BioFactors最新文献

{"title":"Elesclomol Promotes oxLDL-Mediated Foam Cell Formation and Cuproptosis in Macrophages","authors":"Daming Jiang,&nbsp;Yigong Zhang","doi":"10.1002/biof.70091","DOIUrl":"10.1002/biof.70091","url":null,"abstract":"<div>\u0000 \u0000 <p>The formation of macrophage-derived foam cells is a critical factor in the development of atherosclerotic lesions. However, the mechanisms through which the cuproptosis pathway contributes to macrophage foam cell formation remain unclear. This study aimed to investigate the role and mechanisms of the cuproptosis inducer Elesclomol in atherosclerosis. Macrophages were exposed to ox-LDL to establish a foam cell model. Subsequently, CCK8, oil red O staining, and Western blot were used to investigate foam cell formation and the cuproptosis pathway in macrophages. Furthermore, proteomics analysis was employed to explore the molecular mechanisms underlying the effects of Elesclomol. The results demonstrated that Elesclomol promoted foam cell formation by increasing lipid accumulation in ox-LDL-treated macrophages, which was attributed to the inhibition of cholesterol efflux mediated by ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1). Additionally, Elesclomol enhanced the cuproptosis pathway in macrophages, leading to increased intracellular ROS accumulation and consequent cell death. Mechanistically, the cytotoxic effects of Elesclomol were mediated through activation of the mitogen-activated protein kinase (MAPK) pathway and upregulation of metallothionein 2A (MT2A). Collectively, these findings underscore the critical role of cuproptosis in the pathogenesis of atherosclerosis and suggest that targeting this pathway may represent a promising therapeutic strategy for the disease.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147375926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coenzyme Q10 Mitigates Myocardial Infarction by Modulating HDAC4 O-GlcNAcylation","authors":"Wei Xie,&nbsp;Xiang Gao,&nbsp;Shifei Song,&nbsp;Na Li,&nbsp;Liang Zhao","doi":"10.1002/biof.70085","DOIUrl":"10.1002/biof.70085","url":null,"abstract":"<div>\u0000 \u0000 <p>Myocardial infarction (MI) is a major cause of mortality. This study explores the cardioprotective effects of Coenzyme Q10 (CoQ10) and its molecular mechanisms in MI. A rat myocardial ischemia–reperfusion model was established, and infarct size was assessed via triphenyl tetrazolium chloride (TTC) staining. Hematoxylin and eosin (H&amp;E) and Masson's staining analyzed histological changes, while terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and flow cytometry assessed apoptosis. Western blot and immunofluorescence evaluated collagen I, collagen III, α-SMA, histone deacetylases (HDACs) (4,5,7,9,11), O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and O-GlcNAcylation. Enzyme-linked immunosorbent assay (ELISA) measured tumor necrosis factor (TNF)-α, interleukin (IL)-6, transforming growth factor (TGF)-β, suppression of tumorigenicity (ST)-2, galectin (Gal)-3, and growth differentiation factor (GDF)-15, while cell counting kit-8 (CCK-8), EdU, and Transwell migration assays assessed fibroblast proliferation and migration. O-GlcNAcylation of HDAC4 was analyzed using Click-iT labeling and immunoprecipitation. Cycloheximide chase assay and ubiquitination assay detected the impact of O-GlcNAcylation at Ser455 on HDAC4 protein stability. CoQ10 significantly improved cardiac function in rat models, reducing infarct size, apoptosis, fibrosis, and inflammation. CoQ10 treatment in MIRI rats increased ejection fraction (EF) and fractional shortening (FS), reduced infarct volume (TTC staining), and decreased collagen deposition (Masson's, Sirius Red staining). TUNEL and flow cytometry confirmed reduced cardiomyocyte apoptosis, while ELISA showed lower TNF-α, IL-6, and TGF-β, indicating suppressed inflammation. At the molecular level, CoQ10 reduced global O-GlcNAcylation together with decreased OGT and increased OGA expression. Western blot and immunofluorescence confirmed reduced HDAC4 levels, linked to O-GlcNAcylation suppression particularly at Ser455. CoQ10 promoted the degradation of HDAC4 through the precise inhibition of its stabilizing O-GlcNAc modification at Ser455. In vitro, CoQ10 enhanced oxygen–glucose deprivation and reperfusion (OGD/R) cardiomyocyte survival, reduced apoptosis (TUNEL, flow cytometry), and suppressed HDAC4 expression. In fibroblasts, CoQ10 inhibited TGF-β1-induced proliferation/migration (CCK-8, EdU, Transwell assays) and reduced collagen I, collagen III, and α-SMA expression, indicating anti-fibrotic effects. Furthermore, HDAC4 knockdown in vivo improved cardiac function, and in vitro reduced cardiomyocyte apoptosis and fibroblast proliferation/migration, reinforcing HDAC4's role in MI pathology. CoQ10 exerts cardioprotective effects by modulating O-GlcNAc modification and HDAC4 expression.