bims-redobi Biomed News
on Redox Biology
Issue of 2024‒10‒13
sixteen papers selected by
Vanesa Cepas López, Candiolo Cancer Institute
  1. Effective protective mechanisms of HO-1 in diabetic complications: a narrative review.
  2. Progress and limitations in reactive oxygen species quantitation.
  3. The oxygen puzzle in FLASH radiotherapy: A comprehensive review and experimental outlook.
  4. Synergistic ferroptosis in triple-negative breast cancer cells: Paclitaxel in combination with Erastin induced oxidative stress and Ferroportin-1 modulation in MDA-MB-231 cells.
  5. The role of short-chain fatty acids in cancer prevention and cancer treatment.
  6. Tumor integrin-targeted glucose oxidase enzyme promotes ROS-mediated cell death that combines with interferon alpha therapy for tumor control.
  7. Targeting Mitochondria: Influence of Metabolites on Mitochondrial Heterogeneity.
  8. Mechanistic insights on the role of Nrf-2 signalling in Huntington's disease.
  9. Evaluation of oxidative stress, biochemical parameters and in silico markers in different pea accessions in response to drought stress.
  10. Tumour reoxygenation after intratumoural hydrogen peroxide (KORTUC) injection: a novel approach to enhance radiosensitivity.
  11. 53BP1 regulates the self-renewal ability of neural stem/progenitor cells through modulating mitochondrial homeostasis.
  12. Redox control of the deubiquitinating enzyme Ubp2 regulates translation during stress.
  13. The SIRT-1/Nrf2/HO-1 axis: Guardians of neuronal health in neurological disorders.
  14. Revised mechanism of hydroxyurea-induced cell cycle arrest and an improved alternative.
  15. Ferroptosis: A New Strategy for the Treatment of Fibrotic Diseases.
  16. Nrf2 Activation in Keratinocytes: A Central Role in Diabetes-Associated Wound Healing.
  1. Cell Death Discov. 2024 Oct 10. 10(1): 433
    Effective protective mechanisms of HO-1 in diabetic complications: a narrative review.
    Jing-Jing Zhang, Ping Ni, Yi Song, Man-Jun Gao, Xi-Ying Guo, Bao-Qing Zhao.
      Diabetes mellitus is a metabolic disorder with persistent hyperglycemia caused by a variety of underlying factors. Chronic hyperglycemia can lead to diverse serious consequences and diversified complications, which pose a serious threat to patients. Among the major complications are cardiovascular disease, kidney disease, diabetic foot ulcers, diabetic retinopathy, and neurological disorders. Heme oxygenase 1 (HO-1) is a protective enzyme with antioxidant, anti-inflammatory and anti-apoptotic effects, which has been intensively studied and plays an important role in diabetic complications. By inducing the expression and activity of HO-1, it can enhance the antioxidant, anti-inflammatory, and anti-apoptotic capacity of tissues, and thus reduce the degree of damage in diabetic complications. The present study aims to review the relationship between HO-1 and the pathogenesis of diabetes and its complications. HO-1 is involved in the regulation of macrophage polarization and promotes the M1 state (pro-inflammatory) towards to the M2 state (anti-inflammatory). Induction of HO-1 expression in dendritic cells inhibits them maturation and secretion of pro-inflammatory cytokines and promotes regulatory T cell (Treg cell) responses. The induction of HO-1 can reduce the production of reactive oxygen species, thereby reducing oxidative stress and inflammation. Besides, HO-1 also has an important effect in novel programmed cell death such as pyroptosis and ferroptosis, thereby playing a protective role against diabetes. In conclusion, HO-1 plays a significant role in the occurrence and development of diabetic complications and is closely associated with a variety of complications. HO-1 is anticipated to serve as a novel target for addressing diabetic complications, and it holds promise as a potential therapeutic agent for diabetes and its associated complications. We hope to provide inspiration and ideas for future studies in the mechanism and targets of HO-1 through this review.
    DOI:  https://doi.org/10.1038/s41420-024-02205-x
  2. Chem Commun (Camb). 2024 Oct 07.
    Progress and limitations in reactive oxygen species quantitation.
