BioFactorsPub Date : 2026-04-19DOI: 10.1002/biof.70102
Oya Korkmaz, Seda Karabulut, Pelin Macit, İlknur Keskin
{"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":"<div>\u0000 \u0000 <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 (<i>n</i> = 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 (<i>p</i> < 0.05), accompanied by divergent antioxidant responses, including reduced GSH levels in POR and a progressive increase in SOD activity from NOR to HOR (<i>p</i> < 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 (<i>p</i> < 0.05). Consistently, PI3K/AKT/mTOR signaling displayed differential regulation, with reduced activation in POR and enhanced activation in HOR compared to NOR (<i>p</i> < 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>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-19","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":"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":"<div>\u0000 \u0000 <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 × 10<sup>6</sup> 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>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-16","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":"Hydroxy-Safflower Yellow A Inhibits Breast Cancer Growth via Tumor-Associated Macrophages/CCL5/Tissue Resident Memory T Cell Signaling","authors":"Le Zhou, Guowei Lai, Bo Han, Yinjiao Yuan, Zhuowei Dong, Yijing Shi, Huiling Yuan, Guangning He, Linxuan Huang, Baocheng Xie, Yuting Liao, Xuebing Pan, Caixiang Liu, Biao Yao, Ruinian Zheng","doi":"10.1002/biof.70096","DOIUrl":"10.1002/biof.70096","url":null,"abstract":"<p>Hydroxy-safflor yellow A (HSYA), a bioactive compound from <i>Carthamus tinctorius</i>, has reported anti-inflammatory and antitumor activities. However, its effects on breast cancer and the underlying immune mechanisms remain poorly defined. In this study, we investigated the immunomodulatory role of HSYA in breast cancer, with a focus on its impact on tumor-associated macrophages (TAMs) and T cell responses. Using in vitro assays, murine breast cancer models, and single-cell transcriptomic analysis, we found that HSYA significantly inhibited tumor growth and reshaped the tumor immune microenvironment. Flow cytometry and transcriptomic profiling revealed that HSYA treatment reduced tumor-associated macrophages (TAMs) infiltration and suppressed C-C motif chemokine ligand 5 (CCL5) expression, which was associated with enhanced recruitment and activation of tissue-resident memory T (TRM) cells. Co-culture and functional assays further supported a role for the TAM/CCL5 axis in mediating these immune effects. Collectively, our findings demonstrate that HSYA exerts antitumor activity, at least in part, by modulating the TAM/CCL5/TRM axis, highlighting its potential as an immunomodulatory therapeutic strategy in breast cancer.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"52 2","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/biof.70096","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697393","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":"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>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-1<i>β</i>, IL-6, IL-17, IL-18, IL-23, TNF-<i>α</i>) 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<sup>+</sup> and CD206<sup>+</sup> 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":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-13","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}
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