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Chronic kidney disease (CKD) is characterized by fibrosis and inflammation in renal tissues. Several types of cell death have been implicated in CKD onset and progression. Unlike traditional forms of cell death, PANoptosis is characterized by the crosstalk among programmed cell death pathways. However, the interaction between PANoptosis and CKD remains unclear. Here, we used bioinformatics methods to identify differentially expressed genes and differentially expressed PANoptosis-related genes (DE-PRGs) using data from the GSE37171 dataset. Following this, we further performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and gene set enrichment analysis using the data. We adopted a combined approach to select hub genes, using the STRING database and CytoHubba plug-in, and we used the GSE66494 as a validation dataset. In addition, we constructed ceRNA, transcription factor (TF)-gene, and drug-gene networks using Cytoscape. Lastly, we conducted immunohistochemical analysis and western blotting to validate the hub genes. We identified 57 PANoptosis-associated genes as DE-PRGs. We screened nine hub genes from the 57 DE-PRGs. We identified two hub genes (FOS and PTGS2) using the GSE66494 database, Nephroseq, immunohistochemistry, and western blotting. A common miRNA (Hsa-miR-101-3p) and three TFs (CREB1, E2F1, and RELA) may play a crucial role in the onset and progression of PANoptosis-related CKD. In our analysis of the drug-gene network, we identified eight drugs targeting FOS and 52 drugs targeting PTGS2.

Aim H 2 S is emerging as a signaling molecule involved in the regulation of many physiological processes in plants. Here, we investigated the potential antioxidant role of H 2 S in soybean ( Glycine max )-rhizobia ( Sinorhizobium fredii ) symbiotic root nodules. Method An endogenous H 2 S production deficit rhizobia mutant ∆ CSE was constructed to study the effect of decreased content of H 2 S in soybean nodules. Fluorescent probes and confocal microscope were used to observe the production and accumulation of H 2 S and reactive oxygen species. Transmission electronic microscopy was conducted to study the structural changes in ∆ CSE soybean nodules. Finally, qRT-PCR, enzymatic activity, and oxidative damage parameters were measured. Result The results demonstrated that abundant H 2 S was generated in the nitrogen-fixing zone of soybean nodules. The deletion of the cystathionine γ-lyase ( CSE ) gene in S. fredii ( ∆CSE ) caused a sharp decrease in H 2 S production in both free-living rhizobia and soybean nodules. We found that decrease in the H 2 S level in nodule cells inhibited nitrogenase activity. In addition, to elevated H 2 O 2 and malondialdehyde accumulation, increased protein carbonyl content and decreased O 2 − scavenging ability was observed in ∆CSE root nodules. Transmission electron microscopy revealed that an H 2 S deficit caused the deformation of bacteroids and damage of peribacteroid membranes in nodule cells. Moreover, the expression of some rhizobial and soybean genes related to antioxidant defense was up-regulated in ∆CSE nodules. Conclusion H 2 S is crucial for the nitrogen-fixation ability of soybean nodules by acting as an antioxidant element that protects nodule cells and bacteroids from oxidative damage.

Background Hydrogen sulphide (H 2 S) is involved in regulating physiological processes in plants. We investigated how H 2 S ameliorates iron (Fe) deficiency in soybean ( Glycine max L.) seedlings. Multidisciplinary approaches including physiological, biochemical and molecular, and transcriptome methods were used to investigate the H 2 S role in regulating Fe availability in soybean seedlings. Results Our results showed that H 2 S completely prevented leaf interveinal chlorosis and caused an increase in soybean seedling biomass under Fe deficiency conditions. Moreover, H 2 S decreased the amount of root-bound apoplastic Fe and increased the Fe content in leaves and roots by regulating the ferric-chelate reductase (FCR) activities and Fe homeostasis- and sulphur metabolism-related gene expression levels, thereby promoting photosynthesis in soybean seedlings. In addition, H 2 S changed the plant hormone concentrations by modulating plant hormone-related gene expression abundances in soybean seedlings grown in Fe-deficient solution. Furthermore, organic acid biosynthesis and related genes expression also played a vital role in modulating the H 2 S-mediated alleviation of Fe deficiency in soybean seedlings. Conclusion Our results indicated that Fe deficiency was alleviated by H 2 S through enhancement of Fe acquisition and assimilation, thereby regulating plant hormones and organic acid synthesis in plants.

