RESUMO
BACKGROUND: Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity in patient management is largely attributed to an incomplete understanding of the underlying pathological mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent inflammation and heightened excitatory transmission within pain pathways, stands as a significant contributor to persistent pain. Considering the role of the cystine/glutamate exchanger (also designated as system xc-) in modulating glutamate transmission and in supporting neuroinflammatory responses, we investigated the contribution of this exchanger in the development of neuropathic pain. METHODS: We examined the implication of system xc- by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system xc- (using mice lacking the system xc- specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers. RESULTS: The sciatic nerve lesion was found to upregulate system xc- at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system xc- had an analgesic effect in lesioned mice. CONCLUSION: Together, these observations provide evidence for a role of system xc- in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system xc-. These findings suggest that drugs targeting system xc- could contribute to prevent or reduce neuropathic pain.
Assuntos
Sistema y+ de Transporte de Aminoácidos , Neuralgia , Doenças Neuroinflamatórias , Animais , Feminino , Camundongos , Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/deficiência , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Biomarcadores/metabolismo , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/complicações , Gliose/tratamento farmacológico , Gliose/fisiopatologia , Ácido Glutâmico/metabolismo , Hiperalgesia/tratamento farmacológico , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Neuralgia/complicações , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Neuralgia/prevenção & controle , Doenças Neuroinflamatórias/complicações , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/fisiopatologia , Doenças Neuroinflamatórias/prevenção & controle , Fenótipo , Reprodutibilidade dos Testes , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neuropatia Ciática/complicações , Neuropatia Ciática/fisiopatologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêuticoRESUMO
Photothermal therapy has emerged as a promising approach for cancer treatment, which can cause ferroptosis to enhance immunotherapeutic efficacy. However, excessively generated immunogenicity will induce serious inflammatory response syndrome, resulting in a discounted therapeutic effect. Herein, a kind of NIR absorption small organic chromophore nanoparticles (TTHM NPs) with high photothermal conversion efficiency (68.33%) is developed, which can induce mitochondria dysfunction, generate mitochondrial superoxide, and following ferroptosis. TTHM NPs-based photothermal therapy is combined with Sulfasalazine (SUZ), a kind of nonsteroidal anti-inflammatory drugs, to weaken inflammation and promote ferroptosis through suppressing glutamate/cystine (Glu/Cys) antiporter system Xc- (xCT). Additionally, the combination of SUZ with PTT can induce immunogenic cell death (ICD), followed by promoting the maturation of DCs and the attraction of CD8+ T cell, which will secrete IFN-γ and trigger self-amplified ferroptosis via inhibiting xCT and simulating Acyl-CoA synthetase long-chain family member 4 (ACSL4). Moreover, the in vivo results demonstrate that this combination therapy can suppress the expression of inflammatory factors, enhance dendritic cell activation, facilitate T-cell infiltration, and realize effective thermal elimination of primary tumors and distant tumors. In general, this work provides an excellent example of combined medication and stimulates new thinking about onco-therapy and inflammatory response.
Assuntos
Anti-Inflamatórios não Esteroides , Ferroptose , Nanopartículas , Terapia Fototérmica , Microambiente Tumoral , Ferroptose/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Nanopartículas/química , Camundongos , Humanos , Sulfassalazina/farmacologia , Inflamação/patologia , Raios Infravermelhos , Linhagem Celular Tumoral , Neoplasias/terapia , Neoplasias/patologia , Neoplasias/tratamento farmacológicoRESUMO
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.
