bims-redobi 2024-10-27 papers

bims-redobi

Biomed News

on Redox biology

Issue of 2024–10–27
sixteen papers selected by
Vanesa Cepas López, Candiolo Cancer Institute

Reactive oxygen species from non-thermal gas plasma (CAP): implication for targeting cancer stem cells.
Candida albicans pathways that protect against organic peroxides and lipid peroxidation.
Targeting catalase in cancer.
Evidence for endogenous hydrogen peroxide production by E. coli fatty acyl-CoA dehydrogenase.
Potential role of heteroplasmic mitochondrial DNA mutations in modulating the subtype-specific adaptation of oral squamous cell carcinoma to cisplatin therapy.
The LINC00957/miR-17-5p axis regulates the cell cycle and migration in glioblastoma via the cuproptosis-related gene nephronectin.
Activation of autophagy, paraptosis, and ferroptosis by micheliolide through modulation of the MAPK signaling pathway in pancreatic and colon tumor cells.
The Interplay between von Hippel-Lindau Tumor Suppressor Gene, Lon Protease, ROS Accumulation, and Inflammation in Clear Cell Renal Cell Carcinoma.
Nanomaterial-based regulation of redox metabolism for enhancing cancer therapy.
Subfamily C7 Raf-like kinases MRK1, RAF26, and RAF39 regulate immune homeostasis and stomatal opening in Arabidopsis thaliana.
Mitochondrial Maintenance in Skeletal Muscle.
Utilizing stimuli-responsive nanoparticles to deliver and enhance the anti-tumor effects of bilirubin.
Environmentally Persistent Free Radicals stimulate CYP2E1-mediated generation of reactive oxygen species at the expense of substrate metabolism.
In Situ Crystallized Ceria-Vesicle Nanohybrid Therapeutic for Effective Treatment of Inflammatory Intraocular Disease.
Glycolysis: A multifaceted metabolic pathway and signalling hub.
Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury.

Cancer Cell Int. 2024 Oct 22. 24(1): 344

Reactive oxygen species from non-thermal gas plasma (CAP): implication for targeting cancer stem cells.

Amirhesam Babajani, Afshin Eftekharinasab, Sander Bekeschus, Hassan Mehdian, Faezeh Vakhshiteh, Zahra Madjd.

  Cancer remains a major global health challenge, with the persistence of cancer stem cells (CSCs) contributing to treatment resistance and relapse. Despite advancements in cancer therapy, targeting CSCs presents a significant hurdle. Non-thermal gas plasma, also known as CAP, represents an innovative cancer treatment. It has recently gained attention for its often found to be selective, immunogenic, and potent anti-cancer properties. CAP is composed of a collection of transient, high-energy, and physically and chemically active entities, such as reactive oxygen species (ROS). It is acknowledged that the latter are responsible for a major portion of biomedical CAP effects. The dynamic interplay of CAP-derived ROS and other components contributes to the unique and versatile properties of CAP, enabling it to interact with biological systems and elicit various therapeutic effects, including its potential in cancer treatment. While CAP has shown promise in various cancer types, its application against CSCs is relatively unexplored. This review assesses the potential of CAP as a therapeutic strategy for targeting CSCs, focusing on its ability to regulate cellular states and achieve redox homeostasis. This is done by providing an overview of CSC characteristics and demonstrating recent findings on CAP's efficacy in targeting these cells. By contributing insights into the unique attributes of CSCs and the potential of CAP, this work contributes to an advanced understanding of innovative oncology strategies.

Keywords:  Cold atmospheric plasma; Neoplasms; Oxidative stress; Reactive oxygen species; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12935-024-03523-x
PLoS Genet. 2024 Oct 21. 20(10): e1011455

Candida albicans pathways that protect against organic peroxides and lipid peroxidation.

Kara A Swenson, Kyunghun Min, James B Konopka.

