bims-redobi 2024-11-17 papers

bims-redobi

Biomed News

on Redox biology

Issue of 2024–11–17
25 papers selected by
Vanesa Cepas López, Candiolo Cancer Institute

Oxidative stress in gut TH17 cells makes mice susceptible to bacterial infection.
Down-Regulation of Cysteine-Glutamate Antiporter in ALDH1A1 Expressing Oral and Breast Cancer Stem Cells Induced Oxidative Stress-Triggered Ferroptosis.
Aging, ROS, and cellular senescence: a trilogy in the progression of liver fibrosis.
The Relation Between Mitochondrial Membrane Potential and Reactive Oxygen Species Formation.
Lysosomal damage triggers a p38 MAPK-dependent phosphorylation cascade to promote lysophagy via the small heat shock protein HSP27.
Safeguarding the brain from oxidative damage.
Ferritin with methylglyoxal produces reactive oxygen species but remains functional.
Balanced regulation of ROS production and inflammasome activation in preventing early development of colorectal cancer.
SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling.
FXR deficiency induced ferroptosis via modulation of the CBP-dependent p53 acetylation to suppress breast cancer growth and metastasis.
Synergistic Effect of Salinomycin With Budesonide on TNBC Regression via EMT Reversal and Autophagy Induction.
Alpha-synuclein expression in neurons modulates Japanese encephalitis virus infection.
Contribution of p53-dependent and -independent mechanisms to upregulation of p21 in Fanconi anemia.
Passage dependence of NADH redox status and reactive oxygen species level in vitro in triple-negative breast cancer cell lines with different invasiveness.
Procyanidin capsules provide a new option for long-term ROS scavenging in chronic inflammatory diseases.
Amyloid beta-activated alpha-1-syntrophin has ramifications on Rac1 activation, ROS production and neuronal cell death.
Revealing mitochondrial microenvironmental changes triggered by ferroptosis regulation.
Skeletal muscle reactive oxygen species and microvascular endothelial function in age-related hypertension: a study protocol using a microdialysis technique.
4-Hydroxyphenylacetic Acid, a microbial-derived metabolite of Polyphenols, inhibits osteoclastogenesis by inhibiting ROS production.
Tumor Heterogeneity Shapes Survival Dynamics in Drug-Treated Cells, Revealing Size-Drifting Subpopulations.
Role of reactive oxygen species in regulating epigenetic modifications.
Mir-509-3p targets SLC25A13 to regulate ferroptosis and protect retinal endothelial cells in diabetic retinopathy.
Mitochondrial reactive oxygen species-mediated fibroblast activation has a role in tumor microenvironment formation in radiation carcinogenesis.
Processes independent of nonphotochemical quenching protect a high-light-tolerant desert alga from oxidative stress.
TaWRKY17 Interacts With TaWRKY44 to Promote Expression of TaDHN7 for Salt Tolerance in Wheat.

Immunometabolism (Cobham). 2024 Oct;6(4): e00049

Oxidative stress in gut TH17 cells makes mice susceptible to bacterial infection.

Simon O'Shaughnessy, David K Finlay.

  A recent paper published in Cell Metabolism in August 2024 by Dirk Brenner's laboratory highlights the importance of effectively managing reactive oxygen species (ROS) in gut TH17 T cells for minimizing the damage caused by intestinal bacterial infection. This commentary will discuss the control of cellular ROS by glutathione and the emerging understanding that neutralizing ROS in immune cells is essential for the individualized functions of different immune subsets. In the case of this study, managing ROS within TH17 cells in the gut was shown to be essential to sustain the production of IL22 cytokine to maintain gut homeostasis in response to bacterial infection.

Keywords:  CD4; IL17; IL22; TH17; gastrointestinal infection with Citrobacter rodentium; glutamate-cysteine ligase catalytic subunit; glutathione; mTORc1; mitochondria, reactive oxygen species; mitochondrial transcription factor A

DOI:  https://doi.org/10.1097/IN9.0000000000000049
J Cancer. 2024 ;15(19): 6160-6176

Down-Regulation of Cysteine-Glutamate Antiporter in ALDH1A1 Expressing Oral and Breast Cancer Stem Cells Induced Oxidative Stress-Triggered Ferroptosis.

Ravi Shankar Bellala, Prasanthi Chittineedi, Sungey Naynee Sánchez Llaguno, Juan Alejandro Neira Mosquera, Gooty Jaffer Mohiddin, Santhi Latha Pandrangi.

  Background: Sulfasalazine, an xCT inhibitor, is being used as a repurposed antineoplastic drug to induce ferroptosis. Ferroptosis is a regulated necrotic cell death pathway that is dependent on iron reserves. Interestingly, cancer stem cells (CSCs) that are regarded as major drivers of resistance to conventional therapies accompanied with tumor relapse and recurrence have bulk amount of iron reserves in the form of ferritin. This suggests that inducing ferroptosis might disrupt stemness and drug-resistant mechanisms in cancer stem cells, thereby reducing the risk of drug-resistance, cancer recurrence, and relapse. Materials & Methods: In the present study, ALDH1A1 expressing oral (OCSCs) and breast (BCSCs) cancer stem cells were sorted and used to investigate the role of sulfasalazine to induce ferroptosis. To check the self-renewability of CSCs spheroid formation, assay was performed and the resultant CSCs were treated with sulfasalazine (SAS) and subjected to gene expression analysis RT-PCR and flow cytometry. FACS was performed to check stem cell marker expression, cell cycle arrest, and apoptosis. Results: Our results suggest that the cells showed a gradual increase in sphere formation till S3 in the case of OCSCs and S2 in the case of BCSCs, with a gradual decrease in sphere-forming efficiency from the respective generations. When treated with 0.6mM SAS, these cells induced ferroptosis by downregulating stem cell markers like ALDH1A1, SLC7A11, ferritin, and GPx-4 with a concomitant increase in transferrin and STEAP-3. Flow cytometry studies revealed that the cells have undergone mitochondrial dysfunction characterized by loss of membrane potential and the cell cycle progression was halted in the G2/M phase. Conclusion: In the present study, we demonstrate that SAS potentially induced ferroptosis accompanied with oxidative stress in both OCSCs as well as BCSCs by lowering GPx-4 activity, a key enzyme that scavenges the products produced as a result of oxidative stress.

