Angelo Azzi, Jeffrey Atkinson, Nesrin Kartal Ozer, Danny Manor, Maria Wallert, Francesco Galli
{"title":"Vitamin E nomenclature.","authors":"Angelo Azzi, Jeffrey Atkinson, Nesrin Kartal Ozer, Danny Manor, Maria Wallert, Francesco Galli","doi":"10.1016/j.freeradbiomed.2025.04.005","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.04.005","url":null,"abstract":"<p><p>The 3rd Vitamin E Satellite Symposium (VESS3) \"100 years of vitamin E\", held in Ghent, Belgium, August 2022 during the joint meeting of the Society for Free Radical Research (SFRR)-Europe branch and the Plant Oxygen Group (POG) was an occasion to reunite the scientific community interested in vitamin E and debate on its fundamentals in human nutrition one century after its discovery. This conference initiated a discussion forum dedicated to the revision of the nomenclature of vitamin E that was hosted in this journal (https://www.sciencedirect.com/special-issue/10GWS76VWXX). The forum collected 8 papers, including the opening article \"Vitamin E discussion forum - position paper on the revision of the nomenclature of vitamin E\"(Azzi, Atkinson et al. 2023), that addressed the nomenclature issue essentially suggesting \"to restrict to RRR-α-tocopherol the attribute of vitamin E\" and to identify \"… other related molecules, including chroman-6-ols (i.e. non-α-tocopherols and tocotrienols) and chromen-6-ols by their chemical names until a disease is identified that is prevented by the specific compounds.\". The articles published in this forum issue are summarized and their final considerations critically evaluated. The consensus to have come out of these articles favors the original revision proposal, with the modification of including all 2R stereoisomers of α-tocopherol (α-TOH), in addition to RRR-α-TOH, in the definition of vitamin E. Further and more rigorous studies on the molecular and clinical aspects of vitamin E essentiality were also advised together with studies on the essentiality of other vitamin E-related like compounds.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tingting Wang , Qianzhuo Liu , Limin Wu , Luyao Wang , Zhenzhen Jiang , Yike Yue , Pengyu Jiang , Zhihui Ji , Miaozhu Yin , Nian Zhang , Hui Han
{"title":"Endoplasmic reticulum stress-autophagy axis is involved in copper-induced ovarian ferroptosis","authors":"Tingting Wang , Qianzhuo Liu , Limin Wu , Luyao Wang , Zhenzhen Jiang , Yike Yue , Pengyu Jiang , Zhihui Ji , Miaozhu Yin , Nian Zhang , Hui Han","doi":"10.1016/j.freeradbiomed.2025.04.009","DOIUrl":"10.1016/j.freeradbiomed.2025.04.009","url":null,"abstract":"<div><div>Copper (Cu) contamination has emerged a global public health problem due to the extensive use of Cu in industrial production and daily life. Reproductive damage resulting from Cu exposure has been particularly evident. Wilson's disease (WD) is a recessive genetic disease characterized by impaired Cu metabolism. Female WD patients have often been associated with reproductive impairment. Ferroptosis, a form of iron-dependent regulated cell death, has been identified as being caused by massive lipid peroxide-mediated membrane damage. However, it remains unclear whether ferroptosis is associated with Cu-induced ovarian damage. In this study, the role of ferroptosis in ovarian damage induced by Cu accumulation and its underlying mechanisms were examined through both <em>in vivo</em> and <em>in vitro</em> experiments. The findings indicated that excessive Cu deposition in the ovaries could lead to follicular atresia and ovulation dysfunction, and trigger ferroptosis in ovarian and granulosa cells (GCs). The mechanism may be related to endoplasmic reticulum (ER) stress mediated by the protein kinase RNA-like ER kinase (PERK) pathway, and hyperactivation of autophagy. In addition, Cu-induced autophagy in GCs was found to increase intracellular iron levels via the ferritinophagy pathway, thereby inducing ferroptosis. We also found that mitochondrial reactive oxygen species (MitoROS) may be an onstream facilitator of Cu-induced ferroptosis via activation of the ER stress-autophagy pathway. Our findings suggested that ferroptosis is associated with Cu-induced ovarian damage and is regulated by the MitoROS-ER stress-autophagy axes. These results might provide insights for developing treatment for WD and other diseases related to Cu exposure.