To investigate the role and mechanism of METTL14-mediated regulation of cuproptosis in myocardial ischemia-reperfusion injury (MI/RI). An MI/RI rat model was established. H9C2 cells were cultured and subjected to hypoxia/reoxygenation (H/R) modeling. Cells were transfected with siRNAs targeting METTL14 and ATP7A. Cell viability was detected by CCK-8 assay. Intracellular Cu[2+] levels were measured using a biochemical kit. The interaction between METTL14 and ATP7A mRNA was verified by RNA immunoprecipitation (RIP) assay. Adenovirus containing si-METTL14 was constructed and injected into rats, followed by the induction of the MI/RI model. Cardiac function was evaluated by measuring ejection fraction (EF) and fractional shortening (FS) using echocardiography. Rat myocardial tissues were collected for Hematoxylin and Eosin (HE) staining. The mRNA expression of m6A regulatory enzymes was detected by quantitative PCR (qPCR). Cu[2+] levels in myocardial tissue were measured using a biochemical assay kit. The expression of cuproptosis-related proteins was assessed by Western blot. MI/RI rats showed significantly decreased FS and EF values, with necrosis and hemorrhage, increased Cu[2+] content, elevated mRNA levels of FTO, METTL3, ALKBH5, and METTL14, decreased ATP7A protein expression, and increased protein expression of FDX1, LIAS, and DLAT in the myocardial tissue. Intramyocardial injection of adenovirus containing si-METTL14 reversed the MI/RI-induced changes. In vitro, decreased cell viability, increased Cu[2+] content, decreased ATP7A protein expression, and increased FDX1, LIAS, and DLAT protein expression were observed in H/R stimulated H9C2 cells, which were remarkably rescued by si-METTL14. Moreover, co-transfection with both si-METTL14 and si-ATP7A reversed effects induced by si-METTL14 alone. METTL14 promotes cuproptosis-associated changes and exacerbates MI/RI.

Non-enzymatic glycosylation of proteins leads to the formation of advanced glycation end products (AGEs), implicated in oxidative stress and the progression of several chronic diseases. Among the reactive carbonyl compounds, methylglyoxal (MGO) is highly potent in inducing glycoxidative damage by modifying proteins. Herein, we investigated the protective effect of plumbagin, a naphthoquinone derived from Plumbago zeylanica, to counteract MGO-induced glycation of catalase, employing integrated biophysical and computational approaches. AGE-specific fluorescence at 335 and 370 nm, ThT dye fluorescence, and microscopic visualizations confirmed that plumbagin markedly reduces AGEs formation and aggregation. Fluorescence quenching experiments revealed a stable catalase-plumbagin complex formation having binding affinity (Ka): 0.205 × 10[6 ]M[-1] and a stoichiometry of one binding site (n ≈ 1.1), suggesting a single, specific binding pocket. Isothermal titration calorimetry (ITC) confirmed an exothermic, enthalpy-driven interaction. Molecular dynamics simulations (MDS) analysis displayed a more compact and ordered conformation of complex, as evidenced by reduced Rg, SASA, and RMSF values. H-bonds stabilized the complex without altering the catalytic residues (His74, Asn147, Tyr357). PCA and FEL showed complex remained confined to a single deep energy minimum, indicating enhanced thermodynamic stability. These findings highlight plumbagin as a potent multifunctional compound capable of mitigating MGO-induced glycation.

Lung cancer remains a major global health challenge, and the oncogenic function of KDM1B (Lysine-specific Demethylase 1B) is still poorly characterized. This study employed integrated bioinformatics and experimental approaches to investigate KDM1B's function in lung cancer. Pan-cancer analysis using databases such as TIMER revealed notably elevated KDM1B mRNA expression in LUAD datasets, suggesting its potential as a diagnostic biomarker. A strong association was also found between increased KDM1B levels and immune cell infiltration in LUAD datasets. Protein interaction networks constructed using STRING and Cytoscape revealed close associations between KDM1B and key regulatory genes in NSCLC. KEGG enrichment analysis linked KDM1B to the mTOR signaling, which is critical for cell proliferation and survival. RT-PCR and western blotting for experimental validation showed KDM1B expression was significantly increased in A549 and NCI-H460 lung cancer cells. The deletion of KDM1B inhibits cell growth, induces G0/G1 phase cell cycle arrest, and promotes apoptosis in A54 cells. Moreover, cell proliferation was significantly inhibited by the KDM1B inhibitor, tranylcypromine, and induced G0/G1 phase cell cycle arrest, increased apoptosis, ROS, and glycolytic activity in A549 cells. Collectively, these findings highlight KDM1B as a valuable therapeutic target in lung adenocarcinoma and emphasize its key role in lung cancer development.