Human fungal pathogens must survive diverse reactive oxygen species (ROS) produced by host immune cells that can oxidize a range of cellular molecules including proteins, lipids, and DNA. Formation of lipid radicals can be especially damaging, as it leads to a chain reaction of lipid peroxidation that causes widespread damage to the plasma membrane. Most previous studies on antioxidant pathways in fungal pathogens have been conducted with hydrogen peroxide, so the pathways used to combat organic peroxides and lipid peroxidation are not well understood. The most well-known peroxidase in Candida albicans, catalase, can only act on hydrogen peroxide. We therefore characterized a family of four glutathione peroxidases (GPxs) that were predicted to play an important role in reducing organic peroxides. One of the GPxs, Gpx3 is also known to activate the Cap1 transcription factor that plays the major role in inducing antioxidant genes in response to ROS. Surprisingly, we found that the only measurable role of the GPxs is activation of Cap1 and did not find a significant role for GPxs in the direct detoxification of peroxides. Furthermore, a CAP1 deletion mutant strain was highly sensitive to organic peroxides and oxidized lipids, indicating an important role for antioxidant genes upregulated by Cap1 in protecting cells from organic peroxides. We identified GLR1 (Glutathione reductase), a gene upregulated by Cap1, as important for protecting cells from oxidized lipids, implicating glutathione utilizing enzymes in the protection against lipid peroxidation. Furthermore, an RNA-sequencing study in C. albicans showed upregulation of a diverse set of antioxidant genes and protein damage pathways in response to organic peroxides. Overall, our results identify novel mechanisms by which C. albicans responds to oxidative stress resistance which open new avenues for understanding how fungal pathogens resist ROS in the host.

DOI: https://doi.org/10.1371/journal.pgen.1011455
Redox Biol. 2024 Oct 19. pii: S2213-2317(24)00382-3. [Epub ahead of print]77 103404

Targeting catalase in cancer.

Christophe Glorieux, Pedro Buc Calderon.

  Healthy cells have developed a sophisticated network of antioxidant molecules to prevent the toxic accumulation of reactive oxygen species (ROS) generated by diverse environmental stresses. On the opposite, cancer cells often exhibit high levels of ROS and an altered levels of antioxidant molecules compared to normal cells. Among them, the antioxidant enzyme catalase plays an essential role in cell defense against oxidative stress through the dismutation of hydrogen peroxide into water and molecular oxygen, and its expression is often decreased in cancer cells. The elevation of ROS in cancer cells provides them proliferative advantages, and leads to metabolic reprogramming, immune escape and metastasis. In this context, catalase is of critical importance to control these cellular processes in cancer through various mechanisms. In this review, we will discuss the major progresses and challenges in understanding the role of catalase in cancer for this last decade. This review also aims to provide important updates regarding the regulation of catalase expression, subcellular localization and discuss about the potential role of microbial catalases in tumor environment. Finally, we will describe the different catalase-based therapies and address the advantages, disadvantages, and limitations associated with modulating catalase therapeutically in cancer treatment.

Keywords:  Cancer; Catalase; Catalase-based therapy; Regulation; Subcellular localization; Tumor environment

DOI:  https://doi.org/10.1016/j.redox.2024.103404
PLoS One. 2024 ;19(10): e0309988

Evidence for endogenous hydrogen peroxide production by E. coli fatty acyl-CoA dehydrogenase.

Chaiyos Sirithanakorn, James A Imlay.

Aerobic organisms continuously generate internal superoxide and hydrogen peroxide, which can damage enzymes and impair growth. To avoid this problem cells maintain high levels of superoxide dismutases, catalases, and peroxidases. Surprisingly, we do not know the primary sources of these reactive oxygen species (ROS) in living cells. However, in vitro studies have shown that flavoenzymes can inadvertently transfer electrons to oxygen. Therefore, it seems plausible that substantial ROS may be generated when large metabolic fluxes flow through flavoproteins. Such a situation may arise during the catabolism of fatty acids. Acyl-CoA dehydrogenase (FadE) is a flavoprotein involved in each turn of the beta-oxidation cycle. In the present study the catabolism of dodecanoic acid specifically impaired the growth of strains that lack enzymes to scavenge hydrogen peroxide. The defect was absent from fadE mutants. Direct measurements confirmed that the beta-oxidation pathway amplified the rate of intracellular hydrogen peroxide formation. Scavenging-proficient cells did not display the FadE-dependent growth defect. Those cells also did not induce the peroxide stress response during dodecanoate catabolism, indicating that the basal defenses are sufficient to cope with moderately elevated peroxide formation. In vitro work still is needed to test whether the ROS evolve specifically from the FadE flavin site and to determine whether superoxide as well as peroxide is released. At present such experiments are challenging because the natural redox partner of FadE has not been identified. This study supports the hypothesis that the degree of internal ROS production can depend upon the type of active metabolism inside cells.