Keywords:  ALDH1A1; Cancer Stem Cells; Cysteine-Glutamate Antiporter; Ferritin; Ferroptosis

DOI:  https://doi.org/10.7150/jca.89429
Biogerontology. 2024 Nov 15. 26(1): 10

Aging, ROS, and cellular senescence: a trilogy in the progression of liver fibrosis.

Waleed Hassan Almalki, Salem Salman Almujri.

  Ageing is an inevitable and multifaceted biological process that impacts a wide range of cellular and molecular mechanisms, leading to the development of various diseases, such as liver fibrosis. Liver fibrosis progresses to cirrhosis, which is an advanced form due to high amounts of extracellular matrix and restoration of normal liver structure with failure to repair damaged tissue and cells, marking the end of liver function and total liver failure, ultimately death. The most important factors are reactive oxygen species (ROS) and cellular senescence. Oxidative stress is defined as an impairment by ROS, which are by-products of the mitochondrial electron transport chain and other key molecular pathways that induce cell damage and can activate cellular senescence pathways. Cellular senescence is characterized by pro-inflammatory cytokines, growth factors, and proteases secreted by senescent cells, collectively known as the senescence-associated secretory phenotype (SASP). The presence of senescent cells, which disrupt tissue architecture and function and increase senescent cell production in liver tissues, contributes to fibrogenesis. Hepatic stellate cells (HSCs) are activated in response to chronic liver injury, oxidative stress, and senescence signals that drive excessive production and deposition of extracellular matrix. This review article aims to provide a comprehensive overview of the pathogenic role of ROS and cellular senescence in the aging liver and their contribution to fibrosis.

Keywords:  Aging; Cellular senescence; Liver fibrosis; Oxidative stress; Reactive oxygen species; Senescence-associated secretory phenotype

DOI:  https://doi.org/10.1007/s10522-024-10153-3
Methods Mol Biol. 2025 ;2878 133-162

The Relation Between Mitochondrial Membrane Potential and Reactive Oxygen Species Formation.

Magdalena Lebiedzinska-Arciszewska, Jan Suski, Massimo Bonora, Barbara Pakula, Paolo Pinton, Jerzy Duszynski, Patrycja Jakubek-Olszewska, Mariusz R Wieckowski.

  Mitochondria are considered one of the main sites of reactive oxygen species (ROS) production in the eukaryotic cells. For this reason, mitochondrial dysfunction associated with increased ROS production underlies various pathological conditions as well as promotes aging. Chronically increased rates of ROS production contribute to oxidative damage to macromolecules, i.e., DNA, proteins, and lipids. Accumulation of unrepaired oxidative damage may result in progressive cell dysfunction, which can finally trigger cell death. The main by-product of mitochondrial oxidative phosphorylation is superoxide, which is generated by the leak of electrons from the mitochondrial respiratory chain complexes leading to one-electron reduction of oxygen. Mitochondrial superoxide dismutase (MnSOD, SOD2) as well as cytosolic superoxide dismutase (Cu/ZnSOD, SOD1), whose smaller pool is localized in the mitochondrial intermembrane space, converts superoxide to H2O2, which can be then degraded by the catalase to harmless H2O.In this chapter, we focus on the relationship between one of the bioenergetic parameters, which is mitochondrial membrane potential, and the rate of ROS formation. We present a set of various methods enabling the characterization of these parameters applicable to isolated mitochondria or intact cells. We also present examples of experimental data demonstrating that the magnitude and direction (increase or decrease) of a change in mitochondrial ROS production depend on the mitochondrial metabolic state.

Keywords:  Confocal microscopy; Hydrogen peroxide; Mitochondria; Oxygen consumption; Resazurin; Superoxide

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_8
Curr Biol. 2024 Nov 10. pii: S0960-9822(24)01457-X. [Epub ahead of print]

Lysosomal damage triggers a p38 MAPK-dependent phosphorylation cascade to promote lysophagy via the small heat shock protein HSP27.

Elizabeth R Gallagher, Peace T Oloko, Tessa C Fitch, Elizabeth M Brown, Lynn A Spruce, Erika L F Holzbaur.

  Maintenance of lysosomal integrity is essential for cell viability. Upon injury, lysosomes may be targeted for degradation via a selective form of autophagy known as lysophagy. The engulfment of a damaged lysosome by an autophagosome is mediated by the recruitment of adaptor proteins, including SQSTM1/p62. p62 promotes lysophagy via the formation of phase-separated condensates in a mechanism that is regulated by the heat shock protein HSP27. Here, we demonstrate a direct interaction between HSP27 and p62. We used structural modeling to predict the binding interface between HSP27 and p62 and identify several disease-associated mutations that map to this interface. We used proteomics to identify post-translational modifications of HSP27 that regulate HSP27 recruitment to stressed lysosomes, finding robust phosphorylation at several serine residues. Next, we characterized the upstream signaling mechanism leading to HSP27 phosphorylation and found that p38 mitogen-activated protein kinase (MAPK) and its effector kinase MAP kinase-activated protein kinase 2 (MK2) are activated upon lysosomal damage by the kinase mTOR and the production of intracellular reactive oxygen species (ROS). Increased ROS activates p38 MAPK, which in turn allows MK2-dependent phosphorylation of HSP27. Depletion of HSP27 or the inhibition of HSP27 phosphorylation alters the dynamics of p62 condensates on stressed lysosomes, significantly inhibiting p62-dependent lysophagy. Thus, we define a novel lysosomal quality control mechanism in which lysosomal injury triggers a p38 MAPK/MK2 signaling cascade promoting p62-dependent lysophagy. Further, this signaling cascade is activated by many cellular stressors, including oxidative and heat stress, suggesting that other forms of selective autophagy may be regulated by p38 MAPK/MK2/HSP27.

Keywords:  HSP27; SQSTM1/p62; lysophagy; oligomers; p38 MAPK; phase separation; phosphorylation

DOI:  https://doi.org/10.1016/j.cub.2024.10.061
Free Radic Biol Med. 2024 Nov 13. pii: S0891-5849(24)01053-0. [Epub ahead of print]

Safeguarding the brain from oxidative damage.