    Eleni M Spanolios, Riley E Lewis, Rhea N Caldwell, Safia Z Jilani, Christy L Haynes.
      Reactive oxygen species (ROS) are a set of oxygen- and nitrogen-containing radicals. They are produced from a wide range of sources. In biological contexts, cellular stress leads to an overproduction of ROS, which can lead to genetic damage and disease development. In industry, ROS are often productively used for water purification or for analyzing the possible toxicity of an industrial process. Because of their ubiquity, detection of ROS has been an analytical goal across a range of fields. To understand complicated systems and origins of ROS production, it is necessary to move from qualitative detection to quantitation. Analytical techniques that combine quantitation, high spatial and temporal resolution, and good specificity represent detection methods that can fill critical gaps in ROS research. Herein, we discuss the continued progress and limitations of fluorescence, electrochemical, and electron paramagnetic resonance detection of ROS over the last ten years, giving suggestions for the future of the field.
    DOI:  https://doi.org/10.1039/d4cc03578j
  3. Clin Transl Radiat Oncol. 2024 Nov;49 100860
    The oxygen puzzle in FLASH radiotherapy: A comprehensive review and experimental outlook.
    Andrea Scarmelotto, Victor Delprat, Carine Michiels, Stéphane Lucas, Anne-Catherine Heuskin.
      FLASH radiotherapy is attracting increasing interest because it maintains tumor control while inflicting less damage to normal tissues compared to conventional radiotherapy. This sparing effect, the so-called FLASH effect, is achieved when radiation is delivered at ultra-high dose rates (≥40 Gy/s). Although the FLASH effect has already been demonstrated in several preclinical models, a complete mechanistic description explaining why tumors and normal tissues respond differently is still missing. None of the current hypotheses fully explains the experimental evidence. A common point between many of these is the role of oxygen, which is described as a major factor, either through transient hypoxia in the form of dissolved molecules, or reactive oxygen species (ROS). Therefore, this review focuses on both forms of this molecule, retracing old and more recent theories, while proposing new mechanisms that could provide a complete description of the FLASH effect based on preclinical and experimental evidence. In addition, this manuscript describes a set of experiments designed to provide the FLASH community with new tools for exploring the post-irradiation fate of ROS and their potential biological implications.
    Keywords:  FLASH RT; Ferroptosis; Hypoxia; Ionizing radiation; LET; Lipid peroxidation; Particle therapy; Preclinical studies; ROS; UHDR
    DOI:  https://doi.org/10.1016/j.ctro.2024.100860
  4. Naunyn Schmiedebergs Arch Pharmacol. 2024 Oct 11.
    Synergistic ferroptosis in triple-negative breast cancer cells: Paclitaxel in combination with Erastin induced oxidative stress and Ferroportin-1 modulation in MDA-MB-231 cells.
    Filiz Bakar-Ates, Erva Ozkan.
      Ferroptosis is an important regulated cell death mechanism characterized by iron-dependent lipid peroxidation and oxidative stress. In this study, we examined the ferroptosis-inducing effect of the combined use of Paclitaxel, a microtubule-stabilizing agent, and Erastin, a ferroptosis inducer, in breast cancer cells. In this context, the combination of the compounds in question was applied to the cells and the presence of a synergistic effect was determined by calculating the combination index. Glutathione (GSH) levels and glutathione peroxidase (GPX) activity were determined by commercial assay kits, and the effect of the compounds on lipid peroxidation was determined by measurement of malondialdehyde (MDA) levels. Additionally, the effect of combination treatment on ferroptotic protein expression was determined by western blot. Our findings revealed that the combination treatment caused a significant change in mitochondrial function by causing an increase in the depolarized/viable cell population. Additionally, there was a significant increase in intracellular reactive oxygen species (ROS) levels compared to single applications of the compounds. The significant increase observed in malondialdehyde (MDA) levels revealed that the combination treatment increased lipid peroxidation. Moreover, intracellular GSH levels and glutathione peroxidase (GPX) activity significantly decreased by Paclitaxel-Erastin combination. The expression of ferroptosis-regulating proteins was significantly downregulated. The findings showed that the Paclitaxel-Erastin combination synergistically contributed to the accumulation of lipid reactive oxygen species and induced the ferroptotic cell death pathway in breast cancer cells.
