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Frontiers in Oncology 2022Ferroptosis plays an important role in the development of acute myeloid leukemia (AML); however, the exact role of ferroptosis-related genes in the prognosis of AML...
Comprehensive analysis of ferroptosis-related gene signatures as a potential therapeutic target for acute myeloid leukemia: A bioinformatics analysis and experimental verification.
BACKGROUND
Ferroptosis plays an important role in the development of acute myeloid leukemia (AML); however, the exact role of ferroptosis-related genes in the prognosis of AML patients is unclear.
METHODS
RNA sequencing data and the clinicopathological characteristics of AML patients were obtained from The Cancer Genome Atlas database, and ferroptosis-related genes were obtained from the FerrDb database. Cox regression analysis and least absolute shrinkage and selection operator analysis were performed to identify ferroptosis-related gene signatures. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and single-sample gene set enrichment analysis (ssGSEA) were performed to explore the biological functions of the ferroptosis-related genes. Finally, ferroptosis of AML cells was induced by erastin and sulfasalazine to detect the changes in the expression of relevant prognostic genes and explore the underlying mechanisms using quantitative real-time polymerase chain reaction (qRT-PCR).
RESULTS
Seven ferroptosis-related gene signatures (, , , , , , and ) were identified in the training group. Kaplan-Meier and Cox regression analyses confirmed that risk score was an independent prognostic predictor of AML in the training and validation groups (<0.05). Further, functional enrichment analysis revealed that seven ferroptosis-related genes were associated with many immune-related biological processes. Most importantly, erastin and sulfasalazine can induce the ferroptosis of AML cells. Overall, and the SLC7A11/xCT-GSH-GPX4 pathway may be the respective key gene and potential regulatory pathway in erastin- and sulfasalazine-induced ferroptosis of AML cells.
CONCLUSIONS
A novel signature involving seven ferroptosis-related genes that could accurately predict AML prognosis was identified. Further, the Food and Drug Administration-approved drug, sulfasalazine, was demonstrated for the first time to induce the ferroptosis of AML cells. and the SLC7A11/xCT-GSH-GPX4 pathway may be the respective key gene and underlying mechanism in this process, ultimately providing new insights into the strategies for the development of new AML therapies.
PubMed: 36033479
DOI: 10.3389/fonc.2022.930654 -
Frontiers in Pharmacology 2022Diabetes mellitus leads to endothelial dysfunction and accumulation of oxygen radicals. Sulfasalazine-induced Nrf2 activation reduces oxidative stress in vessels. Thus,...
Diabetes mellitus leads to endothelial dysfunction and accumulation of oxygen radicals. Sulfasalazine-induced Nrf2 activation reduces oxidative stress in vessels. Thus, in the present study, we investigated the effects of sulfasalazine on endothelial dysfunction induced by high glucose. We also ascribed the underlying mechanism involved in glucose-induced endothelial dysfunction. For this experiment we used 80 Wistar Albino rats thoracic aorta to calculate the dose response curve of noradrenaline and acetylcholine. Vessels were incubated in normal and high glucose for 2 h. To investigate glucose and sulfasalazine effects the vessels of the high glucose group were pre-treated with sulfasalazine (300 mM), JNK inhibitor (SP600125), and ERK inhibitor (U0126) for 30 min. The dose response curve was calculated through organ bath. The eNOS, TAS, TOS, and HO-1 levels were estimated by commercially available ELISA kits. In the high glucose group, the E for contraction was significantly higher ( < 0.001), and E for relaxation was lower than that of control. These functional changes were parallel with the low levels of eNOS ( < 0.05). High glucose vessel treated with sulfasalazine showed low E value for contraction ( < 0.001) however, the E for relaxation was significantly high ( < 0.001) when compared to high glucose group. In the JNK group, E for contraction and relaxation was inhibited ( < 0.001) compared to sulfasalazine treated vessels. HO-1 enzyme levels were significantly low ( < 0.01) with sulfasalazine but higher with ERK inhibitor ( < 0.05). High glucose induced endothelial dysfunction and sulfasalazine reduced damage in high glucose vessels by activating eNOS, antioxidant effect through HO-1 enzymes and particularly inducing Nrf2 the ERK and JNK pathways.
PubMed: 36353481
DOI: 10.3389/fphar.2022.979300 -
Crystal Growth & Design Aug 2023Sulfasalazine is used as an anti-inflammatory drug to treat large intestine diseases and atrophic arthritis. In the solid state, two tautomers are known: an amide...