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"234 ","pages":"Pages 1-18"},"PeriodicalIF":7.1,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mitochondrial calcium uniporter regulates human fibroblast-like synoviocytes invasion via altering mitochondrial dynamics and dictates rheumatoid arthritis pathogenesis","authors":"Lakra Promila , Kabita Sarkar , Shivika Guleria , Adrija Rakshit , Manisha Rathore , Nishakumari C. Singh , Shaziya Khan , Manendra Singh Tomar , Veena Ammanathan , Manoj Kumar Barthwal , Jagavelu Kumaravelu , Ashutosh Shrivastava , Kalyan Mitra , Rajdeep Guha , Amita Aggarwal , Amit Lahiri","doi":"10.1016/j.freeradbiomed.2025.04.008","DOIUrl":"10.1016/j.freeradbiomed.2025.04.008","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that currently has no cure. Fibroblast-like synoviocytes (FLS), present in the RA synovium, play a pivotal role in RA pathogenesis. Notably, FLS in the RA patients (RA-FLS) exhibit characteristics similar to cancer cells, like enhanced migration, invasiveness, uncontrolled proliferation, resistance to apoptosis, and metabolic reprogramming. RA-FLS invasiveness is linked to radiographic joint damage in the patients, whereas inhibiting the FLS migration mitigates disease pathology. However, the molecular mechanisms underlying the migration and invasion capabilities of RA-FLS are not entirely understood. In this work, we have explored the function of mitochondrial calcium uniporter (MCU) and calcium signaling in FLS invasion. Our findings demonstrate a positive correlation between MCU expression and RA disease score. Interestingly, mitochondrial size was reduced, and peripheral localization was more pronounced in the RA-FLS when compared to the control FLS. Mitochondrial calcium import inhibition in the FLS by specific MCU inhibitor, Ruthenium-360 restored these altered mitochondrial dynamics and reduced the invasive phenotype. Through unbiased transcriptome analysis, we identified that MCU-mediated calcium signaling in RA-FLS leads to the enriched actin cytoskeleton and focal adhesion pathways responsible for the invasion phenotype, which can be effectively suppressed by inhibiting MCU. Additionally, we found that mitochondrial transport facilitator Miro1 binds to MCU in a calcium-dependent manner and regulates MCU-mediated mitochondrial dynamics and RA-FLS invasion. Experiments utilizing mice xenograft model demonstrated that <em>MCU</em> silencing diminishes the migration of RA-FLS toward the sites of inflammation in the immunocompromised SCID mice. Altogether, our findings highlight MCU as a promising therapeutic target to inhibit RA-FLS migration and RA progression.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"234 ","pages":"Pages 55-71"},"PeriodicalIF":7.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zucheng Luo , Shaoluan Zheng , Zhichao Hu , Pengfei Li , Junhao Zeng , Yao Lu , Mohyeddin Ali , Zijian Chen , Qi Wang , Fazhi Qi
{"title":"Ultrasound-responsive taurine lipid nanoparticles attenuate oxidative stress and promote macrophage polarization for diabetic wound healing","authors":"Zucheng Luo , Shaoluan Zheng , Zhichao Hu , Pengfei Li , Junhao Zeng , Yao Lu , Mohyeddin Ali , Zijian Chen , Qi Wang , Fazhi Qi","doi":"10.1016/j.freeradbiomed.2025.04.007","DOIUrl":"10.1016/j.freeradbiomed.2025.04.007","url":null,"abstract":"<div><div>Diabetic wound healing presents a significant clinical challenge due to disrupted neuro-immune interactions. This study identifies the α7 nicotinic acetylcholine receptor (α7nAChR) as a key regulator of wound repair by linking cholinergic signaling to macrophage reprogramming. GEO analysis of diabetic foot ulcer (DFU) microenvironments revealed neuronal loss, M1 macrophage dominance, and chronic inflammation, all driven by impaired acetylcholine (ACh) secretion and α7nAChR inactivation. Mechanistically, taurine (TA) restored PC12 cell function under high glucose conditions by activating AMPK, alleviating oxidative and endoplasmic reticulum stress, and promoting ACh production. ACh activated macrophage α7nAChR, modulating