DOI: https://doi.org/10.1371/journal.pone.0309988
Discov Oncol. 2024 Oct 19. 15(1): 573

Potential role of heteroplasmic mitochondrial DNA mutations in modulating the subtype-specific adaptation of oral squamous cell carcinoma to cisplatin therapy.

Amnani Aminuddin, Pei Yuen Ng, Chee Onn Leong, Suzana Makpol, Eng Wee Chua.

  Cancer cells are constantly evolving to adapt to environmental changes, particularly during exposure to drug treatment. In this work, we aimed to characterize genetic and epigenetic changes in mitochondrial DNA (mtDNA) that may increase the resistance of oral squamous cell carcinoma (OSCC) to cisplatin. We first derived drug-resistant cells from two human OSCC cell lines, namely SAS and H103, by continual cisplatin treatments for about 4 months. To determine mtDNA changes induced by cisplatin, we performed nanopore sequencing and quantitative polymerase chain reaction analysis of mtDNA extracted from the cells pre- and post-treatment. We also assessed the mitochondrial functions of the cells and their capacity to generate intracellular reactive oxygen species (ROS). We found that in the cisplatin-resistant cells derived from SAS, there was a reduction in mtDNA content and significant enrichment of a m.3910G > C mutation in the MT-ND1 gene. However, such changes were not detected in cisplatin-resistant H103 cells. The cisplatin treatment also altered methylation patterns in both SAS and H103 cells and decreased their sensitivity to ROS-induced cytotoxicity. We suggest that the sequence alterations and epigenetic changes in mtDNA and the reduction in mtDNA content could be key drivers of cisplatin resistance in OSCC. These mtDNA alterations may participate in cellular adaptation that serves as a response to adverse changes in the environment, particularly exposure to cytotoxic agents. Importantly, the observed mtDNA changes may be influenced by the distinct genetic landscapes of various cancer subtypes. Overall, this study reveals significant insights into cisplatin resistance driven by complex mtDNA dynamics, particularly in OSCC. This underscores the need for targeted therapies tailored to the genetic profiles of individual OSCC patients to improve disease prognosis.

Keywords:  Cisplatin resistance; Mitochondrial DNA alterations; Oral squamous cell carcinoma; Oxford nanopore technology

DOI:  https://doi.org/10.1007/s12672-024-01445-8
Transl Cancer Res. 2024 Sep 30. 13(9): 4923-4937

The LINC00957/miR-17-5p axis regulates the cell cycle and migration in glioblastoma via the cuproptosis-related gene nephronectin.

Renhua Duan, Xiangmao Zhao, Zejiang Hong, Lisheng Yu.

   Background: Glioblastoma (GBM) is characterized by poor prognosis and a high malignancy. The competing endogenous RNA (ceRNA) network formed by long non-coding RNA (lncRNA) and microRNA (miRNA) can regulate the incidence of GBM. Therapeutic strategies targeting cuproptosis-related genes (CRGs) have helped reduce drug resistance in patients. However, the regulatory mechanism underlying the ceRNA network related to cuproptosis in GBM remains unclear. Therefore, we aim to explore the ceRNA regulatory axis associated with cuproposis in GBM and provide a new protocol for therapy.
Methods: The ceRNA network related to CRG was constructed by bioinformatics. Dual-luciferase reporter assay and other experiments were used to prove the conclusion.
Results: We found that the LINC00957/miR-17-5p axis drove nephronectin (NPNT) expression to promote the malignant progression of GBM. First, by measuring the copper ion concentration and reactive oxygen species (ROS) levels, we found that inhibiting NPNT could promote cuproptosis. Meanwhile, the results of enrichment analysis and phenotypic experiments demonstrated that the LINC00957/miR-17-5p/NPNT axis can regulate the cell cycle and migration in GBM. In terms of mechanistic evidence, findings from reporter gene experiments suggested that LINC00957 acted as a ceRNA to regulate the expression of NPNT via miR-17-5p. In addition, findings from rescue experiments confirmed that the regulation of malignant GBM progression by LINC00957 depended on NPNT to an extent.
Conclusions: Our findings indicate that the ceRNA regulatory network is related to cuproptosis in GBM and provide novel potential targets for the diagnosis and treatment of GBM.

