Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

Initial indicators for the prognosis of Acinetobacter Baumannii bacteremia in children.

BACKGROUND: Risk factors related to mortality due to Acinetobacter baumannii (AB) bacteremia have been unveiled previously, but early clinical manifestations of AB bacteremia based on prognosis remain uncovered. METHODS: The demographic characteristics, clinical features, antibiotic susceptibility, and outcomes of 37 hospitalized children with laboratory-confirmed AB bacteremia from Suzhou, China, were collected and analyzed retrospectively. RESULTS: Of the 37 children with AB bacteremia included in this study, 23 were males and 14 were females, with a median age of 4.83 (0.60 to 10.15) years. Among the children, 18 died (48.65%, 18/37) and 19 survived (51.35%, 19/37). The dead group had a significantly higher incidence of respiratory failure (p = 0.008), shock (P = 0.000), MODS (p = 0.000), neutropenia (< 1.5 × 109/L) (p = 0.000) and serious neutropenia (< 0.5 × 109/L) (p = 0.000) than those in the survival group. The death group had significantly more invasive procedures (2 or more) than that in the survival group at 2 weeks before onset (p = 0.005). The proportion of MDR-AB in the death group was significantly higher than that in the survival group (p = 0.000), while the PICS score was significantly lower in the survival group than that in the death group (p = 0.000). There was no significant difference in effective antibiotic use within 24 h between these two groups (p = 0.295). Among the 37 children with bloodstream infection of AB, 56.76% (21/37) of the underlying diseases were hematological diseases and oncology. Among them, 17 (81.00%) were died in the hospital. The proportion of white blood cells (p = 0.000), neutrophils (p = 0.042), eosinophils (p = 0.029), the ANC (p = 0.000) and lymphocyte (p = 0.000), the NLR(p = 0.011), hemoglobin (p = 0.001), platelets (p = 0.000), prealbumin (P = 0.000), LDH (p = 0.017), blood gas pH (p = 0.000), and serum potassium (p = 0.002) in the death group were significantly lower than those in the survival group. However, CRP (p = 0.000) and blood glucose(p = 0.036) were significantly higher in the death group than those in the survival group. By further multivariate analysis, CRP [OR (95% CI): 1.022(1.003, 1.041), p = 0.021] and neutropenia [OR (95% CI): 21.634 (2.05, 228.313, p = 0.011] within 24 h of infection were independent risk factors for death in children with AB bacteremia. When CRP was higher than 59.02 mg/L, the sensitivity of predicting mortality was 88.9%, and the specificity was 78.9%. And the sensitivity and specificity of neutropenia for predicting mortality were 83.3% and 84.2%. CONCLUSIONS: AB bacteremia has a high mortality in children, especially in patients with hematological diseases and oncology. Many early indicators were associated with poor prognosis, while elevated CRP and neutropenia were the independent predictors for the 30-day mortality of children with laboratory-confirmed AB bacteremia.

Glutathione metabolism rewiring protects renal tubule cells against cisplatin-induced apoptosis and ferroptosis.

Renal proximal tubular cells are highly vulnerable to different types of assaults during filtration and reabsorption, leading to acute renal dysfunction and eventual chronic kidney diseases (CKD). The chemotherapeutic drug cisplatin elicits cytotoxicity causing renal tubular cell death, but its executing mechanisms of action are versatile and elusive. Here, we show that cisplatin induces renal tubular cell apoptosis and ferroptosis by disrupting glutathione (GSH) metabolism. Upon cisplatin treatment, GSH metabolism is impaired leading to GSH depletion as well as the execution of mitochondria-mediated apoptosis and lipid oxidation-related ferroptosis through activating IL6/JAK/STAT3 signaling. Inhibition of JAK/STAT3 signaling reversed cell apoptosis and ferroptosis in response to cisplatin induction. Using a cisplatin-induced acute kidney injury (CAKI) mouse model, we found that inhibition of JAK/STAT3 significantly mitigates cisplatin nephrotoxicity with a reduced level of serum BUN and creatinine as well as proximal tubular distortion. In addition, the GSH booster baicalein also reclaims cisplatin-induced renal tubular cell apoptosis and ferroptosis as well as the in vivo nephrotoxicity. In conclusion, cisplatin disrupts glutathione metabolism, leading to renal tubular cell apoptosis and ferroptosis. Rewiring glutathione metabolism represents a promising strategy for combating cisplatin nephrotoxicity.

Withdrawal of treatment in a pediatric intensive care unit at a Children's Hospital in China: a 10-year retrospective study.

BACKGROUND: Published data and practice recommendations on end-of-life care generally reflect Western practice frameworks; there are limited data on withdrawal of treatment for children in China. METHODS: Withdrawal of treatment for children in the pediatric intensive care unit (PICU) of a regional children's hospital in eastern China from 2006 to 2017 was studied retrospectively. Withdrawal of treatment was categorized as medical withdrawal or premature withdrawal. The guardian's self-reported reasons for abandoning the child's treatment were recorded from 2011. RESULTS: The incidence of withdrawal of treatment for children in the PICU decreased significantly; for premature withdrawal the 3-year average of 15.1% in 2006-2008 decreased to 1.9% in 2015-2017 (87.4% reduction). The overall incidence of withdrawal of care reduced over the time period, and withdrawal of therapy by guardians was the main contributor to the overall reduction. The median age of children for whom treatment was withdrawn increased from 14.5 months (interquartile range: 4.0-72.0) in 2006 to 40.5 months (interquartile range: 8.0-99.0) in 2017. Among the reasons given by guardians of children whose treatment was withdrawn in 2011-2017, "illness is too severe" ranked first, accounting for 66.3%, followed by "condition has been improved" (20.9%). Only a few guardians ascribed treatment withdrawal to economic reasons. CONCLUSIONS: The frequency of withdrawal of medical therapy has changed over time in this children's hospital PICU, and parental decision-making has been a large part of the change.

Novel mutations of the POLR3A gene caused POLR3-related leukodystrophy in a Chinese family: a case report.

BACKGROUND: POLR3-related leukodystrophy is an autosomal recessive neurodegenerative disorder characterized by onset time ranging from the neonatal period to late childhood, progressive motor decline that manifests as spasticity, ataxia, tremor, and cerebellar symptoms, as well as mild cognitive regression and hypodontia. POLR3-related leukodystrophy belongs to the family of RNA polymerase III-related leukodystrophy, which are caused by biallelic mutations in the POLR3A, POLR3B, POLRC1, or POLR3K genes. CASE PRESENTATION: In this study, we report a female child with POLR3-related leukodystrophy manifesting as cognitive decline, moderate dysarthria, motor decline, cerebellar syndrome, short stature, dysphagia, hypodontia, and mild delayed myelination by brain imaging. Interestingly, polytrichia and bronchodysplasia were first observed in a POLR3-related leukodystrophy patient. Medical exome sequencing with high coverage depth was employed to identify potential genetic variants in the patient. Novel compound heterozygous mutations of the POLR3A gene, c.1771-6C > G and c.2611del (p.M871Cfs*8), were detected. One of them is an uncommon splice site mutation, and this is the first report of this mutation in a Chinese family. The father was determined to be a heterozygous carrier of the c.2611del (p.M871Cfs*8) mutation and the mother a heterozygous carrier of the c.1771-6C > G mutation. CONCLUSION: The patient's newly emerged clinical features and mutations provide useful information for further exploration of genotype-phenotype correlations of POLR3-related leukodystrophy.