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Drug Resistance Updates : Reviews and... Nov 2023Therapeutic outcome of sorafenib in hepatocellular carcinoma (HCC) is undermined by the development of drug resistance. This study aimed to identify the critical...
AIMS
Therapeutic outcome of sorafenib in hepatocellular carcinoma (HCC) is undermined by the development of drug resistance. This study aimed to identify the critical microRNA (miRNA) which is responsible for sorafenib resistance at the genomic level.
METHODS
CRISPR/Cas9 screen followed by gain- and loss-of-function assays both in vitro and in vivo were applied to identify the role of miR-3689a-3p in mediating sorafenib response in HCC. The upstream and downstream molecules of miR-3689a-3p and their mechanism of action were investigated.
RESULTS
CRISPR/Cas9 screening identified miR-3689a-3p was the most up-regulated miRNA in sorafenib sensitive HCC. Knockdown of miR-3689a-3p significantly increased sorafenib resistance, while its overexpression sensitized HCC response to sorafenib treatment. Proteomic analysis revealed that the effect of miR-3689a-3p was related to the copper-dependent mitochondrial superoxide dismutase type 1 (SOD1) activity. Mechanistically, miR-3689a-3p targeted the 3'UTR of the intracellular copper chaperone for superoxide dismutase (CCS) and suppressed its expression. As a result, miR-3689a-3p disrupted the intracellular copper trafficking and reduced SOD1-mediated scavenge of mitochondrial oxidative stress that eventually caused HCC cell death in response to sorafenib treatment. CCS overexpression blunted sorafenib response in HCC. Clinically, miR-3689a-3p was down-regulated in HCC and predicted favorable prognosis for HCC patients.
CONCLUSION
Our findings provide comprehensive evidence for miR-3689a-3p as a positive regulator and potential druggable target for improving sorafenib treatment in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Sorafenib; Superoxide Dismutase-1; CRISPR-Cas Systems; Copper; Proteomics; Liver Neoplasms; MicroRNAs; Superoxide Dismutase; Oxidative Stress
PubMed: 37924725
DOI: 10.1016/j.drup.2023.101015 -
The Journal of Physiology Nov 2023Doxorubicin, a conventional chemotherapeutic agent prescribed for cancer, causes skeletal muscle atrophy and adversely affects mobility and strength. Given that...
Doxorubicin, a conventional chemotherapeutic agent prescribed for cancer, causes skeletal muscle atrophy and adversely affects mobility and strength. Given that doxorubicin-induced muscle atrophy is attributable primarily to oxidative stress, its effects could be mitigated by antioxidant-focused therapies; however, these protective therapeutic targets remain ambiguous. The aim of this study was to demonstrate that doxorubicin triggers severe muscle atrophy via upregulation of oxidative stress (4-hydroxynonenal and malondialdehyde) and atrogenes (atrogin-1/MAFbx and muscle RING finger-1) in association with decreased expression of the antioxidant enzyme extracellular superoxide dismutase (EcSOD), in cultured C2C12 myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein elevated EcSOD levels on the cellular membrane of cultured myotubes, consequently inhibiting doxorubicin-induced oxidative stress and myotube atrophy. Furthermore, doxorubicin treatment reduced interleukin-1β (IL-1β) mRNA expression in cultured myotubes and skeletal muscle, whereas transient IL-1β treatment increased EcSOD protein expression on the myotube membrane. Notably, transient IL-1β treatment of cultured myotubes and local administration in mouse skeletal muscle attenuated doxorubicin-induced muscle atrophy, which was associated with increased EcSOD expression. Collectively, these findings reveal that the regulation of skeletal muscle EcSOD via maintenance of IL-1β signalling is a potential therapeutic approach to counteract the muscle atrophy mediated by doxorubicin and oxidative stress. KEY POINTS: Doxorubicin, a commonly prescribed chemotherapeutic agent for patients with cancer, induces severe muscle atrophy owing to increased expression of oxidative stress; however, protective therapeutic targets are poorly understood. Doxorubicin induced muscle atrophy owing to increased expression of oxidative stress and atrogenes in association with decreased protein expression of extracellular superoxide dismutase (EcSOD) in cultured C2C12 myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein increased EcSOD levels on the cellular membrane of cultured myotubes, resulting in inhibition of doxorubicin-induced oxidative stress and myotube atrophy. Doxorubicin treatment decreased interleukin-1β (IL-1β) expression in cultured myotubes and skeletal muscle, whereas transient IL-1β treatment in vivo and in vitro increased EcSOD protein expression and attenuated doxorubicin-induced muscle atrophy. These findings reveal that regulation of skeletal muscle EcSOD via maintenance of IL-1β signalling is a possible therapeutic approach for muscle atrophy mediated by doxorubicin and oxidative stress.
