bims-redobi Biomed News
on Redox Biology
Issue of 2024‒11‒10
sixteen papers selected by
Vanesa Cepas López, Candiolo Cancer Institute
  1. New Emerging Therapeutic Strategies Based on Manipulation of the Redox Regulation Against Therapy Resistance in Cancer.
  2. Sinapine suppresses ROS-induced C2C12 myoblast cell death through MAPK and autophagy pathways.
  3. Interpret the potential role of zinc against oxidative stress in inflammation with a practical fluorescent assay.
  4. Advancing Photodynamic Therapy with Nano-Conjugated Hypocrellin: Mechanisms and Clinical Applications.
  5. Effects of carbon dioxide on germination of Clostridium botulinum spores.
  6. Curcumin inhibits oxidative stress and autophagy in C17.2 neural stem cell through ERK1/2 signaling pathways.
  7. Small Molecules Targeting Mitochondria: A Mechanistic Approach to Combating Doxorubicin-Induced Cardiotoxicity.
  8. The effect of modulating platelet reactive oxygen species by the addition of antioxidants to prevent clearance of cold-stored platelets.
  9. SFRRI Inaugural Alberto Boveris Award Lecture Dynamics of Intracellular and Intercellular Redox Communication.
  10. Biodegradable iridium coordinated nanodrugs potentiate photodynamic therapy and immunotherapy of lung cancer.
  11. Cancer Metabolism: Historical Landmarks, New Concepts, and Opportunities.
  12. The Armillaria response to Gastrodia elata is partially mediated by strigolactone-induced changes in reactive oxygen species.
  13. Activation of lysosomal Ca2+ channels mitigates mitochondrial damage and oxidative stress.
  14. Ferritinophagy is involved in hexavalent chromium-induced ferroptosis in Sertoli cells.
  15. Calcium signals as regulators of ferroptosis in cancer.
  16. ML385, an Nrf2 Inhibitor, Synergically Enhanced Celastrol Triggered Endoplasmic Reticulum Stress in Lung Cancer Cells.
  1. Antioxid Redox Signal. 2024 Nov 06.
    New Emerging Therapeutic Strategies Based on Manipulation of the Redox Regulation Against Therapy Resistance in Cancer.
    Ahmad Nazari, Parisa Osati, Siavash Seifollahy Fakhr, Ferdos Faghihkhorasani, Masoud Ghanaatian, Fereshteh Faghihkhorasani, Fatemeh Rezaei-Tazangi, Nazanin Pazhouhesh Far, Amir Shourideh, Nasim Ebrahimi, Amir Reza Aref.
      Background: Resistance to standard therapeutic methods, including chemotherapy, immunotherapy, and targeted therapy, remains a critical challenge in effective cancer treatment. Redox homeostasis modification has emerged as a promising approach to address medication resistance. Objective: This review aims to explore the mechanisms of redox alterations and signaling pathways contributing to treatment resistance in cancer. Methods: In this study, a comprehensive review of the molecular mechanisms underlying drug resistance governed by redox signaling was conducted. Emphasis was placed on understanding how tumor cells manage increased reactive oxygen species (ROS) levels through upregulated antioxidant systems, enabling resistance across multiple therapeutic pathways. Results: Key mechanisms identified include alterations in drug efflux, target modifications, metabolic changes, enhanced DNA damage repair, stemness preservation, and tumor microenvironment remodeling. These pathways collectively facilitate tumor cells' adaptive response and resistance to various cancer treatments. Conclusion: Developing a detailed understanding of the interrelationships between these redox-regulated mechanisms and therapeutic resistance holds potential to improve treatment effectiveness, offering valuable insights for both fundamental and clinical cancer research. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  antioxidant systems; cancer therapy resistance; epigenetic modifications; oxidative stress; redox state paradox; redox-responsive nanoparticles
    DOI:  https://doi.org/10.1089/ars.2023.0491
  2. Food Sci Biotechnol. 2024 Dec;33(15): 3629-3637
    Sinapine suppresses ROS-induced C2C12 myoblast cell death through MAPK and autophagy pathways.