    Keywords:  Breast cancer; Erastin; Ferroportin-1; Ferroptosis; Oxidative stress; Paclitaxel
    DOI:  https://doi.org/10.1007/s00210-024-03523-8
  5. Arch Biochem Biophys. 2024 Oct 04. pii: S0003-9861(24)00294-7. [Epub ahead of print] 110172
    The role of short-chain fatty acids in cancer prevention and cancer treatment.
    Balaraman Kalyanaraman, Gang Cheng, Micael Hardy.
      Short-chain fatty acids (SCFAs) are microbial metabolites in the gut that may play a role in cancer prevention and treatment. They affect the metabolism of both normal and cancer cells, regulating various cellular energetic processes. SCFAs also inhibit histone deacetylases, which are targets for cancer therapy. The three main SCFAs are acetate, propionate, and butyrate, which are transported into cells through specific transporters. SCFAs may enhance the efficacy of chemotherapeutic agents and modulate immune cell metabolism, potentially reprogramming the tumor microenvironment. Although SCFAs and SCFA-generating microbes enhance therapeutic efficacy of several forms of cancer therapy, published data also support the opposing viewpoint that SCFAs mitigate the efficacy of some cancer therapies. Therefore, the relationship between SCFAs and cancer is more complex, and this review discusses some of these aspects. Clearly, further research is needed to understand the role of SCFAs, their mechanisms and applications in cancer prevention and treatment.
    Keywords:  cancer prevention; chemotherapy; epigenetics; ferroptosis; immunotherapy; oxidative stress
    DOI:  https://doi.org/10.1016/j.abb.2024.110172
  6. Mol Cancer Ther. 2024 Oct 09.
    Tumor integrin-targeted glucose oxidase enzyme promotes ROS-mediated cell death that combines with interferon alpha therapy for tumor control.
    Jordan A Stinson, Allison Sheen, Brianna M Lax, Grace N Yang, Lauren Duhamel, Luciano Santollani, Elizabeth Fink, Joseph Palmeri, K Dane Wittrup.
      While heightened intratumoral levels of reactive oxygen species (ROS) are typically associated with a suppressive tumor microenvironment, under certain conditions ROS contribute to tumor elimination. Treatment approaches, including some chemotherapy and radiation protocols, increase cancer cell ROS levels that influence their mechanism of cell death and subsequent recognition by the immune system. Furthermore, activated myeloid cells rapidly generate ROS upon encounter with pathogens or infected cells to eliminate disease, and recently, this effector function has been noted in cancer contexts as well. Collectively, ROS-induced cancer cell death may help initiate adaptive anti-tumor immune responses that could synergize with current approved immunotherapies, for improved control of solid tumors. In this work, we explore the use of glucose oxidase, an enzyme which produces hydrogen peroxide, a type of ROS, to therapeutically mimic the endogenous oxidative burst from myeloid cells to promote antigen generation within the tumor microenvironment. We engineer the enzyme to target pan-tumor expressed integrins both as a tumor-agnostic therapeutic approach, but also as a strategy to prolong local enzyme activity following intratumoral administration. We found the targeted enzyme potently induced cancer cell death and enhanced cross-presentation by dendritic cells in vitro, and further combined with interferon alpha for long-term tumor control in murine MC38 tumors in vivo. Optimizing the single-dose administration of this enzyme overcomes limitations with immunogenicity noted for other pro-oxidant enzyme approaches. Overall, our results suggest ROS-induced cell death can be harnessed for tumor control, and highlight the potential use of designed enzyme therapies alongside immunotherapy against cancer.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-24-0163
  7. Cell Biochem Funct. 2024 Sep;42(7): e4131
    Targeting Mitochondria: Influence of Metabolites on Mitochondrial Heterogeneity.
