, 46 4 6, 4-6 79. 79 . 7-9) reference 131 1 31 1.3 0.691.84 069184 0.69 69 84 (0.69-1.84 253 53 2.5 1.115.76 111576 1.11 5.76 11 5 76 (1.11-5.76 adjustment Pvalue P value 0045 045 0.045 95CI 184 1.8 1.282.63 128263 1.28 2.63 28 63 (1.28-2.63 252 52 1.574.10 157410 1.57 4.10 57 10 (1.57-4.10 0004 004 0.004 factor COVID1 COVID- 202 281 81 2,8 (PHQ- (GAD- 12. 33 (33 7. 21 (21 6. 18 (18 ( 4- 7-9 13 1. 691 0.691.8 06918 069 0.6 (0.69-1.8 25 2. 115 1.115.7 11157 111 1.1 576 5.7 (1.11-5.7 04 0.04 282 1.282.6 12826 128 1.2 263 2.6 (1.28-2.6 574 1.574.1 15741 157 1.5 410 4.1 (1.57-4.1 000 00 0.00 20 2, (PHQ (GAD (2 (1 7- 0.691. 0691 06 0. (0.69-1. 1.115. 1115 5. (1.11-5. 0.0 1.282. 1282 26 (1.28-2. 1.574. 1574 15 41 4. (1.57-4. 0.691 (0.69-1 1.115 (1.11-5 1.282 (1.28-2 1.574 (1.57-4 (0.69- (1.11- (1.28- (1.57- (0.69 (1.11 (1.28 (1.57 (0.6 (1.1 (1.2 (1.5 (0. (1. (0

Jiawei Xinglou Chengqi Granule (JXCG) is an effective herbal medicine for the treatment of ischemic stroke (IS). JXCG has been shown to effectively ameliorate cerebral ischemic symptoms in clinical practice, but the underlying mechanisms are unclear. In this study, we investigated the mechanisms of action of JXCG in the treatment of IS by combining metabolomics with network pharmacology. The chemical composition of JXCG was analyzed using ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Ultra-high performance liquid chromatography-tandem time-of-flight mass spectrometry (UHPLC-Q-TOF MS) untargeted metabolomics were used to identify differential metabolites within metabolic pathways. Network pharmacology was applied to mine potential targets of JXCG in the treatment of IS. The identified key targets were validated by constructing an integrated network of metabolomics and network pharmacology and by molecular docking using Cytoscape. The effect of JXCG on IS was evaluated in vivo, and the predicted targets and pathways of JXCG in IS therapy were assessed using immunoblotting. Combining metabolomics and network pharmacology, we identified the therapeutic targets of JXCG for IS. Notably, JXCG lessened neuronal damage and reduced cerebral infarct size in rats with IS. Western blot analysis showed that JXCG upregulated PRKCH and downregulated PRKCE and PRKCQ proteins. Our combined network pharmacology and metabolomics findings showed that JXCG may have therapeutic potential in the treatment of IS by targeting multiple factors and pathways. (JXCG . (IS) practice unclear study ultrahigh ultra high chromatographyhigh chromatography UHPLCHRMS. UHPLCHRMS UHPLC HRMS (UHPLC-HRMS) Ultrahigh Ultra chromatographytandem tandem timeofflight time flight UHPLCQTOF Q TOF MS Cytoscape vivo immunoblotting Notably proteins (IS (UHPLC-HRMS