bims-redobi 2024-10-20 papers

bims-redobi

Biomed News

on Redox Biology

Issue of 2024‒10‒20
twenty-one papers selected by
Vanesa Cepas López, Candiolo Cancer Institute

Mitochondria's Role in the Maintenance of Cancer Stem Cells in Hepatocellular Carcinoma.
Role of MTH1 in oxidative stress and therapeutic targeting of cancer.
A comprehensive review of sensors of radiation-induced damage, radiation-induced proximal events, and cell death.
Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.
Protective effects of PDGF-AB/BB against cellular senescence in human intervertebral disc.
A critical factor in reactive oxygen species (ROS) studies: the need to understand the chemistry of the solvent used: the case of DMSO.
Sulodexide protects endothelial cells against 4-hydroxynonenal-induced oxidative stress and glutathione-dependent redox imbalance by modulation of sestrin2/nuclear factor erythroid 2-related factor 2 pathway.
Parthenolide Inhibits Tumor Cell Growth and Metastasis in Melanoma A2058 Cells.
CAV1 inhibits Xc- system through IFNGR1 to promote ferroptosis to inhibit stemness and improves anti-PD-1 efficacy in breast cancer.
Monoamine oxidases: A missing link between mitochondria and inflammation in chronic diseases ?
Targeting Ferroptosis: Small-molecule Inducers as Novel Anticancer Agents.
Changes in reactive oxygen species and autofluorescence under hypoxia at the hippocampal CA3 area: role of calcium and zinc influxes.
Integrating bulk and single-cell transcriptomics to elucidate the role and potential mechanisms of autophagy in aging tissue.
Unraveling the Ozone impact and Oxidative Stress on the Nervous System.
The molecular dynamics between reactive oxygen species (ROS), reactive nitrogen species (RNS) and phytohormones in plant's response to biotic stress.
Ultraviolet (UV) radiation: a double-edged sword in cancer development and therapy.
High glucose-induced senescence contributes to tubular epithelial cell damage in diabetic nephropathy.
Role for NLRP3 inflammasome-mediated, Caspase1-dependent response in glaucomatous trabecular meshwork cell death and regulation of aqueous humor outflow.
Astaxanthin Is a Novel Candidate for Glioblastoma Treatment? A Review.
Dopaminergic neuron metabolism: relevance for understanding Parkinson's disease.
Metformin suppresses metabolic dysfunction-associated fatty liver disease by ferroptosis and apoptosis via activation of oxidative stress.

Stem Cell Rev Rep. 2024 Oct 18.

Mitochondria's Role in the Maintenance of Cancer Stem Cells in Hepatocellular Carcinoma.

Manar A Elhinnawi, Michael Ibrahim Boushra, Donia Mohamed Hussien, Fatema Hesham Hussein, Islam Ahmed Abdelmawgood.

  Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and is recognized as a major contributor to cancer-related mortality worldwide. Cancer stem cells (CSCs) are a tiny group of cancer cells that possess a significant ability to regenerate themselves, form tumors, and undergo differentiation. CSCs have a pivotal role in the initiation, spread, recurrence, and resistance to treatment of cancer. As a result, they are very susceptible to being targeted for therapeutic intervention. The potential to cure HCC may be achieved by efficiently targeting drugs that eradicate cancer stem cells. Mitochondria have a crucial function in granting drug resistance to cancer stem cells by means of mitochondrial metabolism, biogenesis, and dynamics. Dysfunction in mitochondrial metabolic processes, such as mitochondrial oxidative phosphorylation (OXPHOS), calcium signaling, and reactive oxygen species (ROS) generation, contributes to the initiation and progression of human malignancies, including HCC. ROS have both beneficial and detrimental effects depending on their concentration. Consequently, ROS have become a prominent subject in the study of the fundamental mechanisms of HCC. Furthermore, an imbalance in the process of creating new mitochondria is a characteristic feature of CSCs, and an increase in mitochondrial biogenesis is associated with the heightened resistance observed in CSCs. This article provides a detailed examination of the involvement of mitochondria in the preservation of CSCs, as well as the spread of HCC. A deeper understanding of how mitochondria participate in tumorigenesis and drug resistance could result in the discovery of novel cancer treatments.

Keywords:  Cancer; Cancer stem cell; Hepatocellular carcinoma; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1007/s12015-024-10797-1
Redox Biol. 2024 Oct 11. pii: S2213-2317(24)00372-0. [Epub ahead of print]77 103394

Role of MTH1 in oxidative stress and therapeutic targeting of cancer.

Aaliya Taiyab, Anam Ashraf, Md Nayab Sulaimani, Aanchal Rathi, Anas Shamsi, Md Imtaiyaz Hassan.

  Cancer cells maintain high levels of reactive oxygen species (ROS) to drive their growth, but ROS can trigger cell death through oxidative stress and DNA damage. To survive enhanced ROS levels, cancer cells activate their antioxidant defenses. One such defense is MTH1, an enzyme that prevents the incorporation of oxidized nucleotides into DNA, thus preventing DNA damage and allowing cancer to proliferate. MTH1 levels are often elevated in many cancers, and thus, inhibiting MTH1 is an attractive strategy for suppressing tumor growth and metastasis. Targeted MTH1 inhibition can induce DNA damage in cancer cells, exploiting their vulnerability to oxidative stress and selectively targeting them for destruction. Targeting MTH1 is promising for cancer treatment because normal cells have lower ROS levels and are less dependent on these pathways, making the approach both effective and specific to cancer. This review aims to investigate the potential of MTH1 as a therapeutic target, especially in cancer treatment, offering detailed insights into its structure, function, and role in disease progression. We also discussed various MTH1 inhibitors that have been developed to selectively induce oxidative damage in cancer cells, though their effectiveness varies. In addition, this review provide deeper mechanistic insights into the role of MTH1 in cancer prevention and oxidative stress management in various diseases.