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147363858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANO6 Confers Paclitaxel Resistance by Targeting Ferroptosis in Cervical Cancer","authors":"Yanming Cao,&nbsp;Yuping peng,&nbsp;Jian Shen","doi":"10.1002/biof.70070","DOIUrl":"10.1002/biof.70070","url":null,"abstract":"<div>\u0000 \u0000 <p>Paclitaxel (PTX) resistance limits cervical cancer therapy. Ferroptosis suppression via GPX4 and redox remodeling has emerged as a resistance mechanism, but upstream regulators remain unclear. To determine whether ANO6 drives PTX resistance by inhibiting ferroptosis and to define the ANO6–GPX4 axis mechanistically and therapeutically. Transcriptomic analyses, immunohistochemistry on clinical specimens, and cervical cancer cell models with gain/loss of ANO6 were combined with ferroptosis assays, mitochondrial imaging, apoptosis/viability assays, and Co-IP/CHX chase to assess ANO6–GPX4 interaction and stability. GPX4 transcriptional control was probed by ChIP-qPCR and dual-luciferase. PTX sensitivity was tested in vitro and in xenografts, with or without the ferroptosis inducer RSL3. ANO6 was overexpressed in cervical cancer and associated with worse prognosis. ANO6 knockdown reduced GPX4, SLC7A11, and NRF2, increased ACSL4, elevated lipid peroxidation and iron load, disrupted mitochondrial integrity, and heightened PTX cytotoxicity; ANO6 overexpression had opposite effects. ANO6 physically associated with GPX4 and preserved its protein stability; NRF2 enhanced GPX4 promoter activity, supporting a dual (post-translational/transcriptional) maintenance of GPX4 under ANO6 control. In PTX-resistant cells, ANO6 was upregulated; its depletion restored ferroptosis and PTX sensitivity, whereas GPX4 overexpression rescued resistance. In vivo, ANO6 overexpression promoted tumor growth and PTX resistance, while PTX + RSL3 synergistically suppressed tumors and reversed GPX4-axis signaling. ANO6 confers PTX resistance by sustaining GPX4-dependent ferroptosis evasion and mitochondrial homeostasis. Targeting the ANO-GPX4 axis, alone or combined with ferroptosis induction, may improve chemotherapy sensitivity in cervical cancer.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulatory Effect of Natural Antioxidants on Tissue Transglutaminase Levels in Olfactory Ensheathing Cells Exposed to Amyloid-β: Integrated Biochemical and Computational Analysis","authors":"Rosalia Pellitteri,&nbsp;Cristina Tomasella,&nbsp;Maria Assunta Chiacchio,&nbsp;Matteo Pappalardo,&nbsp;Laura Legnani,&nbsp;Michela Spatuzza,&nbsp;Alessandro Massaro,&nbsp;Salvatore Guccione,&nbsp;Agatina Campisi","doi":"10.1002/biof.70088","DOIUrl":"10.1002/biof.70088","url":null,"abstract":"<p>Herein, we adopted a dual approach combining molecular modeling and biological studies, in order to assess the interaction between four selected natural antioxidants (NAs; berberine, curcumin, astaxanthin, indicaxanthin) and tissue transglutaminase (TG2) levels both in the absence and in the presence of full native peptide of amyloid-β (Aβ). Docking studies were performed to ascertain the binding affinity of NAs against the TG2 closed, Ca²⁺-bound closed, and open forms. In the biological investigation, the effect of berberine and curcumin treatment on TG2 in Olfactory Ensheathing Cells (OECs) exposed to Aβ(1–42) or to Aβ(25–35), a Aβ toxic fragment, or to reverse-sequence fragment Aβ(35–25), an Aβ not toxic fragment, was tested. In addition, their effect on the percentage of cell viability and cytoskeleton marker (GFAP, vimentin and nestin) levels were evaluated. The role of berberine and curcumin on both endocellular levels of reactive oxygen species (ROS) and apoptotic pathway activation were also assessed. Our findings demonstrate that pretreatment of OECs with these NAs counteracted the Aβ-induced upregulation of TG2, restoring its expression to control levels and preserving its predominant cytosolic localization. Furthermore, antioxidant pretreatment reinstated cell viability, normalized the expression of GFAP, vimentin, and nestin, reduced intracellular ROS accumulation, and prevented activation of the apoptotic cascade. Our findings demonstrate that integrating computational and biological approaches, enhances the identification of potent therapeutic agents and also highlights berberine and curcumin as promising candidates for the development of novel neuroprotective drugs against neurodegenerative disorders, including Alzheimer's disease.