Kyung Hee Lee, Un Jeng Kim, Bae Hwan Lee, Myeounghoon Cha.

  Oxidative stress imposes a substantial cellular burden on the brain and contributes to diverse neurodegenerative diseases. Various antioxidant signaling pathways have been implicated in oxidative stress and have a protective effect on brain cells by increasing the release of numerous enzymes and through anti-inflammatory responses to oxidative damage caused by abnormal levels of reactive oxygen species (ROS). Although many molecules evaluated as antioxidants have shown therapeutic potentials in preclinical studies, the results of clinical trials have been less than satisfactory. This review focuses on several signaling pathways involved in oxidative stress that are associated with antioxidants. These pathways have a protective effect against stressors by increasing the release of various enzymes and also exert anti-inflammatory responses against oxidative damage. There is no doubt that oxidative stress is a crucial therapeutic target in the treatment of neurological diseases. Therefore, it is essential to understand the discovery of multiple routes that can efficiently repair the damage caused by ROS and prevent neurodegenerative disorders. This paper aims to provide a concise and objective review of the oxidative and antioxidant pathways and their potential therapeutic applications in treating oxidative injury in the brain.

Keywords:  Antioxidant; Neurodegenerative disease; Nrf2; Oxidative stress; Redox system

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.019
Free Radic Res. 2024 Nov 07. 1-21

Ferritin with methylglyoxal produces reactive oxygen species but remains functional.

Adriana Rybnikářová, Richard Buchal, Jan Pláteník.

  Iron is necessary for life, but the simultaneous iron-catalyzed formation of reactive oxygen species (ROS) is involved in pathogenesis of many diseases. One of them is diabetes mellitus, a widespread disease with severe long-term complications, including neuropathy, retinopathy, and nephropathy. Much evidence points to methylglyoxal, a potent glycating agent, as the key mediator of diabetic complications. In diabetes, there is also a peculiar dysregulation of iron homeostasis, leading to an expansion of redox-active iron. This in vitro study focuses on the interaction of methylglyoxal with ferritin, which is the main cellular protein for iron storage. Methylglyoxal effectively liberates iron from horse spleen ferritin, as well as synthetic iron cores; in both cases, it is partially mediated by superoxide. The interaction of methylglyoxal with ferritin increases the production of hydrogen peroxide, much above the generation of peroxide by methylglyoxal alone, in an iron-dependent manner. Glycation with methylglyoxal results in structural changes in ferritin. All of these findings can be demonstrated with pathophysiologically relevant (submillimolar) methylglyoxal concentrations. However, the rate of iron release by ascorbate, the ferroxidase activity, or the diameter of gated pores even in intensely glycated ferritin is not altered. In conclusion, although the functional features of ferritin resist alterations due to glycation, the interaction of methylglyoxal with ferritin liberates iron and markedly increases ROS production, both of which could enhance oxidative stress in vivo. Our findings may have implications for the pathogenesis of long-term diabetic complications, as well as for the use of ferritin as a nanocarrier in chemotherapy.

Keywords:  Glycation; diabetes mellitus; labile iron pool; protein cross-links; resistance to oxidative stress

DOI:  https://doi.org/10.1080/10715762.2024.2417281
Immunol Rev. 2024 Nov 10.

Balanced regulation of ROS production and inflammasome activation in preventing early development of colorectal cancer.

Longjun Li, Tao Xu, Xiaopeng Qi.

  Reactive oxygen species (ROS) production and inflammasome activation are the key components of the innate immune response to microbial infection and sterile insults. ROS are at the intersection of inflammation and immunity during cancer development. Balanced regulation of ROS production and inflammasome activation serves as the central hub of innate immunity, determining whether a cell will survive or undergo cell death. However, the mechanisms underlying this balanced regulation remain unclear. Mitochondria and NADPH oxidases are the two major sources of ROS production. Recently, NCF4, a component of the NADPH oxidase complex that primarily contributes to ROS generation in phagocytes, was reported to balance ROS production and inflammasome activation in macrophages. The phosphorylation and puncta distribution of NCF4 shifts from the membrane-bound NADPH complex to the perinuclear region, promoting ASC speck formation and inflammasome activation, which triggers downstream IL-18-IFN-γ signaling to prevent the progression of colorectal cancer (CRC). Here, we review ROS signaling and inflammasome activation studies in colitis-associated CRC and propose that NCF4 acts as a ROS sensor that balances ROS production and inflammasome activation. In addition, NCF4 is a susceptibility gene for Crohn's disease (CD) and CRC. We discuss the evidence demonstrating NCF4's crucial role in facilitating cell-cell contact between immune cells and intestinal cells, and mediating the paracrine effects of inflammatory cytokines and ROS. This coordination of the signaling network helps create a robust immune microenvironment that effectively prevents epithelial cell mutagenesis and tumorigenesis during the early stage of colitis-associated CRC.

Keywords:  ASC speck; NCF4; NLRP3 Inflammasome; colorectal cancer (CRC); reactive oxygen species (ROS); tumor immune microenvironment

DOI:  https://doi.org/10.1111/imr.13417
Cell Death Dis. 2024 Nov 12. 15(11): 820

SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling.

Jiaguan Zhang, Zeshou Gao, Yi Yang, Zhenhao Li, Binjie Wu, Chunxin Fan, Yuyan Zheng, Ruohan Yang, Fangrong Zhang, Xiaohuang Lin, Daoshan Zheng.

SNF2L encodes an ISWI chromatin remodeling factor that promotes gene transcription and is consistently elevated in cancers. Previous studies have shown that inhibiting SNF2L expression in cancer cells leads to significant growth suppression, DNA damage, and cell death. However, the underlying mechanisms remain poorly understood. In this study, we demonstrated that cancer cells lacking SNF2L show significantly decreased glutathione (GSH) levels, leading to elevated reactive oxygen species (ROS) and increased oxidative stress. SNF2L deficiency also heightened the sensitivity of cancer cells to APR-246, a drug that depletes GSH and induces oxidative stress, consequently decreasing cell viability and increasing ROS levels, regardless of p53 status. Mechanistically, we found that NRF2 recruits SNF2L to the SLC7A11 promoter, leading to increased chromatin accessibility and facilitating SLC7A11 transcription. This results in decreased cystine uptake and impaired GSH biosynthesis. These findings suggest that targeting the SNF2L/SLC7A11 axis could enhance the effectiveness of APR-246 by depleting GSH and increasing ROS level in cancer cells, highlighting SNF2L as a promising therapeutic target.

