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Chemistry and biochemistry of lipid peroxidation products
Abstract
Oxidative stress and resulting lipid peroxidation is involved in various and numerous pathological states including inflammation, atherosclerosis, neurodegenerative diseases and cancer. This review is focused on recent advances concerning the formation, metabolism and reactivity towards macromolecules of lipid peroxidation breakdown products, some of which being considered as 'second messengers' of oxidative stress. This review relates also new advances regarding apoptosis induction, survival/proliferation processes and autophagy regulated by 4-hydroxynonenal, a major product of omega-6 fatty acid peroxidation, in relationship with detoxication mechanisms. The use of these lipid peroxidation products as oxidative stress/lipid peroxidation biomarkers is also addressed.
... Lipid peroxidation, another mechanism that plays an important role in the induction of ferroptosis, is a reaction that causes oxidative damage to cell membranes, organelle membranes, and other lipid-containing molecules [5,18,23]. Increased intracellular lipid peroxidation is closely associated with many diseases such as neurodegenerative disorders, ischemia-reperfusion injury, and cancer [26]. Fatty acids are structural components of biological membranes and are involved in cellular processes such as signal transduction and energy metabolism. ...
... The 'system Xc-/GSH/GPX4 axis' called glutathione metabolism, is an important antioxidant system in cells [24]. The system consists of Xc-, SLC3A2, and SLC7A11 and is located in the cell membrane as an antiporter that takes cystine into the cell, which is necessary for glutathione (GSH) synthesis [25][26][27]. GSH, which is composed of glycine, glutamate and cystine, is an important antioxidant molecule that prevents the accumulation of lipid ROS in the cell [24,27]. Glutathione peroxidase (GPX4) is a GSH-dependent antioxidant system element that converts lipid hyperoxides to lipid alcohols. ...
The use of nanomaterials for cancer ferroptosis presents a promising avenue for research and clinical applications. The unique properties of nanomaterials, such as their small size, large surface area, and ability to be engineered for specific tasks, make them ideal candidates for ferroptosis inducing cancer therapies. Ferroptosis is a new type of cell death mechanism that is distinct from apoptosis and necrosis. It has been shown to be critical in the treatment of various tumors. The ferroptotic mechanism has been mainly linked with the regulation of iron, amino acid, glutathione, and lipid metabolism of cells. The relationship between ferroptosis mechanisms and cancer nanomedicine has attracted considerable interest in recent years. It has been reported that the combination of nanomedicine and ferroptosis can achieve high therapeutic efficacy for the treatment of different cancer types. This review will provide an overview of recent work in ferroptosis-related cancer nanomedicine. First, general information is given about the definition of ferroptosis and its differences from other cell death mechanisms. Later, studies exploring the role of ferroptosis in the cancer nanomedicine field are discussed in detail. Specific focus has been given to the use of combinatorial treatment strategies which combine ferroptosis with chemodynamic therapy, photodynamic therapy, photothermal therapy, immunotherapy and sonodynamic therapy. Considering the fact that ferroptosis inducing nanoparticles (NPs) have already been introduced into clinical studies, nanoscientists can further accelerate this clinical translation as they tailor the physicochemical characteristics of nanomaterials. This review provides enlightening information for all researchers interested in the molecular characterization and relationship between ferroptosis and cancer-directed NPs.
... The inter-conversions of different ROS and their complex reactions with various biomolecules like phospholipids, proteins and nucleic acids are catalyzed at multiple steps by transition metals. For example, Fe 2+ can catalyze the decomposition of H 2 O 2 via Fenton's reactions or catalyze the formation of alkoxyl and peroxyl radicals during lipid peroxidation chain reaction [21,22]. On the other hand, the final inactivation of ROS occurs via different cellular antioxidants consisting of an array of enzymes (superoxide dismutase, catalase, glutathione peroxidase, etc.) or proteins (peroxiredoxins and thioredoxin) or nonprotein antioxidants (α-tocopherol, retinol, ascorbic acid, bilirubin, melatonin and others) present in the tissue [21,22]. ...
