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Inflammopharmacology Apr 2024Ferroptosis has been reported to play a role in rheumatoid arthritis (RA). Sulfasalazine, a common clinical treatment for ankylosing spondylitis, also exerts...
OBJECTIVE
Ferroptosis has been reported to play a role in rheumatoid arthritis (RA). Sulfasalazine, a common clinical treatment for ankylosing spondylitis, also exerts pathological influence on the progression of rheumatoid arthritis including the induced ferroptosis of fibroblast-like synoviocytes (FLSs), which result in the perturbated downstream signaling and the development of RA. The aim of this study was to investigate the underlying mechanism so as to provide novel insight for the treatment of RA.
METHODS
CCK-8 and Western blotting were used to assess the effect of sulfasalazine on FLSs. A collagen-induced arthritis mouse model was constructed by the injection of collagen and Freund's adjuvant, and then, mice were treated with sulfasalazine from day 21 after modeling. The synovium was extracted and ferroptosis was assessed by Western blotting and immunofluorescence staining.
RESULTS
The results revealed that sulfasalazine promotes ferroptosis. Compared with the control group, the expression levels of ferroptosis-related proteins such as glutathione peroxidase 4, ferritin heavy chain 1, and solute carrier family 7, member 11 (SLC7A11) were lower in the experimental group. Furthermore, deferoxamine inhibited ferroptosis induced by sulfasalazine. Sulfasalazine-promoted ferroptosis was related to a decrease in ERK1/2 and the increase of P53.
CONCLUSIONS
Sulfasalazine promoted ferroptosis of FLSs in rheumatoid arthritis, and the PI3K-AKT-ERK1/2 pathway and P53-SLC7A11 pathway play an important role in this process.
Topics: Mice; Animals; Sulfasalazine; Proto-Oncogene Proteins c-akt; Tumor Suppressor Protein p53; MAP Kinase Signaling System; Phosphatidylinositol 3-Kinases; Ferroptosis; Arthritis, Rheumatoid; Cells, Cultured; Cell Proliferation
PubMed: 38407703
DOI: 10.1007/s10787-024-01439-6 -
International Journal of Women's... Jun 2020Sulfasalazine is an aminosalicylate primarily used in the treatment of rheumatoid arthritis and ulcerative colitis. Its immunomodulatory, anti-inflammatory, and... (Review)
Review
Sulfasalazine is an aminosalicylate primarily used in the treatment of rheumatoid arthritis and ulcerative colitis. Its immunomodulatory, anti-inflammatory, and antiproliferative properties make it a potential therapeutic option for various dermatological disorders. Owing to its wide range of effects, it is often used off-label in dermatological diseases, such as alopecia areata, psoriasis and psoriatic arthritis, lichen planus, and pemphigus. However, the level of evidence supporting its efficacy and safety in dermatology is limited. More research is needed to uncover the full potential of sulfasalazine in dermatology. The present article is a detailed review of the pharmacology, modes of action, side effects, and contraindications of sulfasalazine, along with an up-to-date review of the evidence underlying its use in various dermatological conditions.
PubMed: 32637543
DOI: 10.1016/j.ijwd.2020.01.009 -
Current Vascular Pharmacology 2020Patients with rheumatoid diseases have an increased risk of cardiovascular disease (CVD) and CVD-related death compared with the general population. Both the traditional... (Review)
Review
Patients with rheumatoid diseases have an increased risk of cardiovascular disease (CVD) and CVD-related death compared with the general population. Both the traditional cardiovascular risk factors and systemic inflammation are contributors to this phenomenon. This review examines the available evidence about the effects of synthetic, non-biologic disease-modifying antirheumatic drugs (DMARDs) on CVD risk. This is an important issue for clinicians when deciding on individual treatment plans in patients with rheumatic diseases. Evidence suggests that synthetic, non-biologic DMARDs such as methotrexate, sulfasalazine, hydroxychloroquine, leflunomide and tofacitinib show decreased CVD morbidity and mortality. However, the strongest data in favour of a reduction in CVD events in rheumatoid patients are shown with methotrexate, which has been the focus of most studies. Adequate proof for a favourable effect also exists for hydroxychloroquine. Larger, prospective studies and randomized clinical trials are needed to better characterize the effect of synthetic, non-biologic DMARDs on CVD outcomes in these patients. Design of future studies should include areas with lack of evidence, such as the risk for heart failure, arrhythmias and valvular heart disease. The clinically relevant question whether synthetic, non-biologic DMARDs are inferior to biologic DMARDs in terms of CVD outcomes remains not adequately addressed.
Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Cardiovascular Diseases; Cardiovascular System; Heart Disease Risk Factors; Humans; Prognosis; Protective Factors; Risk Assessment
PubMed: 31566134
DOI: 10.2174/1570161117666190930113837 -
Xenobiotica; the Fate of Foreign... Mar 2023BCRP (breast cancer resistance protein) is a crucial efflux transporter involved in the regulation of the pharmacokinetics and pharmacodynamics of a wide range of drugs....
BCRP (breast cancer resistance protein) is a crucial efflux transporter involved in the regulation of the pharmacokinetics and pharmacodynamics of a wide range of drugs. Herein, we aimed to investigate a potential role for the nuclear receptor REV-ERBα in the regulation of BCRP expression and sulfasalazine (a BCRP probe substrate) pharmacokinetics.Regulation of BCRP expression by REV-ERBα was assessed using mice and AML12 and CT26 cells. Pharmacokinetic analysis was performed with and wild-type mice after sulfasalazine administration.We found that the expression levels of BCRP mRNA and protein were downregulated in the liver and small intestine of -dificient mice. In line with this, ablation increased the systemic exposures of oral sulfasalazine.Positive regulation of BCRP expression and function by REV-ERBα was furtherly confirmed in AML12 and CT26 cells. Moreover, indirect regulation of expression by REV-ERBα was potentially mediated by a negative transcription factor DEC2, which is a downstream target of REV-ERBα.In conclusion, REV-ERBα positively regulates BCRP expression in mice, thereby affecting sulfasalazine pharmacokinetics.
Topics: Mice; Animals; Sulfasalazine; ATP Binding Cassette Transporter, Subfamily G, Member 2; Neoplasm Proteins; Gene Expression Regulation; Receptors, Cytoplasmic and Nuclear
PubMed: 37039301
DOI: 10.1080/00498254.2023.2200839 -
Acta Biomaterialia Jun 2022Ferroptosis shows promising potential in tumor treatment; however, factors that compromise the efficiency of the Fenton catalyst have limited its therapeutic...
Ferroptosis shows promising potential in tumor treatment; however, factors that compromise the efficiency of the Fenton catalyst have limited its therapeutic effectiveness. We developed a polydopamine-based nanoplatform constructed with ferric ion and sulfasalazine-loaded nanoparticles (Fe(III)PP@SAS NPs) for dual-functional ferrotherapy strategy of "sword and shield" through enhanced Fenton reaction and inactivation of glutathione peroxidase 4 (GPX4), respectively. Both the Fenton reaction-based hydroxyl radical (OH) production and sulfasalazine-driven GPX4 inhibition induced ferroptotic cell death, thus achieving synergistic cancer therapy. Near-infrared light irradiation and acidic tumor microenvironment enhanced the release of ferric ions and sulfasalazine from the Fe(III)PP@SAS NPs. In addition, the released iron ions underwent valence state change due to Fenton reaction and thus provided a supplementary T1-weighted signal for in situ visualization of the tumor based on magnetic resonance imaging. The Fe(III)PP@SAS NPs exhibited high pro-ferroptosis performance by utilizing OH radicals as a "sword" to attack cancer cells and the GPX4 inhibitor to break down the "shield" of cancer cells, thus showing potential for cancer treatment. STATEMENT OF SIGNIFICANCE: Several strategies of cancer therapy based on ferroptosis have emerged in recent years, which have provided new insights into designing materials for therapeutic applications. The antitumor efficacy of ferroptosis is, however, still unsatisfactory, mainly because of insufficient intracellular pro-ferroptotic stimuli. In the current study, we report a multifunctional theranostic nanoplatform, namely Fe(III)PP@SAS, with three-fold synergistic effect; this nanoplatform has excellent theranostic potential with multifunctional ferrotherapy.
