The Effect of 30-Day Adequate Transitions of Acute Stroke Care on 90-Day Readmission or Death.

OBJECTIVES: We explore patient-reported behaviors and activities within 30-days post-stroke hospitalization and their role in reducing death or readmissions within 90-days post-stroke. METHODS: We constructed the adequate transitions of care (ATOC) composite score, measuring patient-reported participation in eligible behaviors and activities (diet modification, weekly exercise, follow-up medical appointment attendance, medication adherence, therapy use, and toxic habit cessation) within 30 days post-stroke hospital discharge. We analyzed ATOC scores in ischemic and intracerebral hemorrhage stroke patients discharged from the hospital to home or rehabilitation facilities and enrolled in the NIH-funded Transitions of Care Stroke Disparities Study (TCSD-S). We utilized Cox regression analysis, with the progressive adjustment for sociodemographic variables, social determinants of health, and stroke risk factors, to determine the associations between ATOC score within 30-days and death or readmission within 90-days post-stroke. RESULTS: In our sample of 1239 stroke patients (mean age 64+/-14, 58% male, 22% Hispanic, 22% Black, 52% White, 76% discharged home), 13% experienced a readmission or death within 90 days (3 deaths, 160 readmissions, 3 readmissions with subsequent death). Seventy percent of participants accomplished a ≥75% ATOC score. A 25% increase in ATOC was associated with a respective 20% (95% CI 3%-33%) reduced risk of death or readmission within 90-days. CONCLUSION: ATOC represents modifiable behaviors and activities within 30-days post-stroke that are associated with reduced risk of death or readmission within 90-days post-stroke. The ATOC score should be validated in other populations, but it can serve as a tool for improving transitions of stroke care initiatives and interventions.

Comprehensive nursing model for diabetic foot ulcers: A strategy to improve prognosis and quality of life.

Diabetic foot (DF) ulcer is one of the common complications of diabetic patients, with high incidence and amputation rate, which seriously affects the quality of life and health of patients. Therefore, how to effectively prevent and treat DF ulcers and reduce amputation rate has become an urgent problem in the medical field. As a comprehensive nursing model for patients with DF ulcers, comprehensive nursing intervention is designed to improve the therapeutic effect and prognosis and reduce the rate of amputation. Convenient sampling method was used to select 360 patients with DF who received routine care for DF ulcers from July 2013 to July 2023 for retrospective cohort analysis. According to the existence of exposure factors (comprehensive nursing intervention), 180 cases were divided into observation group and comparison group. The basic demographic data, amputation rate, severity of foot ulcer, neuropathy and vascular disease, and blood glucose control were compared between the 2 groups. The data was analyzed using SPSS26.0. Harman single factor test was used to check whether there was common method bias in the study data. Descriptive analysis, Spearman rank correlation analysis and multiple linear regression analysis were used to analyze the current situation of amputation rate of DF patients and the influence of comprehensive nursing intervention on the amputation rate of DF patients. The amputation rate was 2.8% in the Observation group compared to 8.3% in the Comparison group. The amputation rate of the observation group was generally higher in the age group, and the amputation rate of the observation group was higher in the middle school education level and below and the economic status of <5000 yuan. The difference was statistically significant (P < .05). Age (odds ratio [OR] = 1.96; 95% confidence interval [CI]: 0.88-4.38), education level (OR = 1.30; 95% CI: 1.69-6.46), economic status (OR = 2.28; 95% CI: 1.69-10.85) was an independent risk factor for amputation rate (P < .05). Comprehensive nursing interventions have played a positive role in reducing the rate of amputation in patients with DF.

Elevated phagocytic capacity directs innate spinal cord repair.