Keywords:  Glioblastoma (GBM); cell cycle; competing endogenous RNA (ceRNA); cuproptosis; nephronectin (NPNT)

DOI:  https://doi.org/10.21037/tcr-24-450
Pathol Res Pract. 2024 Oct 11. pii: S0344-0338(24)00565-X. [Epub ahead of print]263 155654

Activation of autophagy, paraptosis, and ferroptosis by micheliolide through modulation of the MAPK signaling pathway in pancreatic and colon tumor cells.

Min Hee Yang, Seung Ho Baek, Young Yun Jung, Jae-Young Um, Kwang Seok Ahn.

  Micheliolide (MCL), a naturally occurring sesquiterpene lactone, has demonstrated significant anticancer properties through the induction of various programmed cell death mechanisms. This study aimed to explore MCL's effects on autophagy, paraptosis, and ferroptosis in pancreatic and colon cancer cells, along with its modulation of the MAPK signaling pathway. MCL was found to substantially suppress cell viability in these cancer cells, particularly in MIA PaCa-2 and HT-29 cell lines. The study identified that MCL induced autophagy by enhancing the levels of autophagy markers such as Atg7, p-Beclin-1, and Beclin-1, which was attenuated by the autophagy inhibitor 3-MA. Furthermore, MCL was found to facilitate paraptosis, indicated by decreased Alix and in-creased ATF4 and CHOP levels. It also promoted ferroptosis, as demonstrated by the reduced expression of SLC7A11, elevated TFRC levels, and increased intracellular iron. Additionally, MCL activated the MAPK signaling pathway, marked by the phosphorylation of JNK, p38, and ERK, linked with an increase in ROS production that is vital in regulating these cell death mechanisms. These findings propose that MCL is a versatile anticancer agent, capable of activating various cell death pathways by modulating MAPK signaling and ROS levels. These results emphasize the therapeutic promise of MCL in treating cancer, pointing to the necessity of further in vivo investigations to confirm these effects and determine its potential clinical uses.

Keywords:  Autophagy; Ferroptosis; MAPK; Micheliolide; Paraptosis

DOI:  https://doi.org/10.1016/j.prp.2024.155654
Curr Issues Mol Biol. 2024 Oct 11. 46(10): 11296-11302

The Interplay between von Hippel-Lindau Tumor Suppressor Gene, Lon Protease, ROS Accumulation, and Inflammation in Clear Cell Renal Cell Carcinoma.

Yao-Chou Tsai, Chan-Yen Kuo.

  This study explores the role of the von Hippel-Lindau (VHL) tumor suppressor gene and Lon protease in the development of clear cell renal carcinoma (ccRCC) through mechanisms involving inflammation and reactive oxygen species (ROS) accumulation in kidney cells. By examining the impact of VHL on the early stages of kidney cancer development, this research highlights the contributions of inflammation and ROS, as well as the involvement of Lon protease. The findings reveal increased Lon expression and ROS levels in VHL-knockdown HK-2 cells, along with elevated phospho-c-Jun N-terminal kinase (JNK) levels, emphasizing the complex interplay between VHL, Lon protease, inflammation, and ROS in kidney cell models. These insights point to potential therapeutic pathways for ccRCC.

Keywords:  Lon protease; clear cell renal carcinoma; inflammation; reactive oxygen species; von Hippel–Lindau

DOI:  https://doi.org/10.3390/cimb46100671
Chem Soc Rev. 2024 Oct 21.

Nanomaterial-based regulation of redox metabolism for enhancing cancer therapy.

Xiaodan Jia, Yue Wang, Yue Qiao, Xiue Jiang, Jinghong Li.