DOI: https://doi.org/10.1038/s41419-024-07221-4
Cell Death Dis. 2024 Nov 14. 15(11): 826

FXR deficiency induced ferroptosis via modulation of the CBP-dependent p53 acetylation to suppress breast cancer growth and metastasis.

Ping Huang, Han Zhao, Hua Dai, Jinying Li, Xiafang Pan, Wentian Pan, Chunhua Xia, Fanglan Liu.

Farnesoid X receptor (NR1H4/FXR) functions as a scavenger of lipid peroxide products and drives the proliferation and metastasis of various cancers. However, the underlying molecular mechanisms remain poorly understood. In our study, we found that the expression levels of FXR, vimentin and SLC7A11 were significantly higher in breast cancer tissues, particularly in metastatic cancer tissues compared to non-metastatic ones. Furthermore, the increased FXR expression was positively correlated with vimentin and SLC7A11 in clinical tumor specimens. In addition, a high level of FXR correlated with poor prognosis in patients with breast cancer. Both Z-Guggulsterone (Z-GS), as a pharmacological inhibitor of FXR, and silencing FXR curbed proliferation and migration of breast cancer cells by promoting ferroptosis. Notably, our results showed that FXR competitively bound to CREB-binding protein (CBP) to suppress the interaction between p53 and CBP in the nucleus, and thus prevented p53 acetylation at lys382, which was essential for upregulating the expression of SLC7A11. Conversely, FXR knockdown increased the interaction between p53 and CBP and promoted p53 acetylation, which ultimately led to facilitating ferroptosis in breast cancer cells. More importantly, we also found that Z-GS inhibited TGF-β1-induced tumor growth and metastasis of breast cancer primarily through ferroptosis via regulating CBP-dependent p53 acetylation in nude mice. In conclusion, the FXR was first reported as a tumor promoter that enhanced the proliferation and metastasis of breast cancer cells through regulating CBP-dependent p53 K382 acetylation. It proposes that FXR may serve as a potential therapeutic target for the treatment of breast cancer.

DOI: https://doi.org/10.1038/s41419-024-07222-3
J Biochem Mol Toxicol. 2024 Nov;38(11): e70045

Synergistic Effect of Salinomycin With Budesonide on TNBC Regression via EMT Reversal and Autophagy Induction.

Shilpi Sarkar, Siddhartha Sankar Ghosh.

  Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its aggressive nature, lack of specific therapeutic targets, and drug resistance. Chemotherapy resistance in TNBC is largely driven by the abnormal activation of epithelial-to-mesenchymal transition (EMT) and the associated cancer stem cell-like characteristics. The combination of multiple chemotherapeutic drugs has shown promise as a treatment approach for TNBC. This study evaluates the efficacy of a novel combination therapy involving the anti-inflammatory drug Budesonide and Salinomycin, which targets cancer stem cells. Co-administration of Budesonide and Salinomycin demonstrated a synergistic effect in inhibiting TNBC cell growth by activating the intrinsic apoptosis pathway. It induced a 2- to 3-fold increase in intracellular reactive oxygen species (ROS) generation and a 25%-30% rise in mitochondrial membrane depolarization. Additionally, extensive signaling studies revealed that the co-treatment specifically targeted multiple signaling nodes, limiting downstream crosstalk. The combination also enhanced autophagic activity by inhibiting the AKT/mTOR pathway and reduced cell migration and stemness by suppressing the EMT process. Therefore, the combination of Budesonide and Salinomycin offers a novel therapeutic approach for TNBC.

Keywords:  autophagy; combination treatment; epithelial to mesenchymal transition (EMT); metabolism; triple‐negative breast cancer (TNBC)

DOI:  https://doi.org/10.1002/jbt.70045
J Virol. 2024 Nov 07. e0041824

Alpha-synuclein expression in neurons modulates Japanese encephalitis virus infection.

Anjali Gupta, Vijay Singh Bohara, Aditya Singh Chauhan, Anshuman Mohapatra, Harpreet Kaur, Ajanta Sharma, Nitin Chaudhary, Sachin Kumar.

  Japanese encephalitis virus (JEV) stands as a prominent vector-borne zoonotic pathogen, displaying neurotropism and eliciting Parkinson's disease (PD)-like symptoms among most symptomatic survivors. A characteristic feature of PD is the aggregation of mutated α-synuclein (α-syn) that damages the dopaminergic neurons. Considering this link between JEV-induced PD-like symptoms and α-syn pathogenesis, we explored the role of α-syn in JEV infectivity in neuronal cells. Our investigation revealed a significant increase in endogenous α-syn expression in JEV-infected cells. In addition, exogenous α-syn (Exoα-syn) treatment substantially reduced JEV replication, suggesting its anti-JEV effect. Furthermore, Exoα-syn treatment led to the upregulation of superoxide dismutase 1 (SOD1) and reduction in reactive oxygen species (ROS). The results were validated by endogenous α-syn-silencing, which decreased SOD1 and raised ROS levels in neuronal cells. Similarly, the SOD1 inhibition via LCS-1 also intensified ROS and JEV infection. Silencing of SOD1 in α-syn overexpressing neuro2a cells exhibited increased JEV replication. Overall, our results suggest that α-syn exerts an anti-JEV effect by regulating protein involved in oxidative stress inside neuronal cells. This study contributes valuable insights into the interplay between α-syn expression and JEV infectivity, shedding light on avenues further to investigate the potential role of α-syn in JEV pathogenesis.
IMPORTANCE: Japanese encephalitis virus (JEV) poses a significant threat, particularly to children. Despite extensive research efforts, the development of effective treatments against JEV has been impeded. One of the major setbacks is a lack of comprehensive understanding of neurotropism. The study focuses on alpha-synuclein (α-syn), a neuronal protein, and aims to determine its role in JEV pathogenesis. The present study reveals that the host cell upregulates α-syn in response to JEV infection. α-syn restrains JEV propagation by modulating superoxide dismutase 1 (SOD1) expression which further blocks JEV-induced ROS generation. Endogenous α-syn silencing led to a decrease in SOD1 expression and increased viral titer. α-syn plays a crucial role in counteracting oxidative stress through SOD1, which is essential for limiting JEV replication. This study provides broader implications for antiviral strategies and their possible role in neurodegenerative diseases; however, there is still much to explore, particularly regarding α-syn aggregation kinetics in JEV infection.