Immune cells elicit a continuum of transcriptional and functional states after spinal cord injury (SCI). In mammals, inefficient debris clearance and chronic inflammation impede recovery and overshadow pro-regenerative immune functions. We found that, unlike mammals, zebrafish SCI elicits transient immune activation and efficient debris clearance, without causing chronic inflammation. Single-cell transcriptomics and inducible genetic ablation showed zebrafish macrophages are highly phagocytic and required for regeneration. Cross-species comparisons between zebrafish and mammalian macrophages identified transcription and immune response regulator ( tcim ) as a macrophage-enriched zebrafish gene. Genetic deletion of zebrafish tcim impairs phagocytosis and regeneration, causes aberrant and chronic immune activation, and can be rescued by transplanting wild-type immune precursors into tcim mutants. Conversely, genetic expression of human TCIM accelerates debris clearance and regeneration by reprogramming myeloid precursors into activated phagocytes. This study establishes a central requirement for elevated phagocytic capacity to achieve innate spinal cord repair.

Unveiling divergent treatment prognoses in IDHwt-GBM subtypes through multiomics clustering: a swift dual MRI-mRNA model for precise subtype prediction.

BACKGROUND: IDH1-wildtype glioblastoma multiforme (IDHwt-GBM) is a highly heterogeneous and aggressive brain tumour characterised by a dismal prognosis and significant challenges in accurately predicting patient outcomes. To address these issues and personalise treatment approaches, we aimed to develop and validate robust multiomics molecular subtypes of IDHwt-GBM. Through this, we sought to uncover the distinct molecular signatures underlying these subtypes, paving the way for improved diagnosis and targeted therapy for this challenging disease. METHODS: To identify stable molecular subtypes among 184 IDHwt-GBM patients from TCGA, we used the consensus clustering method to consolidate the results from ten advanced multiomics clustering approaches based on mRNA, lncRNA, and mutation data. We developed subtype prediction models using the PAM and machine learning algorithms based on mRNA and MRI data for enhanced clinical utility. These models were validated in five independent datasets, and an online interactive system was created. We conducted a comprehensive assessment of the clinical impact, drug treatment response, and molecular associations of the IDHwt-GBM subtypes. RESULTS: In the TCGA cohort, two molecular subtypes, class 1 and class 2, were identified through multiomics clustering of IDHwt-GBM patients. There was a significant difference in survival between Class 1 and Class 2 patients, with a hazard ratio (HR) of 1.68 [1.15-2.47]. This difference was validated in other datasets (CGGA: HR = 1.75[1.04, 2.94]; CPTAC: HR = 1.79[1.09-2.91]; GALSS: HR = 1.66[1.09-2.54]; UCSF: HR = 1.33[1.00-1.77]; UPENN HR = 1.29[1.04-1.58]). Additionally, class 2 was more sensitive to treatment with radiotherapy combined with temozolomide, and this sensitivity was validated in the GLASS cohort. Correspondingly, class 2 and class 1 exhibited significant differences in mutation patterns, enriched pathways, programmed cell death (PCD), and the tumour immune microenvironment. Class 2 had more mutation signatures associated with defective DNA mismatch repair (P = 0.0021). Enriched pathways of differentially expressed genes in class 1 and class 2 (P-adjust < 0.05) were mainly related to ferroptosis, the PD-1 checkpoint pathway, the JAK-STAT signalling pathway, and other programmed cell death and immune-related pathways. The different cell death modes and immune microenvironments were validated across multiple datasets. Finally, our developed survival prediction model, which integrates molecular subtypes, age, and sex, demonstrated clinical benefits based on the decision curve in the test set. We deployed the molecular subtyping prediction model and survival prediction model online, allowing interactive use and facilitating user convenience. CONCLUSIONS: Molecular subtypes were identified and verified through multiomics clustering in IDHwt-GBM patients. These subtypes are linked to specific mutation patterns, the immune microenvironment, prognoses, and treatment responses.

Serum Macrophage Colony Stimulating Factor Relates to the Severity and the Pregnancy Outcomes in Hypertensive Disorders Complicating Pregnancy.