M1/M2 polarization through JAK2/STAT3 activation and NF-κB suppression. To enhance TA bioavailability, ultrasound-responsive Ccr2-targeted TA nanoparticles (Ccr2@TA@LNP) were developed for site-specific delivery via Ccl2/Ccr2 chemotaxis. In diabetic neuropathy (DPN) mice, Ccr2@TA@LNP accelerated wound healing by increasing ACh levels, enhancing α7nAChR/CD206 expression, and reducing Ccl2-mediated inflammation. By integrating neuroprotection, macrophage reprogramming, and targeted nanotherapy, this study highlights TA as a multi-target agent that restores neuro-immune balance through the AMPK/α7nAChR/JAK2-STAT3 axis, offering a novel therapeutic strategy for diabetic wound treatment.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 302-316"},"PeriodicalIF":7.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jorge Garcia-Baez , Ivana Chaves-Negrón , Sabzali Javadov , Jason N. Bazil , Xavier R. Chapa-Dubocq
{"title":"Developing a physiologically relevant cell model of ferroptosis in cardiomyocytes","authors":"Jorge Garcia-Baez , Ivana Chaves-Negrón , Sabzali Javadov , Jason N. Bazil , Xavier R. Chapa-Dubocq","doi":"10.1016/j.freeradbiomed.2025.04.006","DOIUrl":"10.1016/j.freeradbiomed.2025.04.006","url":null,"abstract":"<div><div>Excessive intracellular labile iron levels exacerbate reactive oxygen species (ROS) production through the Fenton reaction, leading to lipid peroxidation and ferroptotic cell death. Ferroptosis is commonly induced experimentally using chemical inhibitors such as RSL3 (a GPX4 inhibitor) or erastin (an inhibitor of the cystine-glutamate exchanger, Xc-) or by cysteine deprivation. However, these methods often fail to replicate the physiological complexity of ferroptosis and are associated with off-target effects. This study establishes a physiologically relevant model of ferroptosis in cardiomyocytes using ferric acetate (FAC) and tert-butyl hydroperoxide (TBH) to simulate iron overload and ROS generation. The combined application of FAC and TBH induced ferroptotic cell death, characterized by increased cytoplasmic Fe<sup>2+</sup> levels, elevated lipid peroxidation, and a 2.5-fold rise in cell death, while FAC or TBH alone had minimal effects. Ferroptosis was confirmed by the complete prevention of cell death using ferrostatin-1 (a lipid peroxidation inhibitor) and ML351 (a 15-lipoxygenase inhibitor). Notably, this model bypasses the limitations of traditional synthetic inducers, such as off-target effects and inefficient mimicry of physiological conditions. Additionally, lipid peroxidation levels induced by the FAC-TBH combination were significantly higher than those induced by RSL3, further validating the relevance of this approach. These findings underscore the critical interplay between iron and ROS in ferroptotic cell death and highlight the utility of this model in advancing our understanding of ferroptosis mechanisms. This physiologically relevant system provides a robust platform for investigating therapeutic interventions targeting iron-induced oxidative stress and ferroptosis, particularly in conditions characterized by pathological iron accumulation, such as cardiomyopathies and ischemia-reperfusion injury. By focusing on the intrinsic drivers of ferroptosis, this work lays the groundwork for developing targeted treatments to mitigate ferroptosis-associated cellular damage.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 330-339"},"PeriodicalIF":7.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Highly selective ergosterol binding and impaired redox balance leads to improved antileishmanial efficacy for amphotericin b synthesized silver nanoparticleswith reduced toxicity- In vitro and in vivo studies.","authors":"Cevella Saritha, Vinod K Rajana, Khushboo Choudhary, Amarnath Vairagar, Ayushmitha Mishra, Sudha Madhavi Penumaka, Suparas Jain, Aishwarya Dande, Pothuraju Naresh, Nitesh Kumar, P Ramalingam, Debabrata Mandal","doi":"10.1016/j.freeradbiomed.2025.03.033","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.03.033","url":null,"abstract":"<p><p>We aim to develop a low-cost silver nanoparticle (AgNP)-based delivery of AmB (AmB-AgNP) which can replace the costly AmBisome and toxic Fungizone formulation