Keywords:  Cancer therapy; MTH1 enzyme; MTH1 inhibitors; Oxidative stress; Reactive oxygen species; Therapeutic target

DOI:  https://doi.org/10.1016/j.redox.2024.103394
Immunol Rev. 2024 Oct 19.

A comprehensive review of sensors of radiation-induced damage, radiation-induced proximal events, and cell death.

Saurabh Saini, Prajwal Gurung.

  Radiation, a universal component of Earth's environment, is categorized into non-ionizing and ionizing forms. While non-ionizing radiation is relatively harmless, ionizing radiation possesses sufficient energy to ionize atoms and disrupt DNA, leading to cell damage, mutation, cancer, and cell death. The extensive use of radionuclides and ionizing radiation in nuclear technology and medical applications has sparked global concern for their capacity to cause acute and chronic illnesses. Ionizing radiation induces DNA damage either directly through strand breaks and base change or indirectly by generating reactive oxygen species (ROS) and reactive nitrogen species (RNS) via radiolysis of water. This damage triggers a complex cellular response involving recognition of DNA damage, cell cycle arrest, DNA repair mechanisms, release of pro-inflammatory cytokines, and cell death. This review focuses on the mechanisms of radiation-induced cellular damage, recognition of DNA damage and subsequent activation of repair processes, and the critical role of the innate immune response in resolution of the injury. Emphasis is placed on pattern recognition receptors (PRRs) and related receptors that detect damage-associated molecular patterns (DAMPs) and initiate downstream signaling pathways. Radiation-induced cell death pathways are discussed in detail. Understanding these processes is crucial for developing strategies to mitigate the harmful effects of radiation and improve therapeutic outcomes.

Keywords:  cell death; innate immunity; innate sensors; radiation

DOI:  https://doi.org/10.1111/imr.13409
Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00103-5. [Epub ahead of print]389 67-103

Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.

Sanjay Pandey, Vandana Anang, Michelle M Schumacher.

  Understanding the intricacies of the metabolic phenotype in immune cells and its plasticity within the tumor microenvironment is pivotal in understanding the pathology and prognosis of cancer. Unfavorable conditions and cellular stress in the tumor microenvironment (TME) exert a profound impact on cellular functions in immune cells, thereby influencing both tumor progression and immune responses. Elevated AMP:ATP ratio, a consequence of limited glucose levels, activate AMP-activated protein kinase (AMPK) while concurrently repressing the activity of mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor 1-alpha (HIF-1α). The intricate balance between AMPK, mTOR, and HIF-1α activities defines the metabolic phenotype of immune cells in the TME. These Changes in metabolic phenotype are strongly associated with immune cell functions and play a crucial role in creating a milieu conducive to tumor progression. Insufficiency of nutrient and oxygen supply leads to a metabolic shift in immune cells characterized by a decrease in glycolysis and an increase in oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) rates. In most cases, this shift in metabolism is accompanied by a compromise in the effector functions of these immune cells. This metabolic adaptation prompts immune cells to turn down their effector functions, entering a quiescent or immunosuppressive state that may support tumor growth. This article discusses how tumor microenvironment alters the metabolism in immune cells leading to their tolerance and tumor progression, with emphasis on mitochondrial metabolism (OXPHOS and FAO).

Keywords:  AMPK; CAR-T; Fatty acid oxidation; Glycolysis; HIF1α; MTOR; Metabolism; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mitochondrial metabolism; OXPHOS; T cell exhaustion; T cell metabolism

DOI:  https://doi.org/10.1016/bs.ircmb.2024.07.003
bioRxiv. 2024 Oct 13. pii: 2024.10.11.617862. [Epub ahead of print]

Protective effects of PDGF-AB/BB against cellular senescence in human intervertebral disc.

Changli Zhang, Martha Elena Diaz-Hernandez, Takanori Fukunaga, Shenoy Sreekala, Sangwook Tim Yoon, Lisbet Haglund, Hicham Drissi.