Altered redox metabolism is one of the hallmarks of tumor cells, which not only contributes to tumor proliferation, metastasis, and immune evasion, but also has great relevance to therapeutic resistance. Therefore, regulation of redox metabolism of tumor cells has been proposed as an attractive therapeutic strategy to inhibit tumor growth and reverse therapeutic resistance. In this respect, nanomedicines have exhibited significant therapeutic advantages as intensively reported in recent studies. In this review, we would like to summarize the latest advances in nanomaterial-assisted strategies for redox metabolic regulation therapy, with a focus on the regulation of redox metabolism-related metabolite levels, enzyme activity, and signaling pathways. In the end, future expectations and challenges of such emerging strategies have been discussed, hoping to enlighten and promote their further development for meeting the various demands of advanced cancer therapies. It is highly expected that these therapeutic strategies based on redox metabolism regulation will play a more important role in the field of nanomedicine.

DOI: https://doi.org/10.1039/d4cs00404c
New Phytol. 2024 Oct 24.

Subfamily C7 Raf-like kinases MRK1, RAF26, and RAF39 regulate immune homeostasis and stomatal opening in Arabidopsis thaliana.

Márcia Gonçalves Dias, Bassem Doss, Anamika Rawat, Kristen R Siegel, Tharika Mahathanthrige, Jan Sklenar, Maria Camila Rodriguez Gallo, Paul Derbyshire, Thakshila Dharmasena, Emma Cameron, R Glen Uhrig, Cyril Zipfel, Frank L H Menke, Jacqueline Monaghan.

  The calcium-dependent protein kinase CPK28 regulates several stress pathways in multiple plant species. Here, we aimed to discover CPK28-associated proteins in Arabidopsis thaliana. We used affinity-based proteomics and identified several potential CPK28 binding partners, including the C7 Raf-like kinases MRK1, RAF26, and RAF39. We used biochemistry, genetics, and physiological assays to gain insight into their function. We define redundant roles for these kinases in stomatal opening, immune-triggered reactive oxygen species (ROS) production, and resistance to a bacterial pathogen. We report that CPK28 associates with and trans-phosphorylates RAF26 and RAF39, and that MRK1, RAF26, and RAF39 are active kinases that localize to endomembranes. Although Raf-like kinases share some features with mitogen-activated protein kinase kinase kinases (MKKKs), we found that MRK1, RAF26, and RAF39 are unable to trans-phosphorylate any of the 10 Arabidopsis mitogen-activated protein kinase kinases (MKKs). Overall, our study suggests that C7 Raf-like kinases associate with and are phosphorylated by CPK28, function redundantly in stomatal opening and immunity, and possess substrate specificities distinct from canonical MKKKs.

Keywords:  Arabidopsis thaliana; C7 Raf‐like kinase; CPK28; MRK1; RAF26; RAF39; immunity; stomata

DOI:  https://doi.org/10.1111/nph.20198
Cold Spring Harb Perspect Biol. 2024 Oct 21. pii: a041514. [Epub ahead of print]

Mitochondrial Maintenance in Skeletal Muscle.

Laura M de Smalen, Christoph Handschin.

Skeletal muscle is one of the tissues with the highest range of variability in metabolic rate, which, to a large extent, is critically dependent on tightly controlled and fine-tuned mitochondrial activity. Besides energy production, other mitochondrial processes, including calcium buffering, generation of heat, redox and reactive oxygen species homeostasis, intermediate metabolism, substrate biosynthesis, and anaplerosis, are essential for proper muscle contractility and performance. It is thus not surprising that adequate mitochondrial function is ensured by a plethora of mechanisms, aimed at balancing mitochondrial biogenesis, proteostasis, dynamics, and degradation. The fine-tuning of such maintenance mechanisms ranges from proper folding or degradation of individual proteins to the elimination of whole organelles, and in extremis, apoptosis of cells. In this review, the present knowledge on these processes in the context of skeletal muscle biology is summarized. Moreover, existing gaps in knowledge are highlighted, alluding to potential future studies and therapeutic implications.

DOI: https://doi.org/10.1101/cshperspect.a041514
Biotechnol Adv. 2024 Oct 18. pii: S0734-9750(24)00163-0. [Epub ahead of print]77 108469

Utilizing stimuli-responsive nanoparticles to deliver and enhance the anti-tumor effects of bilirubin.

Elaheh Mirhadi, Alexandra E Butler, Prashant Kesharwani, Amirhossein Sahebkar.