ALKBH5, as an m6A demethylase, plays a crucial regulatory role in various kidney diseases such as acute kidney injury, chronic kidney disease, renal fibrosis and renal cell carcinoma. However, its function often exhibits contradictory effects: In renal fibrosis, ALKBH5 has been reported to both promote and suppress fibrogenesis, whereas in renal cell carcinoma most studies support an oncogenic role, but some clinical observations link ALKBH5 downregulation to poor prognosis. These contradictions may stem from differences in cell types, disease stages, and microenvironments. This manuscript systematically reviews the complex function of ALKBH5 in kidney diseases and its underlying mechanisms, explores its potential as a therapeutic target, evaluates its therapeutic potential, and highlights the need for cell- and pathology-specific strategies to enable precise intervention. Future research should focus on its cell and pathological background specificity to achieve precise intervention.

Notoginsenoside R1 (NR1), an active component of Panax notoginseng, may exert anti-atherosclerotic effects by modulating macrophage M1/M2 polarization. This study aimed to investigate the specific mechanism of NR1 against atherosclerosis based on the JAK1/STAT3 pathway. M1 and M2 macrophage models, as well as an ox-LDL-induced macrophage model, were established. These models were treated with varying concentrations of NR1. Our results demonstrated that NR1 effectively suppressed LPS/IFN-γ or ox-LDL-induced polarization of macrophages toward the pro-inflammatory M1 phenotype and promoted their transition to the anti-inflammatory M2 phenotype. Concurrently, NR1 significantly inhibited the phagocytosis of ox-LDL by macrophages in the atherosclerosis model, reduced lipid accumulation, and improved mitochondrial function. Mechanistically, the regulatory effects of NR1 on macrophage polarization and function primarily depended on the inhibition of the JAK1/STAT3 signaling pathway. In conclusion, this study suggests that NR1 targets the JAK1/STAT3 pathway to balance macrophage M1/M2 polarization, thereby suppressing inflammatory responses, and ultimately alleviating atherosclerosis.

Cardiovascular-Kidney-Metabolic Syndrome (CKM) is a multisystem disorder characterized by interdependent cardiovascular, renal, and metabolic dysfunction. It commonly involves metabolic conditions such as type 2 diabetes and obesity and is associated with substantial morbidity and mortality Recently, stress-induced hormone-like cytokines, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), are emerging as the central two-controllers of the pathophysiological network of CKM. This review is a systemic summary of the biological functions and mechanism of interaction between FGF21 and GDF15 in CKM with a focus on the functions of these two hormones in regulating energy metabolism, insulin sensitivity, inflammation, fibrosis, and cardiovascular protection. We examine their clinical relevance as disease biomarkers and discuss their prospective potential as newer therapeutic targets, in addition to discussing the obstacles that are still in the way of our translations of these findings into therapeutic application. This article will elucidate shared and distinct actions of FGF21 and GDF15 and thereby offer a thorough comprehension of integrative endocrine signaling axis output, as well as its implication to further the development of CKM management.

X. Liu, Y. Ma, X. Wei, and T. Fan, "Neuroprotective Effect of Licochalcone a Against Oxygen-glucose Deprivation/Reperfusion in Rat Primary Cortical Neurons by Attenuating Oxidative Stress Injury and Inflammatory Response via the SIRT1/Nrf2 Pathway," Journal of Cellular Biochemistry 119, no. 4 (2018): 3210-3219, https://doi.org/10.1002/jcb.26477. The above article, published online on 6 November 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Lucie Kalvodova; and Wiley Periodicals LLC. The retraction has been agreed due to concerns raised by third parties. Specifically, multiple image elements in Figure 1 were found to have been previously published in several articles from different author groups and presented in different scientific contexts. The authors did not respond to our requests for clarification. Accordingly, the article has been retracted as the editors consider its conclusions to be invalid. The authors have been informed of the retraction decision but were not available for final confirmation.

