Objective To analyze the nonlinear relationship between hypothermic machine perfusion (HMP) parameters and delayed graft function (DGF) and optimize the construction of a predictive model for DGF. Methods The data of 923 recipients who underwent kidney transplantation from deceased donors were retrospectively analyzed. According to the occurrence of DGF, the recipients were divided into DGF group (n=823) and non-DGF group (n=100). Donor data, HMP parameters and recipient data were analyzed for both groups. The nonlinear relationship between HMP parameters and the occurrence of DGF was explored based on restricted cubic splines (RCS). Over-sampling, under-sampling and balanced sampling were used to address the imbalance in the proportion of DGF to construct logistic regression predictive models. The area under the curve (AUC) of each model was compared in the validation set, and a nomogram model was constructed. Results Donor BMI, cold ischemia time of the donor kidney, and HMP parameters (initial and final pressures, resistance, and perfusion time) were significantly different between the DGF and non-DGF groups (all P<0.05). The RCS analysis revealed a threshold-like nonlinear relationship between HMP parameters and the risk of DGF. Among the models constructed using different sampling methods, the balanced sampling model had the highest AUC. Using this model, a nomogram was constructed to stratify recipients based on risk scores. Recipients in the high-risk group had higher serum creatinine levels at 1, 6, and 12 months after kidney transplantation compared to those in the low-risk group (all P<0.05). Conclusions There is a nonlinear relationship between HMP parameters and the risk of DGF, and the threshold is helpful for organ quality assessment and monitoring of graft function after transplantation. The predictive model for DGF constructed on the base of balanced sampling algorithms helps perioperative decision-making and postoperative graft function monitoring of kidney transplantation.

BACKGROUND: Doxorubicin hydrochloride (DOX) is extensively used in the treatment of various tumors. However, its clinical application is limited due to dose-dependent cardiotoxicity. Currently, few effective strategies exist to mitigate or eliminate DOX-induced cardiomyopathy (DIC). Although ferroptosis is implicated in DIC and its inhibition partially alleviates the condition, the direct targets of DOX in the progression of cardiotoxicity remain unclear. This study aimed to discover the direct targets of DOX in ferroptosis-mediated DIC. METHODS: A DOX pulldown assay was performed to identify proteins specifically binding to DOX in murine hearts, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify candidate proteins. A cardiac injury mouse model was established by DOX treatment. Based on this, multiple ferroptosis biomarkers were detected by flow cytometry, quantitative real-time polymerase chain reaction, western blotting, immunochemistry, etc. Besides, specific activator and inhibitor of signaling pathways were applied to illuminate molecular mechanisms. RESULTS: Glutathione S-transferase P1 (GSTP1) was identified as a DOX target. GSTP1 activity was inhibited in DOX-treated cardiomyocytes, while its overexpression significantly alleviated DIC. Moreover, GSTP1 overexpression inhibited acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. Mechanistically, GSTP1 overexpression suppressed c-Jun N-terminal kinase (JNK) phosphorylation, thereby reducing reactive oxygen species (ROS) production and inhibiting ferroptosis in DIC. CONCLUSIONS This study identifies the DOX/GSTP1/JNK axis as a critical pathway mediating ACSL4-dependent ferroptosis in DIC. GSTP1 is highlighted as a potential key mediator of ferroptosis and a promising therapeutic target for DIC.

Increasing evidence shows that the early lesions of Parkinson's disease (PD) originate from gut, and correction of microbiota dysbiosis is a promising therapy for PD. FLZ is a neuroprotective agent on PD, which has been validated capable of alleviating microbiota dysbiosis in PD mice. However, the detailed mechanisms still need elucidated. Through metabolomics and 16S rRNA analysis, we identified glycoursodeoxycholic acid (GUDCA) was the most affected differential microbial metabolite by FLZ treatment, which was specially and negatively regulated by Clostridium innocuum, a differential microbiota with the strongest correlation to GUDCA production, through inhibiting bile salt hydrolase (BSH) enzyme. The protection of GUDCA on colon and brain were also clarified in PD models, showing that it could activate Nrf2 pathway, further validating that FLZ protected dopaminergic neurons through promoting GUDCA production. Our study uncovered that FLZ improved PD through microbiota-gut-brain axis, and also gave insights into modulation of microbial metabolites may serve as an important strategy for treating PD.

