PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury.

Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLs in ferroptosis caused the instability of biomembranes and signaled the cell death of neighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II) (PAFAH2) or by addition of antibodies against PAF. Genetic knockout or pharmacological inhibition of PAFAH2 increased PAF production, augmented synchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI. Notably, intravenous administration of wild-type PAFAH2 protein, but not its enzymatically inactive mutants, prevented synchronized tubular cell death, nephron loss and AKI. Our findings offer an insight into the mechanisms of synchronized ferroptosis and suggest a possibility for the preventive intervention of AKI.

MFD-Net: Modality Fusion Diffractive Network for Segmentation of Multimodal Brain Tumor Image.

Automatic brain tumor segmentation using multi-parametric magnetic resonance imaging (mpMRI) holds substantial importance for brain diagnosis, monitoring, and therapeutic strategy planning. Given the constraints inherent to manual segmentation, adopting deep learning networks for accomplishing accurate and automated segmentation emerges as an essential advancement. In this article, we propose a modality fusion diffractive network (MFD-Net) composed of diffractive blocks and modality feature extractors for the automatic and accurate segmentation of brain tumors. The diffractive block, designed based on Fraunhofer's single-slit diffraction principle, emphasizes neighboring high-confidence feature points and suppresses low-quality or isolated feature points, enhancing the interrelation of features. Adopting a global passive reception mode overcomes the issue of fixed receptive fields. Through a self-supervised approach, the modality feature extractor effectively utilizes the inherent generalization information of each modality, enabling the main segmentation branch to focus more on multimodal fusion feature information. We apply the diffractive block on nn-UNet in the MICCAI BraTS 2022 challenge, ranked first in the pediatric population data and third in the BraTS continuous evaluation data, proving the superior generalizability of our network. We also train separately on the BraTS 2018, 2019, and 2021 datasets. Experiments demonstrate that the proposed network outperforms state-of-the-art methods.

Investigation of an outbreak of Burkholderia cepacia infection caused by drug contamination in a tertiary hospital in China.

BACKGROUND: Contamination of drugs used in minimally invasive treatment may to lead to infection outbreaks and catastrophic public health events that require prompt detection and control. Our aim was to investigate the outbreak of Burkholderia cepacia infection and its source in a tertiary care, general hospital in Beijing, China. METHODS: We investigated the outbreak of B cepacia infection from January 2017 to March 2018. The investigation included a detailed review of all cases, and field investigations. Environmental and product cultures were performed at the microbiology laboratory in the hospital. Isolates were evaluated for molecular relatedness using pulsed-field gel electrophoresis performed in an independent laboratory. RESULTS: In total, 9 patients were infected from November 2017 to March 2018, and all patients had undergone the following surgeries: transurethral resection of the prostate (n = 4), perineal prostate biopsy (n = 2), transurethral resection of bladder tumors (n = 2), and ureteroscopy (n = 1). B cepacia was isolated from the urine of 9 patients, blood of 2 patients, grilles used for puncturing, and 2 samples in 1 batch of analgesic gels. Pulsed-field gel electrophoresis confirmed that the isolates from the patients and gels were homologous. CONCLUSIONS: Our investigation revealed that the outbreak of B cepacia infection was caused by drug contamination.

FOXO1 inhibition potentiates endothelial angiogenic functions in diabetes via suppression of ROCK1/Drp1-mediated mitochondrial fission.