Assuntos
Artrite Reumatoide , Ferroptose , Camundongos , Animais , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Artrite Reumatoide/metabolismo , Células Cultivadas , Proliferação de CélulasRESUMO
This study employs density functional theory to explore the interaction between ibuprofen (IBU) and silica, emphasizing the influence of the trimethylsilyl (TMS) functional group for designing pH-responsive drug carriers. The surface (S) and drug (D) molecules' neutral (0) or deprotonated (-1) states were taken into consideration during the investigation. The likelihood of these states was determined based on the pKa values and the desired pH conditions. To calculate the pH-dependent interaction energy (EintpH), four different situations have been identified: S0D0, S0D-1, S-1D0, and S-1D-1.The electrostatic component of interaction energy aligns favorably with its theoretical value in both the Debye-Hückel and Grahame models. The investigation has gathered first-hand experimental data on the drug loading and release of pH-responsive mesoporous silica nanoparticles. Effective drug loading was observed in the acidic environment of the stomach (pH 2-5), followed by a release in the slightly basic to neutral pH of the small intestine (pH 7.4), These findings align with existing literature. The results revealed horizontal drug adherence on silica surfaces, improving binding capabilities. Comparisons were made with combinations involving carboxylated carbon nanotubes and ibuprofen, silica, and sulfasalazine, and silica and alendronate, exploring drug loading/release dynamics associated with positive/negative interaction energies. The investigation, supported by experimental data, contributes valuable insights into pH-responsive mesoporous silica nanoparticles, offering new design possibilities for drug carriers.
Assuntos
Ibuprofeno , Nanotubos de Carbono , Ibuprofeno/farmacologia , Portadores de Fármacos , Sulfassalazina/farmacologia , Alendronato , Dióxido de Silício , Concentração de Íons de Hidrogênio , PorosidadeRESUMO
Melanoma is a malignant tumor that originates from melanocytes. The incidence of melanoma is increasing worldwide, partially because of its insensitivity to radiotherapy or chemotherapy. Therefore, effective treatments for melanoma are urgently required. In this study, we employed folic acid-modified sulfasalazine long-circulating liposomes (FA-SSZ-Lips) to precisely target drug delivery to melanoma cells, eliciting ferroptosis effectively. The synthesized FA-SSZ-Lips were characterized as small spheres of a double-layer membrane, a particle size of 110.1 nm, and a ζ-potential of -22.8 ± 0.66 mV. FA-SSZ-Lips are effective drug carriers with SSZ-loading ratio and SSZ release rate of 6.2 ± 0.10%, and 72.63 ± 1.40%, respectively. The liposomes enhanced SSZ solubility, and the folic acid modifications increased the liposome targeting to melanoma cells. Compared with SSZ alone, FA-SSZ-Lips more strongly inhibited B16F10 cell growth, significantly disrupted the intracellular redox balance, and induced ferroptosis. After treatment, considerable differences were observed in the tumor volumes between FA-SSZ-Lips and phosphate-buffered saline control groups. The tumor growth-inhibition value of the FA-SSZ-Lips group reached 70.09%. Thus, FA-SSZ-Lips exhibited favorable antitumor effects in vitro and in vivo and are a promising strategy for melanoma treatment.
Assuntos
Ferroptose , Melanoma , Humanos , Lipossomos , Sulfassalazina/farmacologia , Melanoma/tratamento farmacológico , Ácido Fólico/farmacologia , Ácido Fólico/uso terapêuticoRESUMO
Using a rat autologous orthotopic liver transplantation (AOLT) model and liver cold ischemia-reperfusion (I/R)-induced intestinal injury, we clarified whether ferroptosis occurred in rat AOLT cold I/R-induced intestinal injury. Additionally, the role and possible mechanism of the ferroptosis activator sulfasalazine (SAS) in intestinal injury-induced ferroptosis in rats with AOLT liver cold I/R were investigated. Sixty specific pathogen free (SPF)-grade adult male SpragueâDawley (SD) rats were randomly divided into 5 groups using the random number table method (n = 12). Six rats were randomly selected at 6 hour (h) and 24 h after I/R. Inferior vena cava blood specimens were collected from the portal vein (PV) opening at 6 h and 24 h. The concentrations of serum malondialdehyde (MDA), serum interleukin 6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA). Ileal tissue was obtained from the PV opening in rats in each group at 6 h and 24 h, and ileal tissue sections were observed under light microscopy. The contents of intestinal MDA, superoxide dismutase (SOD), glutathione(GSH), glutathione peroxidase 4 (GPX4), and tissue iron were determined by ELISA, and the expression of GPX4 and the cysteine glutamate reverse transporter light chain protein (xCT) was determined by Western blot. The experimental results show that ferroptosis is involved in the pathophysiological process of intestinal injury induced by cold hepatic ischemia-reperfusion in AOLT rats. In addition, SAS (500 mg/kg) may inhibit the cystine/glutamate antiporters (System Xc¯)/GSH/GPX4 signal axis in intestinal injury induced by cold I/R in rat AOLT liver, or iron overload after reperfusion, causing a massive accumulation of L-ROS and activating cellular ferroptosis, further aggravate the intestinal injury.