Cellular senescence, characterized by a permanent state of cell cycle arrest and a secretory phenotype contributing to inflammation and tissue deterioration, has emerged as a target for age-related interventions. Accumulation of senescent cells is closely linked with intervertebral disc (IVD) degeneration, a prevalent age-dependent chronic disorder causing low back pain. Previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through anti-apoptosis, anti-inflammation, and pro-anabolism. However, its impact on IVD cell senescence remains elusive. In this study, human NP and AF cells derived from aged, degenerated IVDs were treated with recombinant human (rh) PDGF-AB/BB for 5 days and changes of transcriptome profiling were examined through mRNA sequencing. NP and AF cells demonstrated similar but distinct responses to the treatment. However, the effects of PDGF-AB and BB on human IVD cells were comparable. Specifically, PDGF-AB/BB treatment resulted in downregulation of gene clusters related to neurogenesis and response to mechanical stimulus in AF cells while the downregulated genes in NP cells were mainly associated with metabolic pathways. In both NP and AF cells, PDGF-AB and BB treatment upregulated the expression of genes involved in cell cycle regulation, mesenchymal cell differentiation, and response to reduced oxygen levels, while downregulating the expression of genes related to senescence associated phenotype, including oxidative stress, reactive oxygen species (ROS), and mitochondria dysfunction. Network analysis revealed that PDGFRA and IL6 were the top hub genes in treated NP cells. Furthermore, in irradiation-induced senescent NP cells, PDGFRA gene expression was significantly reduced compared to non-irradiated cells. However, rhPDGF-AB/BB treatment increased PDGFRA expression and mitigated the senescence progression through increased cell population in the S phase, reduced SA-β-Gal activity, and decreased expression of senescence related regulators including P21, P16, IL6, and NF-κB. Our findings reveal a novel anti-senescence role of PDGF in the IVD, demonstrating its ability to alleviate the senescent phenotype and protect against the progression of senescence. This makes it a promising candidate for preventing or treating IVD degeneration by targeting cellular senescence.Abstract Figure:

DOI: https://doi.org/10.1101/2024.10.11.617862
Chem Sci. 2024 Oct 08.

A critical factor in reactive oxygen species (ROS) studies: the need to understand the chemistry of the solvent used: the case of DMSO.

Shubham Bansal, Binghe Wang.

Reactive oxygen species (ROS) play critical roles in normal physiological processes including cellular signaling and immune responses. Various pathological conditions including infections of various types, inflammation, cancer, and respiratory conditions are associated with elevated levels of ROS. Therefore, there is widespread interest in understanding ROS concentrations under various pathophysiological conditions for diagnostic and therapeutic applications including ROS-triggered drug delivery. However, in determining ROS concentration, there are major concerns of inappropriate use of various methods that lead to erroneous results; this has prompted the publication of a consensus paper in Nature Metabolism by a group of ROS experts stating "Unfortunately, the application and interpretation of these measurements are fraught with challenges and limitations. This can lead to misleading claims." Along this line, we have identified an overlooked factor, which can significantly skew the results and results interpretation: the organic co-solvent. DMSO is one of the most widely used organic co-solvents to dissolve a reagent for bioassays. Herein, we describe the rapid oxidation of DMSO by hypochlorite and how this oxidation impacts results of ROS determination in buffer, cell culture media, cell culture, and cell lysates. We hope to use this one example to draw attention to the convoluted roles that DMSO and possibly other organic co-solvents can play and skew experimental results. We also hope to stimulate additional studies to bring more rigor to studying ROS concentration and biology.

DOI: https://doi.org/10.1039/d4sc05038j
J Physiol Pharmacol. 2024 Aug;75(4):

Sulodexide protects endothelial cells against 4-hydroxynonenal-induced oxidative stress and glutathione-dependent redox imbalance by modulation of sestrin2/nuclear factor erythroid 2-related factor 2 pathway.

K Bontor, B Gabryel.

The lipid peroxidation product 4-hydroxynonenal (HNE) may be involved in vascular endothelial cell damage by induction of oxidative stress, apoptosis, and loss of redox homeostasis. There is evidence that stimulation of endothelial cells with 4-HNE induces the activation of the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap-1) pathway. Sestrin2 protein (SESN2) is one of the key regulators of Nrf2 and is involved in the cellular response to oxidative stress. However, the function of SESN2 in HNE-induced endothelial injury is not yet understood. Sulodexide (SDX) is a mixture of glycosaminoglycans used in clinical practice in the treatment of chronic venous and arterial diseases. While SDX has well-documented endothelial protective properties, little is known about its antioxidant effects. The aim of this study was to elucidate the molecular mechanisms activated by SDX in human umbilical endothelial cells (HUVECs) under HNE-induced oxidative stress. In this experimental model, we decided to evaluate the anti-apoptotic and antioxidant potential of SDX and its effect on the SESN2/Nrf2/GSH pathway. HUVECs were treated with 25 _M HNE or HNE combined with 0.5 LRU/mL SDX for 4 hours. Cell viability, apoptosis and intracellular reactive oxygen species (ROS) production were assessed by MTT assay and fluorescence microscopy. The expressions of Bax, cleaved caspase-3, Keap-1 and Nrf2 were determined by Western blot analysis. The intracellular concentrations of reduced glutathione (GSH) and oxidized glutathione (GSSG) were measured by colorimetric assay. SESN2, glutamate-cysteine ligase catalytic subunit (GCLc) and glutathione synthase (GSS) were assessed using ELISA. RT-qPCR was performed to detect Nrf2, GCLc and GSS mRNA levels. Transient Nrf2 silencing was obtained by short interfering RNA (siRNA). We have demonstrated that SDX can reduce the negative impact of HNE on HUVECs. SDX significantly protected HNE-treated HUVECs from apoptosis (p<0.001) and oxidative stress (p<0.001). SDX treatment significantly reduced Bax (p<0.05) and cleaved caspase-3 (p<0.01) expression. Co-administration of HNE and SDX increased GSH content (p<0.001) and GSH:GSSG ratio (p<0.001) as well as decreased SESN2 concentration (p<0.001) and Nrf2 (p<0.01), GCLc (p<0.05) and GSS (p<0.01) gene expression compared with the HNE group. Moreover, we revealed a negative correlation between SESN2 levels and GSH concentrations (p<0.001). Nrf2 silencing significantly decreased the effect of HNE and SDX on the induction of GCLc and GSS genes. SDX also significantly ameliorated the increase of nuclear Nrf2 in response to HNE (p<0.05). The results confirmed that SDX may protect against HNE-induced endothelial damage through its antioxidant effect and modulation of the SESN2/Nrf2/GSH signaling pathway.