Diabetes-induced endothelial cell (EC) dysfunction and neovascularization impairment constitute vascular complications with limited treatment regimens. Transcription factor FOXO1 is a key angiogenic regulator and plays a pathologic role in progression of diabetes. The present study was designed to determine the involvement of FOXO1 in impaired EC function and post-ischemic neovascularization in diabetes and investigate underlying mechanisms. We found that FOXO1-selective inhibitor AS1842856 improved blood flow recovery and capillary density in ischemic hindlimb, and rescued the delay of wound closure with a concomitant augmentation of mean perfusion rate in diabetic mice. In vitro, treatment with AS1842856 or FOXO1 siRNA abrogated high glucose-induced apoptosis and ameliorated capillary tube formation in human umbilical vein endothelial cells (HUVECs). FOXO1 inhibition relieved alterations in mitochondrial networks and significantly suppressed the overproduction of mitochondrial reactive oxygen species (mtROS) induced by high glucose in ECs. Expression of dynamin-related protein-1 (Drp1) and phosphorylation at Ser616, a protein required for mitochondrial fission, were enhanced by hyperglycemia, which could be neutralized by FOXO1 inhibition. Moreover, the transcription of Rho-associated coiled-coil containing protein kinase 1 (ROCK1), which phosphorylates Drp1 at Ser616, was shown by luciferase assay to be directly regulated by FOXO1. These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and function in ECs, and FOXO1 may serve as a therapeutic target for microvascular complications of diabetes.

[Tetrahydrobiopterin Synthesis and Biological Function].

Tetrahydrobiopterin (BH4) is an essential cofactor for aromatic amino acid hydroxylases and all three nitric oxide synthase (NOS) isoforms. It has protective effects as an antioxidant and scavenger of reactive nitrogen and oxygen species. It also serves as a cofactor in both normal physiologic and pathological states. In conditions of BH4 deficiency, endothelial nitric oxide synthase (eNOS) becomes 'uncoupled', which leads to endothelial dysfunction in diabetes, pulmonary hypertension and pathologic cardiac remodeling. In this review, we will discuss the pathophysiological role of BH4 in those diseases mentioned above.

[Effects of vascular endothelial growth factor on apoptosis of sinusoidal endothelial cells caused by ethanol: experiment with rats].

OBJECTIVE: To investigate the cell death pattern of sinusoidal endothelial cells (SECs) caused by ethanol and the effects of vascular endothelial growth factor (VEGF) on this cell death, as well as the underlying mechanism involving Ets-1 and Caspase-8. METHODS: SECs were isolated from male Wistar rats and cultured in medium containing ethanol (25 - 100 mmol/L). VEGF (20 - 30 ng/ml) was added into the medium to be co-incubated for up to 6 h. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated d-uridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) technique. The protein expression of Ets-1, prototype of anti-apoptotic Ets family, was determined by Western blotting and the Caspase-8 was measured by FLICE/caspase-8 colorimetric protease assay kit. RESULTS: Three days after culture, the SECs showed spindle-like shapes and nearly confluent, however, the cells tended to shrink and die during the time course of ethanol incubation under phase contrast microscope. The control SECs contained only a few percent of TUNEL-positive cells; however, the TUNEL-positive cells started to increase 2 hours after the addition of ethanol (100 mmol/L), and about 75% of the cells were TUNEL-positive 6 hours after ethanol incubation (P < 0.05) under fluorescent microscope. Again, TUNEL-positive cells increased 6 hours after ethanol (25 - 100 mmol/L) incubation in a dose dependent manner (P < 0.05). Six hours after VEGF (20 - 30 ng/ml) was added into the medium with ethanol (100 mmol/L) the percentage of TUNEL positive SECs decreased in a dose dependent manner (P < 0.05), the level of ethanol-induced apoptotic cells in the presence of VEGF (30 ng/ml) being around 71% 6 hours after ethanol incubation alone. The Ets-1 protein level of the SECs decreased 6 hours after ethanol (100 mmol/L) incubation, which was prevented almost completely by VEGF (30 ng/ml). The Caspase-8 activity level was significantly increased to 44.9 +/- 14.3 2 hours after ethanol (100 mmol/L) incubation, and decrease to 30.4 +/- 2.0 and 25.2 +/- 2.2 respectively after the addition of VEGF (20 - 30 ng/ml) (both P < 0.05). CONCLUSION: VEGF prevents the apoptosis of primary cultured SECs induced by ethanol, through at least in part, inhibition of ethanol-induced down-regulation of Ets-1 protein expression and ethanol-induced up-regulation of Casepase-8 activity in SECs.