    Jung Hyun Kang, Dong Hwan Kim, Jin Yoo, Jun Hong Shin, Ju Hyun Kim, Ji Won Lee, Seung Ho Shin.
      Oxidative stress in skeletal muscle can lead to muscle atrophy through reactive oxygen species (ROS)-induced damage and cell death. tert-Butyl hydroperoxide (TBHP), an exogenous ROS generator, induces oxidative stress and cell death in various cells. Sinapine from cruciferous plants possesses beneficial effects, but its role in protecting skeletal muscle cells against ROS-induced cell death remains unclear. This study demonstrates that sinapine pretreatment significantly reduced TBHP-induced cell death and ROS accumulation in a dose-dependent manner. TBHP activated mitogen-activated protein kinase (MAPK) pathways including Akt, p38, and JNK, and triggered autophagy. Sinapine suppressed the phosphorylation of Akt, MEK3/6, p38, MEK4, and JNK, and modulated key autophagy markers. Notably, the co-treatment of MAPK inhibitors attenuated TBHP-induced cell death and LC3B-II accumulation. These findings suggest that sinapine is a promising phytochemical for mitigating oxidative stress-mediated muscle injury, offering potential therapeutic strategies for maintaining skeletal muscle homeostasis and addressing muscle-related pathologies.
    Keywords:  Autophagy; Muscle atrophy; Oxidative stress; Sinapine; TBHP
    DOI:  https://doi.org/10.1007/s10068-024-01718-6
  3. Bioorg Chem. 2024 Oct 23. pii: S0045-2068(24)00791-0. [Epub ahead of print]153 107886
    Interpret the potential role of zinc against oxidative stress in inflammation with a practical fluorescent assay.
    Zengyan Lin, Lanlan Zhang, Daliang Li.
      Zinc plays a critical role in inflammation and apoptosis, potentially offering new insights into health and disease beyond its established involvement in various biological processes. A fluorescent probe, SPI, has been designed and synthesized for the real-time detection of dynamic changes of zinc ions (Zn2+) in the potential resistance to oxidative stress, showing fluorescence enhancement at approximately 639 nm with a limit of detection of around 65 pM, which allowed it to identify even low concentrations of Zn2+ with intrinsic excellent biocompatibility. By establishing a cellular inflammation and apoptosis model using HT-DNA, hydrogen peroxide (H2O2), and dexamethasone (DXMS), the study effectively simulates conditions that can alter Zn2+ dynamics. Monitoring the fluorescence changes of SPI in response to these conditions allows researchers to observe how Zn2+ levels fluctuate in real-time, providing a clearer picture of its role in maintaining intracellular redox homeostasis. The findings indicate that SPI can be instrumental in elucidating the detailed molecular mechanisms through which Zn2+ influences immune responses and associates with cellular stress pathways. Overall, the development of SPI not only replenishes a potential assay into the toolbox to study Zn2+ in living cells but also opens new avenues for the further investigations into the therapeutic potential of modulating zinc levels in various pathological conditions.
    Keywords:  Fluorescent probe; Immune; Live cell imaging; Zn(2+)
    DOI:  https://doi.org/10.1016/j.bioorg.2024.107886
  4. Int J Nanomedicine. 2024 ;19 11023-11038
    Advancing Photodynamic Therapy with Nano-Conjugated Hypocrellin: Mechanisms and Clinical Applications.
    Sheeja S Rajan, Rahul Chandran, Heidi Abrahamse.
