Key Points: WWP2 expression is elevated in the tubulointerstitium of fibrotic kidneys and contributes to CKD pathogenesis and progression. WWP2 uncouples the profibrotic activation and cell proliferation in renal myofibroblasts. WWP2 controls mitochondrial respiration in renal myofibroblasts through the metabolic regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Background: Renal fibrosis is a common pathologic end point in CKD that is challenging to reverse, and myofibroblasts are responsible for the accumulation of a fibrillar collagen–rich extracellular matrix. Recent studies have unveiled myofibroblasts' diversity in proliferative and fibrotic characteristics, which are linked to different metabolic states. We previously demonstrated the regulation of extracellular matrix genes and tissue fibrosis by WWP2, a multifunctional E3 ubiquitin–protein ligase. Here, we investigate WWP2 in renal fibrosis and in the metabolic reprograming of myofibroblasts in CKD. Methods: We used kidney samples from patients with CKD and WWP2-null kidney disease mice models and leveraged single-cell RNA sequencing analysis to detail the cell-specific regulation of WWP2 in fibrotic kidneys. Experiments in primary cultured myofibroblasts by bulk-RNA sequencing, chromatin immunoprecipitation sequencing, metabolomics, and cellular metabolism assays were used to study the metabolic regulation of WWP2 and its downstream signaling. Results: The tubulointerstitial expression of WWP2 was associated with fibrotic progression in patients with CKD and in murine kidney disease models. WWP2 deficiency promoted myofibroblast proliferation and halted profibrotic activation, reducing the severity of renal fibrosis in vivo. In renal myofibroblasts, WWP2 deficiency increased fatty acid oxidation and activated the pentose phosphate pathway, boosting mitochondrial respiration at the expense of glycolysis. WWP2 suppressed the transcription of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a metabolic mediator of fibrotic response, and pharmacologic inhibition of PGC-1α partially abrogated the protective effects of WWP2 deficiency on myofibroblasts. Conclusions: WWP2 regulates the metabolic reprogramming of profibrotic myofibroblasts by a WWP2-PGC-1α axis, and WWP2 deficiency protects against renal fibrosis in CKD.

Cinnamaldehyde (CA) is marginally soluble in water, making it challenging to evenly disperse it in foods, and resulting in lowered anti-A. flavus efficacy. In the present study, nano-dispersed CA (nano-CA) was prepared to increase its aqueous solubility. Free and nano-dispersed CA were compared in terms of their inhibitory activity against fungal growth and aflatoxin production of A. flavus both in Sabouraud Dextrose (SD) culture and in peanut butter. Our results indicated that free CA inhibited the mycelia growth and aflatoxin production of A. flavus with a minimal inhibitory concentration (MIC) value of 1.0 mM, but promoted the aflatoxin production at some concentrations lower than the MIC. Nano-CA had a lower MIC value of 0.8 mM against A. flavus, and also showed improved activity against aflatoxin production without the promotion at lower dose. The solidity of peanut butter had an adverse impact on the antifungal activity of free CA, whereas nano-dispersed CA showed more than 2-fold improved activity against the growth of A. flavus. Free CA still promoted AFB₁ production at the concentration of 0.25 mM, whereas nano-CA showed more efficient inhibition of AFB1 production in the butter.

Kidney diseases are significant global public health concern, with increasing prevalence and substantial economic impact. Developing novel therapeutic approaches are essential for delaying disease progression and improving patient quality of life. Cell death signifying the termination of cellular life, could facilitate appropriate bodily development and internal homeostasis. Recently, regulated cell death (RCD) forms such as ferroptosis, characterized by iron-dependent lipid peroxidation, has garnered attention in diverse renal diseases and other pathological conditions. This review offers a comprehensive examination of ferroptosis, encompassing an analysis of the involvement of iron and lipid metabolism, the System Xc^-/glutathione/glutathione peroxidase 4 signaling, and additional associated pathways. Meanwhile, the review delves into the potential of targeting ferroptosis as a therapeutic approach in the management of acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy, and renal tumors. Furthermore, it emphasizes the significance of ferroptosis in the transition from AKI to CKD and further accentuates the potential for repurposing drug and utilizing traditional medicine in targeting ferroptosis-related pathways for clinical applications. The integrated review provides valuable insights into the role of ferroptosis in kidney diseases and highlights the potential for targeting ferroptosis as a therapeutic strategy.

Persisters are tolerant to multiple antibiotics, and widely distributed in bacteria, fungi, parasites, and even cancerous human cell populations, leading to recurrent infections and relapse after therapy. In this study, we investigated the potential of cinnamaldehyde and its derivatives to eradicate persisters in Escherichia coli. The results showed that 200 μg/ml of alpha-bromocinnamaldehyde (Br-CA) was capable of killing all E. coli cells during the exponential phase. Considering the heterogeneous nature of persisters, multiple types of persisters were induced and exposed to Br-CA. Our results indicated that no cells in the ppGpp-overproducing strain or TisB-overexpressing strain survived the treatment of Br-CA although considerable amounts of persisters to ampicillin (Amp) and ciprofloxacin (Cip) were induced. Chemical induction by carbonyl cyanide m-chlorophenylhydrazone (CCCP) led to the formation of more than 10% persister to Amp and Cip in the entire population, and Br-CA still completely eradicated them. In addition, the cells in the stationary phase, which are usually highly recalcitrant to antibiotics treatment, were also completely eradicated by 400 μg/ml of Br-CA. Further studies showed that neither thiourea (hydroxyl-radical scavenger) nor DPTA (Fe³⁺ chelator to block the hydroxyl-radical) affected the bactericidal efficiency of the Br-CA to kill E. coli, indicating a ROS-independent bactericidal mechanism. Taken together, we concluded that Br-CA compound has a novel bactericidal mechanism and the potential to mitigate antibiotics resistance crisis.