... For example, Fe 2+ can catalyze the decomposition of H 2 O 2 via Fenton's reactions or catalyze the formation of alkoxyl and peroxyl radicals during lipid peroxidation chain reaction [21,22]. On the other hand, the final inactivation of ROS occurs via different cellular antioxidants consisting of an array of enzymes (superoxide dismutase, catalase, glutathione peroxidase, etc.) or proteins (peroxiredoxins and thioredoxin) or nonprotein antioxidants (α-tocopherol, retinol, ascorbic acid, bilirubin, melatonin and others) present in the tissue [21,22]. During oxidative stress, as a result of redox imbalance, the excess ROS can cause direct oxidative damage to cellular components (membranes, enzymes, ion channels, etc.), initiate aberrant redox signaling, trigger a more regulated cell death pathway, such as ferroptosis, or aggravate an inflammatory reaction [18,[23][24][25][26]. ...
Oxidative burden plays a central role in Alzheimer’s disease (AD) pathology, fostering protein aggregation, inflammation, mitochondrial impairment, and cellular dysfunction that collectively lead to neuronal injury. The role of exosomes in propagating the pathology of neurodegenerative diseases including AD is now well established. However, recent studies have also shown that exosomes are crucial responders to oxidative stress in different tissues. Thus, this offers new insights and mechanistic links within the complex pathogenesis of AD through the involvement of oxidative stress and exosomes. Several studies have indicated that exosomes, acting as intracellular communicators, disseminate oxidatively modified contents from one cell to another, propagating the pathology of AD. Another emerging aspect is the exosome-mediated inhibition of ferroptosis in multiple tissues under different conditions which may have a role in neurodegenerative diseases as well. Apart from their involvement in the pathogenesis of AD, exosomes enter the bloodstream serving as novel noninvasive biomarkers for AD; some of the exosome contents also reflect the cerebral oxidative stress in this disease condition. This review highlights the intricate interplay between oxidative stress and exosome dynamics and underscores the potential of exosomes as a novel tool in AD diagnosis.
... Oxidative stress refers to the state of cellular stress caused by the imbalance of redox status, which is conducive to promoting oxidation conditions [8]. Factors such as radiation, heat stress and chemotherapy can trigger cellular oxidative stress [9,10]. Increased reactive oxygen species (ROS) production and decreased antioxidant ability are the major causes of cellular oxidative stress. ...
... RHOB and SPIDR were selected from the above eight genes for verification. Ras homolog family member B (RHOB) is involved in cellular responses to radiation, cisplatin and hydrogen peroxide, all of which could cause cellular oxidative stress [9,10,28]. Scaffold protein involved in DNA repair (SPIDR) positively regulate DNA double-strand breaks repair [29]. DNA double-strand breaks can be caused by oxidative stress which is a serious cellular damage [11][12][13]. ...
Background
Cellular response to oxidative stress plays significant roles in hepatocellular carcinoma (HCC) development, yet the exact mechanism by which HCC cells respond to oxidative stress remains poorly understood. This study aimed to investigate the role and mechanism of super enhancer (SE)-controlled genes in oxidative stress response of HCC cells.
Methods
The GSE112221 dataset was used to identify SEs by HOMER. Functional enrichment of SE-controlled genes was performed by Metascape. Transcription factors were predicted using HOMER. Prognosis analysis was conducted using the Kaplan-Meier Plotter website. Expression correlation analysis was performed using the Tumor Immune Estimation Resource web server. NRF1 and SPIDR expression in HCC and normal liver tissues was analyzed based on the TCGA-LIHC dataset. ChIP-qPCR was used to detect acetylation of lysine 27 on histone 3 (H3K27ac) levels of SE regions of genes, and the binding of NRF1 to the SE of SPIDR. To mimic oxidative stress, HepG2 and Hep3B cells were stimulated with H2O2. The effects of NRF1 and SPIDR on the oxidative stress response of HCC cells were determined by the functional assays.