To investigate steroid hormone profiles and therapeutic modulation in Chinese postmenopausal rheumatoid arthritis (RA) patients. This cross-sectional study enrolled 138 postmenopausal women, including 88 RA patients stratified by treatment status (23 treatment-naïve, 35 on methotrexate [MTX] monotherapy, and 30 receiving MTX plus glucocorticoids [GC]) and 50 age-matched healthy controls. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we quantified 36 steroid hormones/metabolites to assess treatment-associated endocrine alterations. Group comparisons employed non-parametric Kruskal-Wallis test for multi-group comparisons, with Mann-Whitney U tests and false discovery rate (FDR) correction for multiple comparisons. Statistical significance was defined as p<0.05 after FDR correction. Untreated RA patients demonstrated significant global steroid dysregulation, characterized by marked suppression of multiple adrenal steroids (including aldosterone, cortisol, and testosterone) compared to healthy controls (all FDR<0.05). This was accompanied by profound alterations in estrogen metabolism, notably a hyperactivated 2-hydroxylation pathway and depleted 16-hydroxylation metabolites (FDR<0.001). MTX treatment partially restored steroid homeostasis, significantly improving aldosterone and androgen profiles (FDR<0.05) toward levels observed in healthy controls. However, the addition of GC therapy further disrupted endocrine balance, significantly suppressing cortisol, testosterone, and total estrogens (FDR<0.05), while pathologically amplifying the 4-hydroxylation pathway (FDR<0.001), a process potentially linked to synovial inflammation. This study demonstrates that impaired steroidogenesis and estrogen pathway dysregulation are characteristic features of postmenopausal RA, with MTX showing unexpected hormone-restorative effects. While GC therapy provides symptomatic relief, it paradoxically exacerbates endocrine disruption, suggesting the need for personalized hormonal monitoring in long-term GC-treated patients.

Cerebral small vessel disease (CSVD) is a major neurovascular contributor to stroke and cognitive impairment, yet its interaction with chronic high-altitude adaptation remains poorly understood. This first neuroimaging investigation examined 499 Tibetan natives residing at 2000–4800 m using 3 T MRI to quantify CSVD burden and to assess its association with residential altitude. Multivariable logistic regression, treating altitude as both a continuous variable (per 500 m increment) and a categorical variable (mid-high [2000–3500 m] vs. ultra-high [> 3500 m]), revealed that 51.5% of participants had CSVD (CSVD score ≥ 1), with adjusted odds ratios of 0.94 (95% CI: 0.74–1.21) per 500 m altitude and 0.78 (95% CI: 0.42–1.44) for ultra-high versus mid-high altitude. Partial proportional odds model showed no significant association between altitude and CSVD score (OR = 1.18, 95% CI 0.99–1.40). These null findings, in contrast to the well-established paradoxical impact of altitude on stroke risk, suggest potential neuroprotective mechanisms in altitude-adapted populations. Our results challenge conventional cerebrovascular paradigms and highlight the need for further research into Tibetan-specific genetic adaptations that may modulate CSVD pathophysiology. This study provides essential insights for refining altitude-related cerebrovascular risk models.

