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Subarachnoid hemorrhage (SAH) leads to ferroptosis with clinical evidence like iron metabolism deregulation, increased lipid peroxitation(LPO) and the inhibition of glutathione/glutathione peroxides 4(GSH/GPX4). Ferroptosis mediated early brain injury (EBI) may occur in the 72-hour period following SAH (EBI-SAH) leads to the poor prognosis of SAH. Pharmacological targeting at ferroptosis mitigate EBI-SAH, provides a new target for future treatment and prevention of EBI-SAH through targeting at ferroptosis.

Metastasis is a major contributing factor that affects the prognosis of melanoma patients. Nevertheless, the underlying molecular mechanisms involved in melanoma metastasis are not yet entirely understood. Here, we identified ubiquitin‐specific protease 22 (USP22) as a pro‐oncogenic protein in melanoma through screening the survival profiles of 52 ubiquitin‐specific proteases (USPs). USP22 demonstrates a strong association with poor clinical outcomes and is significantly overexpressed in melanoma. Ablation of USP22 expression remarkably attenuates melanoma migration, invasion, and epithelial–mesenchymal transition in vitro and suppresses melanoma metastasis in vivo. Mechanistically, USP22 controls melanoma metastasis through the SIRT1/PTEN/PI3K pathway. In addition, we conducted an United States Food and Drug Administration‐approved drug library screening and identified topotecan as a clinically applicable USP22‐targeting molecule by promoting proteasomal degradation of USP22. Finally, we found that both pharmacological and genetic silence of USP22 sensitize RSL3‐induced ferroptosis through suppressing the PI3K/Akt/mTOR pathway and its downstream SCD, and ferroptosis inhibitor could partly rescued the decreased lung metastasis by topotecan in vivo. Overall, our findings reveal a prometastatic role of USP22 and identify topotecan as a potent USP22‐targeting drug to limit melanoma metastasis. [ABSTRACT FROM AUTHOR]

Hyperuricemia, i.e., increased plasma uric acid concentration, is a common problem in clinical practice, leading to gout or nephrolithiasis, and is associated with other disorders, such as metabolic syndrome, cardiovascular disease, and chronic renal disease. Xanthine oxidoreductase (XOR) is a critical rate-limiting enzyme involved in uric acid synthesis and a promising target for hyperuricemia therapy. However, XOR inhibitors currently face clinical problems such as a short half-life and side effects. Here, we found that specifically targeting liver Xor with GalNAc-siRNAs had a good therapeutic effect on hyperuricemia. First, siRNAs were designed to target various sites in the homologous region between Homo sapiens and Mus musculus Xor mRNA and were screened in primary mouse hepatocytes. Then, the siRNAs were modified to increase their stability in vivo and conjugated with GalNAc for liver-specific delivery. The effects of GalNAc-siRNAs were evaluated in three hyperuricemia mouse models, including potassium oxonate and hypoxanthine administration in WT and humanized XDH mice and Uox knockout mice. Febuxostat, a specific XOR inhibitor used for hyperuricemia treatment, was used as a positive control. Targeting liver Xor with GalNAc-siRNAs by subcutaneous administration reduced plasma uric acid levels, uric acid accumulation in the kidney, renal inflammation, and fibrosis, thereby alleviating kidney damage in hyperuricemia mouse models without hepatoxicity. The results demonstrated that targeting liver Xor with GalNAc-siRNAs was a promising strategy for hyperuricemia therapy. [ABSTRACT FROM AUTHOR]

Estimating individual treatment effect (ITE) from observational data has attracted great interest in recent years, which plays a crucial role in decision-making across many high-impact domains such as economics, medicine, and e-commerce. Most existing studies of ITE estimation assume that different units at play are independent and do not influence each other. However, many social science experiments have shown that there often exist different levels of interactions between units in observational data, especially in a networked environment. As a result, the treatment assignment of one unit can affect the outcome of other units connected to it in the network, which is referred to as the interference or spillover effect. In this article, we study an important problem of ITE estimation from networked observational data by modeling the interference between different units and provide a principled framework to support such study. Methodologically, we propose a novel framework, SPNet, that first captures the influence of hidden confounders with the aid of graph convolutional network and then models the interference by introducing an environment summary variable and developing a masked attention mechanism. Experimental evaluations on several semi-synthetic datasets based on real-world networks corroborate the superiority of our proposed framework over state-of-the-art individual treatment effect estimation methods. [ABSTRACT FROM AUTHOR]

Wheat stem rust, caused by the fungus Puccinia graminis f. sp. tritici (Pgt), poses a substantial threat to global wheat production. Utilizing stem rust resistance (Sr) genes represents an economically viable, effective, and environmentally friendly approach to disease control. In this study, gene postulation, molecular testing, and pedigree analysis were used to identify the presence of Sr genes in 45 wheat cultivars. In addition, the resistance of these cultivars was evaluated against two predominant Pgt races, 34MRGQM and 21C3CTHTM, at the adult-plant stage during 2021–2022. The results identify seven Sr genes (Sr31, Sr38, Sr30, SrTmp, Sr22, Sr19, and Sr5) within 35 wheat cultivars. Among these, 23 cultivars contained Sr31, whereas Sr5 and SrTmp were present in four cultivars each. Han 5316, Shimai 15, Shiyou 20, and Kenong 1006 exhibited the presence of Sr19, Sr22, Sr30, and Sr38, respectively. Molecular studies confirmed the absence of Sr25 and Sr26 in any of the wheat cultivars. During field evaluation, 37 (82.2%) and 39 (86.7%) wheat cultivars demonstrated resistance to races 34MRGQM and 21C3CTHTM, respectively. Moreover, 33 wheat cultivars (73.3%) exhibited resistance to all the tested races. These study findings will significantly contribute to future research in wheat pre-breeding and abiotic stress tolerance. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that ferroptosis, a unique regulated cell death modality that is morphologically and mechanistically different from other forms of cell death, plays a vital role in the pathophysiological process of neurodegenerative diseases, and strokes. Accumulating evidence supports ferroptosis as a critical factor of neurodegenerative diseases and strokes, and pharmacological inhibition of ferroptosis as a therapeutic target for these diseases. In this review article, the core mechanisms of ferroptosis are overviewed and the roles of ferroptosis in neurodegenerative diseases and strokes are described. Finally, the emerging findings in treating neurodegenerative diseases and strokes through pharmacological inhibition of ferroptosis are described. This review demonstrates that pharmacological inhibition of ferroptosis by bioactive small‐molecule compounds (ferroptosis inhibitors) could be effective for treatments of these diseases, and highlights a potential promising therapeutic avenue that could be used to prevent neurodegenerative diseases and strokes. This review article will shed light on developing novel therapeutic regimens by pharmacological inhibition of ferroptosis to slow down the progression of these diseases in the future. [ABSTRACT FROM AUTHOR]