Xing Yu

Molecular oxygen is vital for life but can generate reactive oxygen species (ROS), leading to oxidative stress and biomolecular damage. Antioxidant peptides mitigate ROS but face scalability challenges in traditional identification methods. To address this, we developed antioxidant peptides deep representation learning (AOP-DRL), a deep learning framework that combines protein language models with hierarchical convolutional networks for high-throughput prediction. The training dataset from the publicly available original study includes experimentally validated antioxidant sequences and negative controls orthogonally verified via public repositories under standard redox proteomics data partitioning protocols. Our architecture overcomes limitations in handling variable peptide lengths and capturing nonlinear residue interactions. Benchmarking experiments reveal that AOP-DRL outperforms state-of-the-art models in terms of accuracy while generalizing well across diverse datasets. Our model achieved accuracy improvements of 7.26 %, 2.57 %, 2.59 %, and 4.20 % on the prepartitioned subsets P60, P70, P80, and P90, respectively, compared with the mean accuracy of previously specialized models for antioxidant peptides. This approach provides a cost-effective, scalable alternative to wet-lab methods, accelerating the discovery of therapeutic and nutraceutical peptides. The adaptability of the framework also suggests broader applications in bioactive peptide prediction for personalized medicine and functional foods.

The advent of polyadenosine diphosphate ribose polymerase inhibitors (PARPi) has brought about significant changes in the field of ovarian cancer treatment. However, in 2022, Rucaparib, Olaparib, and Niraparib, had their marketing approval revoked for third-line and subsequent therapies due to an increased potential for adverse events. Consequently, the exploration of new treatment modalities remains imperative. Recently, the integration of PARPi with immune checkpoint inhibitors (ICIs) has emerged as a potential remedy option within the context of ovarian cancer. This article offers a comprehensive examination of the mechanisms and applications of PARPi and ICIs in the treatment of ovarian cancer. It synthesizes the existing evidence supporting their combined use and discusses key considerations that merit attention in ongoing development efforts.

Intrahepatic cholangiocarcinoma (ICC) is a primary epithelial carcinoma known for its aggressive nature, high metastatic potential, frequent recurrence, and poor prognosis. Heparanase (HPSE) is the only known endogenous β-glucuronidase in mammals. In addition to its well-established enzymatic roles, HPSE critically exerts non-catalytic function in tumor biology. This study herein aimed to investigate the non-enzymatic roles of HPSE as well as relevant regulatory mechanisms in ICC. Our results demonstrated that HPSE was highly expressed in ICC and promoted the proliferation of ICC cells, with elevated HPSE levels implicating a poor overall survival of ICC patients. Notably, HPSE interacted with Bcl-2-associated factor 1 (BCLAF1) to upregulate the expression of Bcl-2, which subsequently activated the PERK/eIF2α-mediated endoplasmic reticulum (ER) stress pathway to promote anti-apoptotic effect of ICC. Moreover, our in vivo experiments revealed that concomitant administration of gemcitabine and the Bcl-2 inhibitor navitoclax enhanced the sensitivity of ICC cells with highly expressed HPSE to chemotherapy. In summary, our findings revealed that HPSE promoted the development and drug resistance of ICC via its non-enzymatic function. Bcl-2 may be considered as an effective target with therapeutic potential to overcome ICC chemotherapy resistance induced by HPSE, presenting valuable insights into the development of novel therapeutic strategies against ICC.

Heparanase, a member of the carbohydrate-active enzyme (CAZy) GH79 family, is an endo-β-glucuronidase capable of degrading the carbohydrate moiety of heparan sulphate proteoglycans, thus modulating and facilitating remodeling of the extracellular matrix. Heparanase activity is strongly associated with major human pathological complications, including but not limited to tumour progress, angiogenesis and inflammation, which make heparanase a valuable therapeutic target. Long-due crystallographic structures of human and bacterial heparanases have been recently determined. Though the overall architecture of human heparanase is generally comparable to that of bacterial glucuronidases, remarkable differences exist in their substrate recognition mode. Better understanding of regulatory mechanisms of heparanase in substrate recognition would provide novel insight into the anti-heparanase inhibitor development as well as potential clinical applications.

Stress‐induced premature senescence may be involved in the pathogeneses of acute liver injury. Hexavalent chromium [Cr(VI)], a common environmental pollutant related to liver injury, likely leads to premature senescence in L02 hepatocytes. However, the underlying mechanisms regarding hepatocyte premature senility in Cr(VI) exposure remain poorly understood. In this study, we found that chronic exposure of L02 hepatocytes to Cr(VI) led to premature senescence characterized by increased β‐galactosidase activity, senescence‐associated heterochromatin foci, G1 phase arrest, and decreased cell proliferation. Additionally, Cr(VI)‐induced senescent L02 hepatocytes showed upregulated inflammation‐related factors, such as IL‐6 and fibroblast growth factor 23 (FGF23), which also exhibited reactive oxygen species (ROS) accumulation derived from mitochondria accompanied with increased concentration of intracellular calcium ions (Ca²⁺) and activity of nuclear factor kappa B (NF‐κB). Of note is that ROS inhibition by N‐acetyl‐Lcysteine pretreatment not only alleviated Cr(VI)‐induced premature senescence but also reduced the elevated intracellular Ca²⁺, activated NF‐κB, and secretion of IL‐6/FGF23. Intriguingly, the toxic effect of Cr(VI) upon premature senescence of L02 hepatocytes and increased levels of IL‐6/FGF23 could be partially reversed by the intracellular Ca²⁺ chelator BAPTA‐AM pretreatment. Furthermore, by utilizing the NF‐κB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that NF‐κB mediated IL‐6/FGF23 to regulate the Cr(VI)‐induced L02 hepatocyte premature senescence, whilst the concentration of intracellular Ca²⁺ was not influenced by PDTC. To the best of our knowledge, our data reports for the first time the role of ROS‐Ca²⁺‐NF‐κB signaling pathway in Cr(VI)‐induced premature senescence. Our results collectively shed light on further exploration of innovative intervention strategies and treatment targeting Cr(VI)‐induced chronic liver damage related to premature senescence.