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12953212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147343588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytoestrogenic Isoflavone Formononetin Attenuates Motor Deficits and Mitochondrial Impairment by Regulating SIRT1/PGC-1α/NRF1/TFAM Axis in Parkinson's Disease.","authors":"Jasleen Kaur, Saba Naqvi","doi":"10.1002/biof.70098","DOIUrl":"https://doi.org/10.1002/biof.70098","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder. An essential early hallmark of PD is disrupted mitochondrial dynamics driven by impaired cellular energy homeostasis. Therapeutic interventions restoring mitochondrial function and biogenesis hold promise for neuroprotection in PD. In the present study, the neuroprotective effects of formononetin (FMN) were evaluated in both MPP⁺-induced SH-SY5Y cells and the MPTP-induced mouse model of Parkinson's disease, using concentrations of 5, 10, 20, and 40 μM in vitro and doses of 25 and 40 mg/kg in vivo. To evaluate its biological activity, we employed western blotting and immunofluorescence assay to quantify the expression of disease-relevant markers. Mitochondrial health was further assessed using Mitotracker, alongside reactive oxygen species (ROS) assessment. Motor behavior and molecular endpoint parameters were also measured. Our results demonstrated that FMN significantly attenuates MPP⁺/MPTP-induced neurotoxicity, improves motor function, and restores the expression of PGC-1α, tyrosine hydroxylase, and key mitochondrial proteins involved in mitochondrial DNA replication. Enhancement of mitochondrial fusion proteins and other transcriptional regulators was also observed in the administered groups. Flow cytometry and imaging analyses confirmed that FMN-mediated PGC-1α activation preserves mitochondrial integrity and reduces oxidative stress. Altogether, these findings provide evidence that formononetin exerts neuroprotective effects in PD by modulating the PGC-1α signaling axis.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":"e70098"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Extremes of Ovarian Response: Divergent PI3K/AKT/mTOR Signaling and Oxidative Stress Patterns in Low and High Responders Undergoing In Vitro Fertilization.","authors":"Oya Korkmaz, Seda Karabulut, Pelin Macit, İlknur Keskin","doi":"10.1002/biof.70102","DOIUrl":"10.1002/biof.70102","url":null,"abstract":"<p><p>Ovarian response extremes are associated with distinct alterations in the follicular microenvironment, yet the underlying molecular mechanisms remain incompletely understood. This study investigated oxidative stress, antioxidant responses, apoptosis, and PI3K/AKT/mTOR signaling in granulosa cells from women undergoing intracytoplasmic sperm injection, stratified into poor (POR), normal (NOR), and high ovarian response (HOR) groups (n = 30). Follicular fluid oxidative stress markers, antioxidant systems, and regulatory factors were analyzed, while intracellular reactive oxygen species, DNA fragmentation, and chromatin integrity were evaluated in granulosa cells. In addition, PI3K/AKT/mTOR pathway activity was assessed using immunohistochemistry and immunofluorescence. Compared with NOR, both POR and HOR groups exhibited increased oxidative stress, reflected by elevated MDA levels (p < 0.05), accompanied by divergent antioxidant responses, including reduced GSH levels in POR and a progressive increase in SOD activity from NOR to HOR (p < 0.05). Although melatonin and TGF-β levels did not differ significantly, melatonin showed a trend toward lower levels in POR and higher levels in HOR. Granulosa cell ROS production and apoptosis-related markers were significantly increased in both response extremes, particularly in POR (p < 0.05). Consistently, PI3K/AKT/mTOR signaling displayed differential regulation, with reduced activation in POR and enhanced activation in HOR compared to NOR (p < 0.05). Overall, NOR appears to reflect a balanced redox and molecular state, whereas both poor and high responses are characterized by oxidative stress, cellular damage, and dysregulated PI3K/AKT/mTOR signaling. These findings suggest that deviation from physiological equilibrium, rather than response magnitude alone, is a key determinant of granulosa cell dysfunction and impaired follicular competence.