  Bilirubin (BR) is among the most potent endogenous antioxidants that originates from the heme catabolic pathway. Despite being considered as a dangerous and cytotoxic waste product at high concentrations, BR has potent antioxidant effects leading to the reduction of oxidative stress and inflammation, which play an important role in the development and progression of cancer. The purpose of this study is to introduce PEGylated BR nanoparticles (NPs), themselves or in combination with other anti-cancer agents. BR is effective when loaded into various nanoparticles and used in cancer therapy. Interestingly, BRNPs can be manipulated to create stimuli-responsive carriers providing a sustained and controlled, as well as on-demand, release of drug in response to internal or external factors such as reactive oxygen species, glutathione, light, enzymes, and acidic pH. This review suggests that BRNPs have the potential as tumor microenvironment-responsive delivery systems for effective targeting of various types of cancers.

Keywords:  Bilirubin; Nanoparticles; Stimuli responsive; Tumor microenvironment; cancer

DOI:  https://doi.org/10.1016/j.biotechadv.2024.108469
Drug Metab Dispos. 2024 Oct 21. pii: DMD-AR-2024-001939. [Epub ahead of print]

Environmentally Persistent Free Radicals stimulate CYP2E1-mediated generation of reactive oxygen species at the expense of substrate metabolism.

George F Cawley, J Patrick Connick, Marilyn K Eyer, Wayne L Backes.

  Environmentally persistent free radicals (EPFRs) are a recently recognized component of particulate matter that cause respiratory and cardiovascular toxicity. The mechanism of EPFR toxicity appears to be related to their ability to generate reactive oxygen species (ROS), causing oxidative damage. EPFRs were shown to affect P450 function, inducing the expression of some forms through the Ah receptor. However, another characteristic of EPFRs lies in their ability to inhibit P450 activities. CYP2E1 is one of the P450s that is inhibited by EPFR (MCP230) exposure. As CYP2E1 is also known to generate ROS, it is important to understand the ability of EPFRs to influence the function of this enzyme and to identify the mechanisms involved. CYP2E1 was shown to be inhibited by EPFRs, and to a lesser extent by non-EPFR particles. As EPFR-mediated inhibition was more robust at subsaturating NADPH-cytochrome P450 reductase (POR) concentrations, disruption of POR·CYP2E1 complex formation and electron transfer were examined. Surprisingly, neither complex formation nor electron transfer between POR and CYP2E1 were inhibited by EPFRs. Examination of ROS production showed that MCP230 generated a greater amount of ROS than the non-EPFR CuO-Si. When a POR/CYP2E1-containing reconstituted system was added to the pollutant-particle systems there was a synergistic stimulation of ROS production. The results indicate that EPFRs cause inhibition of CYP2E1-mediated substrate metabolism, yet do not alter electron transfer and actually stimulate ROS generation. Taken together, the results are consistent with EPFRs affecting CYP2E1 function by inhibiting substrate metabolism and increasing the generation of ROS. Significance Statement Environmentally persistent free radicals affect CYP2E1 function by inhibition of monooxygenase activity. This inhibition is not due to disruption of the POR·CYP2E1 complex or inhibition of electron transfer, but due to uncoupling of NADPH and oxygen consumption from substrate metabolism to the generation of ROS. These results show that EPFRs block the metabolism of foreign compounds, and also synergistically stimulate the formation of reactive oxygen species that lead to oxidative damage within the organism.

Keywords:  CYP2E1; Cytochrome P450 (CYP); enzyme inhibitors; enzyme kinetics; reactive oxygen species (ROS)

DOI:  https://doi.org/10.1124/dmd.124.001939
Adv Healthc Mater. 2024 Oct 23. e2402523

In Situ Crystallized Ceria-Vesicle Nanohybrid Therapeutic for Effective Treatment of Inflammatory Intraocular Disease.

Jiawei Zhao, Yingjie Wang, Yiquan Zhang, Xinyu Guo, Han Bao, Yong Tao.