Keywords:  Japanese encephalitis virus; SOD1; alpha-synuclein; antiviral

DOI:  https://doi.org/10.1128/jvi.00418-24
PLoS Genet. 2024 Nov 07. 20(11): e1011474

Contribution of p53-dependent and -independent mechanisms to upregulation of p21 in Fanconi anemia.

Xavier Renaudin, Baraah Al Ahmad Nachar, Benedetta Mancini, Anna Gueiderikh, Noémie Louis-Joseph, Frédérique Maczkowiak-Chartois, Filippo Rosselli.

Abnormal expression of the cell cycle inhibitor and p53 target CDKN1A/p21 has been associated with paradoxical outcomes, such as hyperproliferation in p53-deficient cancer cells or hypoproliferation that affects hematopoietic stem cell behavior, leading to bone marrow failure (BMF). Notably, p21 is known to be overexpressed in Fanconi anemia (FA), which is a rare syndrome that predisposes patients to BMF and cancer. However, why p21 is overexpressed in FA and how it contributes to the FA phenotype(s) are still poorly understood. Here, we revealed that while the upregulation of p21 is largely dependent on p53, it also depends on the transcription factor microphthalmia (MITF) as well as on its interaction with the nucleolar protein NPM1. Upregulation of p21 expression in FA cells leads to p21 accumulation in the chromatin fraction, p21 immunoprecipitation with PCNA, S-phase lengthening and genetic instability. p21 depletion in FA cells rescues the S-phase abnormalities and reduces their genetic instability. In addition, we observed that reactive oxygen species (ROS) accumulation, another key feature of FA cells, is required to trigger an increase in PCNA/chromatin-associated p21 and to impact replication progression. Therefore, we propose a mechanism by which p21 and ROS cooperate to induce replication abnormalities that fuel genetic instability.

DOI: https://doi.org/10.1371/journal.pgen.1011474
Transl Breast Cancer Res. 2024 ;5 27

Passage dependence of NADH redox status and reactive oxygen species level in vitro in triple-negative breast cancer cell lines with different invasiveness.

Allison Podsednik, He N Xu, Lin Z Li.

   Background: The redox status of nicotinamide adenine dinucleotide (NAD; including oxidized form NAD+ and reduced form NADH) plays key roles in both health and disease and has been actively studied to develop cancer biomarkers and therapeutic strategies. With the optical redox imaging (ORI) technique, we have been investigating the relationship of NADH redox status, reactive oxygen species (ROS), and invasiveness in breast cancer cell cultures, and have associated higher invasiveness with more oxidized NADH redox state. However, the cell cultures may have phenotypic drift and metabolic change with increased passage numbers.
Methods: We investigated the passage-dependence of NADH redox status and ROS levels in two triple-negative breast cancer (TNBC) cell cultures: the more invasive/metastatic MDA-MB-231 and the less invasive/metastatic HCC1806 cell lines. We measured the NADH redox status, redox plasticity, and cytoplasmic and mitochondrial ROS levels under the basal condition and metabolic perturbations of the mitochondrial electron transport chain. We evaluated the dependence of redox and ROS profiles on the cell passage number by comparing the early (<20 passages) with the late (>60 passages) passage cells.
Results: (I) NADH redox and ROS baselines are stable and independent of cell passage number, but can vary with passage number under metabolic perturbations depending on specific perturbation and cell line; (II) NADH redox status and intracellular ROS levels can change discordantly in cancer cells; (III) under both basal and metabolically perturbed conditions, the more invasive cell line has a more oxidized NADH redox status with a higher basal cytoplasmic ROS level than the less invasive line, regardless of passage number.
Conclusions: The general correlation between redox, ROS, and invasiveness in studied TNBC cells is not very sensitive to passage number. These results indicate that NADH redox and basal ROS status in TNBC likely reflect the intrinsic progressive nature of TNBC cells.

Keywords:  Optical redox imaging (ORI); flavin adenine dinucleotide (FAD); nicotinamide adenine dinucleotide reduced form (NADH); oxidized flavoproteins (Fp); prognostic biomarker

DOI:  https://doi.org/10.21037/tbcr-24-36
Mater Today Bio. 2024 Dec;29 101310

Procyanidin capsules provide a new option for long-term ROS scavenging in chronic inflammatory diseases.

Linxiao Sun, Shaoyin Wei, Chenglong Wang, Yipiao Zhang, Xingjie Zan, Lianxin Li, Chunwu Zhang.

  Chronic inflammatory diseases such as diabetic wounds and osteoarthritis are significant threats to human health. Failure to scavenge longstanding excessive reactive oxygen species (ROS) is an important cause of chronic inflammatory diseases, yet existing treatments that provide long-lasting therapeutic effects are limited. Here, procyanidin capsules were synthesized in a simple one-step way using calcium carbonate as a template. The biosafety of procyanidin capsules in vitro and in vivo was monitored by cytotoxicity and pathological sections. The therapeutic effect of procyanidin capsules in diabetic wounds and osteoarthritis was accessed by pathological evaluation combined with the quantification of inflammatory markers. The data showed that procyanidin capsules could long-term scavenge excessive ROS and effectively promote articular cartilage repair in osteoarthritis, accelerating diabetic wound healing. Lastly, transcriptome analysis suggested that procyanidin capsules commonly regulated adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling in diabetic wounds and osteoarthritis. This study provides a straightforward protocol for creating procyanidin capsules, while presenting a promising new therapeutic option for long-term scavenging ROS in chronic inflammatory diseases.