PURPOSE: This study aimed to assess the predictive value of macrophage colony stimulating factor (M-CSF) in the first trimester for hypertensive disorders complicating pregnancy (HDCP) and its association with disease severity and adverse pregnancy outcomes. HDCP pose significant risks to both maternal and fetal health. M-CSF is implicated in the pathogenesis of HDCP by promoting inflammation and endothelial damage. METHODS: Serum levels of M-CSF were measured using enzyme-linked immunosorbent assay, and clinical characteristics and pregnancy outcomes were compared between groups. RESULTS: Pregnant women with HDCP had significantly higher levels of proteinuria, systolic blood pressure, and diastolic blood pressure compared to those with normal pregnancy. Among patients with HDCP, the severity of disease correlated positively with serum levels of M-CSF. Furthermore, M-CSF levels in the first trimester were significantly associated with adverse pregnancy outcomes. The findings suggest that M-CSF may serve as a potential biomarker for predicting HDCP and its severity, as well as adverse pregnancy outcomes. CONCLUSIONS: Early detection and monitoring of M-CSF levels could aid in identifying high-risk pregnancies and implementing appropriate interventions to improve maternal and fetal outcomes.

Low vaporization enthalpy of modified chitosan hydrogel for high performance solar evaporator.

The high vaporization enthalpy of water attributed to the strong hydrogen bonds between water molecules is limiting the performance of solar evaporators. This work demonstrates a deliberate attempt to significantly reduce the vaporization enthalpy of water through the introduction of weak water-amine hydrogen bond interactions in hydrogel evaporators. In this article, bio-based chitosan-agarose/multiwalled carbon nanotube hydrogel film evaporators (CAMFEs) exhibit larger vaporization enthalpy reduction with the presence of primary amine groups in chitosan. An interplay between vaporization enthalpy reduction and water diffusivity leads to an optimal ratio of chitosan to agarose = 7:1 (CAMFE7) showing an impressive evaporation rate of 4.13 kg m-2 h-1 under 1 sun irradiation. CAMFE7 also exhibits excellent salt resistance, with a stable water evaporation rate, using brine water of up to 10 % salinity under continuous 1 sun irradiation. The high mechanical robustness together with its scalability makes CAMFE7 a highly promising material for practical drinking water production.

Klotho accelerates the progression of polycystic ovary syndrome through promoting granulosa cell apoptosis and inflammation.

The morbidity of polycystic ovary syndrome (PCOS) is in highly increasing rate nowadays. PCOS not only affects the fertility in women, but also threatens the health of whole life. Hence, to find the prognostic risk factors is of great value. However, the effective predictors in clinical practice of PCOS are still in blackness. In this study, we found Klotho was increased in FF (Follicular Fluid) and primary luteinized granulosa cells (GCs) from PCOS patients with hyperandrogenism. Furthermore, we found follicular Klotho was negatively correlated with numbers of mature oocytes, and positively correlated with serum testosterone, LH, and LH/FSH levels menstrual cycle and number of total antral follicles in PCOS patients. In primary luteinized GCs, the increased Klotho was accompanied with upregulation of cell apoptosis and inflammation-related genes. In ovaries of PCOS mice and cultured human KGN cell line, Klotho was up-regulated and accompanied by apoptosis, inflammation and mitochondrial dysfunction. Therefore, our findings suggest new mechanisms for granulosa cell injury and revealed to target inhibit Klotho maybe a new therapeutic strategy for treatment of PCOS.

ß-Cyclodextrin and Hyaluronic Acid-Modified Targeted Nanodelivery System for Atherosclerosis Prevention.

Natural products have been widely recognized in clinical treatment because of their low toxicity and high activity. It is worth paying attention to modifying the biopolymer into nanostructures to give natural active ingredients additional targeting effects. In this study, based on the multifunctional modification of ß-cyclodextrin (ß-CD), a nanoplatform encapsulating the unstable drug (-)-epicatechin gallate (ECG) was designed to deliver to atherosclerotic plaques. Acetalization cyclodextrin (PH-CD), which responds to low-pH environments, and hyaluronic acid cyclodextrin, which targets the CD44 receptor on macrophage membranes, were synthesized from ß-CD and hyaluronic acid using acetalization and transesterification, respectively. The resulting dual-carrier nanoparticles (Double-NPs) loaded with ECG were prepared using a solvent evaporation method. The Double-NPs effectively scavenged reactive oxygen species, promoted macrophage migration, inhibited macrophage apoptosis, and suppressed abnormal proliferation and migration of vascular smooth muscle cells. Furthermore, the Double-NPs actively accumulated in atherosclerotic plaques in ApoE-/- mice fed with a high-fat diet, leading to a reduced plaque area, inflammatory infiltration, and plaque instability. Our findings demonstrate that the newly developed ECG nanopreparation represents an effective and safe nanotherapy for diseases such as atherosclerosis.