Topics: Humans; Mice; Animals; Antioxidants; Interleukin-1beta; Muscle, Skeletal; Muscle Fibers, Skeletal; Muscular Atrophy; Doxorubicin; Neoplasms; Superoxide Dismutase; Recombinant Proteins
PubMed: 37815420
DOI: 10.1113/JP285174 -
Biogerontology Oct 2023Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have received widespread attention because of their significant protective effects on the kidney. Previous studies...
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have received widespread attention because of their significant protective effects on the kidney. Previous studies have shown that Sirt1, as which is an antiaging protein, is closely related to the maintenance of redox homeostasis. The goal of this study was to determine whether empagliflozin could ameliorate D-galactose-induced renal senescence in mice, and examine the possible mechanisms of Sirt1. We constructed a rapid ageing model in mice by administering D-galactose. An ageing model was constructed by treating cells with high glucose. Treadmill and Y-maze tests were used to assess exercise tolerance and learning memory ability. Pathologically stained sections were used to assess kidney injury. Tissue and cell senescence were evaluated by senescence-associated β-galactosidase staining. The expression levels of P16, SOD1, SOD2 and Sirt1 were detected by immunoblotting. D-gal-treated mice exhibited significant age-related changes, as measured by behavioural tests and ageing marker protein levels. empagliflozin alleviated these ageing manifestations. In addition, Sirt1, SOD1 and SOD2 levels were downregulated in model mice and upregulated by empagliflozin treatment. Empagliflozin had similar protective effects at the cellular level, and these effects were reduced by the Sirt1 inhibitor. Empagliflozin has an antiaging effect, which may be related to reducing Sirt1-mediated oxidative stress.
Topics: Mice; Animals; Galactose; Sirtuin 1; Superoxide Dismutase-1; Oxidative Stress; Cellular Senescence; Oxidation-Reduction; Kidney; Glucose
PubMed: 37227544
DOI: 10.1007/s10522-023-10038-x -
Chemical Communications (Cambridge,... Apr 2024Superoxide dismutase (SOD) is an important metalloenzyme that catalyzes the dismutation of superoxide radicals (O˙) into hydrogen peroxide (HO) and oxygen (O). However,... (Review)
Review
Superoxide dismutase (SOD) is an important metalloenzyme that catalyzes the dismutation of superoxide radicals (O˙) into hydrogen peroxide (HO) and oxygen (O). However, the clinical application of SOD is severely limited due to its structural instability and high cost. Compared with natural enzymes, nanomaterials with enzyme-like activity, nanoenzymes, are more stable, economical and easy to modify and their activity can be adjusted. Certain nanozymes that exhibit SOD-like activity have been created and shown to help prevent illnesses brought about by oxidative stress. These SOD-like nanozymes offer an important solution to the problems associated with the clinical application of SOD. In this review, we briefly introduce neurodegenerative diseases, present the research progress of SOD-like nanoenzymes in the diagnosis and treatment of brain diseases, review their mechanism of action in the treatment and diagnosis of brain diseases, and discuss the shortcomings of the current research with a view to providing a reference for future research. We expect more highly active SOD-like nanoenzymes to be developed with a wide range of applications in the diagnosis and treatment of brain diseases.