    Amie N Joof, Fangyuan Ren, Yan Zhou, Mengyu Wang, Jiani Li, Yurong Tan.
      Mitochondria are vital organelles that provide energy for the metabolic processes of cells. These include regulating cellular metabolism, autophagy, apoptosis, calcium ions, and signaling processes. Despite their varying functions, mitochondria are considered semi-independent organelles that possess their own genome, known as mtDNA, which encodes 13 proteins crucial for oxidative phosphorylation. However, their diversity reflects an organism's adaptation to physiological conditions and plays a complex function in cellular metabolism. Mitochondrial heterogeneity exists at the single-cell and tissue levels, impacting cell shape, size, membrane potential, and function. This heterogeneity can contribute to the progression of diseases such as neurodegenerative diseases, metabolic diseases, and cancer. Mitochondrial dynamics enhance the stability of cells and sufficient energy requirement, but these activities are not universal and can lead to uneven mitochondria, resulting in heterogeneity. Factors such as genetics, environmental compounds, and signaling pathways are found to affect these cellular processes and heterogeneity. Additionally, the varying roles of metabolites such as NADH and ATP affect glycolysis's speed and efficiency. An imbalance in metabolites can impair ATP production and redox potential in the mitochondria. Therefore, this review will explore the influence of metabolites in shaping mitochondrial morphology, how these changes contribute to age-related diseases and the therapeutic targets for regulating mitochondrial heterogeneity.
    Keywords:  ATP; diseases; fusion/fission; heterogeneity; metabolites; mitochondria; signaling pathway; therapeutic target
    DOI:  https://doi.org/10.1002/cbf.4131
  8. Neurol Sci. 2024 Oct 11.
    Mechanistic insights on the role of Nrf-2 signalling in Huntington's disease.
    Veerta Sharma, Prateek Sharma, Thakur Gurjeet Singh.
      BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder affecting individuals worldwide. It is characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances. The pathogenesis of HD involves oxidative stress, neuroinflammation, and mitochondrial dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating cellular responses to redox imbalance and inflammation, has emerged as a potential target for therapeutic intervention.METHODS: Through the use of a number of different search engines like Scopus, PubMed, Elsevier and Bentham, a literature review was carried out with the keywords 'Huntington's Disease, 'Pathology of HD' and 'Nrf2 signalling pathway'. Using the keywords that were given above, this review was carried out in order to collect the most recent publications and gain an understanding of the breadth of the extensive research that has been conducted on the role of Nrf2 in HD pathogenesis.
    RESULTS: Oxidative stress and neuroinflammation significantly contribute to HD progression. Activation of Nrf2 offers neuroprotection by enhancing anti-oxidant defense mechanisms. Furthermore, several signaling pathways, play crucial roles in HD pathophysiology. Pharmacological modulation of these pathways through selective inhibitors or agonists shows promise for the development of new therapeutic strategies.
    CONCLUSION: The various downstream pathways such as extracellular signal-related kinase (ERK), phosphoinositide 3-Kinase (PI3-K), 5'-AMP-activated protein kinase (AMPK), Sirtuins, Mitogen-activated protein kinases (MAPK) plays a role in alleviating pathophysiology of HD. Diverse reports of these studies demonstrated PI3-K/AMPK/ERK/Sirtuins activators and MAPK inhibitors as encouraging targets in alleviating HD pathophysiology.
    Keywords:  Huntingtin protein; Huntington’s disease; Neuroinflammation; Nrf2 activators; Transcription factor
    DOI:  https://doi.org/10.1007/s10072-024-07802-3
  9. Plant Cell Rep. 2024 Oct 05. 43(10): 251
    Evaluation of oxidative stress, biochemical parameters and in silico markers in different pea accessions in response to drought stress.
    Anamika Dutta, Raghvendra Saxena, Vinay Dwivedi, Baskar Venkidasamy, Raghvendra Kumar Mishra.