Although enteric glial cell (EGC) abnormal activation is reported to be involved in the pathogenesis of Parkinson's disease (PD), and inhibition of EGC gliosis alleviated gut and dopaminergic neuronal dysfunction was verified in our previous study, the potential role of gut microbiota on EGC function in PD still need to be addressed. In the present study, fecal microbiota transplantation revealed that EGC function was regulated by gut microbiota. By employing 16S rRNA and metabolomic analysis, we identified that 3-indolepropionic acid (IPA) was the most affected differential microbial metabolite that regulated EGC gliosis. The protective effects of IPA on PD were validated in rotenone-stimulated EGCs and rotenone (30 mg/kg i.g. for 4 weeks)-induced PD mice, as indicated by decreased inflammation, improved intestinal and brain barrier as well as dopaminergic neuronal function. Mechanistic study showed that IPA targeted pregnane X receptor (PXR) in EGCs, and inhibition of IL-13Rα1 involved cytokine-cytokine receptor interaction pathway, leading to inactivation of downstream JAK1-STAT6 pathway. Our data not only provided evidence that EGC gliosis was critical in spreading intestinal damage to brain, but also highlighted the potential role of microbial metabolite IPA in alleviating PD pathological damages through gut-brain axis.

[This corrects the article DOI: 10.1016/j.apsb.2025.02.029.].

Objective To investigate the characteristics of adverse drug event(ADE)related to tacrolimus(Tac)in pediatric solid organ transplant recipients.Methods The data were retrieved from the US Food and Drug Administration Adverse Event Reporting System database from the first quarter of 2004 to the second quarter of 2023.The ADE data of pediatric organ transplant recipients with Tac as the primary suspected drug were extracted.The relationship between Tac and ADE was quantitatively analyzed by proportional imbalance method.Basic characteristics and signal strength of ADE related to Tac were analyzed.ADE related to Tac in children of different ages and different types of organ transplantation were analyzed.Results A total of 1 443 children's ADE reports involving Tac were screened,including 188 cases(13.0％)of heart transplantation,668 cases(46.3％)of liver transplantation,531 cases(36.8％)of kidney transplantation and 56 cases(3.9％)of lung transplantation.The median age of children was 10 years old.The top three countries with ADE reporting were the United States,France and the United Kingdom.China reported 26 cases,accounting for 1.8％.Infection and infectious diseases accounted for the highest proportion(20.96％)in ADE related to Tac,including EB virus and cytomegalovirus infection,etc.Infection and infectious diseases occupied the largest proportion of ADE related to Tac in children of different ages,whereas the pathogen types were different.Rejection,unstable immunosuppression level and renal function damage were also common ADE related to Tac in children of all ages.Nervous system disease was the main ADE in heart transplant recipients,while infection and infectious diseases were more common in liver and kidney transplant recipients.Rejection was the most common ADE in lung transplant recipients.Conclusions ADE related to Tac possess different distribution characteristics in different types of organ transplantation.Extensive attention should be paid to individualized drug monitoring and risk assessment in pediatric organ transplant recipients,thereby optimizing Tac treatment and reducing the risk of ADE.

Objective To explore the molecular mechanisms and cell-cell interactions in the injury process of pancreatic islet transplantation.Methods Single-cell transcriptome data from mouse islets treated with inflammatory factors were used,and data processing was performed using the Seurat package,with integrated data to remove batch effects.Cell subpopulations were annotated based on known markers.Cell-cell interactions in the inflammatory factor-treated group were analyzed using the CellChat package,and inferred based on the expression of cell surface receptors and ligands.Gene set enrichment analysis was used to clarify the biological processes enriched in β-cells after treatment with inflammatory factors.Finally,differentially expressed transcription factors were identified and verified using microarray datasets of donor islet ischemic injury and Western blotting.Results A total of 7 different cell subpopulations were found in mouse islets,with β-cells being the most abundant.Cell-cell interaction network analysis showed that the number and strength of interactions between ductal cells and other cells were the highest.Gene set enrichment analysis showed that after treatment with inflammatory factors,the immune response was positively enriched in β-cells,while peptide hormone metabolism,bile acid metabolism,and ion homeostasis were downregulated.The common differential transcription factors identified in the mouse single-cell transcriptome and the microarray dataset of donor islet ischemic injury were early growth response 1(EGR1),nuclear factor-κB inhibitor α(NFKBIA),and activating transcription factor 3(ATF3).Among them,NFKBIA and ATF3 were upregulated,while EGR1 was downregulated.The expression of EGR1 protein was downregulated after 24 h,48 h,and 72 h of cold ischemia.Conclusions EGR1 is a transcription factor closely related to islet cold ischemia,and future research should focus on the specific mechanisms of EGR1 and its downstream target genes,in order to provide more effective strategies for clinical treatment of islet transplantation.