Assuntos
Ferroptose , Transplante de Fígado , Traumatismo por Reperfusão , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Transplante de Fígado/efeitos adversos , Sulfassalazina/farmacologia , Traumatismo por Reperfusão/metabolismo , Glutationa/metabolismo , GlutamatosRESUMO
Sulfasalazine is a prodrug known to be effective for the treatment of inflammatory bowel disease (IBD)-associated peripheral spondyloarthritis (pSpA), but the mechanistic role for the gut microbiome in regulating its clinical efficacy is not well understood. Here, treatment of 22 IBD-pSpA subjects with sulfasalazine identifies clinical responders with a gut microbiome enriched in Faecalibacterium prausnitzii and the capacity for butyrate production. Sulfapyridine promotes butyrate production and transcription of the butyrate synthesis gene but in F. prausnitzii in vitro, which is suppressed by excess folate. Sulfasalazine therapy enhances fecal butyrate production and limits colitis in wild-type and gnotobiotic mice colonized with responder, but not non-responder, microbiomes. F. prausnitzii is sufficient to restore sulfasalazine protection from colitis in gnotobiotic mice colonized with non-responder microbiomes. These findings reveal a mechanistic link between the efficacy of sulfasalazine therapy and the gut microbiome with the potential to guide diagnostic and therapeutic approaches for IBD-pSpA.
Assuntos
Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Humanos , Camundongos , Animais , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Resultado do Tratamento , ButiratosRESUMO
AIMS: The cellular defense system against oxidative stress is important for the survival ability and sensitization in chemotherapy; however, the regulatory mechanisms remain unknown in triple-negative breast cancer (TNBC) cells. This study aimed to investigate the relationship between ferroptosis and autophagy by targeting the defense of oxidative stress through the cystine transporter (xCT) using sulfasalazine (SASP), which is a widely employed xCT inhibitor. MAIN METHODS: We analyzed the cell death process of SASP in human TNBC cells, and examined the effects of SASP on tumor progression by using xenograft mouse model. KEY FINDINGS: TNBC cells demonstrated a high defense capacity against reactive oxidative species through xCT. SASP significantly attenuated oxidative stress resistance in MDA-MB-231, which is a generally used model cell as TNBC, through decreased glutathione levels, causing a marked iron-dependent ferroptotic cell death induction. Moreover, autophagy was required to trigger efficient SASP-induced ferroptosis at the early stage of cell death. Tamoxifen, which is currently in clinical use as the gold standard for endocrine therapy of estrogen receptor-positive breast cancer, was a beneficial tool as an autophagy regulator under ferroptotic cell death by SASP. Additionally, SASP suppressed tumor growth and metastasis progression through total glutathione reduction in the primary tumor, indicating high anticancer activity against TNBC without liver injury in vivo. SIGNIFICANCE: We revealed that SASP can efficiently induce ferroptosis associated with autophagy and that an understanding of the mechanism of cell death regulation by SASP is a promising new strategy for TNBC therapy and drug repositioning.
Assuntos
Ferroptose , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Sulfassalazina/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo , Autofagia , Glutationa/metabolismo , Linhagem Celular TumoralRESUMO
Although only Saccharomyces boulardii has been studied for ulcerative colitis (UC), probiotic yeasts have immense therapeutic potential. Herein, we evaluated the kefir yeast Kluyveromyces marxianus A4 (Km A4) and its anti-inflammatory effect with sulfasalazine in BALB/c mice with dextran sulfate sodium (DSS)-induced colitis. Oral administration continued for 7 days after the mice were randomly divided into seven groups: control (CON, normal mice administered with saline), DSS-induced colitis mice administered saline (DSS), and DSS-induced colitis mice administered sulfasalazine only (S), Km A4 only (A4), Km A4 plus sulfasalazine (A4 + S), S. boulardii ATCC MYA-796 (Sb MYA-796) only (Sb), and Sb MYA-796 plus sulfasalazine (Sb + S). The ß-glucan content of Km A4 was significantly higher than that of Sb MYA-796 (P < 0.05). Body weight gain (BWG) significantly correlated with colon length, cyclooxygenase-2 (Cox-2) levels, and Bacteroides abundance (P < 0.05). In colitis-induced mice, the A4 + S group had the lowest histological score (6.00) compared to the DSS group (12.67), indicating the anti-inflammatory effects of this combination. The A4 + S group showed significantly downregulated expression of interleukin (Il)-6, tumor necrosis factor-α (Tnf-α), and Cox-2 and upregulated expression of Il-10 and occludin (Ocln) compared to the DSS group. Mice treated with A4 + S had enhanced Bacteroides abundance in their gut microbiota compared with the DSS group (P < 0.05). Bacteroides were significantly correlated with all colitis biomarkers (BWG, colon length, Il-6, Tnf-α, Il-10, Cox-2, and Ocln; P < 0.05). The anti-inflammatory effects of Km A4 could be attributed to high ß-glucan content and gut microbiota modulation. Thus, treatment with Km A4 and sulfasalazine could alleviate UC.
