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1.
Molecules ; 26(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34299424

RESUMO

The gut epithelium is a mechanical barrier that protects the host from the luminal microenvironment and interacts with the gut microflora, which influences the development and progression of ulcerative colitis (UC). Licochalcone A (LA) exerts anti-inflammatory effects against UC; however, whether it also regulates both the gut barrier and microbiota during colitis is unknown. The current study was conducted to reveal the regulatory effects of LA on the intestinal epithelium and gut microflora in C57BL/6 mice subjected to dextran sodium sulfate (DSS). Sulfasalazine (SASP) was used as the positive control. Results of clinical symptoms evaluation, hematoxylin, and eosin (H&E) staining, and enzyme-linked immunosorbent (ELISA) assays showed that LA significantly inhibited DSS-induced weight loss, disease activity index (DAI) increase, histological damage, and gut inflammation. Additionally, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and immunohistochemical (IHC) analysis showed that LA maintained the integrity of the intestinal barrier by suppressing cell apoptosis and preserving the expression of tight junction (TJ) proteins. Notably, the optimal dose of LA for gut barrier preservation was low, while that for anti-inflammatory effects was high, indicating that LA might preserve gut barrier integrity via direct effects on the epithelial cells (ECs) and TJ proteins. Furthermore, 16S rRNA analysis suggested that the regulatory effect of LA on the gut microbiota differed distinctly according to dose. Correlation analysis indicated that a low dose of LA significantly modulated the intestinal barrier-associated bacteria as compared with a moderate or high dose of LA. Western blot (WB) analysis indicated that LA exhibited anti-UC activity partly by blocking the mitogen-activated protein kinase (MAPK) pathway. Our results further elucidate the pharmacological activity of LA against UC and will provide valuable information for future studies regarding on the regulatory effects of LA on enteric diseases.


Assuntos
Chalconas/farmacologia , Colite/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Chalconas/metabolismo , Colite/fisiopatologia , Colite Ulcerativa/induzido quimicamente , Colo/metabolismo , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sulfassalazina/farmacologia , Proteínas de Junções Íntimas/metabolismo
2.
Cell Death Dis ; 12(7): 698, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257282

RESUMO

Sorafenib, a protein kinase inhibitor approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma, has been repeatedly reported to induce ferroptosis by possibly involving inhibition of the cystine/glutamate antiporter, known as system xc-. Using a combination of well-defined genetically engineered tumor cell lines and canonical small molecule ferroptosis inhibitors, we now provide unequivocal evidence that sorafenib does not induce ferroptosis in a series of tumor cell lines unlike the cognate system xc- inhibitors sulfasalazine and erastin. We further show that only a subset of tumor cells dies by ferroptosis upon sulfasalazine and erastin treatment, implying that certain cell lines appear to be resistant to system xc- inhibition, while others undergo ferroptosis-independent cell death. From these findings, we conclude that sorafenib does not qualify as a bona fide ferroptosis inducer and that ferroptosis induced by system xc- inhibitors can only be achieved in a fraction of tumor cell lines despite robust expression of SLC7A11, the substrate-specific subunit of system xc-.


Assuntos
Antineoplásicos/farmacologia , Ferroptose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe/farmacologia , Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Células HEK293 , Humanos , Camundongos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Piperazinas/farmacologia , Sulfassalazina/farmacologia
3.
Sci Adv ; 7(27)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34193418

RESUMO

The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the rapid development of new therapies against coronavirus disease 2019 (COVID-19) infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein network, based on disease signatures defined by COVID-19 multiomics datasets, and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials, testifying to the validity of the approach. Using artificial neural network analysis, we classified these 200 drugs into nine distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (126) and immune response (74). Two drugs (proguanil and sulfasalazine) implicated in viral replication were shown to inhibit replication in cell assays. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.