Keywords:  Diabetic wounds; Long-term ROS scavenging; Osteoarthritis; Procyanidin capsules

DOI:  https://doi.org/10.1016/j.mtbio.2024.101310
Eur J Neurosci. 2024 Nov 14.

Amyloid beta-activated alpha-1-syntrophin has ramifications on Rac1 activation, ROS production and neuronal cell death.

Umar Mushtaq, Rais A Ganai, Muzamil Ahmad, Firdous Ahmad Khanday.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of β-amyloid (Aβ)-containing extracellular neuritic plaques and phosphorylated tau-containing intracellular neurofibrillary tangles. It remains the primary neuropathological criteria for the diagnosis of AD. Additionally, several other processes are currently being recognized as significant risk factors for AD development, including the brain's susceptibility to reactive oxygen species (ROS). The ROS production is among the early signs in the progression of AD. However, the underlying mechanisms behind increased ROS production in AD remain poorly understood. We have observed SNTA1 plays critical role in regulating ROS levels in different pathological conditions. Here, we wanted to gain further insight into the role of SNTA1 in the development of AD by using IMR32 cell line. Our results show that the accumulation of Aβ plaques in Alzheimer's model neuroblastoma cells significantly increases the expression and activation of SNTA1 and MKK6 kinase. The activation of MKK6 results in the phosphorylation of SNTA1, creating a binding site for Rac1, leading to its activation and subsequent production of ROS. Excessive ROS production leads to cell cycle arrest in the G2/M phase, a hallmark of AD. Our study provides new insight into the mechanism of Aβ-mediated cell death in AD and suggests that MKK6-mediated activation of alpha-1-syntrophin promotes ROS production in neuronal cells, resulting in cell death. This study presents a mechanistic insight into Aβ-mediated cell death and could serve as a paradigm for reducing neuronal cell death in AD.

Keywords:  Alzheimer's; IMR32; MKK6; ROS; SNTA1; syntrophins

DOI:  https://doi.org/10.1111/ejn.16609
Anal Bioanal Chem. 2024 Nov 13.

Revealing mitochondrial microenvironmental changes triggered by ferroptosis regulation.

Lili Cong, Yanting Shen, Jiaqi Wang, Fanxiang Meng, Weiqing Xu, Weixia Sun, Shuping Xu.

  Ferroptosis is a unique form of iron-dependent cell death characterized by dramatic ultrastructural changes in mitochondria. Since mitochondria are intracellular energy factories and binding sites for producing reactive oxygen species, there is increasing evidence that mitochondria are closely related to ferroptosis and play a crucial role in the regulation and execution of ferroptosis. The pH of the mitochondrial microenvironment is an important parameter for cellular physiological activities. Its abnormal fluctuations are commonly thought to be associated with cancers and other diseases. Herein, a surface-enhanced Raman scattering (SERS)-based pH nanosensor with high sensitivity and targeting function was utilized to quantify and monitor mitochondrial pH value. This nanosensor was constructed by gold nanorods (AuNRs) functionalized with pH-responsive molecules (4-mercaptopyridine, MPy) and mitochondrion-targeting peptides (AMMT) that can precisely deliver AuNRs to mitochondria. Super-resolution fluorescence imaging was employed to evidence the mitochondrial targeting feature of this nanosensor. Ferroptosis regulation induces intracellular accumulation of lipid peroxide (LPO) and reactive oxygen species (ROS), which cause changes in the mitochondrial pH. This method reveals that ferroptosis leads to the gradual acidification of the mitochondrial internal environment. The conclusion deduced by this study will be helpful for the evaluation and diagnosis of diseases according to intracellular abnormal microenvironments.

Keywords:  Ferroptosis; Mitochondrial microenvironment; Nanosensor; Surface-enhanced Raman spectroscopy; pH-responsive

DOI:  https://doi.org/10.1007/s00216-024-05638-6
J Physiol. 2024 Nov 09.

Skeletal muscle reactive oxygen species and microvascular endothelial function in age-related hypertension: a study protocol using a microdialysis technique.

Hollie Speer, Mostafa M Ali, Nathan M D'Cunha, Nenad Naumovski, Stephan F E Praet, Robert C Hickner, Andrew J McKune.

  Increased reactive oxygen species (ROS) generation and microvascular endothelial disruptions occur with natural ageing, but often transpire before the detection of cardiometabolic conditions including hypertension. Age-related increases in blood pressure are driven by complex systemic changes with poorly understood integrated mechanisms. The deconditioning experienced by ageing skeletal muscle from mid-life is associated with reduced microvascular blood flow and increased peripheral resistance, suggesting that vasodilatory decrements in the muscle may precede the age-related increases in blood pressure. Structural and functional changes within the vascular and skeletal muscle systems with advancing age can influence redox homeostasis, and vice versa, further compounding microvascular endothelial dysfunction. Therefore, comparisons between the microvascular environments of healthy and hypertensive cohorts can provide insights into the changes that occur during significant periods of functional decline. This comprehensive study protocol describes a microdialysis technique to assess the interactions of microvascular health and functional changes in the muscle, which currently cannot be otherwise addressed. Here, we detail an experimental protocol to simultaneously detect skeletal muscle ROS (H2O2 and indirect O2 -), determine nutritive blood flow and assess microvascular endothelial function in response to acetylcholine stimulation. We expect that healthy middle-aged individuals should not have increased ROS generation in the muscle at rest, compared to their hypertensive or older counterparts, but may exhibit perturbed microvascular function. The described technique allows for intricate exploration of microvascular physiology that will provide a critically novel insight into benchmarking potential age-related mechanisms involved in the development of age-related hypertension, and aid in early identification and prevention. KEY POINTS: Increased reactive oxygen species (ROS) production and microvascular endothelial dysfunction precede the onset of age-related cardiometabolic and vascular conditions such as hypertension. The profound structural and functional changes that occur within the vasculature and in skeletal muscle from middle age prompt a need to mechanistically explore the microvascular environment in healthy and hypertensive individuals. Using a novel microdialysis technique, we detail an experimental protocol to simultaneously detect skeletal muscle ROS (H2O2 and indirect O2 -), determine nutritive blood flow and assess microvascular endothelial function in response to acetylcholine stimulation. With this technique and study protocol, we can reveal functional insights into potential perturbations in ROS generation at rest and the microvascular endothelium, which play important roles in the development of age-related hypertension.