      Hypocrellin-based photodynamic therapy (PDT) is developing as a viable cancer therapeutic option, especially when enhanced by nanoconjugation. This review investigates the methods by which nano-conjugated hypocrellin enhances therapeutic efficacy and precision when targeting cancer cells. These nanoconjugates encapsulate or covalently bind hypocrellin photosensitizers (PSs), allowing them to accumulate preferentially in malignancies. When activated by light, the nanoconjugates produce singlet oxygen and other reactive oxygen species (ROS), resulting in oxidative stress that selectively destroys cancer cells while protecting healthy tissues. We look at how they can be used to treat a variety of cancers. Clinical and preclinical studies show that they have advantages such as increased water solubility, improved tumor penetration, longer circulation times, and tailored delivery, all of which contribute to fewer off-target effects and overall toxicity. Ongoing research focuses on improving these nanoconjugates for better tumor targeting, drug release kinetics, and overcoming biological obstacles. Furthermore, the incorporation of developing technologies such as stimuli-responsive nanocarriers and combination therapies opens exciting opportunities for enhancing hypocrellin-based PDT. In conclusion, the combination of hypocrellin and nanotechnology constitutes a significant approach to cancer treatment, increasing the efficacy and safety of PDT. Future research will seek to create conjugates including hypocrellin, herceptin, and gold nanoparticles to induce apoptosis in human breast cancer cells in vitro, opening possibilities for therapeutic applications.
    Keywords:  cancer; hypocrellin; nanoparticles; photodynamic therapy; photosensitizer
    DOI:  https://doi.org/10.2147/IJN.S486014
  5. Int J Food Microbiol. 2024 Oct 30. pii: S0168-1605(24)00402-1. [Epub ahead of print]427 110958
    Effects of carbon dioxide on germination of Clostridium botulinum spores.
    Didier Majou.
      Clostridium botulinum is a Gram -positive, strict anaerobic, rod -shaped, spore -forming, SOD -positive and catalase -negative bacterium. Its antioxidant defenses are not suited to chronic oxidative stress. H₂O₂ and reactive oxygen species have deleterious effects on C. botulinum. Spore germination is one of the key steps in its development. However, the mechanisms that trigger this germination have yet to be described. To manage C. botulinum growth, it is essential to understand the mechanisms that underlie the germination process. In this article, a series of complementary cascade reactions with water -dissolved CO₂ as an initiating germinant, and bicarbonate is suggested. It seems clear that ATP production is achieved through the use of various anaplerotic reactions with dissolved CO₂ as the carbon source. In addition to the production of oxaloacetate, an intermediate metabolite pyruvate would also be synthesized. Pyruvate would initiate the second phase of germination by producing hydrogen, which is a powerful reducing agent, via two enzymes (pyruvate -ferredoxin oxidoreductase and ferredoxin hydrogenase). These conditions would activate proteolytic enzymes and would reduce and would break the disulfide bridges of the proteins that make up the spore coats, thereby opening them. Thus, the phosphoenolpyruvate -pyruvate -acetyl -CoA pathway, in the presence of CO₂, would play a major role in the germination of spores of C. botulinum.
    Keywords:  Bicarbonate; CO₂; Clostridium botulinum; Cogerminants; Redox
    DOI:  https://doi.org/10.1016/j.ijfoodmicro.2024.110958
  6. Aging Med (Milton). 2024 Oct;7(5): 559-570
    Curcumin inhibits oxidative stress and autophagy in C17.2 neural stem cell through ERK1/2 signaling pathways.
    Yuting Ruan, Haoyu Luo, Jingyi Tang, Mengyao Ji, Dapeng Yu, Qun Yu, Zhiyu Cao, Yingren Mai, Bei Zhang, Yan Chen, Jun Liu, Wang Liao.