Topics: Humans; Superoxide Dismutase; Hydrogen Peroxide; Superoxides; Oxidative Stress; Oxygen; Brain Diseases
PubMed: 38566603
DOI: 10.1039/d3cc06288k -
Nutrients Jul 2023Copper and zinc are micronutrients that play a crucial role in many cellular pathways, act as cofactors in enzymatic systems, and hence, modulate enzyme activity. The... (Review)
Review
Copper and zinc are micronutrients that play a crucial role in many cellular pathways, act as cofactors in enzymatic systems, and hence, modulate enzyme activity. The regulation of these elements in homeostasis is precisely controlled by various mechanisms. Superoxide dismutase (SOD) is an enzyme requiring both copper and zinc for proper functioning. Additionally, there is an interaction between the concentrations of copper and zinc. Dietary ingestion of large amounts of zinc augments intestinal absorption of this trace element, resulting in copper deficiency secondary to zinc excess. The presence of an overabundance of copper and zinc has a detrimental impact on the cardiovascular system; however, the impact on vascular contractility varies. Copper plays a role in the modulation of vascular remodeling in the cardiac tissue, and the phenomenon of cuproptosis has been linked to the pathogenesis of coronary artery disease. The presence of copper has an observable effect on the vasorelaxation mediated by nitric oxide. The maintenance of proper levels of zinc within an organism influences SOD and is essential in the pathogenesis of myocardial ischemia/reperfusion injury. Recently, the effects of metal nanoparticles have been investigated due to their unique characteristics. On the other hand, dietary introduction of metal nanoparticles may result in vascular dysfunction, oxidative stress, and cellular DNA damage. Copper and zinc intake affect cardiovascular function, but more research is needed.
Topics: Zinc; Copper; Trace Elements; Superoxide Dismutase; Heart
PubMed: 37447366
DOI: 10.3390/nu15133040 -
Discovery Medicine Dec 2023Ischemic stroke is an acute cerebrovascular disease with high mortality rates and poor prognoses. The influence of ischemic stroke includes a heavy economic burden to...
BACKGROUND
Ischemic stroke is an acute cerebrovascular disease with high mortality rates and poor prognoses. The influence of ischemic stroke includes a heavy economic burden to patients and society, making the exploration of new therapeutic targets for preventing and treating ischemic stroke urgent. This study aimed to explore the effect of phosphoglycerate mutase family member 5 () on oxidative stress and mitochondrial dysfunction in ischemic stroke.
METHODS
The model of ischemic neuronal brain injury was established through culturing purchased human neuroblastoma cells (SH-SY5Y) by oxygen-glucose deprivation/reoxygenation (OGD/R). There were six experimental groups, including the OGD/R model group (SH-cells of OGD/R model), OE-NC group (cells of OGD/R model transfected with scramble cDNA), OE- group (cells of OGD/R model transfected with full-length sequence of ), si-NC group (cells of OGD/R model transfected with negative control small interference (si)RNA), si- group (cells of OGD/R model transfected with siRNA for knockdown), and a control group (cells cultured normally). Cell counting kit-8 (CCK-8) and flow cytometry were used to determine the activity and apoptosis of cells. Subsequently, the effects of expression on oxidative stress and mitochondrial dysfunction were analyzed. Mitochondrial morphology was observed by transmission electron microscopy (TEM), and mitochondrial membrane potential (MMP) was determined by JC-1 fluorescent probe. The levels of reactive oxygen species (ROS) were measured by flow cytometry, and levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured by enzyme-linked immunosorbent assay (ELISA) assay. The expression of light chain (LC)3-II/I and autophagy-related gene 5 (ATG5) proteins were measured, and the regulation of expression on -induced putative protein kinase 1 ()/ pathway was also explored.
RESULTS
overexpression in OGD/R cells decreased the cell viability ( < 0.001) while increasing cell apoptosis ( < 0.01) compared to the OGD/R group. Inhibition of expression reversed the decreased cell viability ( < 0.001) and the increased cell apoptosis ( < 0.01). The JC-1 fluorescence showed that OGD/R treatment reduced mitochondrial membrane potential ( < 0.001) and TEM showed an obvious increase in phagosomes. In addition, OGD/R treatment enhanced oxidative stress (increased ROS, < 0.01; increased MDA, < 0.001; decreased SOD, < 0.001), which could be further enhanced by overexpression of (ROS, < 0.001; MDA, < 0.001; SOD, < 0.001) while reversed by the inhibition of (ROS, < 0.01; MDA, < 0.001; SOD, < 0.001). The OGD/R-activated / pathway was inhibited by the knockdown of ( < 0.01) but promoted by the overexpression of ( < 0.05).