for applications against visceral leishmaniasis (VL) caused by the parasite Leishmania donovani (LD). Using different molar ratios of AmB and silver nitrate, we have identified a specific NP of ∼110 nm (zeta potential of -36.7 mV and PDI of 0.15) as the ideal antileishmanial agent with increased efficacy than AmB against LD promastigotes and amastigotes. These NPs were characterized by UV-visible, DLS, Zeta potential, FT-IR, DSC, and FE-SEM studies.The uptake of metallic silver by ICP-MS studies indicate that AmB-AgNP is internalized >3.4 and >2.8 fold more than citrate-reduced AgNPs inside the LD and murine macrophage cells, respectively. AmB-AgNPs are less cytotoxic than AmB and show more necrotic mode of death than AmB. Here, production of high amount of recative oxygen speccies, lipid peroxides, protein carbonylations and decreased expression of antioxidant enzymes are also observed. AmB-AgNP LD causes a dose-dependent ergosterol (ERG) depletion which can be reversed by ERG supplementation. Further, ITC studies established selective and enhanced binding efficacy of AmB-AgNPagainst ERG and not choesterol. The selective and enhanced inhibition of the ERG and trypanothione biosynthesis pathway by AmB-AgNP, compared to AmB, was proven by proteomics studies. The rate-limiting enzyme of ERG biosynthesis, HMG-CoA-reductase, was downregulated >9-fold in the presence of AmB-AgNP treatment. The acute toxicity studies on mice showed that AmB-AgNP has a selectivity index of > 6-fold compared to AmB. However, AgNP is <30% less effective than AmB in antileishmanial efficacy with equivalent doses in vivo. The higher selectivity index of AmB-AgNP provides a better therapeutic window than Fungizone, whereas the lost-cost synthesis, compared to AmBisome, makes the AmB-AgNP a viable cheaper delivery option against VL for future investigations.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
José Luis García-Giménez , Irene Cánovas-Cervera , Elena Nacher-Sendra , Enric Dolz-Andrés , Álvaro Sánchez-Bernabéu , Ana Belén Agúndez , Javier Hernández-Gil , Salvador Mena-Mollá , Federico V. Pallardó
{"title":"Oxidative stress and central metabolism pathways impact epigenetic modulation in inflammation and immune response","authors":"José Luis García-Giménez , Irene Cánovas-Cervera , Elena Nacher-Sendra , Enric Dolz-Andrés , Álvaro Sánchez-Bernabéu , Ana Belén Agúndez , Javier Hernández-Gil , Salvador Mena-Mollá , Federico V. Pallardó","doi":"10.1016/j.freeradbiomed.2025.04.004","DOIUrl":"10.1016/j.freeradbiomed.2025.04.004","url":null,"abstract":"<div><div>Oxidative stress, metabolism, and epigenetics are deeply interconnected processes that collectively influence cellular function, health status, and contribute to disease progression. This review highlights the critical role of metabolic intermediates in epigenetic regulation, focusing on lactate, glutathione (GSH), and S-adenosylmethionine (SAM). Beyond its traditional role in energy metabolism, lactate modulates epigenetic mechanisms, influencing gene expression and cellular adaptation. Meanwhile, GSH and SAM serve as key regulators of DNA methylation and histone post-translational modifications, maintaining epigenetic homeostasis. These processes are tightly controlled by redox balance and oxidative stress, underscoring the intricate interplay between metabolism and epigenetic regulation. GSH depletion disrupts methylation homeostasis, while oxidative post-translational modifications (oxPTMs) on histones—including S-glutathionylation, carbonylation, and nitrosylation—alter chromatin architecture and transcriptional regulation. Additionally, we focus on histone lactylation, particularly its role in regulating innate and adaptive immune responses. We also explore how GSH and oxidative stress influence lactate levels, potentially inducing histone lactylation or S-glutathionylation through S,D-lactoylglutathione (LGSH), thereby impacting epigenetic regulation.</div><div>By integrating insights into metabolic-epigenetic crosstalk, this review underscores the role of oxidative stress and central metabolic pathways in regulating epigenetic mechanisms, a concept known as \"redox epigenetics.\" Understanding these intricate interactions offers new perspectives for therapeutic strategies aimed at restoring redox homeostasis and metabolic integrity to counteract disturbances in the epigenetic landscape.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 378-399"},"PeriodicalIF":7.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anne Lene Nordengen , Annika Krutto , Ane S. Kværner , Dena T. Alavi , Hege B. Henriksen , Åshild Kolle , Christine Henriksen , Sigbjørn Smeland , Siv K. Bøhn , Congying Zheng , Sergey Shaposhnikov , Andrew R. Collins , Rune Blomhoff