      KEY MESSAGE: ARG6 and ARG10 pea accessions exhibited better tolerance to drought by keeping drought-associated attributes stable and higher, that is, stable chlorophyll content, high antioxidant activity, and the presence of polymorphic bands with stress-responsive EST-SSR markers. Each year, a significant portion of crops is lost due to various abiotic stresses, and even pea (Pisum sativum) crop growth and yield are severely affected by the challenges posed by drought stress. Drought is a critical factor that limits crop growth and development, and its impact is exacerbated by changes in the magnitude of climatic conditions. Drought induces oxidative stress in plants, leading to the accumulation of high concentrations of reactive oxygen species that damage cell structures and vital functioning of cells. The primary objective was to identify stress-tolerant plants by evaluating different morphological and biochemical attributes, such as biomass, chlorophyll content, relative water content, ascorbate peroxidase (APX), superoxide dismutase (SOD), and DPPH scavenging activity, as well as protein, proline, and phenolic content. Our study revealed that pea accessions (ARG6 and ARG10) were more resilient to drought stress as their chlorophyll, relative water, protein, and proline contents increased under drought conditions. Antioxidant enzymes, such as SOD, APX, and DPPH activities, also increased under drought stress in ARG10 and ARG6, suggesting that these accessions could bolster the antioxidant defense system in response to drought stress. Based on putative (cellular, biological, and metabolic) functions, ten EST-SSR primers were selected for the amplification study. Three EST-SSR primers, AUMP06_110, AUMP18_300, and AUMP31_250, were used for ARG6 and ARG10. Based on the correlation between the presence or absence of specific EST-SSR alleles, various physiological and morphological traits, and DPPH scavenging activity, both ARG10 and ARG6 demonstrated resistance to drought stress.
    Keywords:   Pisum sativum ; DPPH scavenging activity; Drought stress; EST-SSR; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s00299-024-03311-x
  10. BJC Rep. 2024 Dec;2(1): 78
    Tumour reoxygenation after intratumoural hydrogen peroxide (KORTUC) injection: a novel approach to enhance radiosensitivity.
    Samantha Nimalasena, Selvakumar Anbalagan, Carol Box, Sheng Yu, Jessica K R Boult, Nigel Bush, Louise Howell, Victoria Sinnett, William Murphy, John Yarnold, Simon P Robinson, Navita Somaiah.
      Background: KORTUC (0.5% hydrogen peroxide (H2O2) in 1% sodium-hyaluronate) releases cytotoxic levels of H2O2 in tissues after intratumoural injection. High levels of tumour control after radiotherapy plus KORTUC are reported in breast cancer patients. Here, we use human xenograft models to test the hypothesis that oxygen microbubbles released post-KORTUC are effective in modifying the hypoxic tumour microenvironment.Methods and materials: Pimonidazole and Image-iT™ Red (live hypoxia marker) were utilised to assess dose-dependent changes in hypoxia post-H2O2 in HCT116 and LICR-LON-HN5 spheroids. Using a dual 2-nitroimidazole-marker technique and phospho-ATM we evaluated changes in hypoxia and reactive oxygen species (ROS) respectively, in HCT116 and LICR-LON-HN5 xenografts following intratumoural KORTUC.
    Results: A significant reduction in Image-iT™ Red fluorescence was observed in spheroids 1 h post-H2O2 at ≥1.2 mM, maintained at 24 h. Ultrasound demonstrated sustained release of oxygen microbubbles within tumours, 1 h post-KORTUC. Hypoxia markers demonstrated significant tissue reoxygenation in both models post-KORTUC and significantly increased phospho-ATM foci reflecting increased ROS production.
    Conclusion: Intratumoural KORTUC represents a novel oxygen delivery method, which can be exploited to enhance radiation response. If efficacy is confirmed in the ongoing phase 2 breast trial it could improve treatment of several tumour types where hypoxia is known to affect radiotherapy outcomes.
    DOI:  https://doi.org/10.1038/s44276-024-00098-y
  11. Biochem Biophys Res Commun. 2024 Oct 02. pii: S0006-291X(24)01312-3. [Epub ahead of print]734 150776
    53BP1 regulates the self-renewal ability of neural stem/progenitor cells through modulating mitochondrial homeostasis.