Assuntos
Anti-Inflamatórios , Colite Ulcerativa , Microbioma Gastrointestinal , Kluyveromyces , Camundongos Endogâmicos BALB C , Probióticos , Sulfassalazina , Animais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/microbiologia , Colite Ulcerativa/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Sulfassalazina/farmacologia , Camundongos , Anti-Inflamatórios/farmacologia , Probióticos/farmacologia , Masculino , Kefir/microbiologia , Sulfato de Dextrana/efeitos adversos , Humanos , Colo/microbiologia , Colo/metabolismo , Colo/efeitos dos fármacos , Colo/patologia , Modelos Animais de Doenças , FemininoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) which has a global impact on the health care system with its recurrent and incompletely curable characteristics, affects the patients' quality of life. Gilaburu (GB; Viburnum opulus L.) is a fruit with rich polyphenol ingredient which is used ethnobotanically in Türkiye for medicinal purposes (for example, to pass kidney stones, to treat stomach, heart, and liver diseases, hemorrhages, hypertension, ulcers, common cold, tuberculosis, rheumatic and menstrual pain, and diabetes). On the other hand, the effects of GB in the experimental UC model have not been studied. AIM OF THE STUDY: This study aimed to explore the potential antioxidant and anti-inflammatory effects of GB fruit extract in improving acetic acid (AA)-induced UC. MATERIALS AND METHODS: Starting immediately after (AA + GB group) or 1 week before (GB + AA + GB group) the colitis induced by intrarectal AA (5%; v/v) administration, the rats orally received GB (100 mg/kg) once per day for 3 days. The control and AA groups were administered orally saline (1 ml), while the AA + SS group were administered sulfasalazine (SS; 100 mg/kg; orally) as a positive control once per day for 3 days. Distal colonic tissue specimens were obtained for the histological and biochemical [myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), chemiluminescence (CL), caspase-3, 8-hydroxy-2'-deoxyguanosine (8-OHdG), matrix metalloproteinase (MMP)-9, transforming growth factor (TGF)-ß1, smad-3 and cytokine (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, interferon (IFN)-γ), measurements] evaluations on the 3rd day. RESULTS: Elevated macroscopic and microscopic damage scores, high tissue wet weight values, increased tissue-associated MPO, MDA, CL, caspase-3, 8-OHdG, cytokines (TNF-α, IL-1ß, IL-6, IL-8), MMP-9, TGF-ß1, smad-3 levels, and decreased GSH values of the AA group were all reversed by GB treatments (AA + GB and GB + AA + GB groups) (p < 0.05-0.001). However, sulfasalazine treatment (AA + SS group) did not change the IL-8, 8-OHdG, MMP-9, and TGF-ß1 measurements significantly. CONCLUSIONS: Gilaburu shows both anti-inflammatory and antioxidant effects against AA-induced colonic damage by suppressing neutrophil infiltration, regulating inflammatory mediators, inhibiting reactive species production, lipid peroxidation, and apoptosis, conserving endogenous antioxidant glutathione, and ameliorating oxidative DNA damage. Since the current ulcerative colitis drugs display limited benefits and adverse side effects, potential therapeutic and/or prophylactic role of gilaburu can be evaluated in ulcerative colitis.