DOI: https://doi.org/10.26402/jpp.2024.4.03
Curr Med Chem. 2024 Oct 16.

Parthenolide Inhibits Tumor Cell Growth and Metastasis in Melanoma A2058 Cells.

Zahra Dorostgou, Malihe Hoseyni, Afsaneh Bahrami, Rahele Zhiani, Mahnaz Mohtashami.

  BACKGROUND: Skin melanoma is a potentially lethal cancer and ranks as the 17th most common cancer worldwide. Overcoming resistance to advanced-stage melanoma is a significant challenge in its treatment. Parthenolide (PAR) is recognized as a potent anticancer small molecule, yet its potential in treating melanoma is poorly investigated.OBJECTIVE: Our objective was to investigate the apoptotic and anti-metastatic properties of PAR against the A2058 melanoma cells in vitro.
METHODS: This study employed various assays, such as cytotoxicity, apoptosis, cell cycle analysis, reactive oxygen species (ROS) production, mRNA expressions, western blotting, gelatin zymography, and scratch assay. The synergy between PAR and dacarbazine, a chemotherapy drug for treating skin cancer, was also assessed.
RESULTS: Our study revealed that PAR significantly reduced the viability of A2058 cancer cells, demonstrating greater potency against cancer cells compared to normal L929 cells (IC50: 20 μM vs. 27 μM after 24h). PAR increased ROS production, elevated mRNA expression of pro-apoptotic Bax and NME1 genes, and decreased expression of the MITF gene. PAR induced apoptosis and cell cycle arrest in A2058 cells, as evidenced by the increased proportion of cells in the late apoptotic phase and sub-G1 cell cycle arrest. MMP-2 and MMP-9 mRNA and protein expressions, gelatinase activity, and the migration of A2058 cells were also decreased by PAR, suggesting its potential to suppress cancer cell invasion.
CONCLUSION: These results, along with the synergic effect with dacarbazine, indicated that PAR may have the potential to be a therapeutic drug for melanoma by triggering apoptosis and suppressing invasion and migration.

Keywords:  Parthenolide; apoptosis; cell cycle arrest; melanoma.; migration; p53

DOI:  https://doi.org/10.2174/0109298673334309240924081449
Transl Oncol. 2024 Oct 11. pii: S1936-5233(24)00276-6. [Epub ahead of print]50 102149

CAV1 inhibits Xc- system through IFNGR1 to promote ferroptosis to inhibit stemness and improves anti-PD-1 efficacy in breast cancer.

Wenhong Liu, Guanghua Luo.

  Breast cancer is the most prevalent malignancy among women worldwide, with breast cancer stem cells (BCSCs) being the primary drivers of metastasis and recurrence. Numerous studies have elucidated the relationship between ferroptosis and cellular stemness, identifying the Xc- system as a key regulatory mechanism governing ferroptosis. However, the interplay between CAV1 and ferroptosis, along with its implications for stemness in breast cancer, remains inadequately understood. This gap in knowledge impedes advancements in targeted therapies for breast cancer. We employed immunohistochemistry and bioinformatics analyses to demonstrate the downregulation of CAV1 in breast cancer tissues. Additionally, we utilized CCK-8 assays, EDU staining, and Transwell assays to assess cell proliferation, migration, and invasion capabilities. Furthermore, we evaluated indicators associated with ferroptosis while examining markers related to stemness through sphere culture experiments and flow cytometry techniques. Our findings indicate that CAV1 expression can induce cell death via ferroptosis while simultaneously inhibiting both cell proliferation and features of stemness by upregulating IFNGR1 and promoting ferroptosis. Moreover, our in vivo experiments revealed that overexpression of CAV1 enhances the efficacy of anti-PD-1 therapy. In conclusion, our study elucidates the regulatory role of CAV1 on ferroptosis within breast cancer contexts; it suppresses BCSC characteristics while positioning CAV1 as a promising therapeutic target for combating this disease.

Keywords:  Breast cancer; CAV1; Ferroptosis; PD-1; Stemness

DOI:  https://doi.org/10.1016/j.tranon.2024.102149
Redox Biol. 2024 Oct 11. pii: S2213-2317(24)00371-9. [Epub ahead of print]77 103393

Monoamine oxidases: A missing link between mitochondria and inflammation in chronic diseases ?

Lise Beucher, Claudie Gabillard-Lefort, Olivier R Baris, Jeanne Mialet-Perez.