  Posterior uveitis is a leading cause of vision impairment and blindness globally due to its detrimental effects on the choroid and retina. The condition is worsened by oxidative stress, which heightens inflammation and perpetuates a cycle of damage that current treatments only temporarily relieve. To address this, a novel treatment involving the in situ crystallization of ultrasmall cerium oxide nanoparticles (≈3 nm) on mesenchymal stem cell (MSC) extracellular vesicles (EVs) for the management of primed mycobacterial uveitis (PMU) is developed. This nanohybrid leverages the individual and synergistic effects of its components for a comprehensive therapeutic approach. The cerium oxide nanoparticles act as a nanozyme to reduce inflammation and scavenge excessive reactive oxygen species (ROS), while the MSC EVs, with their biocompatibility, modulate inflammatory cell infiltration and alleviate tissue damage. This synergistic system offers a promising new treatment strategy for ocular diseases characterized by oxidative stress and inflammation.

Keywords:  antioxidative treatment; ceria‐vesicle; intraocular inflammation; nanozyme; uveitis

DOI:  https://doi.org/10.1002/adhm.202402523
J Biol Chem. 2024 Oct 21. pii: S0021-9258(24)02408-6. [Epub ahead of print] 107906

Glycolysis: A multifaceted metabolic pathway and signalling hub.

Sarah J Kierans, Cormac T Taylor.

Glycolysis is a highly conserved metabolic pathway responsible for the anaerobic production of adenosine triphosphate (ATP) from the breakdown of glucose molecules. While serving as a primary metabolic pathway in prokaryotes, glycolysis is also utilised by respiring eukaryotic cells, providing pyruvate to fuel oxidative metabolism. Furthermore, glycolysis is the primary source of ATP production in multiple cellular states (e.g. hypoxia) and is particularly important in maintaining bioenergetic homeostasis in the most abundant cell type in the human body, the erythrocyte. Beyond its role in ATP production, glycolysis also functions as a signalling hub, producing several metabolic intermediates which serve roles in both signalling and metabolic processes. These signals emanating from the glycolytic pathway can profoundly impact cell function, phenotype and fate, and have previously been overlooked. In this review, we will discuss the role of the glycolytic pathway as a source of signalling molecules in eukaryotic cells, emphasising the newfound recognition of glycolysis' multifaceted nature and its importance in maintaining cellular homeostasis, beyond its traditional role in ATP synthesis.

DOI: https://doi.org/10.1016/j.jbc.2024.107906
Exp Mol Pathol. 2024 Oct 18. pii: S0014-4800(24)00058-3. [Epub ahead of print]140 104939

Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury.

Yasushi Ishii, Aya Fukui-Miyazaki, Sari Iwasaki, Takahiro Tsuji, Kiyohiko Hotta, Hajime Sasaki, Shimpei Nakagawa, Takuma Yoshida, Eri Murata, Koji Taniguchi, Nobuo Shinohara, Akihiro Ishizu, Masanori Kasahara, Utano Tomaru.

  Oxidative stress caused by reactive oxygen species (ROS) is involved in the pathogenesis of renal ischemia-reperfusion injury (I/R injury), a major cause of acute kidney injury and delayed graft function (DGF). DGF is an early transplant complication that worsens graft prognosis and patient survival, but the underlying molecular changes are unclear. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and recent studies have revealed that the immunoproteasome, a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides, plays critical roles in the cellular response against oxidative stress. In this study, we demonstrate the impact of the immunoproteasome in human DGF and in a mouse model of I/R injury. In patients with DGF, the expression of β5i, a specific immunoproteasome subunit, was decreased in vascular endothelial cells. In a mouse model, β5i knockout (KO) exacerbated renal I/R injury. KO mice showed greater inflammation, oxidative stress, and endothelial damage compared with wild-type mice. Impaired immunoproteasomal activity also caused increased cell death, ROS production, and expression of inflammatory factors in mouse renal vascular endothelial cells under conditions of hypoxia and reoxygenation. In conclusion, reduced expression of the immunoproteasomal catalytic subunit β5i exacerbates renal I/R injury in vivo, potentially increasing the risk of DGF. Further research targeting β5i expression in DGF could lead to the development of novel therapeutic strategies and biomarkers.

Keywords:  Acute kidney injury; Delayed graft function; Endothelial cell injury; Immunoproteasome; Ischemia-reperfusion injury; Oxidative stress; ROS

DOI:  https://doi.org/10.1016/j.yexmp.2024.104939