Results
A total of 318 HCC-specific SE-controlled genes were identified. The functions of these genes was significant association with oxidative stress response. SPIDR and RHOB were enriched in the “response to oxidative stress” term and were chosen for validation. SE regions of SPIDR and RHOB exhibited strong H3K27ac modification, which was significantly inhibited by JQ1. JQ1 treatment suppressed the expression of SPIDR and RHOB, and increased reactive oxygen species (ROS) levels in HCC cells. TEAD2, TEAD3, NRF1, HINFP and TCFL5 were identified as potential transcription factors for HCC-specific SE-controlled genes related to oxidative stress response. The five transcription factors were positively correlated with SPIDR expression, with the highest correlation coefficient for NRF1. NRF1 and SPIDR expression was up-regulated in HCC tissues and cells. NRF1 activated SPIDR transcription by binding to its SE. Silencing SPIDR or NRF1 significantly promoted ROS accumulation in HCC cells. Under oxidative stress, silencing SPIDR or NRF1 increased ROS, malondialdehyde (MDA) and γH2AX levels, and decreased superoxide dismutase (SOD) levels and cell proliferation of HCC cells. Furthermore, overexpression of SPIDR partially offset the effects of NRF1 silencing on ROS, MDA, SOD, γH2AX levels and cell proliferation of HCC cells.
Conclusion
NRF1 driven SPIDR transcription by occupying its SE, protecting HCC cells from oxidative stress-induced damage. NRF1 and SPIDR are promising biomarkers for targeting oxidative stress in the treatment of HCC.
... The process by which they generate lipid ROS is illustrated in Figure 2A,B. These lipid ROS attack the polyunsaturated fatty acids (PUFAs) within cell membrane phospholipids, initiating a chain reaction of lipid peroxidation that yields a substantial amount of lipid peroxides, ultimately metabolizing into reactive aldehydes such as 4-HNE and MDA [24] ( Figure 2C). The effects of RJP on lipid peroxidation in AAPH-or t-BuOOH-stressed HDFs were detected using flow cytometry and BODIPY 581/591 C11 staining, a fluorescent probe labeling lipid peroxide [25]. ...
Hydrolyzed royal jelly peptide (RJP) has garnered attention for its health-promoting functions. However, the potential applications of RJP in skincare have not been fully explored. In this study, we prepared RJP through the enzymatic hydrolysis of royal jelly protein with trypsin and investigated its antioxidant and anti-inflammatory properties on primary human dermal fibroblasts (HDFs). Our results demonstrate that RJP effectively inhibits oxidative damage induced by H2O2 and lipid peroxidation triggered by AAPH and t-BuOOH in HDFs. This effect may be attributed to the ability of RJP to enhance the level of glutathione and the activities of catalase and glutathione peroxidase 4, as well as its excellent iron chelating capacity. Furthermore, RJP modulates the NLRP3 inflammasome-mediated inflammatory response in HDFs, suppressing the mRNA expressions of NLRP3 and IL-1β in the primer stage induced by LPS and the release of mature IL-1β induced by ATP, monosodium urate, or nigericin in the activation stage. RJP also represses the expressions of COX2 and iNOS induced by LPS. Finally, we reveal that RJP exhibits superior antioxidant and anti-inflammatory properties over unhydrolyzed royal jelly protein. These findings suggest that RJP exerts protective effects on skin cells through antioxidative and anti-inflammatory mechanisms, indicating its promise for potential therapeutic avenues for managing oxidative stress and inflammation-related skin disorders.
... In this context, the accumulation of lipids in LDs could serve as a defense against excessive IR-induced oxidative stress, which can cause lipid peroxidation resulting in the production of unstable lipid radicals, such as lipid hydroperoxide (LOOH), and more stable, yet reactive and toxic, compounds, such as aldehydes. These latter compounds have been implicated in the pathogenesis of many diseases [34,35] and have been proven to be genotoxic by interacting with the DNA molecule [36]. Such an interaction might amplify the damaging effects of radiation treatments on membranes and newly synthesized DNA molecules during the S phase. ...
Background
Cancer radiation treatments have seen substantial advancements, yet the biomolecular mechanisms underlying cancer cell radioresistance continue to elude full understanding. The effectiveness of radiation on cancer is hindered by various factors, such as oxygen concentrations within tumors, cells’ ability to repair DNA damage and metabolic changes. Moreover, the initial and radiation-induced cell cycle profiles can significantly influence radiotherapy responses as radiation sensitivity fluctuates across different cell cycle stages. Given this evidence and our prior studies establishing a correlation between cancer radiation resistance and an increased number of cytoplasmic Lipid Droplets (LDs), we investigated if LD accumulation was modulated along the cell cycle and if this correlated with differential radioresistance in lung and bladder cell lines.