ObjectiveTo explore the relationships between internet gaming disorder (IGD), interpersonal needs, loneliness, and depression in adolescents through the construction of a chain mediation model, to clarify the underlying mechanisms of these associations, and to provid a theoretical basis for depression prevention and intervention. MethodsBased on the data of the 7th Population Census, using convenient sampling method 1 106 adolescents aged between 10‒19 years in South China (176), North China (147), Central China (332), and East China (451) were selected to conduct a cross-sectional survey, with a ratio of 1∶1∶1.5∶2.5. The survey was conducted with a questionnaire consisting of general information (sex, age, grade, parents’ education level), the Chinese version of the IGDS9-SF, the INQ-15, the short-form of the ULS-8 and the PHQ-9 were used to evaluate the depression status of adolescents. Spearman correlation analysis was used to explore the correlation between the variables. A multiple-mediator model was constructed using IBM SPSS Statistics 22.0 PROCESS to examine the mediating effects of interpersonal needs and loneliness on the relationship between IGD and depression. The significance of the chain mediating effect was tested using the Bootstrap method. ResultsOverall, 39.06% (432/1 106) adolescents experienced depression. The incidence of depression among adolescents with smoking and without smoking was 62.50% and 38.36%, respectively. Similarly, the incidence of depression among adolescents with alcohol consuming and without alcohol consuming was 61.94% and 35.94%, respectively. There were statistically significant differences between IGD, interpersonal needs, loneliness, and depression (P<0.01). The chain mediation model demonstrated a good fit, and the bootstrap test showed that the 95%CI of each mediation path did not include 0, indicating significant mediation effects. The overall effect was 0.337. The direct effect of IGD on depression was significant (effect value=0.138, 95%CI:0.102-0.173, P<0.001). The mediation effects included three paths: ① IGD →interpersonal needs → depression (effect value=0.073, P<0.05), accounting for 21.47% of the total effect;② IGD→ loneliness → depression (effect value=0.093, P<0.05), accounting for 27.35%; and ③ IGD → interpersonal needs → loneliness → depression (effect value=0.036, P<0.05), accounting for 10.59%. ConclusionInterpersonal needs and loneliness independently and jointly mediate the relationship between IGD and depression among adolescents. To reduce depression and improve mental health in this population, measures should be taken to prevent and intervene in IGD, address adolescents’ social and emotional needs, enhance satisfaction of interpersonal needs, and reduce loneliness.