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":"e70102"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of YTHDF2-Mediated Epigenetic Modification in the Proliferation and Invasion of Renal Cell Carcinoma Cells.","authors":"Xiaomeng Zhang, Yan Zhang, Xin Yang, Ye Fan, Yingying Zhu","doi":"10.1002/biof.70099","DOIUrl":"https://doi.org/10.1002/biof.70099","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) ranks as the most prevalent form of urogenital cancer. This research aims to investigate the role of YTHDF2 in the RCC progression and identify new therapeutic targets for RCC. YTHDF2, E2F2, and CORO6 were assayed via qRT-PCR and Western blot. YTHDF2 was downregulated in RCC cells, while E2F2 and CORO6 were upregulated. After overexpressing YTHDF2 in RCC cells, cell viability, proliferation, invasion, and migration were measured. m6A levels were assessed. The binding of YTHDF2 to E2F2 was detected. The E2F2 mRNA stability was detected. The binding of E2F2 to the CORO6 promoter was analyzed. Overexpression of E2F2 or CORO6 was combined with YTHDF2 overexpression to validate the mechanism. Tumor growth and metastasis were observed. Results confirmed that YTHDF2 overexpression decreased cell proliferation, invasion, and migration. YTHDF2 bound to the m6A sites on E2F2 mRNA, promoted E2F2 degradation, and inhibited E2F2 expression. E2F2 bound to the CORO6 promoter to enhance CORO6 expression. Overexpression of E2F2 or CORO6 partially reversed the suppressive effects of YTHDF2 overexpression on RCC cell proliferation and invasion. YTHDF2 overexpression suppressed tumor growth and metastasis. In conclusion, YTHDF2 overexpression suppresses RCC progression by inhibiting E2F2 expression and reducing CORO6 expression via m6A modification.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":"e70099"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147761177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fermented Cabbage Brine as a Functional Dietary Modulator of Neuroinflammation, Oxidative Stress, and Anxiety-Like Behavior in Lipopolysaccharide-Challenged Mice.","authors":"Vukojevic Andjela, Prvulovic Milica, Simeunovic Valentina, Pavlovic Sladjan, Borković-Mitic Slavica, Mladenovic Aleksandra, Milanovic Desanka, Pracer Smilja","doi":"10.1002/biof.70100","DOIUrl":"10.1002/biof.70100","url":null,"abstract":"<p><p>Fermented foods are increasingly recognized for their health-promoting properties, but little is known about the effects of sauerkraut brine (SB), a by-product of cabbage fermentation, on systemic inflammation and neuro-inflammatory responses. This study aimed to investigate the immunomodulatory, antioxidant, and behavioral effects of SB oral treatment in a mouse model of low-dose lipopolysaccharide (LPS) challenge. The SB was prepared by traditional spontaneous cabbage fermentation and analyzed for pH, microbiological profile, and acidity. At the end of fermentation, the brine contained a high level of viable lactic acid bacteria (LAB) (1.8 × 10⁶ CFU/ml). Mice were pretreated orally with SB, heat-treated SB (htSB), or saline for 4 weeks before single or repeated LPS injection (0.5 mg/kg). Safety assessments, including body weight, food intake, and locomotor activity, did not indicate adverse effects with either form of SB. In the acute LPS model, SB pretreatment significantly reduced mRNA expression of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in the prefrontal cortex compared to the saline-pretreated group. Interestingly, the expression of IL-10, strongly induced by LPS, was also significantly reduced by SB, suggesting modulation of both pro- and anti-inflammatory signaling pathways. These protective effects were less pronounced in the heat-treated SB group, suggesting that viable bacteria or heat-sensitive components may be critical for bioactivity. In the repeated LPS model, SB prevented LPS-induced depletion of glutathione (GSH) and preserved total antioxidant capacity (TAC), while heat-treated SB provided no protection and resulted in increased protein carbonylation and decreased TAC. No significant changes in the activities of antioxidant enzymes (SOD1/2, CAT, GR, GSH-Px, GST) were observed. Behavioral tests using the open-field paradigm showed that all groups exhibited prolonged sickness behavior after repeated LPS exposure, despite a two-day washout period. However, only the SB group showed delayed recovery, with reduced horizontal and vertical activity lasting 1 day longer than in the other groups. Nevertheless, pretreatment with SB and heat-treated SB prevented the LPS-induced reduction in time spent in the central zone, a commonly used measure of anxiety-like behavior, suggesting a possible anxiolytic effect. In conclusion, SB exhibits anti-inflammatory and antioxidant properties associated with systemic LPS-induced neuroinflammation and may reduce anxiety-like behavior. These effects appear to be dependent on heat-sensitive constituents or microbial viability. The findings support further investigation of SB as a functional dietary intervention targeting neuro-immune health.