CONCLUSIONS
stimulates oxidative stress and impairs mitochondrial function in ischemic stroke, and regulates the / signaling pathway. Therefore, is likely to be a target for the therapy of ischemic stroke.
Topics: Humans; Reactive Oxygen Species; Ischemic Stroke; Neuroblastoma; Oxygen; Protein Kinases; Ubiquitin-Protein Ligases; Superoxide Dismutase; Mitochondrial Diseases; Glucose; Apoptosis; Phosphoprotein Phosphatases; Mitochondrial Proteins
PubMed: 38058078
DOI: 10.24976/Discov.Med.202335179.109 -
F1000Research 2023Superoxide dismutase [Cu-Zn] 1 (SOD1), is an antioxidant enzyme encoded by the gene , responsible for regulating oxidative stress levels by sequestering free radicals....
Superoxide dismutase [Cu-Zn] 1 (SOD1), is an antioxidant enzyme encoded by the gene , responsible for regulating oxidative stress levels by sequestering free radicals. Identified as the first gene with mutations in Amyotrophic lateral sclerosis (ALS), is a determinant for studying diseases of aging and neurodegeneration. With guidance on well-characterized anti-SOD1 antibodies, the reproducibility of SOD1 research would be enhanced. In this study, we characterized eleven SOD1 commercial antibodies for Western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.
Topics: Superoxide Dismutase-1; Reproducibility of Results; Superoxide Dismutase; Blotting, Western; Antibodies; Immunoprecipitation; Fluorescent Antibody Technique; Zinc
PubMed: 37860271
DOI: 10.12688/f1000research.132952.1 -
BMC Complementary Medicine and Therapies Dec 2023The aim of the present study was to investigate the therapeutic effect of ammidin on hypoxia/reoxygenation (H/R) injury in primary neonatal rat cardiomyocytes by...
OBJECTIVE
The aim of the present study was to investigate the therapeutic effect of ammidin on hypoxia/reoxygenation (H/R) injury in primary neonatal rat cardiomyocytes by observing the role of ferroptosis in the process of H/R injury, and to verify its target and regulatory signaling pathways.
METHODS
The network pharmacology analysis was used to predict the biological processes, core targets and related signaling pathways of Angelica dahurica in the treatment of ferroptosis. Cell viability was assessed using live cell imaging and cell counting kit-8. Lactate dehydrogenase (LDH), reactive oxygen species (ROS) production, and malondialdehyde (MDA), superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) content were determined to assess the level of ferroptosis. Western blotting was performed to measure protein expression.
RESULTS
Network pharmacology predicted that Acyl-CoA synthetase long chain family member 4 (ACSL4) was highly associated with myocardial H/R injury in the intersection of Angelica dahurica and ferroptosis. The top three active components of Angelica dahurica were found to be mandenol, alloisoimperatorin and ammidin, among which ammidin was found to have the strongest binding to the target proteins of the ACSL4/AMPK/mTOR pathway. H/R reduced the viability of cardiomyocytes, while the inhibition of ferroptosis by ferrostatin-1 alleviated the H/R-induced inhibition of cardiomyocyte viability. This was evidenced by the increased cell viability, SOD release, MMP level and glutathione peroxidase 4 (GPX4) protein expression, as well as the decreased LDH and MDA release and ROS production and ACSL4 protein expression (P < 0.05). To verify the existence of ferroptosis in myocardial hypoxia/reoxygenation injury. In addition, ammidin increased cell viability and GPX4 protein expression (P < 0.05), decreased ROS generation, and MDA and MTT expression (P < 0.05), then inhibited ferroptosis, and finally alleviated myocardial H/R injury by regulating the ACSL4/AMPK signaling pathway.