{"title":"Plant-based diet and oxidative stress-induced DNA damage in post-surgery colorectal cancer patients: Results from a randomized controlled trial","authors":"Anne Lene Nordengen , Annika Krutto , Ane S. Kværner , Dena T. Alavi , Hege B. Henriksen , Åshild Kolle , Christine Henriksen , Sigbjørn Smeland , Siv K. Bøhn , Congying Zheng , Sergey Shaposhnikov , Andrew R. Collins , Rune Blomhoff","doi":"10.1016/j.freeradbiomed.2025.03.047","DOIUrl":"10.1016/j.freeradbiomed.2025.03.047","url":null,"abstract":"<div><div>Oxidative stress-induced DNA damage may impact long-term outcomes in colorectal cancer (CRC) patients. While bioactive compounds in plant foods have been linked to DNA protection, evidence among patients in remission remains limited. The present study aimed to investigate the effect of a one-year personalized intensive dietary intervention on DNA damage in post-surgery, non-metastatic CRC patients. Participants were enrolled 2–9 months after surgery in the ongoing randomized controlled trial, Norwegian dietary guidelines and colorectal cancer survival (CRC-NORDIET). Eligible participants (aged 50–80 years, primary stage I-III CRC) were randomized to either a plant-based dietary intervention targeting oxidative stress and inflammation, or to a control group that received standard dietary advice as a part of routine cancer care. As a secondary analysis, this study included 156 participants (78 in the intervention group and 78 in the control group) from the total 503 patients enrolled in CRC-NORDIET study. DNA damage in peripheral mononuclear blood cells (PBMCs) was assessed using the enzyme-modified comet assay during a 12-month follow-up period. A significant intervention effect on DNA base oxidation from baseline to 12 months was observed (P = 0.04), representing a 32 % reduction in the intervention group compared to the control group. No significant effect on DNA strand breaks was found. In conclusion, adherence to a plant-based dietary pattern may reduce DNA base oxidation in post-surgery CRC patients.</div></div><div><h3>Trial registration</h3><div>ClinicalTrials.gov Identifier: <span><span>NCT01570010</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 240-249"},"PeriodicalIF":7.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Arunkumar Venkatesan , Marc Ridilla , Nileyma Castro , J Mario Wolosin , Jessica L. Henty-Ridilla , Barry E. Knox , Preethi S. Ganapathy , Jamin S. Brown , Anthony F. DeVincentis III , Sandra Sieminski , Audrey M. Bernstein
{"title":"Mitochondrial and microtubule defects in Exfoliation Glaucoma","authors":"Arunkumar Venkatesan , Marc Ridilla , Nileyma Castro , J Mario Wolosin , Jessica L. Henty-Ridilla , Barry E. Knox , Preethi S. Ganapathy , Jamin S. Brown , Anthony F. DeVincentis III , Sandra Sieminski , Audrey M. Bernstein","doi":"10.1016/j.freeradbiomed.2025.03.046","DOIUrl":"10.1016/j.freeradbiomed.2025.03.046","url":null,"abstract":"<div><div>Exfoliation Syndrome is an age-related systemic condition characterized by large aggregated fibrillar material deposition in the anterior eye tissues. This aggregate formation and deposition on the aqueous humor outflow pathway are significant risk factors for developing Exfoliation Glaucoma (XFG). XFG is a multifactorial late-onset disease that shares common features of neurodegenerative diseases, such as increased protein aggregation, impaired protein degradation, and oxidative and cellular stress. XFG patients display decreased mitochondrial membrane potential and mitochondrial DNA deletions. Here, using Tenon Capsule Fibroblasts (TFs) from patients without glaucoma (No Glaucoma, NG) and XFG patients, we found that XFG TFs have impaired