      Objectives: This study investigates curcumin's neuroprotective role and its potential in promoting neurogenesis in progenitor cells within the brain. Notably, curcumin's antioxidant properties have been implicated in Alzheimer's disease treatment. However, the association between curcumin's antioxidative effects and its impact on neural stem cells (NSCs) remains to be elucidated.Methods: C17.2 neural stem cells were utilized as a model to simulate oxidative stress, induced by hydrogen peroxide (H2O2). We quantified the levels of superoxide dismutase (SOD), malondialdehyde (MDA), and intracellular reactive oxygen species (ROS), alongside the gene expression of SOD1 and SOD2, to assess intracellular oxidative stress. Additionally, Western blot analysis was conducted to measure the expressions of LC3-II, Beclin-1, and phosphorylated ERK (p-ERK), thereby evaluating autophagy and ERK signaling pathway activation.
    Results: Treatment with curcumin resulted in a reduction of MDA and ROS levels, suggesting a protective effect on NSCs against oxidative damage induced by H2O2. Furthermore, a decrease in the relative expressions of LC3-II, Beclin-1, and p-ERK was observed post-curcumin treatment.
    Conclusions: The findings suggest that curcumin may confer protection against oxidative stress by attenuating autophagy and deactivating the ERK1/2 signaling pathways, which could contribute to therapeutic strategies for Alzheimer's disease.
    Keywords:  autophagy; curcumin; oxidative stress
    DOI:  https://doi.org/10.1002/agm2.12361
  7. Cardiovasc Toxicol. 2024 Nov 04.
    Small Molecules Targeting Mitochondria: A Mechanistic Approach to Combating Doxorubicin-Induced Cardiotoxicity.
    Chinmay Pal.
      Doxorubicin (Dox) is a commonly used chemotherapy drug effective against a range of cancers, but its clinical application is greatly limited by dose-dependent and cumulative cardiotoxicity. Mitochondrial dysfunction is recognized as a key factor in Dox-induced cardiotoxicity, leading to oxidative stress, disrupted calcium balance, and activation of apoptotic pathways. Recent research has emphasized the potential of small molecules that specifically target mitochondria to alleviate these harmful effects. This review provides a comprehensive analysis of small molecules that offer cardioprotection by preserving mitochondrial function in the context of doxorubicin-induced cardiotoxicity (DIC). The mechanisms of action include the reduction of reactive oxygen species (ROS) production, stabilization of mitochondrial membrane potential, enhancement of mitochondrial biogenesis, and modulation of key signaling pathways involved in cell survival and apoptosis. By targeting mitochondria, these small molecules present a promising therapeutic strategy to prevent or reduce the cardiotoxic effects associated with Dox treatment. This review not only discusses the mechanistic actions of these agents but also emphasizes their potential in improving cardiovascular outcomes for cancer patients. Gaining insight into these mechanisms can help in creating more effective strategies to safeguard the heart during chemotherapy, allowing for the ongoing use of Dox with a lower risk to the patient's cardiovascular health. This review highlights the critical role of mitochondria-targeted therapies as a promising approach in addressing DIC.
    Keywords:  Apoptosis; Cardiotoxicity; Doxorubicin; Mitochondria; Reactive oxygen species; Small molecules
    DOI:  https://doi.org/10.1007/s12012-024-09941-7
  8. Hematol Transfus Cell Ther. 2024 Oct 18. pii: S2531-1379(24)02827-X. [Epub ahead of print]
    The effect of modulating platelet reactive oxygen species by the addition of antioxidants to prevent clearance of cold-stored platelets.
    Rufeng Xie, Yiming Yang, Xueyu Jiang, Li Gao, Juan Sun, Jie Yang.
      BACKGROUND: It is known that the rapid clearance of cold-stored platelets is attributed to various storage lesions, including an abnormal increase in reactive oxygen species when platelets are exposed to cold temperatures. As an antioxidant, N-acetylcysteine exhibits some significant effects on scavenging various reactive oxygen species and inhibiting cell damage and apoptosis.AIMS: This study aimed to investigate the effects of N-acetylcysteine on reducing reactive oxygen species production and protecting cold-stored platelets from phagocytosis and clearance, and to determine the optimal concentration of N-acetylcysteine.