Sulfasalazine is used as an anti-inflammatory drug to treat large intestine diseases and atrophic arthritis. In the solid state, two tautomers are known: an amide tautomer (triclinic polymorph) and an imide tautomer (monoclinic polymorph). Crystallization of six new multicomponent solids of sulfasalazine with three cocrystal formers and three salt formers has been achieved by slurry, liquid-assisted grinding and slow evaporation methods. All of the solid forms are characterized by X-ray diffraction techniques, thermal analysis, and Fourier transform infrared spectroscopy. The crystal structural analysis reveals that two sulfasalazine molecules or anions arrange in a head-to-head fashion involving their pyridyl, amide, and sulfonyl groups in an (7):(8):(7) motif. This is the key structural unit appearing in both sulfasalazine imide polymorph and all six multicomponent crystals. In addition, sulfasalazine exists in the amide form in all unsolvated multicomponent crystals obtained in this work and adopts the imide tautomer in the solvated cocrystals and salt. Hirshfeld surface analysis and the associated two-dimensional (2D) fingerprint plots demonstrate that sulfasalazine has significant hydrogen bond donor capability when cocrystallized and is a significant hydrogen bond acceptor in the salts. The frontier molecular orbital analysis indicates that sulfasalazine cocrystals are chemically more stable than the salts.
PubMed: 37547882
DOI: 10.1021/acs.cgd.2c01403 -
Journal of Nephrology Nov 2023
PubMed: 38015314
DOI: 10.1007/s40620-023-01820-8 -
European Journal of Pharmacology Jun 2022To assess which immunosuppressive drugs have been investigated and proven efficacious in patients with cardiovascular disease (CVD) or type 2 diabetes (T2D) without... (Review)
Review
OBJECTIVE
To assess which immunosuppressive drugs have been investigated and proven efficacious in patients with cardiovascular disease (CVD) or type 2 diabetes (T2D) without preexisting immune mediated disorders to validate in vitro and animal model findings on low grade inflammation (bedside-to-bench).
METHODS
Clinical trials on immunosuppressive drugs in CVD or T2D were found in PubMed. Studies on patients with preexisting immune mediated inflammatory disease were excluded. A total of 19 clinical trials testing canakinumab, anakinra, methotrexate, colchicine, hydroxychloroquine, etanercept and sulfasalazine were found.
RESULTS
Canakinumab and colchicine significantly reduced the risk of CVD, whereas methotrexate did not. Sulfasalazine showed no effect on vascular function. Anakinra and hydroxychloroquine had a positive effect on glycemic control and β-cell function in T2D. Etanercept had no effect in patients with T2D.
CONCLUSION
The observed results indicate that immunosuppressive drugs specifically targeting IL-1β hold promise for dampening CVD and T2D. These findings validate in vitro and animal models showing involvement of the IL-1-axis in the pathogenesis of CVD and T2D. The use of immunosuppressive drugs targeting the chronic inflammation in these diseases could be a possible future treatment strategy as an add-on to the existing pharmacological treatment of CVD and T2D. However, potential treatment effects, adverse events and cost-effectiveness should be carefully considered with importance for drug development.
Topics: Animals; Antibodies, Monoclonal, Humanized; Cardiovascular Diseases; Colchicine; Diabetes Mellitus, Type 2; Etanercept; Humans; Hydroxychloroquine; Immunomodulating Agents; Immunosuppression Therapy; Immunosuppressive Agents; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-1beta; Methotrexate; Sulfasalazine
PubMed: 35533739
DOI: 10.1016/j.ejphar.2022.174998 -
Frontiers in Bioengineering and... 2023Neointimal hyperplasia (NH) is a crucial pathophysiological feature in vascular transplant and in-stent restenosis. Excessive proliferation and migration of vascular...