Keywords:  ageing; blood pressure; endothelium; microdialysis; reactive oxygen species

DOI:  https://doi.org/10.1113/JP287187
Int Immunopharmacol. 2024 Nov 08. pii: S1567-5769(24)02093-9. [Epub ahead of print]143(Pt 3): 113571

4-Hydroxyphenylacetic Acid, a microbial-derived metabolite of Polyphenols, inhibits osteoclastogenesis by inhibiting ROS production.

Zhanchi Zhang, Junchuan Liu, Yijun Li, Yunsheng Wang, Xiao Zheng, Feng Wang, Tong Tong, Dechao Miao, Wenshuai Li, Lei Chen, Linfeng Wang.

  Intracellular reactive oxygen species (ROS) accumulation is key to osteoclast differentiation. Plant-derived polyphenols that have reduced ROS production have been widely studied for the treatment of osteoporosis. However, these compounds are rarely absorbed in the small intestine and are instead converted to phenolic acids by the microbiota in the colon. These large quantities of low-molecular-weight phenolic acids can then be absorbed by the body. 4-Hydroxyphenylacetic acid (4-HPA) is an important metabolite of these polyphenols that is generated by the human intestinal microbiota. However, its potential mechanism is not fully understood. In this study, we aimed to elucidate the role of 4-HPA on osteoclastogenesis and treating osteoporosis. Our study showed that 4-HPA inhibited osteoclast differentiation and function and downregulated osteoclast-specific genes, including NFATc1, Atp6v0d2, MMP9, CTSK, Acp5, and c-Fos. As for further mechanism exploration, 4-HPA reduced ROS accumulation by regulating nuclear factor erythroid 2-related factor (Nrf2) and subsequently inhibited the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. To evaluate the effect of 4-HPA on postmenopausal osteoporosis, an ovariectomized (OVX) mouse model was used. The Micro-CT and histomorphometry analyses showed that 4-HPA effectively prevents bone loss. Encouragingly, 4-HPA demonstrated efficacy in treating osteoporosis induced by OVX. In conclusion, our study revealed that 4-HPA, a polyphenol metabolite produced by intestinal microorganisms, also inhibits osteoclast formation and treats osteoporosis, which provides a new experimental basis and candidate drug for the treatment of osteoporosis.

Keywords:  4-Hydroxyphenylacetic acid; Osteoclast; Osteoporosis; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.intimp.2024.113571
ACS Pharmacol Transl Sci. 2024 Nov 08. 7(11): 3573-3584

Tumor Heterogeneity Shapes Survival Dynamics in Drug-Treated Cells, Revealing Size-Drifting Subpopulations.

Venugopal Vangala, Yu-Chi Chen, Saketh S Dinavahi, Krishne Gowda, Nazir A Lone, Meenhard Herlyn, Joseph Drabick, Klaus Helm, Jiyue Zhu, Rogerio I Neves, Arun K Sharma, Arthur Berg, Marco Archetti, Shantu Amin, Todd D Schell, Gavin P Robertson.

The goal of this project was to demonstrate that subpopulations of cells in tumors can uniquely fluctuate in size in response to environmental conditions created during drug treatment, thereby acting as a dynamic "rheostat" to create a favorable tumor environment for growth. The cancer modeling used for these studies was subpopulations of melanoma cells existing in cultured and tumor systems that differed in aldehyde dehydrogenase (ALDH) activity. However, similar observations were found in other cancer types in addition to melanoma, making them applicable broadly across cancer. The approach was designed to show that either ALDHhigh and ALDHlow subpopulations rapidly epigenetically transition between stem-cell-like high into nonstem-like low production states to create an environment during drug treatment that would enable optimal cellular proliferation and tumor expansion to facilitate drug resistance. The controlled experiments showed proportional changes in each cell population to reach an evolutionarily stable equilibrium mediated by the needed levels of ALDH enzyme activity. Mechanistically, cell population size changes served to functionally move the aldehyde and the resulting reactive oxygen species (ROS) levels to those compatible with optimal cellular proliferation with population fluctuations dependent on the levels of drug induced tumor stress. This is the first report documenting fluctuations in the sizes of cell populations in tumors to cooperatively assist in drug resistance development.

DOI: https://doi.org/10.1021/acsptsci.4c00453
Cell Signal. 2024 Nov 07. pii: S0898-6568(24)00477-7. [Epub ahead of print]125 111502

Role of reactive oxygen species in regulating epigenetic modifications.

Yutong Chen, Ying-Qiang Shen.

  Reactive oxygen species (ROS) originate from diverse sources and regulate multiple signaling pathways within the cellular environment. Their generation is intricately controlled, and disruptions in their signaling or atypical levels can precipitate pathological conditions. Epigenetics, the examination of heritable alterations in gene expression independent of changes in the genetic code, has been implicated in the pathogenesis of various diseases through aberrant epigenetic modifications. The significant contribution of epigenetic modifications to disease progression underscores their potential as crucial therapeutic targets for a wide array of medical conditions. This study begins by providing an overview of ROS and epigenetics, followed by a discussion on the mechanisms of epigenetic modifications such as DNA methylation, histone modification, and RNA modification-mediated regulation. Subsequently, a detailed examination of the interaction between ROS and epigenetic modifications is presented, offering new perspectives and avenues for exploring the mechanisms underlying specific epigenetic diseases and the development of novel therapeutics.

Keywords:  DNA methylation; Epigenetics; Histone PTMs; Mechanism diseases; RNA modifications; ROS

DOI:  https://doi.org/10.1016/j.cellsig.2024.111502
Acta Diabetol. 2024 Nov 07.

Mir-509-3p targets SLC25A13 to regulate ferroptosis and protect retinal endothelial cells in diabetic retinopathy.

Meiqing Ren, Qian Xu, Jie Luan, Yan Ni, Bo Xie.