    Yumi Sunatani, Ryo Sakasai, Tadashi Matsui, Kuniyoshi Iwabuchi.
      The regulation of intracellular reactive oxygen species (ROS) levels is important for maintaining the self-renewal ability of neural stem/progenitor cells (NSCs). In this study, we demonstrate that 53BP1, a DNA damage response factor known to facilitate the repair of DNA double-strand breaks, supports the maintenance of NSC stemness. ReNcell VM human NSCs with depleted 53BP1 exhibited reduced self-renewal ability compared with control NSCs, as revealed by a decrease in neurosphere size and an increase in differentiation into neural or glial cells within an NSC culture. Furthermore, 53BP1 depletion elevated cellular ROS levels, accompanied by mitochondrial abnormalities. The reduced self-renewal ability and elevated ROS levels in 53BP1-deficient NSCs were restored with the treatment of a radical scavenger, N-acetyl-l-cysteine. In addition, we investigated the functional relationship in the NSC self-renewal ability between 53BP1 and ataxia-telangiectasia mutated (ATM) or forkhead box O3a (FOXO3a), factors required for mitochondrial homeostasis, and the maintenance of NSC stemness. We found that ATM inhibition or FOXO3a deficiency, in addition to 53BP1 deficiency, did not induce further NSC stemness impairment. Collectively, our findings show that 53BP1, by cooperatively functioning with ATM and FOXO3a, supports the maintenance of NSC stemness by modulating mitochondrial homeostasis.
    Keywords:  53BP1; Ataxia-telangiectasia mutated (ATM); Forkhead box O3a (FOXO3a); Neural stem cell; Reactive oxygen species (ROS); Stemness
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150776
  12. J Biol Chem. 2024 Oct 07. pii: S0021-9258(24)02372-X. [Epub ahead of print] 107870
    Redox control of the deubiquitinating enzyme Ubp2 regulates translation during stress.
    Clara M Santos, Blanche K Cizubu, Dinachi A Okonkwo, Chia-Yu Chen, Natori Maske, Nathan A Snyder, Vanessa Simoes, Erica J Washington, Gustavo M Silva.
      Protein ubiquitination is essential to govern cells' ability to cope with harmful environments by regulating many aspects of protein dynamics from synthesis to degradation. As important as the ubiquitination process, the reversal of ubiquitin chains mediated by deubiquitinating enzymes (DUBs) is critical for proper recovery from stress and re-establishment of proteostasis. Although it is known that ribosomes are decorated with K63-linked polyubiquitin (K63-ub) chains that control protein synthesis under stress, the mechanisms by which these ubiquitin chains are reversed and regulate proteostasis during stress recovery remain elusive. Here, we showed in budding yeast that the DUB Ubp2 is redox-regulated during oxidative stress in a reversible manner, which determines the levels of K63-ub chains present on ribosomes. We also demonstrate that Ubp2 can cleave single ubiquitin moieties out of chain and its activity is modulated by a series of repeated domains and the formation of disulfide bonds. By combining cellular, biochemical, and proteomics analyses, we showed that Ubp2 is crucial for restoring translation after stress cessation, indicating an important role in determining the cellular response to oxidative stress. Our work demonstrates a novel role for Ubp2, revealing that a range of signaling pathways can be controlled by redox regulation of DUB activity in eukaryotes, which in turn will define cellular states of health and diseases.
    Keywords:  deubiquitylation (deubiquitination); oxidative stress; redox regulation; translation control; yeast
    DOI:  https://doi.org/10.1016/j.jbc.2024.107870
  13. Behav Brain Res. 2024 Oct 04. pii: S0166-4328(24)00436-4. [Epub ahead of print]476 115280
    The SIRT-1/Nrf2/HO-1 axis: Guardians of neuronal health in neurological disorders.