Topics: Cell Line, Tumor; Humans; Indoles; Ions; Iron; Nanoparticles; Neoplasms; Phospholipid Hydroperoxide Glutathione Peroxidase; Polymers; Sulfasalazine; Tumor Microenvironment
PubMed: 35470077
DOI: 10.1016/j.actbio.2022.04.024 -
Cell Biochemistry and Function Mar 2021Cystine/glutamic acid reverse transporter (System X ), a member of the amino acid transporter family, consists of two subunits, light chain xCT and heavy chain 4F2hc.... (Review)
Review
Cystine/glutamic acid reverse transporter (System X ), a member of the amino acid transporter family, consists of two subunits, light chain xCT and heavy chain 4F2hc. xCT is the cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11), which promotes cystine uptake and glutathione biosynthetic, thus protecting against oxidative stress and ferroptosis. Studies have confirmed that xCT is highly expressed in a variety of tumour and is associated with tumour proliferation, invasion, metastasis, drug resistance and ferroptosis, and can be used as a potential target for tumour treatment. This review provides insights into the biological effects of xCT and contribute to the development of new xCT-based strategies.
Topics: Amino Acid Transport System y+; Anti-Inflammatory Agents, Non-Steroidal; Ferroptosis; Glutathione; Humans; Neoplasms; Oxidative Stress; RNA, Small Interfering; Reactive Oxygen Species; Sulfasalazine
PubMed: 32749001
DOI: 10.1002/cbf.3581 -
Biochemical Pharmacology Aug 2023Ulcerative Colitis (UC) is a chronic idiopathic inflammatory bowel disease in which the colon's lining becomes inflamed. Exploring herbal remedies that can recover...
Genistein and/or sulfasalazine ameliorate acetic acid-induced ulcerative colitis in rats via modulating INF-γ/JAK1/STAT1/IRF-1, TLR-4/NF-κB/IL-6, and JAK2/STAT3/COX-2 crosstalk.
Ulcerative Colitis (UC) is a chronic idiopathic inflammatory bowel disease in which the colon's lining becomes inflamed. Exploring herbal remedies that can recover mucosal damage is becoming popular in UC. The study aims to investigate the probable colo-protective effect of a natural isoflavone, genistein (GEN), and/or a drug, sulfasalazine (SZ), against acetic acid (AA)-induced UC in rats, in addition to exploring the possible underlying mechanisms. UC was induced by the intrarectal installation of 1-2 ml of 5% diluted AA for 24 h. Ulcerated rats were allocated into the disease group and three treated groups, with SZ (100 mg/kg), GEN (100 mg/kg), and their combination for 14 days, besides the control groups. The anti-colitic efficacy of GEN and/or SZ was evidenced by hindering the AA-induced weight loss, colon edema, and macroscopic scores, besides reduced disease activity index and colon weight/length ratio. Furthermore, treatments attenuated the colon histopathological injury scores, increased the number of goblet cells, and lessened fibrosis. Both treatments reduced the up-regulation of INF-γ/JAK1/STAT1 and INF-γ /TLR-4/ NF-κB signaling pathways and modulated the IRF-1/iNOS/NO and IL-6/JAK2/STAT3/COX-2 pathways and consequently, reduced the levels of TNF-α and IL-1β. Moreover, both treatments diminished oxidative stress, which appeared by reducing the MPO level and elevating the SOD activity, and hindered apoptosis; proved by the decreased immunohistochemical expression of caspase-3. The current findings offer novel insights into the protective effects of GEN and suggest a superior benefit of combining GEN with SZ, over either drug alone, in the UC management.
Topics: Rats; Animals; Colitis, Ulcerative; Sulfasalazine; NF-kappa B; Interleukin-6; Cyclooxygenase 2; Genistein; Toll-Like Receptor 4; Acetic Acid; Colon
PubMed: 37414101
DOI: 10.1016/j.bcp.2023.115673 -
Blood Advances Jan 2024Cysteine is a nonessential amino acid required for protein synthesis, the generation of the antioxidant glutathione, and for synthesizing the nonproteinogenic amino acid...