  The role of mitochondria spans from the regulation of the oxidative phosphorylation, cell metabolism and survival/death pathways to a more recently identified function in chronic inflammation. In stress situations, mitochondria release some pro-inflammatory mediators such as ATP, cardiolipin, reactive oxygen species (ROS) or mitochondrial DNA, that are believed to participate in chronic diseases and aging. These mitochondrial Damage-Associated Molecular Patterns (mito-DAMPs) can modulate specific receptors among which TLR9, NLRP3 and cGAS-STING, triggering immune cells activation and sterile inflammation. In order to counter the development of chronic diseases, a better understanding of the underlying mechanisms of low grade inflammation induced by mito-DAMPs is needed. In this context, monoamine oxidases (MAO), the mitochondrial enzymes that degrade catecholamines and serotonin, have recently emerged as potent regulators of chronic inflammation in obesity-related disorders, cardiac diseases, cancer, rheumatoid arthritis and pulmonary diseases. The role of these enzymes in inflammation embraces their action in both immune and non-immune cells, where they regulate monoamines levels and generate toxic ROS and aldehydes, as by-products of enzymatic reaction. Here, we discuss the more recent advances on the role and mechanisms of action of MAOs in chronic inflammatory diseases.

Keywords:  Chronic diseases; DAMPs; Inflammation; Mitochondria; Monoamine oxidases; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2024.103393
Anticancer Agents Med Chem. 2024 Oct 15.

Targeting Ferroptosis: Small-molecule Inducers as Novel Anticancer Agents.

Shihao Jin, Huannan Wang, Zhen Zhang, Maocai Yan.

  Ferroptosis, a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation and reactive oxygen species (ROS) accumulation, is increasingly recognized for its role in cancer development and as a potential therapeutic target. This review consolidates insights into the molecular mechanisms underpinning ferroptosis and evaluates the therapeutic potential of small-molecule inducers, such as erastin, RSL3, sulfasalazine, and sorafenib, which selectively trigger ferroptosis in cancer cells. It highlights the distinct morphological and molecular signatures of ferroptosis, its complex interplay with iron, lipid, and amino acid metabolic pathways, and the resultant implications for cancer treatment strategies. Strategic manipulation of the ferroptosis pathway offers a groundbreaking approach to cancer treatment, potentially circumventing the resistance that cancers develop against traditional apoptosis-inducing agents. Furthermore, it also emphasizes the necessity of refining these small molecules for clinical application and exploring their synergistic potential when combined with current therapies to augment overall treatment efficacy and improve patient outcomes. Ferroptosis thus emerges as a promising avenue in the realm of cancer therapy. Moving forward, research endeavors should focus on a more nuanced understanding of the interconnections between ferroptosis and other cell death modalities. Additionally, comprehensive evaluations of the long-term safety and therapeutic indices of the involved compounds are imperative. Such investigations are poised to herald a transformative shift in the paradigm of oncology, paving the way for innovative and targeted interventions.

Keywords:  Ferroptosis; ROS.; anticancer; cell death; mechanism; small-molecule inducers

DOI:  https://doi.org/10.2174/0118715206342278241008081126
Neurochem Int. 2024 Oct 14. pii: S0197-0186(24)00209-2. [Epub ahead of print] 105882

Changes in reactive oxygen species and autofluorescence under hypoxia at the hippocampal CA3 area: role of calcium and zinc influxes.

João L Alves, Patrícia M Reis, Rosa M Quinta-Ferreira, M Emília Quinta-Ferreira, Carlos M Matias.

  Reactive oxygen species (ROS) have an important role in cellular biology, being involved, in a way that depends on their levels, in cell signaling processes or in oxidative stress, probably associated with neurodegenerative and other diseases. Most of the studies about ROS formation were performed in ischemic conditions, and thus, there is limited knowledge about ROS formation in less severe hypoxic conditions. This study investigates neuronal ROS generation and autofluorescence changes in hypoxic conditions, focusing on the involvement of calcium and zinc. Using hippocampal slices from Wistar rats, ROS production was monitored by the permeant fluorescent indicator H2DCFDA under different oxygenation levels. Moderate hypoxia (40% O2) led to a small ROS increase, while severe hypoxia (0% O2) showed a more pronounced rise. KCl-induced depolarization significantly enhanced ROS formation, particularly under severe hypoxia. Inhibition of NMDA receptors reduced ROS generation without affecting autofluorescence, while chelation of zinc ions decreased ROS production and increased flavin adenine dinucleotide (FAD) autofluorescence. These findings suggest that, in hypoxic conditions, ROS formation is mediated by calcium entry through NMDA receptors and also by zinc influxes. Thus, these ions play a crucial role in oxidative stress, which may be related with neurodegenerative diseases associated with ROS dysregulation.

Keywords:  FAD-linked autofluorescence; Mitochondria; Mossy fiber synapses; ROS probe H(2)DCFDA

DOI:  https://doi.org/10.1016/j.neuint.2024.105882
Cell Oncol (Dordr). 2024 Oct 16.

Integrating bulk and single-cell transcriptomics to elucidate the role and potential mechanisms of autophagy in aging tissue.

Zhenhua Zhu, Linsen Li, Youqiong Ye, Qing Zhong.

