PRMT4 interacts with NCOA4 to inhibit ferritinophagy in cisplatin-induced acute kidney injury.

Cisplatin-induced acute kidney injury (AKI) is commonly seen in the clinical practice, and ferroptosis, a type of non-apoptotic cell death, plays a pivotal role in it. Previous studies suggested that protein arginine methyltransferase 4 (PRMT4) was incorporated in various bioprocesses, but its role in renal injuries has not been investigated. Our present study showed that PRMT4 was highly expressed in renal proximal tubular cells, and it was downregulated in cisplatin-induced AKI. Besides, genetic disruption of PRMT4 exacerbated, while its overexpression attenuated, cisplatin-induced redox injuries in renal proximal epithelia. Mechanistically, our work showed that PRMT4 interacted with NCOA4 to inhibit ferritinophagy, a type of selective autophagy favoring lipid peroxidation to accelerate ferroptosis. Taken together, our study demonstrated that PRMT4 interacted with NCOA4 to attenuate ferroptosis in cisplatin-induced AKI, suggesting that PRMT4 might present as a new therapeutic target for cisplatin-related nephropathy.

Identification of TACSTD2 as novel therapeutic targets for cisplatin-induced acute kidney injury by multi-omics data integration.

Cisplatin-induced acute kidney injury (CP-AKI) is a common complication in cancer patients. Although ferroptosis is believed to contribute to the progression of CP-AKI, its mechanisms remain incompletely understood. In this study, after initially processed individual omics datasets, we integrated multi-omics data to construct a ferroptosis network in the kidney, resulting in the identification of the key driver TACSTD2. In vitro and in vivo results showed that TACSTD2 was notably upregulated in cisplatin-treated kidneys and BUMPT cells. Overexpression of TACSTD2 accelerated ferroptosis, while its gene disruption decelerated ferroptosis, likely mediated by its potential downstream targets HMGB1, IRF6, and LCN2. Drug prediction and molecular docking were further used to propose that drugs targeting TACSTD2 may have therapeutic potential in CP-AKI, such as parthenolide, progesterone, premarin, estradiol and rosiglitazone. Our findings suggest a significant association between ferroptosis and the development of CP-AKI, with TACSTD2 playing a crucial role in modulating ferroptosis, which provides novel perspectives on the pathogenesis and treatment of CP-AKI.

Exploration of the prognostic effect of costimulatory genes in bladder cancer.

BACKGROUND: A prognostic model of bladder cancer was constructed based on costimulatory molecules, and its stability and accuracy were verified in different datasets. METHOD: The expression profile of bladder cancer RNA and the corresponding clinical data in The Cancer Genome Atlas (TCGA) database were analyzed employing computational biology, and a prognostic model was constructed for costimulating molecule-related genes. The model was applied in GSE160693, GSE176307, Xiangya_Cohort, GSE13507, GSE19423, GSE31684, GSE32894, GSE48075, GSE69795 and GSE70691 in TCGA dataset and Gene Expression Omnibus database. The role of costimulating molecules in bladder cancer tumor subtypes was also explored. By consistent cluster analysis, bladder cancer in the TCGA dataset was categorized into two subtypes: C1 and C2. The C1 subtype exhibited a poor prognosis, high levels of immune cell infiltration and significant enrichment of natural killer cells, T cells and dendritic cells in the C1 subtype. In addition, the ImmuneScore calculated by the ESTIMATE algorithm differed greatly between the two subtypes, and the ImmuneScore of the C1 subtype was greater than the C2 subtype in a significant manner. RESULTS: This study also assessed the relationship between costimulating molecules and immunotherapy response. The high-risk group responded poorly to immunotherapy, with significant differences in the amount of most immune cells between the two groups. Further, three indices of the ESTIMATE algorithm and 22 immune cells of the CIBERSORT algorithm were significantly correlated with risk values. These findings suggest the potential value of costimulating molecules in predicting immunotherapy response. CONCLUSION: A costimulatory molecule-based prognostic model for bladder cancer was established and validated across multiple datasets. This model introduces a novel mode for tailoring treatments to each individual with bladder cancer, and offers valuable insights for informed clinical choices. Simultaneously, this research also delved into the significance of costimulating molecules within distinct bladder cancer subtypes, shedding novel insights into improving immunotherapy strategies for the treatment of bladder cancer.