Immune cell activation and differentiation are tightly coupled to metabolic reprogramming, with glucose availability and intracellular glycolytic flux serving as central determinants of immune cell fate and function. While increased glucose uptake and aerobic glycolysis support rapid proliferation and effector programs, persistent glucose abundance or dysregulated glycolytic signaling can contribute to immune dysfunction, chronic inflammation, and impaired host defense. Conversely, controlled limitation of glucose availability-through altered systemic supply, tissue microenvironmental competition, or targeted modulation of glycolysis-can rebalance immune metabolism toward oxidative phosphorylation, fatty acid oxidation, and mitochondrial fitness. This review examines how glucose availability and glycolytic flux operate as metabolic checkpoints that integrate with nutrient-sensing pathways, including mTORC1, AMPK, and HIF-1α, to shape immune activation, effector differentiation, and memory formation. We discuss evidence across disease contexts, including hyperglycemia-associated immune dysfunction, viral infection, autoimmunity, and cancer, and summarize emerging strategies to therapeutically modulate glucose metabolism using dietary interventions and pharmacologic tools. By distinguishing dietary carbohydrate intake from systemic glucose availability and cell-intrinsic glycolytic control, this review provides a coherent framework for understanding when glucose modulation can enhance immunity and when it risks immune suppression or metabolic exhaustion.

The aim of this study was to investigate the therapeutic effects of parthenolide (PTL), the active constituent of Tanacetum parthenium, on paclitaxel (PTX)-induced cardiotoxicity at both gene and protein expression levels. 48 male Sprague-Dawley rats were divided into 6 groups. While no intervention was performed in the control group, the second group received 8 mg/kg PTX. The third group was administered dimethyl sulfoxide (DMSO) as the vehicle control, whereas the fourth, fifth, and sixth groups were treated with 1, 2, and 4 mg/kg PTL, respectively, following PTX administration. The results demonstrated that oxidative stress biomarkers, including glutathione (GSH) and malondialdehyde (MDA), were significantly altered following PTX treatment, indicating oxidative damage; however, PTL administration restored these levels to physiological ranges. Histopathological analyses revealed that PTX caused pathological alterations in cardiac tissue, such as hemorrhage and mononuclear cell infiltration, whereas PTL treatment substantially ameliorated these histopathological lesions. Additionally, 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, indicative of DNA damage, as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) levels, markers of inflammation, were significantly elevated following PTX treatment. PTL administration mitigated these changes, bringing biomarker levels closer to normal. Furthermore, antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPX), and glutathione S-transferase (GST) were assessed at gene expression, enzymatic activity, and protein expression levels. The findings indicate that PTL exerts a potent therapeutic effect against PTX-induced cardiotoxicity. These results support the cardioprotective potential of PTL, suggesting that it mitigates PTX-induced oxidative stress and inflammatory responses.

Polyethylene glycols (PEG)-assisted strategies for the development of functionalized and compatible carbohydrate polymers are always an exciting topic for polymer research. However, PEGs, a carbohydrate-mimicking stealth polymer, act as a macromolecular crowding agent that has a significant impact on protein aggregation depending on their concentration and molecular weight. The study systematically investigated the impact of PEG molecules with different molecular weights and concentrations on the thermal aggregation of α-Lactalbumin (α-LA). As the concentration was increased from 10 to 200 mg/mL of each PEG molecule (PEG6000, PEG10000, and PEG20000), the β-sheet aggregates and surface hydrophobicity progressively decreased, indicating the aggregation prevention. Spectroscopic and microscopic results showed that PEGs stabilize α-LA toward its native conformation, indicating the modulation of the protein surface. PEG10000 effectively showed its protective role even at its lowest concentration (10 mg/mL), suggesting its potential role in preserving protein stability and functionality. Thus, this study provides potential therapeutics and industrial applications for the prevention of protein aggregation in different environments.

