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BioImpacts : BI 2016Sulfasalazine is a drug commonly administrated against inflammatory-based disorders. On the other hand, kidney and liver injury are serious adverse events accompanied by...
INTRODUCTION
Sulfasalazine is a drug commonly administrated against inflammatory-based disorders. On the other hand, kidney and liver injury are serious adverse events accompanied by sulfasalazine administration. No specific therapeutic option is available against this complication. The current investigation was designed to evaluate the potential protective effects of taurine against sulfasalazine-induced kidney and liver injury in rats.
METHODS
Male Sprague-Dawley rats were administered with sulfasalazine (600 mg/kg, oral) for 14 consecutive days. Animals received different doses of taurine (250, 500 and 1000 mg/ kg, i.p.) every day. Markers of organ injury were evaluated on day 15(th), 24 h after the last dose of sulfasalazine.
RESULTS
Sulfasalazine caused renal and hepatic injury as judged by an increase in serum level of creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP). The levels of reactive oxygen species (ROS) and lipid peroxidation were raised in kidney and liver of sulfasalazine-treated animals. Moreover, tissue glutathione reservoirs were depleted after sulfasalazine administration. Histopathological changes of kidney and liver also endorsed organ injury. Taurine administration (250, 500 and 1000 mg/kg/day, i.p) alleviated sulfasalazine-induced renal and hepatic damage.
CONCLUSION
Taurine administration could serve as a potential protective agent with therapeutic capabilities against sulfasalazine adverse effects.
PubMed: 27340618
DOI: 10.15171/bi.2016.01 -
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 -
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 -
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 -
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 -
Mediators of Inflammation 2017Behçet's disease (BD) is a multisystemic disorder of unknown etiology mainly defined by recurrent oral aphthosis, genital ulcers, and chronic relapsing bilateral... (Review)
Review
Behçet's disease (BD) is a multisystemic disorder of unknown etiology mainly defined by recurrent oral aphthosis, genital ulcers, and chronic relapsing bilateral uveitis, all of which represent the "stigmata" of disease. However, many other organs including the vascular, neurological, musculoskeletal, and gastrointestinal systems can be affected. The gastrointestinal involvement in Behçet's disease (GIBD), along with the neurological and vascular ones, represents the most feared clinical manifestation of BD and shares many symptoms with inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. Consequently, the differential diagnosis is often a daunting task, albeit the presence of typical endoscopic and pathologic findings may be a valuable aid to the exact diagnosis. To date, there are no standardized medical treatments for GIBD; therefore therapy should be tailored to the single patient and based on the severity of the clinical features and their complications. This work provides a digest of all current experience and evidence about pharmacological agents suggested by the medical literature as having a potential role for managing the dreadful features of GIBD.
Topics: Adrenal Cortex Hormones; Animals; Behcet Syndrome; Gastrointestinal Tract; Humans; Immunologic Factors; Mesalamine; Sulfasalazine; Thalidomide
PubMed: 28210071
DOI: 10.1155/2017/1460491 -
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 -
Molecules (Basel, Switzerland) Feb 2021Sulfasalazine (SAS), an anti-inflammatory drug with potent cysteine/glutamate antiporter system xc-(SXC) inhibition has recently shown beneficial effects in...
Sulfasalazine (SAS), an anti-inflammatory drug with potent cysteine/glutamate antiporter system xc-(SXC) inhibition has recently shown beneficial effects in brain-related diseases. Despite many reports related to central nervous system (CNS) effect of SAS, pharmacokinetics (PK) and metabolite identification studies in the brain for SAS were quite limited. The aim of this study was to investigate the pharmacokinetics and metabolite identification of SAS and their distributions in mouse brain. Using in vivo brain exposure studies (neuro PK), the PK parameters of SAS was calculated for plasma as well as brain following intravenous and oral administration at 10 mg/kg and 50 mg/kg in mouse, respectively. In addition, in vivo metabolite identification (MetID) studies of SAS in plasma and brain were also conducted. The concentration of SAS in brain was much lower than that in plasma and only 1.26% of SAS was detected in mouse brain when compared to the SAS concentration in plasma (brain to plasma ratio (%): 1.26). In the MetID study, sulfapyridine (SP), hydroxy-sulfapyridine (SP-OH), and N-acetyl sulfapyridine (Ac-SP) were identified in plasma, whereas only SP and Ac-SP were identified as significant metabolites in brain. As a conclusion, our results suggest that the metabolites of SAS such as SP and Ac-SP might be responsible for the pharmacological effect in brain, not the SAS itself.
Topics: Animals; Brain; Male; Mass Spectrometry; Mice; Mice, Inbred ICR; Sulfasalazine; Time Factors
PubMed: 33671835
DOI: 10.3390/molecules26041179 -
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