CHIP protects against septic acute kidney injury by inhibiting NLRP3-mediated pyroptosis.

Septic acute kidney injury (S-AKI), the most common type of acute kidney injury (AKI), is intimately related to pyroptosis and oxidative stress in its pathogenesis. Carboxy-terminus of Hsc70-interacting protein (CHIP), a U-box E3 ligase, modulates oxidative stress by degrading its targeted proteins. The role of CHIP in S-AKI and its relevance with pyroptosis have not been investigated. In this study, we showed that CHIP was downregulated in renal proximal tubular cells in lipopolysaccharide (LPS)-induced S-AKI. Besides, the extent of redox injuries in S-AKI was attenuated by CHIP overexpression or activation but accentuated by CHIP gene disruption. Mechanistically, our work demonstrated that CHIP interacted with and ubiquitinated NLRP3 to promote its proteasomal degradation, leading to the inhibition of NLRP3/ACS inflammasome-mediated pyroptosis. In summary, this study revealed that CHIP ubiquitinated NLRP3 to alleviate pyroptosis in septic renal injuries, suggesting that CHIP might be a potential therapeutic target for S-AKI.

WBP2 restrains the lysosomal degradation of GPX4 to inhibit ferroptosis in cisplatin-induced acute kidney injury.

Cisplatin is one of the major causes of acute kidney injury (AKI) in clinical practice, and ferroptosis is an essential form of cell death in cisplatin-induced AKI (CP-AKI). WW domain binding protein-2 (WBP2), a molecular chaperon, is involved in the progression of various malignancies, but its role in renal injuries has not been investigated. Our present study employed bioinformatics analysis to identify WBP2 as a potential modulator of AKI and ferroptosis. Preliminary laboratory investigations showed that WBP2, highly expressed in renal proximal tubular cells, was downregulated in CP-AKI. Further studies demonstrated that WBP2 decelerated ferroptosis to alleviate CP-AKI. Mechanistically, WBP2 interacted with glutathione peroxidase 4 (GPX4, a key detoxicating enzyme for ferroptosis) via its PPXY1 motif to inhibit ferroptosis. Furthermore, the in-depth investigations revealed that WBP2 competed with heat shock cognate protein 70 (HSC70) for the binding with the KEFRQ-like motifs of GPX4, leading to the deceleration of chaperon-mediated autophagy of GPX4. All in all, this study indicated the beneficial effect of WBP2 in CP-AKI and its relevance with ferroptosis, thus providing a novel insight into the modulation of ferroptosis in cisplatin-related nephropathy.

Identification of RPS7 as the Biomarker of Ferroptosis in Acute Kidney Injury.

Objective: This paper aims to explore novel ferroptosis-related biomarkers for acute kidney injury (AKI). Methods: Various bioinformatic methods, such as differential expression analysis, functional annotation analysis, machine learning, and chemical-gene network analysis, were used in this study. Furthermore, the expression and proferroptotic role of RPS7 were validated with further bioinformatics analysis and biochemical experiments. Results: GSE30718 dataset and GSE139061 dataset were used, and the differentially expressed genes (DEGs) were screened. The DEGs were overlapped with ferroptosis-related genes and genes associated with AKI, which led to the identification of four candidate genes. Machine learning and ROC curve analysis were conducted, and RPS7 and TRIB3 were selected for diagnostic model analysis and functional analysis. Finally, the upregulation of RSP7 in cisplatin-induced AKI was validated in cisplatin-induced AKI, and its proferroptotic role was confirmed in cisplatin-treated proximal tubular cells. Conclusion: Our results indicated that RPS7 might present as a novel ferroptosis-related biomarker for AKI, and it derived ferroptosis to accentuate cisplatin-induced AKI.

Performance Enhancement of the Poplar Wood Composites Biomimetic Mineralized by CaCO3.