    METHODS: Platelet concentrates were divided into three groups: room-temperature-stored platelets, cold-stored platelets, and cold-stored platelets with the addition of different concentrations of N-acetylcysteine. After five days of storage, reactive oxygen species production, lipid peroxidation levels, activation marker expressions, GPIb/ɑ desialylation with exposure of glycan residues and other quality parameters of platelets were measured and compared between the groups. Phagocytosis of platelets was detected by phorbol 12-myristate 13-acetate-activated THP-1 or Hep G2 cells. Moreover, the recovery of infused platelets was measured in severe combined immunodeficient mice at different timepoints.
    RESULTS: After 5 days of storage, cytoplasmic reactive oxygen species significantly increased in chilled compared to non-chilled platelets; they were notably reduced with the addition of N-acetylcysteine, particularly at a concentration of 5 mM. Compared with chilled platelets, the P-selectin and phosphatidylserine expressions, as well as exposure of GPIb/ɑ glycan residues, were significantly reduced with 5 mM of N-acetylcysteine. Phagocytosis of platelets by THP-1 or Hep G2 cells was significantly lower in 5 mM of N-acetylcysteine compared to cold-stored platelets without N-acetylcysteine.
    CONCLUSIONS: This study demonstrated correlations between reactive oxygen species production and their pro-oxidant effects on platelet clearance after cold storage. The addition of N-acetylcysteine at an appropriate concentration do not only protects chilled platelets from storage lesions caused by reactive oxygen species overproduction but also prevents platelet phagocytosis in vitro and clearance in vivo, thereby extending circulating time.
    Keywords:  Clearance; Cold-stored platelets; N-acetylcysteine (NAC); Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.htct.2024.09.2479
  9. Free Radic Biol Med. 2024 Nov 02. pii: S0891-5849(24)01024-4. [Epub ahead of print]
    SFRRI Inaugural Alberto Boveris Award Lecture Dynamics of Intracellular and Intercellular Redox Communication.
    Helmut Sies.
      Cell and organ metabolism is organized through various signaling mechanisms, including redox, Ca2+, kinase and electrochemical pathways. Redox signaling operates at multiple levels, from interactions between individual molecules in their microenvironment to communication among subcellular organelles, single cells, organs, and the entire organism. Redox communication is a dynamic and ongoing spatiotemporal process. This article focuses on hydrogen peroxide (H2O2), a key second messenger that targets redox-active protein cysteine thiolates. H2O2 gradients across cell membranes are controlled by peroxiporins, specialized aquaporins. Redox-active endosomes, known as redoxosomes, form at the plasma membrane. Cell-to-cell redox communication involves direct contacts, such as per gap junctions that connect cells for transfer of molecules via connexons. Moreover, signaling occurs through the release of redox-active molecules and enzymes into the surrounding space, as well as through various extracellular vesicles (EVs) that transport these signals to nearby or distant target cells.
    Keywords:  Redox regulation; compartmentation; exosomes; extracellular vesicles; hydrogen peroxide; membraneless organelles; oxidative stress; redox code; redox heterogeneity; redoxosomes
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.002
  10. J Colloid Interface Sci. 2024 Oct 28. pii: S0021-9797(24)02511-6. [Epub ahead of print]680(Pt A): 9-24
    Biodegradable iridium coordinated nanodrugs potentiate photodynamic therapy and immunotherapy of lung cancer.
    Jingyao Li, Huixi Yi, Yuanyuan Fu, Jiani Zhuang, Zhixiong Zhan, Liyou Guo, Ji Zheng, Xiyong Yu, Dong-Yang Zhang.