Results
Our findings identified the S phase as the most radioresistant cell cycle phase being characterized by an increase in LDs. Analysis of the expression of perilipin genes (a family of proteins involved in the LD structure and functions) throughout the cell cycle also uncovered a unique gene cell cycle pattern.
Conclusions
In summary, although these results require further molecular studies about the mechanisms of radioresistance, the findings presented here are the first evidence that LD accumulation could participate in cancer cells’ ability to better survive X-Ray radiation when cells are in the S phase. LDs can represent new players in the radioresistance processes associated with cancer metabolism. This could open new therapeutic avenues in which the use of LD-interfering drugs might enhance cancer sensitivity to radiation.
... Then, 2 µL of iron (II) chloride (FeCl 2 ) and 2 µL of ammonium thiocyanate (NH 4 SCN) were added in a 96-well plate and incubated in the dark at 37 • C for 3 min. The absorbance was measured at 500 nm using a microplate reader (Green Lane, NY, USA) [34], and the positive control comprised Trolox. The percentage of inhibition was calculated using the Equation (3) and calculated IC 50 . ...
Capsaicin and curcumin, the active components of chili and turmeric, are prone to instability when exposed to light. Therefore, this research aimed to enhance the photostability of both extracts via the use of antioxidants, natural sunscreen, and nanostructured lipid carriers (NLCs). NLCs were chosen for this this study due to their advantages in terms of stability, drug loading capacity, occlusive effect, skin penetration, and controlled release. The photostability of each extract and extracts mixed with antioxidants, including grape seed extract, tea extract, and chlorogenic acid, were determined. Chlorogenic acid can enhance the photostability of capsaicin from 6.79 h to 16.50 h, while the photostability of curcumin increased from 9.63 h to 19.25 h. In addition, the use of natural sunscreen (sunflower oil) also increased the photostability of capsaicin and curcumin. The mixed extracts were then loaded into NLCs. The particle size of the formulation was 153.73 nm with a PDI value of 0.25. It exhibited high entrapment efficiency (more than 95%). In addition, it effectively reduced the decomposition of capsaicin and curcumin. Importantly, the natural stabilizers chosen for NLC fabrication significantly improved the photostability of curcumin and capsaicin by 600% and 567% compared to the unstabilized counterparts. This improvement contributes to the sustainability and bioavailability of these compounds in both cosmeceutical and pharmaceutical products.
... Astragalus active ingredients mainly involve several signaling pathways during the treatment of periodontitis, including cancer pathways, lipid and atherosclerosis pathways, the AGE-RAGE signaling pathway in diabetic complications, and proteoglycan pathways in cancer. Oxidative stress and lipid peroxidation are implicated in various pathological conditions, including in ammation, atherosclerosis, neurodegenerative diseases, cancer, and periodontitis [54]. In a rat model of ligation-induced periodontitis, increased lipid peroxidation was observed in the serum, aorta, and periodontal tissue [55]. ...
Background: Periodontitis, a common oral inflammatory disease which may cause premature tooth loss, was proved can be treated by Astragalus, but the detailed mechanisms are still not clear. We validated and discussed the molecular mechanism by using bioinformatics methods and cell experimental, and in order to clarify the mechanism of Astragalus during the treatment of periodontitis.
Methods:The active ingredients of Astragalus and their corresponding targets were obtained using the TCMSP database, and the periodontitis-related targets were obtained from DrugBank database, GeneCards database etc., then GO and KEGG analyses were performed based on Metascape database. Astragalus active ingredients and related targets network, Astragalus-active components-targets of periodontitis network, and Astragalus-active components- periodontitis targets-signaling pathways network were constructed by using Cytoscape3.9.0 software. Thereafter, Molecular docking and molecular dynamic simulation were analyzed in Discovery Studio 2019 software and Gromacs 2021.2 software package respectively, in order to evaluate the stability of combination between active components and core targets.