(-)-Epicatechin gallate prevented atherosclerosis by reducing abnormal proliferation of VSMCs and oxidative stress of AML 12 cells.

(-)-Epicatechin gallate (ECG) is beneficial to the treatment of cardiovascular diseases (CVDs), especially atherosclerosis (AS) through antioxidant stress, but there is a lack of detailed mechanism research. In this study, the therapeutic target of ECG was determined by crossing the drug target and disease target of CVDs and AS. The combination ability of ECG with important targets was verified by Discovery Studio software. The abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by Ang-II and the oxidative damage of AML 12 induced by H2O2 were established to verify the reliability of ECG intervention on the target protein. A total of 120 ECG targets for the treatment of CVDs-AS were predicted by network pharmacology. The results of molecular docking showed that ECG has strong binding force with VEGFA, MMP-9, CASP3 and MMP-2 domains. In vitro experiments confirmed that ECG significantly reduced the expression of VEGFA, MMP-9, CASP3 and MMP-2 in Ang-II-induced VSMCs, and also blocked the abnormal proliferation, oxidative stress and inflammatory reaction of VSMCs by inhibiting the phosphorylation of PI3K signaling pathway. At the same time, ECG also interfered with H2O2-induced oxidative damage of AML 12 cells, decreased the expression of ROS and MDA and cell foaming, and increased the activities of antioxidant enzymes such as SOD, thus playing a protective role.

FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury.

Acute kidney injury (AKI) is in high prevalence worldwide but with no therapeutic strategies. Programmed cell death in tubular epithelial cells has been reported to accelerate a variety of AKI, but the major pathways and underlying mechanisms are not defined. Herein, we identified that pyroptosis was responsible for AKI progression and related to ATP depletion in renal tubular cells. We found that FAM3A, a mitochondrial protein that assists ATP synthesis, was decreased and negatively correlated with tubular cell injury and pyroptosis in both mice and patients with AKI. Knockout of FAM3A worsened kidney function decline, increased macrophage and neutrophil cell infiltration, and facilitated tubular cell pyroptosis in ischemia/reperfusion injury model. Conversely, FAM3A overexpression alleviated tubular cell pyroptosis, and inhibited kidney injury in ischemic AKI. Mechanistically, FAM3A promoted PI3K/AKT/NRF2 signaling, thus blocking mitochondrial reactive oxygen species (mt-ROS) accumulation. NLRP3 inflammasome sensed the overload of mt-ROS and then activated Caspase-1, which cleaved GSDMD, pro-IL-1ß, and pro-IL-18 into their mature forms to mediate pyroptosis. Of interest, NRF2 activator alleviated the pro-pyroptotic effects of FAM3A depletion, whereas the deletion of NRF2 blocked the anti-pyroptotic function of FAM3A. Thus, our study provides new mechanisms for AKI progression and demonstrates that FAM3A is a potential therapeutic target for treating AKI.

Temperature-Driven Rotation Symmetry-Breaking States in an Atomic Kagome Metal KV3Sb5.

Kagome lattice AV3Sb5 has attracted tremendous interest because it hosts correlated and topological physics. However, an in-depth understanding of the temperature-driven electronic states in AV3Sb5 is elusive. Here we use scanning tunneling microscopy to directly capture the rotational symmetry-breaking effect in KV3Sb5. Through both topography and spectroscopic imaging of defect-free KV3Sb5, we observe a charge density wave (CDW) phase transition from an a0 × a0 atomic lattice to a robust 2a0 × 2a0 superlattice upon cooling the sample to 60 K. An individual Sb-atom vacancy in KV3Sb5 further gives rise to the local Friedel oscillation (FO), visible as periodic charge modulations in spectroscopic maps. The rotational symmetry of the FO tends to break at the temperature lower than 40 K. Moreover, the FO intensity shows an obvious competition against the intensity of the CDW. Our results reveal a tantalizing electronic nematicity in KV3Sb5, highlighting the multiorbital correlation in the kagome lattice framework.