    Pranshul Sethi, Sidharth Mehan, Zuber Khan, Pankaj Kumar Maurya, Nitish Kumar, Aakash Kumar, Aarti Tiwari, Tarun Sharma, Ghanshyam Das Gupta, Acharan S Narula, Reni Kalfin.
      SIRT1 (Sirtuin 1) is a NAD+-dependent deacetylase that functions through nucleoplasmic transfer and is present in nearly all mammalian tissues. SIRT1 is believed to deacetylate its protein substrates, resulting in neuroprotective actions, including reduced oxidative stress and inflammation, increased autophagy, increased nerve growth factors, and preserved neuronal integrity in aging or neurological disease. Nrf2 is a transcription factor that regulates the genes responsible for oxidative stress response and substance detoxification. The activation of Nrf2 guards cells against oxidative damage, inflammation, and carcinogenic stimuli. Several neurological abnormalities and inflammatory disorders have been associated with variations in Nrf2 activation caused by either pharmacological or genetic factors. Recent evidence indicates that Nrf2 is at the center of a complex cellular regulatory network, establishing it as a transcription factor with genuine pleiotropy. HO-1 is most likely a component of a defense mechanism in cells under stress, as it provides negative feedback for cell activation and mediator synthesis. This mediator is upregulated by Nrf2, nitric oxide (NO), and other factors in various inflammatory states. HO-1 or its metabolites, such as CO, may mitigate inflammation by modulating signal transduction pathways. Neurological diseases may be effectively treated by modulating the activity of HO-1. Multiple studies have demonstrated that SIRT1 and Nrf2 share an important connection. SIRT1 enhances Nrf2, activates HO-1, protects against oxidative injury, and decreases neuronal death. This has been associated with numerous neurodegenerative and neuropsychiatric disorders. Therefore, activating the SIRT1/Nrf2/HO-1 pathway may help treat various neurological disorders. This review focuses on the current understanding of the SIRT1 and Nrf2/HO-1 neuroprotective processes and the potential therapeutic applications of their target activators in neurodegenerative and neuropsychiatric disorders.
    Keywords:  HO-1; Inflammation; Neurodegeneration, Neuropsychiatric disorders; Nrf2; Oxidative stress; SIRT1; Therapeutic interventions
    DOI:  https://doi.org/10.1016/j.bbr.2024.115280
  14. Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2404470121
    Revised mechanism of hydroxyurea-induced cell cycle arrest and an improved alternative.
    Alisa E Shaw, Mattias N Mihelich, Jackson E Whitted, Hannah J Reitman, Adam J Timmerman, Muhammad Tehseen, Samir M Hamdan, Grant D Schauer.
      Replication stress describes endogenous and exogenous challenges to DNA replication in the S-phase. Stress during this critical process causes helicase-polymerase decoupling at replication forks, triggering the S-phase checkpoint, which orchestrates global replication fork stalling and delayed entry into G2. The replication stressor most often used to induce the checkpoint response in yeast is hydroxyurea (HU), a clinically used chemotherapeutic. The primary mechanism of S-phase checkpoint activation by HU has thus far been considered to be a reduction of deoxynucleotide triphosphate synthesis by inhibition of ribonucleotide reductase (RNR), leading to helicase-polymerase decoupling and subsequent activation of the checkpoint, facilitated by the replisome-associated mediator Mrc1. In contrast, we observe that HU causes cell cycle arrest in budding yeast independent of both the Mrc1-mediated replication checkpoint response and the Psk1-Mrc1 oxidative signaling pathway. We demonstrate a direct relationship between HU incubation and reactive oxygen species (ROS) production in yeast and human cells and show that antioxidants restore growth of yeast in HU. We further observe that ROS strongly inhibits the in vitro polymerase activity of replicative polymerases (Pols), Pol α, Pol δ, and Pol ε, causing polymerase complex dissociation and subsequent loss of DNA substrate binding, likely through oxidation of their integral iron-sulfur (Fe-S) clusters. Finally, we present "RNR-deg," a genetically engineered alternative to HU in yeast with greatly increased specificity of RNR inhibition, allowing researchers to achieve fast, nontoxic, and more readily reversible checkpoint activation compared to HU, avoiding harmful ROS generation and associated downstream cellular effects that may confound interpretation of results.