Assuntos
Reposicionamento de Medicamentos , SARS-CoV-2/fisiologia , Antivirais/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Humanos , Redes Neurais de Computação , Proguanil/farmacologia , Proguanil/uso terapêutico , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Sulfassalazina/farmacologia , Replicação Viral/efeitos dos fármacos
4.
Toxicol Lett ; 349: 12-29, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089816

RESUMO

The cholestatic liver injury could occur in response to a variety of diseases or xenobiotics. Although cholestasis primarily affects liver function, it has been well-known that other organs such as the kidney could be influenced in cholestatic patients. Severe cholestasis could lead to tissue fibrosis and organ failure. Unfortunately, there is no specific therapeutic option against cholestasis-induced organ injury. Hence, finding the mechanism of organ injury during cholestasis could lead to therapeutic options against this complication. The accumulation of potentially cytotoxic compounds such as hydrophobic bile acids is the most suspected mechanism involved in the pathogenesis of cholestasis-induced organ injury. A plethora of evidence indicates a role for the inflammatory response in the pathogenesis of several human diseases. Here, the role of nuclear factor-kB (NFkB)-mediated inflammatory response is investigated in an animal model of cholestasis. Bile duct ligated (BDL) animals were treated with sulfasalazine (SSLZ, 10 and 100 mg/kg, i.p) as a potent inhibitor of NFkB signaling. The NFkB proteins family activity in the liver and kidney, serum and tissue levels of pro-inflammatory cytokines, tissue biomarkers of oxidative stress, serum markers of organ injury, and the liver and kidney histopathological alterations and fibrotic changes. The oxidative stress-mediated inflammatory-related indices were monitored in the kidney and liver at scheduled time intervals (3, 7, and 14 days after BDL operation). Significant increase in serum and urine markers of organ injury, besides changes in biomarkers of oxidative stress and tissue histopathology, were evident in the liver and kidney of BDL animals. The activity of NFkB proteins (p65, p50, p52, c-Rel, and RelB) was significantly increased in the liver and kidney of cholestatic animals. Serum and tissue levels of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-7, IL-12, IL-17, IL-18, IL-23, TNF-α, and INF-γ) were also higher than sham-operated animals. Moreover, TGF- ß, α-SMA, and tissue fibrosis (Trichrome stain) were evident in cholestatic animals' liver and kidneys. It was found that SSLZ (10 and 100 mg/kg/day, i.p) alleviated cholestasis-induced hepatic and renal injury. The effect of SSLZ on NFkB signaling and suppression of pro-inflammatory cytokines could play a significant role in its protective role in cholestasis. Based on these data, NFkB signaling could receive special attention to develop therapeutic options to blunt cholestasis-induced organ injury.


Assuntos
Anti-Inflamatórios/farmacologia , Colestase/tratamento farmacológico , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Sulfassalazina/farmacologia , Animais , Colestase/metabolismo , Colestase/patologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Regulação para Baixo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
5.
J Cell Mol Med ; 25(12): 5372-5380, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33988296

RESUMO

The aim of this study was to explore the role of sulfasalazine on proliferation and metastasis in gastric cancer by inhibition of xCT. The relationships between clinical characteristics and xCT expression were analysed. An immunohistochemical staining assay and Western blot were performed among gastric cancers and normal gastric tissues. qPCR and Western blot were also used to evaluate the mRNA and protein expression in the normal gastric cell and eight gastric cancer cells, respectively. CCK-8 and colony formation assays were used to evaluate the effect of sulfasalazine on the proliferation and colony formation ability of three gastric cancers. The effect of sulfasalazine on the migration and invasion abilities of three cancer cells was assessed by the Transwell assay. xCT protein is up-regulated in gastric cancer specimens and cells. Three gastric cancer cells with high, medium and low expression of xCT were selected for the following analyses. CCK-8 assays revealed that sulfasalazine could attenuate the proliferation of HGC-27 and AGS. Also, the colony formation assay revealed that sulfasalazine might attenuate the colony formation ability in HGC-27 and AGS cells. Plus, the Transwell assays demonstrated that sulfasalazine might attenuate the migration and invasion abilities in HGC-27 and AGS cells. In conclusion, higher expression of xCT is associated with advanced tumour stage and poor overall survival of gastric cancer. Sulfasalazine can attenuate the proliferation, colony formation, metastasis and invasion of gastric cancer in vitro. Further study is required to validate our findings.