TRIM25 predominately associates with anti-viral stress granules.

Stress granules (SGs) are induced by various environmental stressors, resulting in their compositional and functional heterogeneity. SGs play a crucial role in the antiviral process, owing to their potent translational repressive effects and ability to trigger signal transduction; however, it is poorly understood how these antiviral SGs differ from SGs induced by other environmental stressors. Here we identify that TRIM25, a known driver of the ubiquitination-dependent antiviral innate immune response, is a potent and critical marker of the antiviral SGs. TRIM25 undergoes liquid-liquid phase separation (LLPS) and co-condenses with the SG core protein G3BP1 in a dsRNA-dependent manner. The co-condensation of TRIM25 and G3BP1 results in a significant enhancement of TRIM25's ubiquitination activity towards multiple antiviral proteins, which are mainly located in SGs. This co-condensation is critical in activating the RIG-I signaling pathway, thus restraining RNA virus infection. Our studies provide a conceptual framework for better understanding the heterogeneity of stress granule components and their response to distinct environmental stressors.

Comparison of brain gray matter volume changes in peritoneal dialysis and hemodialysis patients with chronic kidney disease: a VBM study.

Objective: This study aims to compare gray matter volume changes in patients with chronic kidney disease (CKD) undergoing peritoneal dialysis (PD) and hemodialysis (HD) using voxel-based morphometry (VBM). Methods: A total of 27 PD patients, 25 HD patients, and 42 healthy controls were included. VBM analysis was performed, and cognitive function was assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment Scale (MoCA). The correlation between cognitive function and changes in brain gray matter volume was analyzed. Results: Both peritoneal dialysis and hemodialysis patients had partial gray matter volume reduction compared to the controls, but the affected brain regions were not uniform. The hemodialysis patients had greater volume reduction in certain brain regions than the PD patients. The MMSE and MoCA scores were positively correlated with gray matter volume changes. Conclusion: Different dialysis modalities cause damage to specific areas of the brain, which can be detected using VBM. VBM, combined with cognitive function assessment, can help detect structural brain changes and cognitive impairment in patients with different dialysis modalities. The comprehensive application of VBM in the field of neurological function deserves further exploration.

Roles of RNA m5C modification patterns in prognosis and tumor microenvironment infiltration of diffuse large B-cell lymphoma.

Genetic and epigenetic aberrations display an essential role in the initiation and progression of diffuse large B-cell lymphoma (DLBCL). 5-methylcytosine (m5C), a common RNA modification, regulates various cellular processes and contributes to tumorigenesis and cancer progression. However, m5C alterations in DLBCL remain unclear. Our research constructed an m5C prognostic model utilizing GEO data sets, which can efficiently predict the prognosis of patients with DLBCL, and verified the m5C prognostic model genes by immunohistochemistry analysis. This model was constructed using unsupervised consensus clustering analyses, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses. Based on the expression of m5C genes in the model, patients with DLBCL could be effectively divided into groups with significant survival time differences. The m5C risk-score signature demonstrated a highly significant independent prognostic value. Results from tumor microenvironment analyses revealed that m5C genes altered the infiltration of eosinophils, Tregs, and M2 macrophages. Additionally, they regulated T cell activation by modulating the expression of CTLA4, PDL1, B2M, CD8A, ICOS, and other relevant immune checkpoint expressions. In conclusion, our study presents a robust m5C prognostic model that effectively predicts prognosis in DLBCL. This model may offer a new approach for prognostic stratification and potential therapeutic interventions for patients with DLBCL.