Results:17 compounds of Astragalus and 464 corresponding targets were obtained and 5 major active ingredients were screened from the drug active ingredients- periodontitis gene network. PPI network analysis revealed the top 10 core potential targets, 7 of them have suitable crystal structure and can be used for molecular docking, including interleukin-6 (IL6), tumor necrosis factor (TNF), RAC-α serine/threonine protein kinase (AKT1), interleukin-1β(IL1β), prostaglandin G/H synthase-2 (PTGS2), matrix metalloproteinase-9 (MMP9), and Caspase3 (CASP3). In addition, 58 GO terms and 146 KEGG pathways were identified. 5 major active ingredients and 7 core targets which mentioned above were docked molecularly in Discovery Studio 2019 software. Molecular dynamics simulations confirmed that there has a stable combination between Caspase3 and Kaempferol ligand system.
Conclusions: Based on the results of network pharmacology, molecular docking and molecular dynamics, it can be concluded that Astragalus has multiple active ingredients, and targets different signaling pathways to regulate the inflammatory response, immune response and oxidative stress in order to play a beneficial role in the treatment of periodontitis, especially Kaempferol can combine with Caspase3 stably to inhibit the cell apoptosis, our data provide solid evidences and enlightenment for the clinical application of Astragalus in future.
The unprecedented pandemic of COVID-19 swept millions of lives in a short period, yet its menace continues among its survivors in the form of post-COVID syndrome. An exponentially growing number of COVID-19 survivors suffer from cognitive impairment, with compelling evidence of a trajectory of accelerated aging and neurodegeneration. The novel and enigmatic nature of this yet-to-unfold pathology demands extensive research seeking answers for both the molecular underpinnings and potential therapeutic targets. Ferroptosis, an iron-dependent cell death, is a strongly proposed underlying mechanism in post-COVID-19 aging and neurodegeneration discourse. COVID-19 incites neuroinflammation, iron dysregulation, reactive oxygen species (ROS) accumulation, antioxidant system repression, renin-angiotensin system (RAS) disruption, and clock gene alteration. These events pave the way for ferroptosis, which shows its signature in COVID-19, premature aging, and neurodegenerative disorders. In the search for a treatment, melatonin shines as a promising ferroptosis inhibitor with its repeatedly reported safety and tolerability. According to various studies, melatonin has proven efficacy in attenuating the severity of certain COVID-19 manifestations, validating its reputation as an anti-viral compound. Melatonin has well-documented anti-aging properties and combating neurodegenerative-related pathologies. Melatonin can block the leading events of ferroptosis since it is an efficient anti-inflammatory, iron chelator, antioxidant, angiotensin II antagonist, and clock gene regulator. Therefore, we propose ferroptosis as the culprit behind the post-COVID-19 trajectory of aging and neurodegeneration and melatonin, a well-fitting ferroptosis inhibitor, as a potential treatment.
Atherosclerosis is a multifactorial disease of medium and large arteries, characterized by the presence of lipid-rich plaques lining the intima over time. It is the main cause of cardiovascular diseases and death worldwide. Redox imbalance and lipid peroxidation could play key roles in atherosclerosis by promoting a bundle of responses, including endothelial activation, inflammation, and foam cell formation. The oxidation of polyunsaturated fatty acids generates various lipid oxidation products such as reactive carbonyl species (RCS), including 4-hydroxy alkenals, malondialdehyde, and acrolein. RCS covalently bind to nucleophilic groups of nucleic acids, phospholipids, and proteins, modifying their structure and activity and leading to their progressive dysfunction. Protein lipoxidation is the non-enzymatic post-translational modification of proteins by RCS. Low-density lipoprotein (LDL) oxidation and apolipoprotein B (apoB) modification by RCS play a major role in foam cell formation. Moreover, oxidized LDLs are a source of RCS, which form adducts on a huge number of proteins, depending on oxidative stress intensity, the nature of targets, and the availability of detoxifying systems. Many systems are affected by lipoxidation, including extracellular matrix components, membranes, cytoplasmic and cytoskeletal proteins, transcription factors, and other components. The mechanisms involved in lipoxidation-induced vascular dysfunction are not fully elucidated. In this review, we focus on protein lipoxidation during atherogenesis.
