Ferroptosis is a recently recognized form of regulated cell death, characterized by iron-dependent accumulation of lipid peroxidation. Ample evidence has depicted that ferroptosis plays an essential role in the cause or consequence of human diseases, including cancer, neurodegenerative disease and acute kidney injury. However, the exact role and underlying mechanism of ferroptosis in fibrotic kidney remain unknown. Acyl-CoA synthetase long-chain family member 4 (ACSL4) has been demonstrated as an essential component in ferroptosis execution by shaping lipid composition. In this study, we aim to discuss the potential role and underlying mechanism of ACSL4-mediated ferroptosis of tubular epithelial cells (TECs) during renal fibrosis. The unbiased gene expression studies showed that ACSL4 expression was tightly associated with decreased renal function and the progression of renal fibrosis. To explore the role of ACSL4 in fibrotic kidney, ACSL4 specific inhibitor rosiglitazone (ROSI) was used to disturb the high expression of ACSL4 in TECs induced by TGF-β, unilateral ureteral obstruction (UUO) and fatty acid (FA)-modeled mice in vivo, and ACSL4 siRNA was used to knockdown ACSL4 in TGF-β-induced HK2 cells in vitro. The results demonstrated that inhibition and knockdown of ACSL4 effectively attenuated the occurrence of ferroptosis in TECs and alleviated the interstitial fibrotic response. In addition, the expression of various profibrotic cytokines all decreased after ROSI-treated in vivo and in vitro. Further investigation showed that inhibition of ACSL4 obviously attenuates the progression of renal fibrosis by reducing the proferroptotic precursors arachidonic acid- and adrenic acid- containing phosphatidylethanolamine (AA-PE and AdA-PE). In conclusion, these results suggest ACSL4 is essential for tubular ferroptotic death during kidney fibrosis development and ACSL4 inhibition is a viable therapeutic approach to preventing fibrotic kidney diseases.

Kidney fibrosis is a hallmark of chronic kidney disease (CKD) progression that is caused by tubular injury and dysregulated lipid metabolism. Genetic abolition fatty acid-binding protein 4 (FABP4), a key lipid transporter, has been reported to suppress kidney interstitial fibrosis. However, the role and underlying mechanism of chemical inhibition of FABP4 in fibrotic kidney have not been well-documented. Here, we examined preemptive the effect of a FABP4 inhibitor, BMS309403, on lipid metabolism of tubular epithelial cells (TECs) and progression of kidney fibrosis. The expression of FABP4 was significantly elevated, concomitated with the accumulation of lipid droplets in TECs during kidney fibrosis. Treatment with BMS309403 alleviated lipid deposition of TECs, as well as interstitial fibrotic responses both in unilateral ureteral obstruction (UUO)-engaged mice and TGF-β-induced TECs. Moreover, BMS309403 administration enhanced fatty acid oxidation (FAO) in TECs by regulating peroxisome proliferator-activated receptor γ (PPARγ) and restoring FAO-related enzyme activities; In addition, BMS309403 markedly reduced cell lipotoxicity, such as endoplasmic reticulum (ER) stress and apoptosis in fibrotic kidney. Taken together, our results suggest that preemptive pharmacological inhibition of FABP4 by BMS309403 rebalances abnormal lipid metabolism in TECs and attenuates the progression of kidney fibrosis, thus may hold therapeutic potential for the treatment of fibrotic kidney diseases.

Background: The epidemic of COVID-19 presents a special threat to older adults. However, information on kidney damage in older patients with COVID-19 is limited. Acute kidney injury (AKI) is common in hospitalized adults and associated with poor prognosis. We sought to explore the association between AKI and mortality in older patients with COVID-19.Methods: We conducted a retrospective, observational cohort study in a large tertiary care university hospital in Wuhan, China. All consecutive inpatients older than 65 years with COVID-19 were enrolled in this cohort. Demographic data, laboratory values, comorbidities, treatments, and clinical outcomes were all collected. Data were compared between patients with AKI and without AKI. The association between AKI and mortality was analyzed.Results: Of 1764 in-hospital patients, 882 older adult cases were included in this cohort. The median age was 71 years (interquartile range: 68–77), 440 (49.9%) were men. The most presented comorbidity was cardiovascular diseases (58.2%), followed by diabetes (31.4%). Of 882 older patients, 115 (13%) developed AKI and 128 (14.5%) died. Patients with AKI had higher mortality than those without AKI (68 [59.1%] vs 60 [7.8%]; p < .001). Multivariable Cox regression analysis showed that increasing odds of in-hospital mortality are associated with higher interleukin-6 on admission, myocardial injury, and AKI.Conclusions: Acute kidney injury is not an uncommon complication in older patients with COVID-19 but is associated with a high risk of death. Physicians should be aware of the risk of AKI in older patients with COVID-19.