Neointimal hyperplasia (NH) is a crucial pathophysiological feature in vascular transplant and in-stent restenosis. Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) play important roles in neointimal hyperplasia. This study aims to explore the potentialities and mechanism of sulfasalazine (SSZ) in the prevention of restenosis. Sulfasalazine was encapsulated in nanoparticles made of poly (lactic-co-glycolic acid) (PLGA). , carotid ligation injury was induced in mice to induce Neointimal hyperplasia, with or without sulfasalazine containing nanoparticles (NP-SSZ) treatment. After 4 weeks, the arteries were collected for histology, immunofluorescence, Western blotting (WB) and qRT-PCR. , vascular smooth muscle cells were treated with TNF-α to induce cell proliferation and migration, followed by SSZ or vehicle treatment. WB was performed to further explore its mechanism. The ratio of intima to media thickness (I/M) was increased after ligation injury on day 28, while the ratio was significantly reduced in the NP-SSZ treatment group. The dual positive nuclei of Ki-67 and α-SMA were 47.83% ± 9.15%, whereas only 29.83% ± 5.98% in the NP-SSZ-treated group ( < 0.05). Both MMP-2 and MMP-9 were decreased in the NP-SSZ treatment group ( < 0.05, < 0.05, respectively) compared to the control group. The levels of the targeted inflammatory genes (TNF-α, VCAM-1, ICAM-1, MCP-1) were lower in the NP-SSZ treatment group compared with the control group. , the proliferating cell nuclear antigen (PCNA) expression was significantly decreased in the SSZ treatment group. The cell viability of VSMCs was markedly increased in the TNF-α treatment group, whereas sulfasalazine treatment inhibited this effect. LC3 II and P62 protein expression were higher in the SSZ group than in the vehicle group both and . The phosphorylation of NF-kB (p-NF-kB) and the phosphorylation of mTOR (p-mTOR) were decreased in the TNF-α+ SSZ group, whereas the P62 and LC3 II expression levels were increased. However, the expression level of p-mTOR, P62, and LC3 II was reversed after co-treatment with the agonist of mTOR MHY1485, whereas the p-NF-kB expression level was unchanged. sulfasalazine inhibited vascular smooth muscle cells proliferation and migration and Neointimal hyperplasia through NF-kB/mTOR-mediated autophagy.
PubMed: 37288359
DOI: 10.3389/fbioe.2023.1199785 -
Journal of Orthopaedic Research :... Mar 2020Joint stiffness due to fibrosis/capsule contracture is a seriously disabling complication of articular injury that surgical interventions often fail to completely...
Joint stiffness due to fibrosis/capsule contracture is a seriously disabling complication of articular injury that surgical interventions often fail to completely resolve. Fibrosis/contracture is associated with the abnormal persistence of myofibroblasts, which over-produce and contract collagen matrices. We hypothesized that intra-articular therapy with drugs targeting myofibroblast survival (sulfasalazine), or collagen production (β-aminopropionitrile and cis-hydroxyproline), would reduce joint stiffness in a rabbit model of fibrosis/contracture. Drugs were encapsulated in poly[lactic-co-glycolic] acid pellets and implanted in joints after fibrosis/contracture induction. Capsule α-smooth muscle actin (α-SMA) expression and intimal thickness were evaluated by immunohistochemistry and histomorphometry, respectively. Joint stiffness was quantified by flexion-extension testing. Drawer tests were employed to determine if the drugs induced cruciate ligament laxity. Joint capsule fibroblasts were tested in vitro for contractile activity and α-SMA expression. Stiffness in immobilized joints treated with blank pellets (control) was significantly higher than in non-immobilized, untreated joints (normal) (p = 0.0008), and higher than in immobilized joints treated with sulfasalazine (p = 0.0065). None of the drugs caused significant cruciate ligament laxity. Intimal thickness was significantly lower than control in the normal and sulfasalazine-treated groups (p = 0.010 and 0.025, respectively). Contractile activity in the cells from controls was significantly increased versus normal (p = 0.001). Sulfasalazine and β-aminopropionitrile significantly inhibited this effect (p = 0.005 and 0.0006, respectively). α-SMA expression was significantly higher in control versus normal (p = 0.0021) and versus sulfasalazine (p = 0.0007). These findings support the conclusion that sulfasalazine reduced stiffness by clearing myofibroblasts from fibrotic joints. Statement of clinical significance: The results provide proof-of-concept that established joint stiffness can be resolved non-surgically. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:629-638, 2020.
Topics: Aminopropionitrile; Animals; Collagen; Contracture; Disease Models, Animal; Fibrosis; Hydroxyproline; Joint Capsule; Joint Diseases; Male; Muscle Contraction; Myofibroblasts; Rabbits; Stress, Mechanical; Sulfasalazine
PubMed: 31692083
DOI: 10.1002/jor.24499 -
Materials Today. Bio Feb 2024Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by the infiltration of inflammatory cells and proliferation of synovial cells. It can cause...