Assuntos
Colite Ulcerativa , Viburnum , Humanos , Ratos , Animais , Colite Ulcerativa/tratamento farmacológico , Ácido Acético/toxicidade , Ácido Acético/metabolismo , Oxidantes/metabolismo , Caspase 3/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Sulfassalazina/farmacologia , Interleucina-6/metabolismo , Frutas/metabolismo , Interleucina-8/metabolismo , Qualidade de Vida , Colo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Citocinas/metabolismo , Glutationa/metabolismo , Anti-Inflamatórios/efeitos adversosRESUMO
BACKGROUND: Inflammatory bowel disease (IBD) is a type of immune-mediated condition associated with intestinal homeostasis. Our preliminary studies disclosed that Cichorium intybus L., a traditional medicinal plant, also known as Chicory in Western countries, contained substantial phenolic acids displaying significant anti-inflammatory activities. We recognized the potential of harnessing Chicory for the treatment of IBD, prompting a need for in-depth investigation into the underlying mechanisms. METHODS: On the third day, mice were given 100, 200 mg/kg of total phenolic acids (PA) from Chicory and 200 mg/kg of sulfasalazine (SASP) via gavage, while dextran sodium sulfate (DSS) concentration was 2.5 % for one week. The study measured and evaluated various health markers including body weight, disease activity index (DAI), colon length, spleen index, histological score, serum concentrations of myeloperoxidase (MPO), nitric oxide (NO), superoxide dismutase (SOD), lipid oxidation (MDA), and inflammatory factors. We evaluated the TRP family and the NLRP3 inflammatory signaling pathways by Western blot, while 16S rDNA sequencing was used to track the effects of PA on gut microbes. RESULTS: It was shown that PA ameliorated the weight loss trend, attenuated inflammatory damage, regulated oxidative stress levels, and repaired the intestinal barrier in DSS mice. Analyses of Western blots demonstrated that PA suppressed what was expressed of transient receptor potential family TRPV4, TRPA1, and the expression of NLRP3 inflammatory signaling pathway, NLRP3 and GSDMD. In addition, PA exerted therapeutic effects on IBD by regulating gut microbiota richness and diversity. Meanwhile, the result of the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis showed that gut microbiota was mainly related to Membrane Transport, Replication and Repair, Carbohydrate Metabolism and Amino Acid Metabolism. CONCLUSION: PA derived from Chicory may have therapeutic effects on IBD by regulating the TRPV4/NLRP3 signaling pathway and gut microbiome. This study provides new insights into the effects of phenolic acids from Chicory on TRP ion channels and gut microbiota, revealing previously unexplored modes of action.
Assuntos
Cichorium intybus , Colite , Sulfato de Dextrana , Microbioma Gastrointestinal , Hidroxibenzoatos , Raízes de Plantas , Transdução de Sinais , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Cichorium intybus/química , Transdução de Sinais/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Colite/tratamento farmacológico , Colite/induzido quimicamente , Raízes de Plantas/química , Masculino , Camundongos , Anti-Inflamatórios/farmacologia , Camundongos Endogâmicos C57BL , Colo/efeitos dos fármacos , Colo/metabolismo , Extratos Vegetais/farmacologia , Sulfassalazina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/induzido quimicamente , Canais de Cátion TRPV/metabolismoRESUMO
Chemodynamic therapy (CDT) is a promising strategy for cancer treatment, however, its application is restricted by low hydrogen peroxide (H2O2) concentration, insufficient reactive oxygen species (ROS) generation, and high glutathione (GSH) levels. Here, we developed an injectable thermosensitive hydrogel (DSUC-Gel) based on "sea urchin-like" copper sulfide nanoparticles (UCuS) loaded with dihydroartemisinin (DHA) and sulfasalazine (SAS) to overcome these limitations of CDT. DSUC was cleaved to release DHA, SAS and Cu2+ under acidic tumor microenvironment to enhance CDT. DHA with peroxide bridge responded to intracellular Fe2+ to alleviate H2O2 deficiency. SAS prevented GSH synthesis by targeting SLC7A11 and inhibited glutathione peroxidase (GPX4) activity to induce endogenous ferroptosis. ROS produced by Fenton-like reaction of Cu2+ promoted lipid peroxidation (LPO) accumulation to promote ferroptosis. Enhanced CDT and ferroptosis induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration. As a result, DSUC-Gel significantly inhibited tumor growth both in vitro and in vivo. Our study provides a novel approach for enhancing anti-tumor efficacy by combining CDT, endogenous ferroptosis and ICD.