  PURPOSE: Autophagy is frequently observed in tissues during the aging process, yet the tissues most strongly correlated with autophagy during aging and the underlying regulatory mechanisms remain inadequately understood. The purpose of this study is to identify the tissues with the highest correlation between autophagy and aging, and to explore the functions and mechanisms of autophagy in the aging tissue microenvironment.METHODS: Integrated bulk RNA-seq from over 7000 normal tissue samples, single-cell sequencing data from blood samples of different ages, more than 2000 acute myeloid leukemia (AML) bulk RNA-seq, and multiple sets of AML single-cell data. The datasets were analysed using various bioinformatic approaches.
RESULTS: Blood tissue exhibited the highest positive correlation between autophagy and aging among healthy tissues. Single-cell resolution analysis revealed that in aged blood, classical monocytes (C. monocytes) are most closely associated with elevated autophagy levels. Increased autophagy in these monocytes correlated with a higher proportion of C. monocytes, with hypoxia identified as a crucial contributing factor. In AML, a representative myeloid blood disease, enhanced autophagy was accompanied by an increased proportionof C. monocytes. High autophagy levels in monocytes are associated with pro-inflammatory gene upregulation and Reactive Oxygen Species (ROS) accumulation, contributing to tissue aging.
CONCLUSION: This study revealed that autophagy is most strongly correlated with aging in blood tissue. Enhanced autophagy levels in C. monocytes demonstrate a positive correlation with increased secretion of pro-inflammatory factors and elevated production of ROS, which may contribute to a more rapid aging process. This discovery underscores the critical role of autophagy in blood aging and suggests potential therapeutic targets to mitigate aging-related health issues.

Keywords:  Aging; Autophagy; Hypoxia; Monocytes; Reactive oxygen species

DOI:  https://doi.org/10.1007/s13402-024-00996-w
Toxicology. 2024 Oct 16. pii: S0300-483X(24)00254-3. [Epub ahead of print] 153973

Unraveling the Ozone impact and Oxidative Stress on the Nervous System.

Paola Rodriguez, Alejandro López-Landa, Héctor Romo-Parra, Moisés Rubio-Osornio, Carmen Rubio.

  Ozone (O₃), a potent oxidant, can penetrate the body through breathing, generating reactive oxygen species (ROS) and triggering inflammatory processes. Oxidative stress, an imbalance between the production of ROS and the body's antioxidant capacity, plays a crucial role in the pathophysiology of various neurodegenerative diseases. This phenomenon can negatively impact the Central Nervous System (CNS), inducing structural and functional alterations that contribute to the development of neurological pathologies. This review examines how O₃-induced oxidative stress affects the nervous system by analyzing existing literature on the involved molecular mechanisms and potential antioxidant systems to mitigate its effects. Through a comprehensive review of experimental studies, our objective is to shed light on the interaction between O₃ and the nervous system, as well as its signaling pathways and altered genes, providing a foundation for future research in this field. Several studies have demonstrated that prolonged exposure to O₃ leads to increased expression of reactive oxygen species, causing alterations in the blood-brain barrier and damage to astrocytes and microglia. These effects can lead to an increase in the production of proinflammatory cytokines, neurotoxins, and genes, exacerbating neuronal damage and accelerating the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and other neurological disorders. The results of this review suggest that exposure to O₃ may induce oxidative damage to the nervous system, which could have significant implications for public health.

Keywords:  Central Nervous System; Ozone; genes; inflammatory

DOI:  https://doi.org/10.1016/j.tox.2024.153973
Plant Cell Rep. 2024 Oct 16. 43(11): 263

The molecular dynamics between reactive oxygen species (ROS), reactive nitrogen species (RNS) and phytohormones in plant's response to biotic stress.

Krishna Gogoi, Hunmoyna Gogoi, Manashi Borgohain, Ratul Saikia, Channakeshavaiah Chikkaputtaiah, Shridhar Hiremath, Udita Basu.

  Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are critical for plant development as well as for its stress response. They can function as signaling molecules to orchestrate a well-defined response of plants to biotic stress. These responses are further fine-tuned by phytohormones, such as salicylic acid, jasmonic acid, and ethylene, to modulate immune response. In the past decades, the intricacies of redox and phytohormonal signaling have been uncovered during plant-pathogen interactions. This review explores the dynamic interplay of these components, elucidating their roles in perceiving biotic threats and shaping the plant's defense strategy. Molecular regulators and sites of oxidative burst have been explored during pathogen perception. Further, the interplay between various components of redox and phytohormonal signaling has been explored during bacterial, fungal, viral, and nematode infections as well as during insect pest infestation. Understanding these interactions highlights gaps in the current knowledge and provides insights into engineering crop varieties with enhanced resistance to pathogens and pests. This review also highlights potential applications of manipulating regulators of redox signaling to bolster plant immunity and ensure global food security. Future research should explore regulators of these signaling pathways as potential target to develop biotic stress-tolerant crops. Further insights are also needed into roles of endophytes and host microbiome modulating host ROS and RNS pool for exploiting them as biocontrol agents imparting resistance against pathogens in plants.

Keywords:  Biotic stress; Phytohormone; RNS; ROS; Signalling

DOI:  https://doi.org/10.1007/s00299-024-03343-3
Mol Biomed. 2024 10 17. 5(1): 49

Ultraviolet (UV) radiation: a double-edged sword in cancer development and therapy.

Zhen-Wei Yu, Min Zheng, Hua-Yang Fan, Xin-Hua Liang, Ya-Ling Tang.