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":"e70100"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioaccessible Sulforaphane Drives Macrophage Migration and Differentiation by Reprogramming the Interleukin Profile in Intestinal Inflammation.","authors":"Sonia Medina, Concepción Medrano-Padial, Cristina García-Viguera, Raúl Domínguez-Perles","doi":"10.1002/biof.70101","DOIUrl":"10.1002/biof.70101","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) arises from dysregulated interactions between the immune system and the intestinal microenvironment. Finding new therapeutic targets could help to develop treatments that attenuate its severity. The present study investigated the immunomodulatory potential of bioaccessible sulforaphane (SFN, 0.100 μg/mL) from broccoli by-products. Interestingly, the main results evidenced that at this physiological concentration, SFN contributed to reducing the secretion of pro-inflammatory interleukins (IL-1β, IL-6, IL-17, IL-18, IL-23, TNF-α) by intestinal epithelium up to ~56%, whereas enhancing anti-inflammatory cytokines (IL-10, IL-4, IL-13) between ~24% and ~71%. These changes adjusted the proportion of CD86⁺ and CD206⁺ during macrophage differentiation, associated with the prevention of immune-mediated IBD. In addition, a reduction in the expression of macrophage-dependent pro-inflammatory cytokines and an augmentation of the tolerogenic classes were observed. The combined use of intestinal epithelial (Caco-2) and monocytic (THP-1) cell lines established an in vitro model of the epithelium-macrophage crosstalk, thereby enhancing the physiological relevance of our findings. These results were confirmed using a pure SFN-based model system, which demonstrated SFN's contribution to the anti-inflammatory properties of broccoli stalk and bridged the gap between in vitro findings and potential dietary/therapeutic applications. Thereby, this work demonstrated that dietary SFN contributes to a large extent to the reshaping capacity of the phytochemical burden of broccoli stalks, on the interleukin profile secreted by epithelium and macrophages, as well as the macrophage differentiation, thus supporting the valorisation of broccoli by-products for preventing and managing inflammatory conditions, such as IBD.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":"e70101"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13077025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ISG15 Mediates Oxidative Stress Modulation in T2DM Patients by Directly Targeting PIK3R2.","authors":"Mei-Qi He, Jie Liu, Gao-Peng Guan, Hong Liu, Li-Ping Luo, Yi-Wen Fu, Xin-Xing Wan, Ping Jin","doi":"10.1002/biof.70103","DOIUrl":"https://doi.org/10.1002/biof.70103","url":null,"abstract":"<p><p>Type 2 diabetes (T2DM), a chronic metabolic disorder characterized by pancreatic β-cell dysfunction and insulin resistance, is closely associated with oxidative stress. Interferon-stimulated gene 15 (ISG15), a ubiquitin-like modifier, has been implicated in redox regulation; however, its mechanistic role in T2DM progression remains unclear. To identify novel bio-factors contributing to T2DM, peripheral blood mononuclear cells (PBMCs) and serum samples were collected from T2DM patients and age-/BMI-matched healthy controls to quantify ISG15 expression. Complementary studies utilized a T2DM mouse model to assess β-cell-specific ISG15 expression within pancreatic islets. In parallel, MIN6 pancreatic β-cells were exposed to pathophysiological stressors, including hyperglycemic/hyperlipidemic (HG/PG) conditions and hydrogen peroxide (H₂O₂)-induced oxidative stress, to mimic the diabetic microenvironment. Protein-protein interactions were evaluated, and functional analyses were conducted following ISG15 genetic ablation. The results demonstrated that ISG15 expression was significantly elevated in PBMCs and serum from T2DM patients compared to healthy controls. Similarly, T2DM mouse models exhibited marked upregulation of ISG15 in islet β-cells. In vitro, exposure to HG/PG or H₂O₂ increased ISG15 levels, reduced MIN6 cell viability, and heightened reactive oxygen species (ROS) accumulation. Mechanistic studies revealed that ISG15 directly interacts with the PI3K regulatory subunit PIK3R2, suppressing its activity and thereby disrupting the PI3K/AKT/Nrf2 antioxidant signaling axis. This disruption led to exacerbated oxidative stress. Collectively, these findings indicate that ISG15 acts as a novel mediator of oxidative stress in T2DM by targeting and inhibiting the PIK3R2-dependent PI3K/AKT/Nrf2 pathway. These results uncover a previously unrecognized molecular mechanism driving β-cell dysfunction and identify ISG15 as a potential therapeutic target for mitigating oxidative damage in diabetes.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":"e70103"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147761235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}