Cysteine is a nonessential amino acid required for protein synthesis, the generation of the antioxidant glutathione, and for synthesizing the nonproteinogenic amino acid taurine. Here, we highlight the broad sensitivity of leukemic stem and progenitor cells to cysteine depletion. By CRISPR/CRISPR-associated protein 9-mediated knockout of cystathionine-γ-lyase, the cystathionine-to-cysteine converting enzyme, and by metabolite supplementation studies upstream of cysteine, we functionally prove that cysteine is not synthesized from methionine in acute myeloid leukemia (AML) cells. Therefore, although perhaps nutritionally nonessential, cysteine must be imported for survival of these specific cell types. Depletion of cyst(e)ine increased reactive oxygen species (ROS) levels, and cell death was induced predominantly as a consequence of glutathione deprivation. nicotinamide adenine dinucleotide phosphate hydrogen oxidase inhibition strongly rescued viability after cysteine depletion, highlighting this as an important source of ROS in AML. ROS-induced cell death was mediated via ferroptosis, and inhibition of glutathione peroxidase 4 (GPX4), which functions in reducing lipid peroxides, was also highly toxic. We therefore propose that GPX4 is likely key in mediating the antioxidant activity of glutathione. In line, inhibition of the ROS scavenger thioredoxin reductase with auranofin also impaired cell viability, whereby we find that oxidative phosphorylation-driven AML subtypes, in particular, are highly dependent on thioredoxin-mediated protection against ferroptosis. Although inhibition of the cystine-glutamine antiporter by sulfasalazine was ineffective as a monotherapy, its combination with L-buthionine-sulfoximine (BSO) further improved AML ferroptosis induction. We propose the combination of either sulfasalazine or antioxidant machinery inhibitors along with ROS inducers such as BSO or chemotherapy for further preclinical testing.
Topics: Humans; Cysteine; Reactive Oxygen Species; Antioxidants; Ferroptosis; Cystathionine; Sulfasalazine; Amino Acids; Glutathione; Buthionine Sulfoximine; Leukemia, Myeloid, Acute
PubMed: 37906522
DOI: 10.1182/bloodadvances.2023010786 -
Molecular Biology Reports May 2023With advancing age of stem cells, dysregulation of various processes at the cellular level occurs, thereby decreasing their regeneration potential. One of the changes...
BACKGROUND
With advancing age of stem cells, dysregulation of various processes at the cellular level occurs, thereby decreasing their regeneration potential. One of the changes that occurs during the aging process is the accumulation of reactive oxygen species (ROS), which accelerates the processes of cellular senescence and cell death. The aim of this study is to evaluate two antioxidant compounds; Chromotrope 2B and Sulfasalazine, for their antioxidant effects on young and old rat bone marrow mesenchymal stem cells (MSCs).
METHODS AND RESULTS
Oxidative stress was induced in MSCs by 5 µM dexamethasone for 96 h and the cells were treated with Chromotrope 2B or Sulfasalazine, 50 µM each. The effects of antioxidant treatment following oxidative stress induction was evaluated by transcriptional profiling of genes involved in the oxidative stress and telomere maintenance. Expression levels of Cat, Gpx7, Sod1, Dhcr24, Idh1, and Txnrd2 were found to be increased in young MSCs (yMSCs) as a result of oxidative stress, while Duox2, Parp1, and Tert1 expression were found to be decreased as compared to the control. In old MSCs (oMSCs), the expressions of Dhcr24, Txnrd2, and Parp1 increased, while that of Duox2, Gpx7, Idh1, and Sod1 decreased following oxidative stress. In both MSC groups, Chromotrope 2B prompted decrease in the ROS generation before and after the induction of oxidative stress. In oMSCs, ROS content was significantly reduced in the Sulfasalazine treated group.
CONCLUSION
Our findings suggest that both Chromotrope 2B and Sulfasalazine possess the potential to reduce the ROS content in both age groups, though the latter was found to be more potent. These compounds can be used to precondition MSCs to enhance their regenerative potential for future cell-based therapeutics.
Topics: Mice; Rats; Animals; Antioxidants; Reactive Oxygen Species; Sulfasalazine; Superoxide Dismutase-1; Bone Marrow; Dual Oxidases; Oxidative Stress; Mesenchymal Stem Cells; Thioredoxin Reductase 2
PubMed: 36877347
DOI: 10.1007/s11033-023-08321-8 -
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