CONCLUSIONS
Network pharmacology was used to predict the correlation between ammidin and ferroptosis following myocardial H/R injury. It was demonstrated that ammidin may regulate ferroptosis by inhibiting the ACSL4/AMPK/mTOR signaling pathway and reduce H/R injury in cardiomyocytes.
Topics: Rats; Animals; Reactive Oxygen Species; AMP-Activated Protein Kinases; Ferroptosis; Myocardial Ischemia; TOR Serine-Threonine Kinases; Hypoxia; Superoxide Dismutase
PubMed: 38102654
DOI: 10.1186/s12906-023-04289-x -
Current Opinion in Ophthalmology Jan 2024Oxidative stress plays a central role in cataract pathogenesis, a leading cause of global blindness. This review delves into the role of oxidative stress in cataract... (Review)
Review
PURPOSE OF REVIEW
Oxidative stress plays a central role in cataract pathogenesis, a leading cause of global blindness. This review delves into the role of oxidative stress in cataract development and key biomarkers - glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) - to clarify their functions and potential applications in predictive diagnostics and therapies.
RECENT FINDINGS
Antioxidants serve as pivotal markers in cataract pathogenesis. GSH affects the central lens due to factors such as enzyme depletion and altered connexin expression, impairing GSH diffusion. Age-related oxidative stress may hinder GSH transport via connexin channels or an internal microcirculation system. N-acetylcysteine, a GSH precursor, shows promise in mitigating lens opacity when applied topically. Additionally, SOD, particularly SOD1, correlates with increased cataract development and gel formulations have exhibited protective effects against posterior subscapular cataracts. Lastly, markers of lipid peroxidation, MDA and 4-HNE, have been shown to reflect disease severity. Studies suggest a potential link between 4-HNE and connexin channel modification, possibly contributing to reduced GSH levels.
SUMMARY
Oxidative stress is a significant contributor to cataract development, underscoring the importance of antioxidants in diagnosis and treatment. Notably, GSH depletion, SOD decline, and lipid peroxidation markers are pivotal factors in cataract pathogenesis, offering promising avenues for both diagnosis and therapeutic intervention.
Topics: Humans; Antioxidants; Oxidative Stress; Cataract; Lens, Crystalline; Glutathione; Superoxide Dismutase; Connexins
PubMed: 37882550
DOI: 10.1097/ICU.0000000000001009 -
Animal Biotechnology Dec 2023The aim of this study is to determine the effects of 50% of 96 h LC (5.25 ppm) diazinon on the expression of superoxide dismutase (SOD) enzyme genes (, , and ) and...
The aim of this study is to determine the effects of 50% of 96 h LC (5.25 ppm) diazinon on the expression of superoxide dismutase (SOD) enzyme genes (, , and ) and SOD enzyme activity at the end of 24, 48, 72, and 96 h in platyfish liver and gill tissues. To this end, we determined the tissue-specific distribution of , , and genes and performed analyses in platyfish (). It was determined that malondialdehyde (MDA) level and SOD enzyme activity were increased in the liver [(43.90 EU mg protein (control), 62.45 EU mg protein (24 h), 73.17 EU mg protein (48 h), 82.18 EU mg protein (72 h), 92.93 EU mg protein (96 h)] and gill [(16.44 EU mg protein (control), 33.47 EU mg protein (24 h), 50.38 EU mg protein (48 h), 64.62 EU mg protein (72 h), 74.04 EU mg protein (96 h)] tissues of platyfish exposed to diazinon, while the expression of the genes was down-regulated. The tissue-specific distribution of the genes varied, with the tissues and the genes expression were being predominant in the liver (628.32 in , 637.59 in , 888.5 in ). Thus, the liver was considered a suitable tissue for further gene expression studies. Based on the phylogenetic analyses, platyfish genes can be reported to be orthologs of / genes from other vertebrates. Identity/similarity analyses supported this determination. Conserved gene synteny proved that there are conserved genes in platyfish, zebrafish, and humans.
Topics: Humans; Animals; Diazinon; Phylogeny; Zebrafish; Superoxide Dismutase; Superoxide Dismutase-1; Genomics; Cyprinodontiformes
PubMed: 36811494
DOI: 10.1080/10495398.2023.2178931