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by the infiltration of inflammatory cells and proliferation of synovial cells. It can cause cartilage and bone damage as well as disability and is regarded as an incurable chronic disease. Available therapies cannot prevent the development of diseases due to the high toxicity of the therapeutic agents and the inefficient drug delivery. Ferroptosis, an iron-dependent manner of lipid peroxidative cell death, indicates great potential for RA therapy due to ability to damage the infiltrated inflammatory cells and proliferated fibroblast-like synoviocytes. Here, we use macrophages as vector to deliver FeO nanoparticles and sulfasalazine (SSZ) for ferroptosis and photothermal therapy of RA. The inherent property of migration towards the inflamed joints under the guidance of inflammatory factors enables macrophages to targetedly deliver the payload into the RA. Upon the irradiation of the near infrared light, the FeO nanoparticles convert the light into heat to damage the proliferated synovium. Meanwhile, the iron released from FeO nanoparticles works with SSZ to generate synergetic ferroptosis effect. The resident inflammatory cells and proliferated synovium are efficiently damaged by the ferroptosis and photothermal effect, showing pronounced therapeutic effect for RA.
PubMed: 38226012
DOI: 10.1016/j.mtbio.2023.100925 -
International Journal of Clinical... Aug 2022Sulfasalazine has been widely used in treatment of rheumatoid arthritis and spondyloarthritis. This study aims to assess persistence with sulfasalazine and also... (Observational Study)
Observational Study
OBJECTIVES
Sulfasalazine has been widely used in treatment of rheumatoid arthritis and spondyloarthritis. This study aims to assess persistence with sulfasalazine and also frequency and severity of adverse drug reactions (ADRs) encountered with this very well-established disease-modifying anti-rheumatoid drug.
MATERIALS AND METHODS
This retrospective study was done in 1,114 patients from medicine and rheumatology outpatient departments of six centers across India. The inclusion criteria was patients taking sulfasalazine. Patients receiving sulfasalazine for rheumatoid arthritis or spondyloarthritis were selected and details on drugs used, duration of taking sulfasalazine, ADRs to sulfasalazine and whether sulfasalazine had to be stopped due to ADRs were analyzed.
RESULTS
Of the total of patients included in the study, 10.1% had ADRs with sulfasalazine, and stopped the drug. Gastritis, deranged liver enzymes, hepatitis, skin rashes were the most commonly encountered ADRs. Of the total number of patients recruited for the study, 11% were lost to follow-up, as most of the centers were army hospitals and the officers and staff were posted to other places. Sulfasalazine was taken for less than 1 month by 3.8% patients while 12.5% had taken the drug for less than 6 months. Of the study patients, 28.6% had taken the drug for 24 - 60 months and 4.6% (51 patients) had taken it for more than 5 years. It was found that ADRs were most commonly encountered within the first year of using the drug, and persistence was seen in patients on long-term therapy.
CONCLUSION
Sulfasalazine is a safe option in chronic therapy of rheumatoid arthritis and spondyloarthritis. Although frequency of ADRs with patients taking sulfasalazine is minimal, it did necessitate the stoppage of drug. If not well tolerated, sulfasalazine would not have been continued for more than 12 months as evidenced from this study.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Retrospective Studies; Spondylarthritis; Sulfasalazine; Treatment Outcome
PubMed: 35713159
DOI: 10.5414/CP204120 -
Methods in Molecular Biology (Clifton,... 2022Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that can lead to severe joint damage and is often associated with a high morbidity and disability....
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that can lead to severe joint damage and is often associated with a high morbidity and disability. Disease-modifying anti-rheumatic drugs (DMARDs) are the mainstay of treatment in RA. DMARDs not only relieve the clinical signs and symptoms of RA but also inhibit the radiographic progression of disease and reduce the effects of chronic systemic inflammation. Since the introduction of biologic DMARDs in the late 1990s, the therapeutic range of options for the management of RA has significantly expanded. However, patients' response to these agents is not uniform with considerable variability in both efficacy and toxicity. There are no reliable means of predicting an individual patient's response to a given DMARD prior to initiation of therapy. In this chapter, the current published literature on the pharmacogenetics of traditional DMARDS and the newer biologic DMARDs in RA is highlighted. Pharmacogenetics may help individualize drug therapy in patients with RA by providing reliable biomarkers to predict medication toxicity and efficacy.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Humans; Inflammation; Methotrexate; Pharmacogenetics
PubMed: 36068476
DOI: 10.1007/978-1-0716-2573-6_19