      Hypoxia, which is a common characteristic of most solid tumors, not only contributes to the immunosuppressive nature of the tumor microenvironment (TME) but also reduces the efficacy of many oxygen-depleting therapies, including photodynamic therapy (PDT). In this study, we developed acidity-responsive biodegradable iridium-coordinated (IPC) nanodrugs consisting of iridium ions, the photosensitizer chlorin e6 (Ce6), and polyvinylpyrrolidone to potentiate the effects of PDT and immunotherapy by modulating the TME. IPC nanodrugs that accumulate at high levels in tumors catalyze excess hydrogen peroxide to produce oxygen while depleting glutathione levels within cancer cells; thus, the released Ce6 is more efficient at producing reactive oxygen species (ROS) in response to laser irradiation. In addition, IPC nanodrugs alleviate tumor hypoxia, induce more immunogenic cell death by amplifying PDT responses, and synergistically inhibit tumor growth by initiating robust antitumor immunity and reversing the immunosuppressive nature of the TME. As a result, IPC nanodrugs exert pronounced combined therapeutic effects in vitro and in vivo, without obvious toxic effects due to acidity-responsive degradation. These iridium-coordinated nanodrugs have the potential to modulate the TME, amplify the effects of PDT, and substantially inhibit tumors, and they are expected to provide novel ideas for combination therapy of hypoxic cancer.
    Keywords:  Hypoxia; Immunotherapy; Iridium; Photodynamic therapy; Self-assembly; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jcis.2024.10.156
  11. Cold Spring Harb Perspect Med. 2024 Nov 05. pii: a041814. [Epub ahead of print]
    Cancer Metabolism: Historical Landmarks, New Concepts, and Opportunities.
    Navdeep S Chandel, Karen H Vousden, Ralph J DeBerardinis.
      Cancer cells undergo changes in metabolism that distinguish them from non-malignant tissue. These may provide a growth advantage by promoting oncogenic signaling and redirecting intermediates to anabolic pathways that provide building blocks for new cellular components. Cancer metabolism is far from uniform, however, and recent work has shed light on its heterogenity within and between tumors. This work is also revealing how cancer metabolism adapts to the tumor microenvironment, as well as ways in which we may capitalize on metabolic changes in cancer cells to create new therapies.
    DOI:  https://doi.org/10.1101/cshperspect.a041814
  12. Microbiol Res. 2023 Oct 28. pii: S0944-5013(23)00238-0. [Epub ahead of print]278 127536
    The Armillaria response to Gastrodia elata is partially mediated by strigolactone-induced changes in reactive oxygen species.
    Zhongyi Hua, Xiying Teng, Jingwen Huang, Junhui Zhou, Yuyang Zhao, Luqi Huang, Yuan Yuan.
      Armillaria root diseases, caused by Armillaria spp., pose a significant threat to woody plants worldwide and result in substantial economic losses. However, certain species in the genus Armillaria can establish a unique symbiotic relationship with Gastrodia elata, which is the only known example of a plant benefiting from Armillaria. Although various plant signals that play a role in this interaction have been identified, the mechanism remains largely unknown from the Armillaria's perspective. In this study, we performed whole-genome sequencing of an Armillaria gallica strain named NRC001 isolated from G. elata. Comparative genomic analysis showed it is low-pathogenic Armillaria spp., which possesses 169 expanded gene families compared to high-pathogenic Armillaria spp. Among these expanded families, transcriptomic analysis revealed a significant increase in expression levels of four reactive oxygen species (ROS)-related gene families in A. gallica on G. elata compared to A. gallica on wood. Thus, a systematic survey of ROS-related gene families was carried out, and a total of 218 genes belonging to 44 ROS-related gene families in A. gallica were identified. Physiological experiments and transcriptome analysis showed that strigolactones (SLs) released by G. elata have a mediation impact on ROS, particularly enhancing the ROS scavenging activities by increasing the expression level and activity of several enzymes, such as catalase and glutathione reductase. Among the ROS-related genes, the aquaporin (AQP) is crucial as it is responsible for transporting hydrogen peroxide (H2O2) across the cell membrane. Five orthologs of AQP genes in A. gallica were identified and overexpressed in yeast. Only AgAQPA from the so-called 'other aquaglyceroporin' subfamily was demonstrated to be capable of mediating H2O2 transport in A. gallica. To our best knowledge, this is the first 'other aquaglyceroporins' gene in fungi to be identified as having transporter capacity. This study not only provides new insights into the mechanisms by which SL signaling regulates interactions between Armillaria and G. elata, but also sheds light on the function of fungal AQPs.