  It has long been widely acknowledged that ultraviolet (UV) light is an environment risk factor that can lead to cancer, particularly skin cancer. However, it is worth noting that UV radiation holds potential for cancer treatment as a relatively high-energy electromagnetic wave. With the help of nanomaterials, the role of UV radiation has caught increasing attention in cancer treatment. In this review, we briefly summarized types of UV-induced cancers, including malignant melanoma, squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma. Importantly, we discussed the primary mechanisms underlying UV carcinogenesis, including mutations by DNA damage, immunosuppression, inflammation and epigenetic alterations. Historically limited by its shallow penetration depth, the introduction of nanomaterials has dramatically transformed the utilization of UV light in cancer treatment. The direct effect of UV light itself generally leads to the suppression of cancer cell growth and the initiation of apoptosis and ferroptosis. It can also be utilized to activate photosensitizers for reactive oxygen species (ROS) production, sensitize radiotherapy and achieve controlled drug release. Finally, we comprehensively weigh the significant risks and limitations associated with the therapeutic use of UV radiation. And the contradictory effect of UV exposure in promoting and inhibiting tumor has been discussed. This review provides clues for potential clinical therapy as well as future study directions in the UV radiation field. The precise delivery and control of UV light or nanomaterials and the wavelength as well as dose effects of UV light are needed for a thorough understanding of UV radiation.

Keywords:  Cancer; Cancer therapy; Carcinogenesis; Nanoparticles; Ultraviolet (UV) light; Ultraviolet (UV) radiation

DOI:  https://doi.org/10.1186/s43556-024-00209-8
Exp Gerontol. 2024 Oct 13. pii: S0531-5565(24)00255-9. [Epub ahead of print]197 112609

High glucose-induced senescence contributes to tubular epithelial cell damage in diabetic nephropathy.

Deping Xu, Puseletso Moru, Kainan Liao, Wei Song, Ping Yang, Dandan Zang, Chunlin Cai, Haisheng Zhou.

  Dysfunctional renal tubular epithelial cells, induced by high glucose, are commonly observed in the kidney tissues of diabetic nephropathy (DN) patients. The epithelial-mesenchymal transition (EMT) of these cells often leads to renal interstitial fibrosis and kidney damage in DN. High glucose also triggers mitochondrial damage and apoptosis, contributing further to the dysfunction of renal tubular epithelial cells. Cellular senescence, a recognized characteristic of DN, is primarily caused by high glucose. However, it remains unclear whether high glucose-induced cellular senescence in DN exacerbates the functional impairment of tubular epithelial cells. In this study, we examined the relationship between EMT and cellular senescence in kidney tissues from streptozotocin (STZ)-induced DN and HK-2 cells treated with high glucose (HG). We also investigated the impact of HG concentrations on tubular epithelial cells, specifically mitochondrial dysfunction, cellular senescence and apoptosis. These damages were primarily associated with the secretion of cytokines (such as IL-6, and TNF-α), production of reactive oxygen species (ROS), and an increase of intracellular Ca2+. Notably, resveratrol, an anti-aging agent, could effectively attenuate the occurrence of EMT, mitochondrial dysfunction, and apoptosis induced by HG. Mechanistically, anti-aging treatment leads to a reduction in cytokine secretion, ROS production, and intracellular Ca2+ levels.

Keywords:  Diabetic nephropathy; Epithelial-mesenchymal transition; Mitochondrial dysfunction; Senescence

DOI:  https://doi.org/10.1016/j.exger.2024.112609
Heliyon. 2024 Oct 15. 10(19): e38258

Role for NLRP3 inflammasome-mediated, Caspase1-dependent response in glaucomatous trabecular meshwork cell death and regulation of aqueous humor outflow.

Xiaomei Feng, Zhao Chen, Wenjun Cheng, Changgeng Liu, Qian Liu.

  Purpose: Acute ocular hypertension (AOH) is the defining feature of acute glaucoma. The mechanical stress and excessive production of reactive oxygen species (ROS) during episodes can directly or indirectly damage the trabecular meshwork (TM). Despite its significance, a clear understanding of its pathogenesis and an effective therapeutic target remain lacking in acute glaucoma. In the present study, we explored the potential molecular mechanisms underlying TM cell death following oxidative damage and AOH. The use of NAC/VX-765 as a potential pharmaceutical intervention for reducing intraocular pressure (IOP) was discussed.Methods: The levels of NLRP3 and caspase-1 were compared between normal and glaucomatous TM samples. An in vitro oxidative damage model and an AOH rat model were used to investigate the potential molecular mechanism behind TM cell death. The ROS scavenger N-acetyl-L-cysteine (NAC) and caspase-1 inhibitor VX-765 were used to counteract TM damage.
Results: Elevated levels of NLRP3 and caspase-1 were observed in patients with acute glaucoma. H2O2 exposure decreased the viability of human trabecular meshwork (HTM) cells and increased intracellular ROS levels. Both Gene and protein expressions of NLRP3, caspase-1, GSDMD-N, and IL-1β were notably upregulated in H2O2-induced HTM cells and the rodent AOH model. Both NAC and VX-765 demonstrated protective effects against TM injury by inhibiting pyroptosis. The IOP-lowering effects of NAC and VX-765 persisted for 7 days.
Conclusions: Our findings indicate that the classical pyroptosis pathway, NLRP3/caspase-1/IL-1β, plays a key role in acute glaucomatous TM injury. Targeting pyroptosis provides novel therapeutic avenues for treating AOH-induced irreversible TM injury. This provides not only a promising therapeutic target for glaucoma but also introduces a new approach to intervention.

Keywords:  Glaucoma; Human trabecular meshwork cell; NLRP3; Pyroptosis; ROS

DOI:  https://doi.org/10.1016/j.heliyon.2024.e38258
Curr Med Chem. 2024 Oct 14.