Anti-inflammatory effect of proanthocyanidins from blueberry through NF-κß/NLRP3 signaling pathway in vivo and in vitro.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is an uncontrolled systemic inflammatory response. Proanthocyanidins (PC) is a general term of polyphenol compounds widely existed in blueberry fruits and can treat inflammation-related diseases. This study aimed to explore the regulatory effect of PC on lipopolysaccharide (LPS)-induced systemic inflammation and its potential mechanism, providing effective strategies for the further development of PC. METHODS: Here, RAW264.7 macrophages were stimulated with LPS to establish an inflammation model in vitro, while endotoxin shock mouse models were constructed by LPS in vivo. The function of PC was investigated by MTT, ELISA kits, H&E staining, immunohistochemistry, and Western blot analysis. RESULTS: Functionally, PC could demonstrate the potential to mitigate mortality in mice with endotoxin shock, as well as attenuated the levels of inflammatory cytokines (IL-6, TNF-α) and biochemical indicators (AST, ALT, CRE and BUN). Moreover, it had a significant protective effect on lung and kidney tissues damage. Mechanistically, PC exerted anti-inflammatory effects by inhibiting the activation of the NF-κB/NLRP3 signaling pathway. CONCLUSION: PC might have the potential ability of anti-inflammatory effects via modulation of the NF-κB/NLRP3 signaling pathway.

Targeting circadian transcriptional programs in triple negative breast cancer through a cis-regulatory mechanism.

Circadian clock genes are emerging targets in many types of cancer, but their mechanistic contributions to tumor progression are still largely unknown. This makes it challenging to stratify patient populations and develop corresponding treatments. In this work, we show that in breast cancer, the disrupted expression of circadian genes has the potential to serve as biomarkers. We also show that the master circadian transcription factors (TFs) BMAL1 and CLOCK are required for the proliferation of metastatic mesenchymal stem-like (mMSL) triple-negative breast cancer (TNBC) cells. Using currently available small molecule modulators, we found that a stabilizer of cryptochrome 2 (CRY2), the direct repressor of BMAL1 and CLOCK transcriptional activity, synergizes with inhibitors of proteasome, which is required for BMAL1 and CLOCK function, to repress a transcriptional program comprising circadian cycling genes in mMSL TNBC cells. Omics analyses on drug-treated cells implied that this repression of transcription is mediated by the transcription factor binding sites (TFBSs) features in the cis-regulatory elements (CRE) of clock-controlled genes. Through a massive parallel reporter assay, we defined a set of CRE features that are potentially repressed by the specific drug combination. The identification of cis -element enrichment may serve as a new way of defining and targeting tumor types through the modulation of cis -regulatory programs, and ultimately provide a new paradigm of therapy design for cancer types with unclear drivers like TNBC.

Clinical efficacy of bronchoalveolar lavage in the treatment of small airway diseases in children.

Objective: This study aimed to evaluate the efficacy of bronchoalveolar lavage (BAL) in the treatment of children with small airway diseases. Methods: Children [n = 112; boys: 76, girls: 36 (ratio 2.1:1); age range: 1 month-10 years; median age: 12 months] with small airway diseases diagnosed by high-resolution computed tomography (HRCT) were enrolled in this study. The patients were assigned to either the BAL group (BAL and conventional therapy) or the control group (conventional therapy only). The duration of cough, fever, wheezing, hospitalization duration, disease course before admission, treatment cost, HRCT recovery time, and re-hospitalization rate were compared between the two groups. Results: The median disease course before admission of the BAL group patients was longer than that of the controls (p = 0.006). The duration of cough and wheezing in the BAL group was significantly longer than that in the control group (p = 0.012 and p = 0.001, respectively). The recovery time of cough, the re-hospitalization rate, and the total expenditure incurred for the BAL group were lower than those for the control group (p = 0.027, p = 0.026, and p = 0.000, respectively). At 2 months after discharge, the small airway lesions were found to be absorbed in 86.2% of BAL group patients vs. 64.1% of control group patients. At 6 months after discharge, the lesions were not fully absorbed in 3.4% of the BAL group patients compared to 20.5% in the control group patients. Conclusion: BAL is suitable for patients with a long disease course before admission, a long duration of coughing, and recurrent wheezing. BAL treatment of small airway diseases in children can promote the disappearance of clinical symptoms, accelerate the improvement of imaging, reduce the rate of re-hospitalization, and reduce the cost of treatment.

Mitochondrial calcium uniporter promotes kidney aging in mice through inducing mitochondrial calcium-mediated renal tubular cell senescence.