    Keywords:  Aquaporin; Armillaria; Gastrodia elata; Strigolactone
    DOI:  https://doi.org/10.1016/j.micres.2023.127536
  13. J Cell Biol. 2025 Jan 06. pii: e202403104. [Epub ahead of print]224(1):
    Activation of lysosomal Ca2+ channels mitigates mitochondrial damage and oxidative stress.
    Xinghua Feng, Weijie Cai, Qian Li, Liding Zhao, Yaping Meng, Haoxing Xu.
      Elevated levels of plasma-free fatty acids and oxidative stress have been identified as putative primary pathogenic factors in endothelial dysfunction etiology, though their roles are unclear. In human endothelial cells, we found that saturated fatty acids (SFAs)-including the plasma-predominant palmitic acid (PA)-cause mitochondrial fragmentation and elevation of intracellular reactive oxygen species (ROS) levels. TRPML1 is a lysosomal ROS-sensitive Ca2+ channel that regulates lysosomal trafficking and biogenesis. Small-molecule agonists of TRPML1 prevented PA-induced mitochondrial damage and ROS elevation through activation of transcriptional factor EB (TFEB), which boosts lysosome biogenesis and mitophagy. Whereas genetically silencing TRPML1 abolished the protective effects of TRPML1 agonism, TRPML1 overexpression conferred a full resistance to PA-induced oxidative damage. Pharmacologically activating the TRPML1-TFEB pathway was sufficient to restore mitochondrial and redox homeostasis in SFA-damaged endothelial cells. The present results suggest that lysosome activation represents a viable strategy for alleviating oxidative damage, a common pathogenic mechanism of metabolic and age-related diseases.
    DOI:  https://doi.org/10.1083/jcb.202403104
  14. Toxicol Appl Pharmacol. 2024 Oct 30. pii: S0041-008X(24)00338-7. [Epub ahead of print]492 117139
    Ferritinophagy is involved in hexavalent chromium-induced ferroptosis in Sertoli cells.
    Ruijian Zhuge, Le Zhang, Qian Xue, Rui Wang, Jiayunzhu Xu, Chaofan Wang, Chunyang Meng, Rifeng Lu, Fei Yin, Li Guo.
      Hexavalent chromium [Cr(VI)] has significant adverse effects on the environment and human health, particularly on the male reproductive system. Previously, we observed ferroptosis and autophagy in rat testicular injury induced by Cr(VI). In the present study, we focused on the association between ferroptosis and autophagy in mouse Sertoli cells (TM4) exposed to concentrations of 2.5 μМ, 5 μМ, and 10 μМ Cr(VI). Cr(VI) exposure altered mitochondrial ultrastructure; increased intracellular iron, malondialdehyde, and reactive oxygen species (ROS) levels; decreased glutathione content; increased TfR1 protein expression; and decreased GPX4, FPN1, and SLC7A11 protein expression, ultimately resulting in ferroptosis. Additionally, we observed ferritinophagy, increased expression of BECLIN1, LC3B, and NCOA4, and decreased expression of FTH1 and P62. Inhibition of autophagy and ferritinophagy via 3-MA and small interfering RNA (siRNA)-mediated silencing of NCOA4 ameliorated changes in ferritinophagy- and ferroptosis-associated protein expression, and reduced ROS levels. Rats exposed to Cr(VI) exhibited atrophy of testicular seminiferous tubules, a reduction in germ and Sertoli cells, and the occurrence of ferritinophagy and ferroptosis in cells of the rat testes. These results indicate that ferroptosis, triggered by NCOA4-mediated ferritinophagy, is one of the mechanisms that contribute to Cr(VI)-induced damage in Sertoli cells.