mitochondrial bioenergetics and increased reactive oxygen species accumulation. These defects are associated with mitochondrial abnormalities as XFG TFs exhibit smaller mitochondria that contain dysmorphic cristae, with increased mitochondrial localization to lysosomes and slowed mitophagic flux. Mitochondrial dysfunction in the XFG TFs was associated with hyperdynamic microtubules, decreased acetylated tubulin, and increased HDAC6 activity. Treatment of XFG TFs with a mitophagy inducer, Urolithin A (UA), and a mitochondrial biogenesis inducer, Nicotinamide Ribose (NR), improved mitochondrial bioenergetics and reduced ROS accumulation. Our results demonstrate that XFG TFs have abnormal mitochondria and suggest that mitophagy inducers may represent a potential class of therapeutics for reversing mitochondrial dysfunction in XFG patients.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 226-239"},"PeriodicalIF":7.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yawen Li , Tongxing Wang , Hongrong Li , Yuning Jiang , Xiaogang Shen , Ning Kang , Zhifang Guo , Runtao Zhang , Xuan Lu , Tianyu Kang , Mengnan Li , Yunlong Hou , Yiling Wu
{"title":"Targeting LKB1–AMPK–SIRT1–induced autophagy and mitophagy pathways improves cerebrovascular homeostasis in APP/PS1 mice","authors":"Yawen Li , Tongxing Wang , Hongrong Li , Yuning Jiang , Xiaogang Shen , Ning Kang , Zhifang Guo , Runtao Zhang , Xuan Lu , Tianyu Kang , Mengnan Li , Yunlong Hou , Yiling Wu","doi":"10.1016/j.freeradbiomed.2025.03.045","DOIUrl":"10.1016/j.freeradbiomed.2025.03.045","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer's disease (AD) is the most common and severe degenerative disorder of the central nervous system in the elderly, profoundly impacting patients' quality of life. However, effective therapeutic agents for AD are still lacking. Bazi Bushen capsule (BZBS) is a traditional Chinese herbal compound with potential neuroprotective effects, yet its underlying mechanisms remain poorly understood.</div></div><div><h3>Methods</h3><div>In this study, we utilized APP/PS1 transgenic mice to assess the therapeutic efficacy of BZBS. Initially, we evaluated the spatial learning and memory of the mice using the Barnes maze. The brain microcirculation was assessed through a small-animal ultrasound system, two-photon <em>in vivo</em> imaging, and micro-computed tomography angiography. Molecular, biochemical, and pathological analyses were conducted on brain tissues. Through network pharmacology, we identified potential intervention pathways and targets for BZBS in the treatment of AD, which we subsequently validated both <em>in vivo</em> and <em>in vitro</em>. Additionally, we employed molecular virtual docking screening and biolayer interferometry to elucidate the direct interactions of ginsenoside Rg5 and ginsenoside Ro in BZBS with AMPK and LKB1 proteins.</div></div><div><h3>Results</h3><div>The BZBS intervention significantly enhanced spatial learning and memory in APP/PS1 mice while decreasing Aβ deposition. Furthermore, BZBS protected cerebrovascular homeostasis and mitigated neuroinflammation, as evidenced by decreased blood–brain barrier permeability, increased expression of tight-junction proteins, and restored cerebral blood flow. Mechanistically, ginsenosides Rg5 and Ro in BZBS directly bind to AMPK and LKB1 proteins, activating the LKB1–AMPK–SIRT1 signaling pathway, promoting autophagy and mitochondrial autophagy, and alleviating oxidative stress damage in endothelial cells.</div></div><div><h3>Conclusions</h3><div>BZBS enhances autophagy-related activity, decreases Aβ deposition, and improves endothelial cell homeostasis through the activation of the LKB1–AMPK–SIRT1 signaling pathway, ultimately leading to improved cognitive function in mice with AD. This study highlights the importance of enhancing autophagic activity and maintaining cerebrovascular homeostasis in mitigating cognitive decline in AD, providing evidence and new insights into the application of compound medicines for treating age-related neurological disorders.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"233 ","pages":"Pages 400-418"},"PeriodicalIF":7.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}