Renal tubular epithelial cell senescence plays a critical role in promoting and accelerating kidney aging and age-related renal fibrosis. Senescent cells not only lose their self-repair ability, but also can transform into senescence-associated secretory phenotype (SASP) to trigger inflammation and fibrogenesis. Recent studies show that mitochondrial dysfunction is critical for renal tubular cell senescence and kidney aging, and calcium overload and abnormal calcium-dependent kinase activities are involved in mitochondrial dysfunction-associated senescence. In this study we investigated the role of mitochondrial calcium overload and mitochondrial calcium uniporter (MCU) in kidney aging. By comparing the kidney of 2- and 24-month-old mice, we found calcium overload in renal tubular cells of aged kidney, accompanied by significantly elevated expression of MCU. In human proximal renal tubular cell line HK-2, pretreatment with MCU agonist spermine (10 µM) significantly increased mitochondrial calcium accumulation, and induced the production of reactive oxygen species (ROS), leading to renal tubular cell senescence and age-related kidney fibrosis. On the contrary, pretreatment with MCU antagonist RU360 (10 µM) or calcium chelator BAPTA-AM (10 µM) diminished D-gal-induced ROS generation, restored mitochondrial homeostasis, retarded cell senescence, and protected against kidney aging in HK-2 cells. In a D-gal-induced accelerated aging mice model, administration of BAPTA (100 µg/kg. i.p.) every other day for 8 weeks significantly alleviated renal tubuarl cell senescence and fibrosis. We conclude that MCU plays a key role in promoting renal tubular cell senescence and kidney aging. Targeting inhibition on MCU provides a new insight into the therapeutic strategy against kidney aging.

Ferroptosis: A double-edged sword.

Ferroptosis represents a form of programmed cell death that is propelled by iron-dependent lipid peroxidation, thereby being distinguished by the prominent features of iron accumulation and lipid peroxidation. Ferroptosis has been implicated in numerous physiological and pathological phenomena, with mounting indications that it holds significant implications for cancer and other medical conditions. On one side, it demonstrates anti-cancer properties by triggering ferroptosis within malignant cells, and on the other hand, it damages normal cells causing other diseases. Therefore, in this paper, we propose to review the paradoxical regulation of ferroptosis in tumors and other diseases. First, we introduce the development history, concept and mechanism of ferroptosis. The second part focuses on the methods of inducing ferroptosis in tumors. The third section emphasizes the utilization of ferroptosis in different medical conditions and strategies to inhibit ferroptosis. The fourth part elucidates the key contradictions in the control of ferroptosis. Finally, potential research avenues in associated domains are suggested.

A systematic evaluation of population pharmacokinetic models for polymyxin B in patients with liver and/or kidney dysfunction.

Polymyxin B (PMB) is considered a last-line treatment for multidrug-resistant (MDR) gram-negative bacterial infections. Model-informed precision dosing with population pharmacokinetics (PopPK) models could help to individualize PMB dosing regimens and improve therapy. However, the external prediction ability of the established PopPK models has not been fully elaborated. This study aimed to systemically evaluate eleven PMB PopPK models from ten published literature based on a new independent population, which was divided into four different populations, patients with liver dysfunction, kidney dysfunction, liver and kidney dysfunction, and normal liver and kidney function. The whole data set consisted of 146 patients with 391 PMB concentrations. The prediction- and simulation-based diagnostics and Bayesian forecasting were conducted to evaluate model predictability. In the overall evaluation process, none of the models exhibited satisfactory predictive ability in both prediction- and simulation-based diagnostic simultaneously. However, the evaluation of the models in the subgroup of patients with normal liver and kidney function revealed improved predictive performance compared to those with liver and/or kidney dysfunction. Bayesian forecasting demonstrated enhanced predictability with the incorporation of two to three prior observations. The external evaluation highlighted a lack of consistency between the prediction results of published models and the external validation dataset. Nonetheless, Bayesian forecasting holds promise in improving the predictive performance of the models, and feedback from therapeutic drug monitoring is crucial in optimizing individual dosing regimens.