   AIMS: Diabetic retinopathy (DR) is a major complication of diabetes that leads to vision impairment. The aim of this study was to investigate the regulatory role of miR-509-3p in DR, focusing on its interaction with SLC25A13 and its impact on retinal endothelial cell function, oxidative stress, apoptosis, and ferroptosis.
METHODS: HRVECs were cultured in high-glucose (HG) conditions to establish an in vitro DR model. miR-509-3p mimics and inhibitors were transfected into HRVECs to assess their effects on SLC25A13 expression, cell viability, apoptosis, reactive oxygen species (ROS) levels, and ferroptosis markers. A luciferase reporter assay and RNA immunoprecipitation were used to confirm the binding of miR-509-3p to SLC25A13 mRNA. For in vivo validation, agomiR-509-3p was injected into the vitreous of DR mice, and retinal thickness, pathological damage, and apoptosis were evaluated. Ferroptosis-related markers (GPX4, TlR4, ASCL4) were analyzed in HRVECs to explore the mechanism of miR-509-3p in regulating ferroptosis.
RESULTS: In vitro, miR-509-3p significantly decreased SLC25A13 expression, resulting in enhanced HRVEC viability, reduced apoptosis, and lower ROS levels under HG conditions. Overexpression of SLC25A13 reversed these protective effects, while miR-509-3p knockdown exacerbated oxidative stress and apoptosis. In vivo, agomiR-509-3p increased retinal thickness, reduced pathological damage, and decreased apoptosis in DR mice. Ferroptosis marker analysis revealed that miR-509-3p upregulated GPX4 expression and downregulated TlR4 and ASCL4, whereas SLC25A13 overexpression reversed these effects, further linking miR-509-3p to the regulation of ferroptosis.
CONCLUSIONS: miR-509-3p exerts a protective effect in DR by targeting SLC25A13, reducing oxidative stress, apoptosis, and ferroptosis in retinal endothelial cells. These findings highlight the potential of miR-509-3p as a therapeutic target for DR management.

Keywords:  Diabetic retinopathy; HRVECs; MiR-509-3p; SLC25A13

DOI:  https://doi.org/10.1007/s00592-024-02400-3
Radiat Prot Dosimetry. 2024 Nov 13. 200(16-18): 1590-1593

Mitochondrial reactive oxygen species-mediated fibroblast activation has a role in tumor microenvironment formation in radiation carcinogenesis.

Tsutomu Shimura, Akira Ushiyama.

Cancer risks attributable to low-dose and low-dose-rate radiation are a serious concern for public health. Radiation risk assessment is based on lifespan studies among Hiroshima-Nagasaki A-bomb survivors; however, there are statistical limitations due to a small sample size for low-dose radiation. Therefore, basic biological studies are helpful in understanding the mechanism of radiation carcinogenesis. The detrimental effects of ionising radiation (IR) are caused by reactive oxygen species (ROS)-mediated oxidative DNA damage. IR-induced delayed ROS are produced in the electron transport chain reaction of the mitochondrial complex. Thus, mitochondria are a source of ROS and a primary target for ROS attacks. Consequently, mitochondrial dysfunction is thought to be a key event in the metabolic changes of cancer cells and is important in radiation-induced carcinogenesis. In this paper, we present recent findings on radiation carcinogenesis effect assessment, focusing on mitochondrial function as stress sensors.

DOI: https://doi.org/10.1093/rpd/ncae027
Plant Physiol. 2024 Nov 09. pii: kiae608. [Epub ahead of print]

Processes independent of nonphotochemical quenching protect a high-light-tolerant desert alga from oxidative stress.

Guy Levin, Michael Yasmin, Oded Liran, Rawad Hanna, Oded Kleifeld, Guy Horev, Francis-André Wollman, Gadi Schuster, Wojciech J Nawrocki.

Non-photochemical quenching (NPQ) mechanisms are crucial for protecting photosynthesis from photoinhibition in plants, algae, and cyanobacteria, and their modulation is a long-standing goal for improving photosynthesis and crop yields. The current work demonstrates that Chlorella ohadii, a green micro-alga that thrives in the desert under high light intensities that are fatal to many photosynthetic organisms does not perform nor require NPQ to protect photosynthesis under constant high light. Instead of dissipating excess energy, it minimizes its uptake by eliminating the photosynthetic antenna of photosystem II. In addition, it accumulates antioxidants that neutralize harmful reactive oxygen species (ROS) and increases cyclic electron flow around PSI. These NPQ-independent responses proved efficient in preventing ROS accumulation and reducing oxidative damage to proteins in high-light-grown cells.

DOI: https://doi.org/10.1093/plphys/kiae608
Plant Cell Environ. 2024 Nov 11.

TaWRKY17 Interacts With TaWRKY44 to Promote Expression of TaDHN7 for Salt Tolerance in Wheat.

Zhenzhen Jia, Tuo Zeng, Lei Gu, Hongcheng Wang, Bin Zhu, Mingjian Ren, Xuye Du.

  Wheat is a crucial food crop, yet its production is continually threatened by abiotic stresses, particularly salt stress. Understanding the molecular mechanisms by which wheat responds to salt stress is essential for developing salt-tolerant varieties. In this study, we investigated the molecular pathway involving the wheat TaDHN7 in response to salt stress. The overexpression of TaDHN7 enhances salt tolerance and reactive oxygen species (ROS) scavenging in wheat, while the knockout of TaDHN7 significantly impairs salt tolerance. Furthermore, we identified that TaWRKY44 promotes the expression of TaDHN7 by binding to the W-box within the TaDHN7 promoter. Additionally, TaWRKY17 interacts with TaWRKY44, and this interaction enhances the protein stability of TaWRKY44 under salt stress, thereby enhancing its transcriptional regulatory capacity on TaDHN7. This study elucidates the TaWRKY17-TaWRKY44-TaDHN7 pathway in response to salt stress in wheat, providing valuable insights for the development of salt-tolerant wheat cultivars.

Keywords:  ROS; TaWRKY17‐TaWRKY44‐TaDHN7; salt; wheat

DOI:  https://doi.org/10.1111/pce.15277