    Keywords:  ROS; S-phase checkpoint; cell cycle; hydroxyurea; replication stress
    DOI:  https://doi.org/10.1073/pnas.2404470121
  15. Adv Biol (Weinh). 2024 Oct 08. e2400383
    Ferroptosis: A New Strategy for the Treatment of Fibrotic Diseases.
    Zhuo Pei, Jing Fan, Maolin Tang, Yuhong Li.
      Ferroptosis is a new type of cell death characterized by iron dependence and the excessive accumulation of lipid reactive oxygen species (lipid ROS) that has gradually become better characterized. There is sufficient evidence indicating that ferroptosis is associated with a variety of human life activities and diseases, such as tumor suppression, ischemic organ injury, and degenerative disorders. Notably, ferroptosis is also involved in the initiation and development of fibrosis in various organs, including liver fibrosis, pulmonary fibrosis, renal fibrosis, and cardiac fibrosis, which is usually irreversible and refractory. Although a large number of patients with fibrosis urgently need to be treated, the current treatment options are still limited and unsatisfactory. Organ fibrosis involves a series of complex and orderly processes, such as parenchymal cell damage, recruitment of inflammatory cells and activation of fibroblasts, which ultimately leads to the accumulation of extracellular matrix (ECM) and the formation of fibrosis. An increasing number of studies have confirmed the close association between these pathological processes and ferroptosis. This review summarizes the role and function of ferroptosis in fibrosis and proposes several potential therapeutic strategies and pathways based on ferroptosis.
    Keywords:  Iron; ferroptosis; fibrosis; treatment
    DOI:  https://doi.org/10.1002/adbi.202400383
  16. Exp Dermatol. 2024 Oct;33(10): e15189
    Nrf2 Activation in Keratinocytes: A Central Role in Diabetes-Associated Wound Healing.
    Srinivasan Kaussikaa, Murali Krishna Prasad, Kunka Mohanram Ramkumar.
      Wound healing is a complex biological process crucial for tissue repair, wherein keratinocytes play a pivotal role in initiating, sustaining and completing the cascade. Various local and systemic factors, such as lifestyle, age metabolic disorders and vascular insufficiency, can influence this process, and in the context of diabetic wounds, disrupted biological mechanisms, including inflammation, tissue hypoxia, decrease in collagen production along with increased oxidative stress and keratinocyte dysfunction, contribute to delayed healing. During re-epithelialisation, keratinocytes undergo rapid multiplication and migration, forming a dense hyperproliferative epithelial layer that restores the epidermal barrier. Nuclear factor-erythroid 2-related factor (Nrf2), a vital transcription factor, emerges as a central regulator in managing antioxidant proteins and detoxifying enzymes, serving as a guardian against elevated reactive oxygen species (ROS) levels during stress. Nrf2 also orchestrates angiogenesis and anti-inflammatory responses crucial for wound repair. Studies demonstrate that under high-glucose conditions, Nrf2 activation promotes wound healing by enhancing cell proliferation and migration while reducing apoptosis. Nrf2 activators stimulate endogenous antioxidant production, thereby mitigating oxidative stress. Furthermore, Nrf2 upregulation is associated with decreased expression of cytokines such as TNF-α and IL- 6. Recent research underscores the potential of bioactive molecules, including dietary polyphenols, traditional medicinal compounds and pharmacological agents, in activating Nrf2 and preventing diseases such as diabetes due to their robust antioxidative properties. This review aims to investigate the activation of Nrf2 by these bioactive molecules in cultured keratinocytes and animal models, elucidating the key molecular regulatory mechanisms involved in alleviating oxidative stress and facilitating the diabetic wound healing process. Understanding these complex pathways may offer insights into novel therapeutic strategies for enhanced wound healing in diabetes-associated complications.
    Keywords:  NRF2; hyperglycaemia; keratinocytes; oxidative stress; wound healing
    DOI:  https://doi.org/10.1111/exd.15189
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