Inspired by the natural matrix-mediated biomineralization, wood composites were prepared by vacuum impregnation using the gel effect of sodium alginate (SA) on calcium ions, which improved the mechanical properties, flame retardant, and smoke suppression properties of the wood composites. Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and scanning electron microscopy (SEM) confirmed that the SA inducer had promoted the orderly deposition and directional crystallization of calcium carbonate (CaCO3) inside the wood cell walls and intercellular spaces. The density and weight gain rate of the biomimetic mineralized wood showed that CaCO3 effectively adhered to the interior of wood with SA as an inducer. The compressive and flexural strengths were 15.65% and 37.66% higher than those of the control, respectively. Thermogravimetric analysis (TG) proved that SA alleviated the thermal decomposition and complete combustion of the mineralized wood and improved the thermal stability. Microcalorimetry (MCC) and cone calorimetry (CONE) analyses revealed that the maximum heat release rate (HRR), total heat release (THR), and the total smoke production (TSP) rate of the mineralized wood was reduced by 59.51%, 48.52%, and 51.67%, respectively, compared with those of the control. This research demonstrates the in situ synthesis of CaCO3 within the cellular microstructure of the poplar which is using it as a biotemplate. With the enhancement of the flame retardant property and others, the wood composite biomimetic mineralized materials modified by CaCO3 and SA could be utilized more widely in the construction industry or other fields.

Cocaine detection using aptamer and molybdenum disulfide-gold nanoparticle-based sensors.

Aim: The current work highlighted a novel colorimetric sensor based on aptamer and molybdenum disulfide (MoS2)-gold nanoparticles (AuNPs) that was developed for cocaine detection with high sensitivity. Materials & methods: Due to the presence of the plasmon resonance band on the surface of AuNPs, AuNPs aggregated and the color was changed from red to blue after adding a certain concentration of NaCl. We used MoS2 to optimize the sensing system of AuNPs. The folded conformation of the aptamer in combination with cocaine enhanced the salt tolerance of the MoS2-AuNPs, effectively preventing their aggregation. Results & conclusion: The detection limit of cocaine was 7.49 nM with good selectivity. The method based on MoS2-AuNPs colorimetry sensor is simple, quick, label-free and low cost.

Highly sensitive protein detection via covalently linked aptamer to MoS2 and exonuclease-assisted amplification strategy.

Molybdenum disulfide (MoS2) has shown highly attractive superiority as a platform for sensing. However, DNA physisorption on the surface of MoS2 was susceptible to nonspecific probe displacement and false-positive signals. To solve these problems, we have developed a novel MoS2-aptamer nanosheet biosensor for detecting thrombin using a covalently linked aptamer to the MoS2 nanosheet. Ten percent Tween 80 was used to prevent thrombin from nonspecific binding and to rapidly form thiol-DNA/gold nanoparticle (AuNP) conjugates. Furthermore, an MoS2 and exonuclease coassisted signal amplification strategy was developed to improve the detection limit for thrombin. We used the hybridization of the aptamer molecules and the matched strand with a 5' terminal thiol to immobilize the aptamer molecules on the surface of AuNPs in AuNPs@MoS2 nanocomposites. Exonuclease digested the single-strand aptamer and released the thrombin, which was then detected in the next recycle. With the coassisted amplification strategy, a 6 fM detection limit was achieved, showing that this method has higher sensitivity than most reported methods for thrombin detection. The results presented in this work show that this method of covalently attaching the aptamer and using the coassisted amplification is a promising technique for the detection of protein in medical diagnostics.

Protein determination using graphene oxide-aptamer modified gold nanoparticles in combination with Tween 80.

Recently, graphene oxide (GO) has shown superiority for disease detection arising from its unique physical and chemical properties. However, proteins adsorbed on the surface of GO prevent sensitivity improvement in fluorescence-based detection methods. In this paper, a label-free method based on aptamer modified gold nanoparticles (GNPs) combined with Tween 80 was shown to solve this problem using the detection of thrombin as an example. An aptamer was designed and bound to thrombin by changing its conformation. Tween 80 was used for rapid and reproducible synthesis of stable DNA-functionalized GNPs and prevented the thrombin from nonspecific binding to GO. Thrombin was detected with a limit of 0.68 pM by taking advantage of the efficient cross-linking effect of aptamer-GNPs to GO. The sensor was validated by determining thrombin concentration in human blood serum samples. The results indicate that this method has promising analytical application in medical diagnostic.