Macrophage metabolism has been increasingly studied in recent years for its potential as a therapeutic target across multiple pathologies. In this article, we propose that the tricarboxylic acid (TCA) cycle enzyme alpha-ketoglutarate (KG) dehydrogenase (KGDH) serves as a nexus for regulating macrophage polarization toward pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes. This is achieved through modulation of mitochondrial hydrogen peroxide (mtH2O2) and the availability of the TCA cycle metabolites KG and succinate, which are important immunomodulatory molecules. We discuss the evidence showing KGDH is a potent source of mtH2O2 in various cell types and how it could use this reactive oxygen species (ROS) to modulate signaling pathways involved in macrophage differentiation. Coupled to this, we describe emerging evidence showing that KG and succinate exert opposite signaling effects in macrophages, with the former metabolite inducing an anti-inflammatory phenotype and the latter (succinate) promoting inflammation. This occurs through the regulation of dioxygenases involved in hypoxic signaling and epigenetic programming and the activation of G-protein coupled receptor 91 (GPR91) by succinate. Importantly, we contend that regulating KGDH influences the availability of these two metabolites, which, along with controlling mtH2O2 availability, helps control macrophage polarization. Collectively, increased mtH2O2 generation and succinate are known to induce a pro-inflammatory phenotype, whereas low mtH2O2 and high KG have the opposite effect. This suggests that KGDH is a key regulator of macrophage polarization by controlling the availabilities of these immunomodulatory metabolites.

Organ fibrosis represents a terminal pathological consequence of chronic tissue injury and contributes substantially to global morbidity and mortality, yet effective therapeutic options remain limited. Characterized by the persistent activation of fibroblasts into myofibroblasts, fibrosis results in excessive extracellular matrix (ECM) deposition and progressive disruption of normal organ architecture, ultimately leading to functional failure. Increasing evidence places zinc finger proteins (ZNFs) as key mediators within the regulatory hierarchy of fibrotic diseases. As the largest and most diverse family of transcriptional regulators in the human genome, ZNFs utilize specialized zinc-coordinating motifs to regulate gene expression, protein stability, and intracellular signaling pathways. Beyond their classical roles in DNA binding and transcriptional control, ZNFs are now recognized as key orchestrators of fibrotic programs through regulation of ubiquitin-mediated protein turnover, cytoskeletal dynamics, and core pro-fibrotic signaling pathways, including transforming growth factor-β/Smad, mitogen-activated protein kinase, and phosphoinositide 3-kinase/protein kinase B cascades. Dysregulation of specific ZNFs has emerged as a critical driver of myofibroblast differentiation, ECM synthesis, and pathological tissue remodeling across multiple organ systems, including the liver, lung, kidney, skin, and heart. This review provides a comprehensive synthesis of the molecular roles of ZNFs in organ-specific fibrosis, integrating their structural classification with their mechanistic influence on key signaling networks. Furthermore, we discuss the clinical potential of ZNFs as biomarkers of fibrotic progression and evaluate emerging therapeutic strategies aimed at targeting ZNF-mediated pathways. Finally, we outline key knowledge gaps and future research directions. By consolidating recent advances, this review highlights ZNFs as promising molecular targets for the next generation of anti-fibrotic interventions.

SARS-CoV-2 infection is driven by extensive interactions between viral proteins and host cellular factors, yet the structural properties of host proteins within these interaction networks remain incompletely understood. Intrinsically disordered proteins and regions are key contributors to protein-protein interaction networks due to their conformational flexibility and associated with it multifunctionality, binding promiscuity, and regulatory versatility. In this study, we performed a systematic, proteome-wide analysis of intrinsic disorder in human proteins interacting with SARS-CoV-2 by integrating five experimentally validated interaction datasets comprising 2055 unique host proteins. Using disorder prediction, structural confidence assessment, functional and domain annotation, protein-protein interaction network analysis, phase-separation propensity estimation, and independent validation with the D2P2 platform on a selected set of proteins, we characterized the structural organization of the SARS-CoV-2 human interactome. Our results reveal a balanced distribution of ordered and disordered host proteins, distinct functional and domain signatures across disorder classes, consistent inverse relationships between disorder and structural confidence, and increased network connectivity and phase-separation propensity among highly disordered interactors. These findings indicate that SARS-CoV-2 exploits structural diversity within the host proteome rather than preferentially targeting a single disorder class and highlight intrinsic disorder as a key contributor to interaction plasticity and network organization at the systems level.