OBJECTIVE To evaluate the mechanisms underlying the antidepressant effect of ZBH2012001,a novel serotonin and norepinephrine reuptake inhibitor(SNRI),in general and its ability to enhance monoaminergic transmission and suppress neuroinflammation in particular.METHODS① Male ICR mice were divided into vehicle(distilled water),duloxetine(DLX,10 or 20 mg·kg-1)and ZBH2012001(5,10 and 20 mg·kg-1)groups.One hour following ig administration,the antidepressant effect of ZBH2012001 was evaluated using the tail suspension test(TST)and forced swimming test(FST).② Radioligand binding assay was conducted to evaluate the affinity of ZBH2012001 for human serotonin transporters(hSERTs)and human norepinephrine transporters(hNETs).③ Mice were divided into vehicle(distilled water),DLX(10 or 20 mg·kg-1)and ZBH2012001(5,10 and 20 mg·kg-1)groups.One hour following drug administration,the 5-hydroxytryptophan(5-HTP)-induced head-twitch test or yohimbine-induced lethality test were performed to evaluate the effect of ZBH2012001 on the function of the 5-hydroxytryptamine(5-HT)and norepinephrine(NE)systems.④ Mice were divided into vehicle(distilled water+0.1%acetic acid),reserpine model(distilled water+reserpine 5 mg·kg-1),DLX(DLX 20 mg·kg-1+reserpine 5 mg·kg-1)and ZBH2012001(ZBH2012001 5,10 and 20 mg·kg-1+reserpine 5 mg·kg-1)groups.One hour following drug administration,reserpine was injected intraperitoneally to establish a monoamine-depletion model.The ptosis,akinesia,and hypothermia assays were performed to evaluate the effect of ZBH2012001 on the down-regulation of the reserpine-induced monoamine system.The TST in mice was used to evaluate the effect of ZBH2012001 on reserpine-induced depressive-like behavior while high-performance liquid chromatography with electrochemical detection(HPLC-ECD)was used to measure the levels of monoamines and their metabolites in the hippocampal tissue of reserpine-induced monoamine-depletion mice.ELISA was employed to detect the contents of tumor necrosis factor-alpha(TNF-α)and interleukin-6(IL-6)in the hippocampal tissue of reserpine-induced monoamine-depletion mice.Western blotting was used to assess the expressions of ionized calcium-binding adapter molecule-1(Iba-1)and nuclear factor-kappa B(NF-κB)in the hippocampal tissue of reserpine-induced monoamine-depletion mice.RESULTS ① Compared with the vehicle group,ZBH2012001(5,10 and 20 mg·kg-1)significantly reduced the immobility time both in the TST in mice(P<0.01,respectively),and ZBH2012001(20 mg·kg-1)and in the FST in mice(P<0.05).② ZBH2012001 competitively inhibited the binding of[3H]-imipramine to hSERTs and[3H]-nisoxetine to hNETs,with the half maximal inhibitory concentration(IC50)values of 84.95 and 712.90 nmol·L-1,respectively.③Com-pared with the vehicle group,ZBH2012001(10 and 20 mg·kg-1)significantly increased the head twitches induced by 5-HTP in mice(P<0.01,respectively)and increased the mortality rate in mice induced by yohimbine(P<0.05,P<0.01).④ In the reserpine-induced monoamine-depletion model in mice,compared with the vehicle group,mice in the reserpine model group exhibited ptosis,akinesia and hypothermia feature(P<0.01,respectively),significantly prolonged immobility time in the TST(P<0.01),significantly decreased the levels of NE,5-HT and dopamine(DA)(P<0.05,P<0.01),significantly increased the metabolic conversion rate of 5-HT and DA(P<0.01,respectively),significantly elevated levels of TNF-α and IL-6(P<0.05,respectively),and significantly increased expressions of Iba-1 and NF-κB(P<0.05,respectively)in the hippocampus.Compared with the model group,ZBH2012001(5,10 and 20 mg·kg-1)significantly antagonized ptosis and hypothermia behaviors induced by reserpine(P<0.01,respectively),ZBH2012001(10 and 20 mg·kg-1)significantly shortened the immobility time in reserpine-treated mice(P<0.05,P<0.01),ZBH2012001(20 mg·kg-1)significantly increased the levels of NE and 5-HT in the hippocampus of reserpine-treated mice(P<0.05,respectively),decreased the metabolic conversion rate of 5-HT(P<0.05),significantly reduced the contents of TNF-α and IL-6 in the hippocampus of reserpine-treated mice(P<0.05,respectively),ZBH2012001(5,10 and 20 mg·kg-1)significantly reduced the expression of Iba-1 protein in the hippocampus of reserpine-treated mice(P<0.01,respec-tively),and ZBH2012001(20 mg·kg-1)significantly reduced the expression of NF-κB protein in the hippocampus of reserpine-treated mice(P<0.05).CONCLUSION ZBH2012001 exerts its antidepres-sant effect through a dual mechanism involving monoamine enhancement and inflammation suppres-sion.

Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8⁺ T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.