Rivaroxaban is commonly used for the prophylaxis of venous thromboembolism (VTE) for patients undergoing major orthopedic surgery. Rivaroxaban is primarily eliminated by hepatic CYP450 metabolism and renal excretion. Rifampin is a commonly used antibiotic for prosthetic joint infections (PJI) and a potent inducer of CYP450 enzymes. Clinical data about drug-drug interactions of rivaroxaban and rifampin are limited. The present study is to describe DDI of rivaroxaban and rifampin in several prosthetic joint infections patients undergoing major orthopedic surgery. We retrospectively identified six patients concomitantly administered with rivaroxaban and rifampin between 2019 and 2020. Plasma samples of these patients with accurate sampling time were chosen from the biobank and plasma levels of rivaroxaban were measured at each time point. A physiologically based pharmacokinetic model for the rivaroxaban-rifampin interaction was developed to predict the optimal dosing regimen of rivaroxaban in the case of co-medication with rifampin. The model was validated by the observed plasma concentration of rivaroxaban from the above patients. From this model, it could be simulated that when rifampin starts or stops, gradually changing rivaroxaban dose during the first few days would elevate the efficacy and safety of rivaroxaban.

To evaluate the impact and cost-benefit value of pharmacist interventions for prophylactic antibiotic use in surgical patients undergoing clean or clean-contaminated operations. A pre-to-post intervention study was performed in the Department of Urological Surgery of a tertiary hospital. Patients admitted from January through June 2011, undergoing clean or clean-contaminated surgery, served as the pre-intervention group; patients admitted from January through June 2012 formed the post-intervention group. Pharmacist interventions were performed for the surgeries in the post-intervention group. The criteria for the rational use of antibiotic prophylaxis were established by the hospital administration. The pharmacist interventions included real-time monitoring of medical records and controlling of the prescriptions of prophylactic antibiotics against the criteria. The pre- and post-intervention groups were then compared to evaluate the outcomes of the pharmacist interventions. A cost-benefit analysis was performed to determine the economic effects of implementing the pharmacist intervention on preoperative antibiotic prophylaxis. After the pharmacist intervention, a significant decrease was found in the rate of no indications for prophylactic antibiotic use (p = 0.004), the rate of broad-spectrum antibiotic use (p<0.001), the rate of drug replacement (p<0.001) and the rate of prolonged duration of prophylaxis (p<0.001). Significant reductions were observed in the mean antibiotic cost (p<0.001), the mean duration of antibiotic prophylaxis (p<0.001) and the mean number of antibiotics used (p<0.001). A significant increase was observed in the rate of correct choice of antibiotics (p<0.001). The ratio of the net mean cost savings for antibiotics to the mean cost of pharmacist time was approximately 18.79:1. Real-time interventions provided by a clinical pharmacist promoted rational use of prophylactic antibiotics, with a significant reduction in antibiotic costs, thus leading to favorable economic outcomes.

Background: Hypercoagulability and thromboembolic events are associated with poor prognosis in coronavirus disease 2019 (COVID-19) patients. Whether chronic oral anticoagulation (OAC) improve the prognosis is yet controversial. The present study aimed to investigate the association between the chronic OAC and clinical outcomes in COVID-19 patients. Methods: PubMed, Embase, Web of Science, and the Cochrane Library were comprehensively searched to identify studies that evaluated OAC for COVID-19 until 24 July 2021. Random-effects model meta-analyses were performed to pool the relative risk (RR) and 95% confidence interval (CI) of all-cause mortality and intensive care unit (ICU) admission as primary and secondary outcomes, respectively. According to the type of oral anticoagulants [direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs)], subgroup and interaction analyses were performed to compare DOACs and VKAs. Meta-regression was performed to explore the potential confounders on all-cause mortality. Results: A total of 12 studies involving 30,646 patients met the inclusion criteria. The results confirmed that chronic OAC did not reduce the risk of all-cause mortality (RR: 0.92; 95% CI 0.82–1.03; p = 0.165) or ICU admission (RR: 0.65; 95% CI 0.40–1.04; p = 0.073) in patients with COVID-19 compared to those without OAC. The chronic use of DOACs did not reduce the risk of all-cause mortality compared to VKAs ( P interaction = 0.497) in subgroup and interaction analyses. The meta-regression failed to detect any potential confounding on all-cause mortality. Conclusion: COVID-19 patients with chronic OAC were not associated with a lower risk of all-cause mortality and ICU admission compared to those without OAC, and the results were consistent across DOACs and VKA subgroups. Systematic Review Registration: clinicaltrials.gov , identifier CRD42021269764.