Astaxanthin Is a Novel Candidate for Glioblastoma Treatment? A Review.

Arian Rezaee, Mehrsa Radmanesh, Atena Asghari, Ahmad Nazari, Amir Abbas Shahidi, Amir Modarresi Chahardehi, Reza Arefnezhad, Tahreh Farkhondeh, Mohammad Saminin, Saeed Samarghandian.

  Glioblastoma (GBM) is a malignant primary brain tumor with a poor prognosis and high recurrence rates. At present, the current treatments available for GBM patients can only prolong their overall survival and cannot provide a complete cure. Discovering an effective therapy against the disease is a challenge due to its recurrence and resistance to common available treatments for GBM. Several natural products have been documented to possess the potential to function as anticancer agents through diverse mechanisms. Astaxanthin (AXT) is an orange-red pigment that is a natural lipophilic and xanthophyll carotenoid derived mostly from microalgae. Numerous studies have examined that AXT impacts GBM cells in laboratory settings and animal models. This review aims to provide the latest information about the potential of astaxanthin as a novel therapeutic option for GBM. AXT has been targeted more on reactive oxygen species (ROS), and suppressed tumor growth in vitro and in vivo conditions. The available data suggests that AXT might serve as a key component in the development of innovative cancer therapies, especially for glioblastoma.

Keywords:  Glioblastoma; astaxanthin; carotenoid; natural product; therapy.

DOI:  https://doi.org/10.2174/0109298673311502240930043117
Metabolomics. 2024 Oct 13. 20(6): 116

Dopaminergic neuron metabolism: relevance for understanding Parkinson's disease.

Xóchitl Flores-Ponce, Iván Velasco.

  BACKGROUND: Dopaminergic neurons from the substantia nigra pars compacta (SNc) have a higher susceptibility to aging-related degeneration, compared to midbrain dopaminergic cells present in the ventral tegmental area (VTA); the death of dopamine neurons in the SNc results in Parkinson´s disease (PD). In addition to increased loss by aging, dopaminergic neurons from the SNc are more prone to cell death when exposed to genetic or environmental factors, that either interfere with mitochondrial function, or cause an increase of oxidative stress. The oxidation of dopamine is a contributing source of reactive oxygen species (ROS), but this production is not enough to explain the differences in susceptibility to degeneration between SNc and VTA neurons.AIM OF REVIEW: In this review we aim to highlight the intrinsic differences between SNc and VTA dopamine neurons, in terms of gene expression, calcium oscillations, bioenergetics, and ROS responses. Also, to describe the changes in the pentose phosphate pathway and the induction of apoptosis in SNc neurons during aging, as related to the development of PD.
KEY SCIENTIFIC CONCEPTS OF REVIEW: Recent work showed that neurons from the SNc possess intrinsic characteristics that result in metabolic differences, related to their intricate morphology, that render them more susceptible to degeneration. In particular, these neurons have an elevated basal energy metabolism, that is required to fulfill the demands of the constant firing of action potentials, but at the same time, is associated to higher ROS production, compared to VTA cells. Finally, we discuss how mutations related to PD affect metabolic pathways, and the related mechanisms, as revealed by metabolomics.

Keywords:  Aging; Complex axonal arborization; Metabolic alterations; Neurodegeneration; Pacemaking activity; ROS production

DOI:  https://doi.org/10.1007/s11306-024-02181-4
Free Radic Res. 2024 Oct 18. 1-16

Metformin suppresses metabolic dysfunction-associated fatty liver disease by ferroptosis and apoptosis via activation of oxidative stress.

Zhiyu Li, Chao Cui, Liang Xu, Mingfeng Ding, Yinghui Wang.

  Metformin is known for its antioxidant properties and ability to ameliorate metabolic dysfunction-associated fatty liver disease (MAFLD) and is the focus of this study. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is linked to MAFLD risk. This study investigated the effects of metformin on ferroptosis in free fatty acid (FFA)-treated Huh7 hepatoma cells and its association with MAFLD risk. Using Western blot, immunofluorescence, and ELISA, this study revealed that FFA treatment led to increased intracellular fat and iron accumulation, heightened Lp-PLA2 expression, reduced levels of the cysteine transporter SLC7A11 and glutathione peroxidase 4 (GPX4), altered glutathione (GSH)/oxidized glutathione (GSSG) ratios, generation of reactive oxygen species (ROS), and initiation of lipid peroxidation, which ultimately resulted in cell ferroptosis. Importantly, metformin reversed FFA-induced iron accumulation, and this effect was attenuated by ferrostatin-1 but enhanced by erastin, RSL3, and si-GPX4. Additionally, metformin activated antioxidant and antiapoptotic mechanisms, which reduced lipid peroxidation and suppressed Lp-PLA2 expression in FFA-treated Huh7 cells. In conclusion, our findings indicate that metformin may protect against MAFLD by inhibiting iron accumulation and Lp-PLA2 expression through the ROS, ferroptosis, and apoptosis signaling pathways. This study highlights potential therapeutic strategies for managing MAFLD-related risks and emphasizes the diverse roles of metformin in maintaining hepatocyte balance.

Keywords:  Lp-PLA2; MAFLD; antioxidant; apoptosis; ferroptosis; metformin

DOI:  https://doi.org/10.1080/10715762.2024.2417279