    Keywords:  Environmental impact; Ferritinophagy; Ferroptosis; Hexavalent chromium; Sertoli cells
    DOI:  https://doi.org/10.1016/j.taap.2024.117139
  15. Cell Calcium. 2024 Oct 29. pii: S0143-4160(24)00124-6. [Epub ahead of print]124 102966
    Calcium signals as regulators of ferroptosis in cancer.
    Ioana Stejerean-Todoran, Christine S Gibhardt, Ivan Bogeski.
      The field of ferroptosis research has grown exponentially since this form of cell death was first identified over a decade ago. Ferroptosis, an iron- and ROS-dependent type of cell death, is controlled by various metabolic pathways, including but not limited to redox and calcium (Ca2+) homeostasis, iron fluxes, mitochondrial function and lipid metabolism. Importantly, therapy-resistant tumors are particularly susceptible to ferroptotic cell death, rendering ferroptosis a promising therapeutic strategy against numerous malignancies. Calcium signals are important regulators of both cancer progression and cell death, with recent studies indicating their involvement in ferroptosis. Cells undergoing ferroptosis are characterized by plasma membrane rupture and the formation of nanopores, which facilitate influx of ions such as Ca2+ into the affected cells. Furthermore, mitochondrial Ca²⁺ levels have been implicated in directly influencing the cellular response to ferroptosis. Despite the remarkable progress made in the field, our understanding of the contribution of Ca2+ signals to ferroptosis remains limited. Here, we summarize key connections between Ca²⁺ signaling and ferroptosis in cancer pathobiology and discuss their potential therapeutic significance.
    Keywords:  Calcium; Cancer; Ferroptosis; Mitochondria; ROS
    DOI:  https://doi.org/10.1016/j.ceca.2024.102966
  16. ACS Omega. 2024 Oct 29. 9(43): 43697-43705
    ML385, an Nrf2 Inhibitor, Synergically Enhanced Celastrol Triggered Endoplasmic Reticulum Stress in Lung Cancer Cells.
    Chenxin Xu, Yinghua Chen, Zhuoen Zhou, Ying Yan, Wenying Fu, Peng Zou, Daoyong Ni.
      Lung cancer is one of the leading causes of death. Celastrol is a natural product that has shown anticancer activity but has not yet been applied in clinical settings due to its narrow therapeutic window. In this study, we discovered that celastrol stimulates an abnormal rise in the reactive oxygen species (ROS) level in lung cancer cells and that the ROS scavenger N-acetylcysteine (NAC) could counteract the cell death caused by celastrol. At the same time, celastrol upregulated the expression of cytoprotective transcription factor Nrf2 and its downstream proteins, which are effective in preventing the oxidative damage caused by ROS accumulation. Notably, we found that the overexpression of Nrf2 enhances the tolerance of lung cancer cells to celastrol and that lung cancer cells H460 with a Keap1 mutation are insensitive to celastrol. This indicates that the increase in Nrf2 contributes to the survival of lung cancer cells. Thus, we brought in an Nrf2 inhibitor ML385 to suppress the activation of Nrf2. We found that when ML385 and celastrol were added together the survival rates of lung cancer cells decreased more and the detected ROS level became much higher compared to treatment with celastrol alone. We also discovered that ML385 suppressed the expression of HO-1 and GCLC, which amplified celastrol-induced ATF4/CHOP-dependent endoplasmic reticulum stress (ER stress). Above all, our study found that ML385 enhanced celastrol-induced increases in ROS and ER stress, leading to lung cancer cell death. This research provides a potential strategy for the preclinical investigation of celastrol.
    DOI:  https://doi.org/10.1021/acsomega.4c06152
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