Background: Patients who received warfarin require constant monitoring by hospital staff. However, social distancing and stay-at-home orders, which were universally adopted strategies to avoid the spread of COVID-19, led to unprecedented challenges. This study aimed to optimize warfarin treatment during the COVID-19 pandemic by determining the role of the Internet clinic and developing a machine learning (ML) model to predict anticoagulation quality. Methods: This retrospective study enrolled patients who received warfarin treatment in the hospital anticoagulation clinic (HAC) and “Internet + Anticoagulation clinic” (IAC) of the Nanjing Drum Tower Hospital between January 2020 and September 2021. The primary outcome was the anticoagulation quality of patients, which was evaluated by both the time in therapeutic range (TTR) and international normalized ratio (INR) variability. Anticoagulation quality and incidence of adverse events were compared between HAC and IAC. Furthermore, five ML algorithms were used to develop the anticoagulation quality prediction model, and the SHAP method was introduced to rank the feature importance. Results: Totally, 241 patients were included, comprising 145 patients in the HAC group and 96 patients in the IAC group. In the HAC group and IAC group, 73.1 and 69.8% ( p = 0.576) of patients achieved good anticoagulation quality, with the average TTR being 79.9 ± 20.0% and 80.6 ± 21.1%, respectively. There was no significant difference in the incidence of adverse events between the two groups. Evaluating the five ML models using the test set, the accuracy of the XGBoost model was 0.767, and the area under the receiver operating characteristic curve was 0.808, which showed the best performance. The results of the SHAP method revealed that age, education, hypertension, aspirin, and amiodarone were the top five important features associated with poor anticoagulation quality. Conclusion: The IAC contributed to a novel management method for patients who received warfarin during the COVID-19 pandemic, as effective as HAC and with a low risk of virus transmission. The XGBoost model could accurately select patients at a high risk of poor anticoagulation quality, who could benefit from active intervention.

Gestational diabetes mellitus (GDM) is a metabolic disorder during mid- to late-pregnancy characterized by hyperglycemia, insulin resistance and fetal mal-development. Glucose transporter type 2 (GLUT2) and sodium-coupled glucose cotransporters 2 (SGLT2) in the proximal tubules play a critical role in the reabsorption of glucose and have been linked to the occurrence of type 2 diabetes mellitus (T2DM). Our study was designed to investigate the role of GLUT2 and SGLT2 in the pathogenesis of GDM, which is considered a forerunner of T2DM, and investigate the related molecular mechanism. High-fat diet (HFD) was utilized to build a GDM mouse model that closely induces metabolic abnormalities similar to human GDM. Body weight, blood glucose and serum insulin were recorded in the experimental process. Glucose tolerance was determined by the use of an intraperitoneal glucose tolerance test (IPGTT). In addition, levels of GLUT2 and SGLT2 were evaluated to further explore the underlying mechanism of GDM. HFD feeding induced abnormal glucose metabolism as manifested by increased levels of blood glucose and insulin and prominent glucose intolerance. Additionally, fetal mice from mother feed on HFD showed higher mean body weight. Furthermore, HFD feeding led to an increase in the number of positive cells of GLUT2 and SGLT2 in the renal proximal tubule and the expressions of renal GLUT2 and SGLT2 mRNA and proteins in mice. However, no obvious change was observed in renal morphology. Our study demonstrates a potential involvement of renal GLUT2 and SGLT2 in GDM pathology in an HFD-induced GDM mouse model, which further supports the role of renal GLUT2 and SGLT2 not only in T1DM and T2DM but also in GDM.