Ferroptosis is a non-apoptotic form of regulated cell death that involves an imbalance in the homeostasis of two elements: iron and lipid hydroperoxides. The accumulation of lipid hydroperoxide serves as a key trigger for initiating ferroptosis. Recent studies have identified ferroptosis as a critical pathophysiology contributing to kidney disease progression. However, the specific mechanisms underlying the role of ferroptosis in chronic kidney disease (CKD) have not been elucidated. Tubular epithelial cells (TECs) ferroptosis was evaluated in unilateral ureteral obstruction (UUO) models and in TGF-β-treated HK-2 cells to explore the relationship between ferroptosis and fibrosis. Ferroptosis inhibitors (ferrostatin-1) and TECs-targeted glutathione peroxidase 4 (GPX4) overexpression in vivo and in vitro were used to investigate the effect and mechanism of TECs ferroptosis on fibrosis progression. Our findings indicate that ferroptosis is persistently activated during various states of the UUO model. As the results, ferroptosis was identified as a core facilitator of renal interstitial fibrosis in TECs during UUO. The reduction in TECs ferroptosis significantly ameliorated renal fibrosis and maintained the structure in the proximal tubules. Persistent activation of TECs ferroptosis effectively aggravated fibrosis progression through the TGF-β/Smad pathway. Inhibiting ferroptosis effectively rescues the accumulation of profibrotic cytokines, thereby alleviating renal fibrosis. The profibrotic mechanism of ferroptosis is closely related to the TGF-β/Smad pathway, and targeting ferroptosis and increasing GPX4 expression could be an effective strategy for treating CKD. The occurrence of TECs ferroptosis in CKD is due to an imbalance in iron and lipid regulation, which drives the occurrence of lipid peroxidation and the accumulation of lipid hydroperoxide. One of the primary drivers of ferroptosis, lipid peroxidation, further stimulates TGF-β/Smad signaling and exacerbates fibrosis progression. Abbreviations: TFRC, transferrin receptor protein 1; DMT1, divalent metal transporter 1; FPN, ferroportin; ACSL4, acyl-CoA synthetase long-chain family 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; GPX4, glutathione peroxidase 4; CTGF, connective tissue growth factor; PDGFB, platelet-derived growth factor subunit b; FGF2, fibroblast growth factor 2; TECs, tubular epithelial cells; CKD, chronic kidney disease. (The figure was drawn with BioRender.)

Candida commonly adheres to implanted medical devices and forms biofilms. Due to the minimal activity of current antifungals against biofilms, new drugs or drug-delivery systems to treat these persistent infections are urgently needed. In the present investigation, voriconazole-loaded nanostructured lipid carriers (Vrc-NLCs) were formulated for enhanced drug-delivery efficiency to C. albicans to increase the antifungal activity of Vrc and to improve the treatment of infectious Candida diseases. Vrc-NLCs were prepared by a hot-melt, high-pressure homogenization method, and size distribution, ζ-potential, morphology, drug-encapsulation efficiency, drug loading, and physical stability were characterized. The antifungal activity of Vrc-NLCs in vitro was tested during planktonic and biofilm growth in C. albicans. The mean particle size of the Vrc-NLCs was 45.62±0.53 nm, and they exhibited spheroid-like morphology, smooth surfaces, and ζ-potential of -0.69±0.03 mV. Encapsulation efficiency and drug loading of Vrc-NLCs were 75.37%±2.65% and 3.77%±0.13%, respectively. Physical stability results revealed that despite the low measured ζ-potential, the dispersion of the Vrc-NLCs was stable during their 3-week storage at 4°C. The minimum inhibitory concentration of Vrc-NLCs was identical to that of Vrc. However, the inhibition rate of Vrc-NLCs at lower concentrations was significantly higher than that of Vrc during planktonic growth in C. albicans in yeast-extract peptone dextrose medium. Surprisingly, Vrc-NLCs treatment reduced cell density in biofilm growth in C. albicans and induced more switches form hyphal cells to yeast cells compared with Vrc treatment. In conclusion, Vrc-NLCs maintain antifungal activity of Vrc and increase antifungal drug-delivery efficiency to C. albicans. Therefore, Vrc-NLCs will greatly contribute to the treatment of infectious diseases caused by C. albicans.

Objective: To find out the pathways and key genes and to reveal disc degeneration pathogenesis based on bioinformatic analyses. Design: The GSE70362 dataset was downloaded from the GEO (Gene Expression Omnibus) database. Differentially expressed genes (DEGs) between the patients having disc degeneration and healthy controls were screened by Limma package in R language. Critical genes were identified by adopting gene ontologies (GOs), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and protein-protein interaction (PPI) networks. Results: We identified 112 DEGs, including 60 genes which were upregulated and 52 that were downregulated. Analyses, such as GO and KEGG demonstrated that the DEGs got enriched in 4 biological processes and 2 signaling pathways, mainly related to disc degeneration. The PPI network analyses identified 5 key proteins, CCND1 (cyclin D1), GATA3, TNFSF11, LEF1, and DKK1 (Dickkopf related protein 1). Conclusion: In this study, the DEGs and pathways determined promoted us understand the disc degeneration mechanisms. Also, the study may contribute novel biomarkers for the diagnosis and prevention of disc degeneration, and seek new treatment methods to repair and even regenerate degenerative intervertebral disc.