Assuntos
Artemisininas , Cobre , Ferroptose , Hidrogéis , Espécies Reativas de Oxigênio , Sulfassalazina , Ferroptose/efeitos dos fármacos , Animais , Cobre/química , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Artemisininas/farmacologia , Artemisininas/administração & dosagem , Artemisininas/química , Linhagem Celular Tumoral , Sulfassalazina/farmacologia , Sulfassalazina/administração & dosagem , Humanos , Sulfetos/farmacologia , Sulfetos/administração & dosagem , Sulfetos/química , Nanopartículas , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Peroxidação de Lipídeos/efeitos dos fármacos , Feminino , Peróxido de Hidrogênio , Glutationa/metabolismo , Camundongos Endogâmicos BALB CRESUMO
This paper reports the development, characterization and
O trabalho reporta o desenvolvimento, caracterização e estudo
Assuntos
Humanos , Química Farmacêutica , Sulfassalazina/administração & dosagem , Sulfassalazina/farmacocinética , Sulfassalazina/farmacologia , Sistemas de Liberação de Medicamentos , Gastroenterite/tratamento farmacológicoRESUMO
En 1942 la reumatóloga sueca Dra. Nana Svartz comunicó los favorables resultados obtenidos con la administración de asulfidina a pacientes portadores de artritis y diarrea
Assuntos
Sulfassalazina/uso terapêutico , Ácidos Aminossalicílicos/farmacologia , Sulfapiridina/farmacologia , Sulfassalazina , Sulfassalazina/química , Sulfassalazina/farmacologiaRESUMO
1. Evidence is presented for the occurrence of type 1 prostaglandin 15-hidroxydehydrogenase in human rectal mucosa. No evidence of the presence of type 2 dnzyme was found. 2. A 15-keto-prostaglandin reductase, responsible for the breakdown of 13, 14-dihydro 15-keto prostaglandins to 13, 14-dihydro prostaglandins, was also present in human rectal mucosa. 3. Ulcerative colitis patients catabolized prostaglandins to the same extent as the control group. PGE was catabolized significantly better than PGF2 alfa. 4. 5-Aminosalicylic acid and sulphapyridine did not affect prostaglandin catabolism. Sulphasalazine, methilsulphasalazine, indomethacin, flurbiprofen, disodium cromoglycate, sodium salicylate and carbenoxolone sodium inhibited prostaglandin catabolism to the same extent in both groups.Salicylazosulphadimidine was a more potent inhibitor of PGE1 catabolism than of PGF2alfa. 5. The increased prostaglandin synthesis reported for ulcerative colitis patients was not paralleled by increased catabolism, a fact possibly contributing to the accumulation of such compounds in the diseased state
Assuntos
Adulto , Pessoa de Meia-Idade , Humanos , Masculino , Feminino , Ácidos Aminossalicílicos/farmacologia , Colite Ulcerativa/metabolismo , Prostaglandinas E/metabolismo , Prostaglandinas F/metabolismo , Sulfassalazina/farmacologia , Ácidos Aminossalicílicos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Mucosa Intestinal/patologia , NADP/metabolismo , Sulfassalazina/uso terapêuticoRESUMO
The in vitro action of sulphaslazine, BW 755-C and indomethacin on phytohemaglutinin P-induced human peripheral brood mononuclear cell activation was studied. Sulphasalazine increased, while indomethacin and BW 755-C decreased, prostaglandin E2 (PGE2) accumulation in activated cultures. When used together with indomethacin or BW 755-C, sulpjasalazine did not counteract the inhibiton of PGE2 caused by the other two. Sulphasalazine inhibited phytohemagglutinin P-induced cell activation in a concentration-dependent manner even when used together with indomethacin or BW 755-C. BW 755-C inhibited cell activation at 350 micronM, wehreas at 11, whereas at 11 micronM only increased sulphasalazine-induced inhibition. The implications of these findings on the etiopathology of inflammatory bowel disease are discussed