Assuntos
Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/farmacologia , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Sulfassalazina/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Humanos , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Células Tumorais Cultivadas
6.
Life Sci ; 278: 119500, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33862111

RESUMO

BACKGROUND: Cerium (IV) oxide (CeO2) exhibit anti-inflammatory activity via scavenge free radicals and decreasing the oxygen species (ROS) production. Here we aimed to exhibit the therapeutic effect of this nanoparticle in experimental colitis models. METHODS: Cerium oxide nanoparticles (CeONPs) were synthesized via using UiO-66 as a precursor. We used dextran sodium sulfate (DSS) to induce colitis in experimental models to investigate the anti-inflammatory effect of CeONPs. Colitis models are divided into four groups to receive the treatment, including control, colitis, cerium oxide, and sulfasalazine. We evaluated the therapeutic effects of CeONPs for the increased colitis clinical symptoms and attenuated the histological damage to colon tissue in colitis. RESULT: This nanoparticle was significantly able to reduce the clinical symptoms of colitis. Moreover, CeONPs can enhance the disease activity index such as body lose weight, diarrhea, rectal bleeding, colon length, and spleen weight. Moreover, CeONPs showed a significant reduction in the histological characteristics of the colitis models. CONCLUSION: These results suggest that CeONPs can be considered as promising therapeutic agents in treating the ulcerative colitis.


Assuntos
Antioxidantes/farmacologia , Cério/farmacologia , Colite Ulcerativa/tratamento farmacológico , Nanopartículas Metálicas/química , Animais , Anti-Inflamatórios/farmacologia , Colo/efeitos dos fármacos , Sulfato de Dextrana/química , Sequestradores de Radicais Livres , Radicais Livres , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Nanomedicina , Estresse Oxidativo , Espectroscopia de Infravermelho com Transformada de Fourier , Sulfassalazina/farmacologia , Superóxido Dismutase , Difração de Raios X
7.
J Ethnopharmacol ; 274: 113997, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-33705918

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng is a valuable medicinal herb used in China for the prevention and treatment of cancer, diabetes, cardiovascular diseases and other diseases. As the main active ingredient of ginseng, ginsenoside has a wide range of pharmacological effects. Ginsenoside Rh2, a protopanaxadiol saponin from ginseng, exhibits anti-inflammatory and anticancer effects. AIM OF THE STUDY: The potential biological mechanism of Rh2 in the treatment of ulcerative colitis (UC) has not been clarified clearly. In our research, we aimed to explore the therapeutic effects of Rh2 on dextran sodium sulfate (DSS)-induced colitis and elucidate the mechanism of Rh2 in treating UC. METHODS: DSS-induced UC mice were established and randomly divided into the following four groups: control group, DSS group, Rh2 (50 mg/kg) group and sulfasalazine (SASP, 200 mg/kg) group. Except for the control group, 3% DSS drinking water was given to each group for 7 days, and the other two groups were intragastrically administered with Rh2 and SASP for 10 days. At the end of the experiment, colon samples were collected, and phenotypic and pathological analyses were performed in UC mice. Then, Western blot, immunohistochemistry and quantitative real-time PCR analyses were performed to determine the expression of signaling pathway-related factors. RESULTS: Rh2 markedly alleviated DSS-induced body weight loss, intestinal damage, colon length shortening and disease activity index (DAI) scores. Furthermore, proinflammatory cytokines, such as TNF-α, IL-6 and IL-1ß, were reduced by Rh2. Additionally, STAT3/miR-214 activation was also suppressed by Rh2 administration. In vitro, we demonstrated that Rh2 effectively inhibited IL-6-induced STAT3 phosphorylation and miR-214 expression in cultured normal colonic epithelial cells. CONCLUSION: Our results suggested that Rh2 exhibits potential application value in the treatment of UC, and its mechanism is related to the downregulation of STAT3/miR-214 levels, which is expected to be applicable in the treatment of clinical UC.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Ginsenosídeos/farmacologia , MicroRNAs/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Ginsenosídeos/química , Ginsenosídeos/uso terapêutico , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêutico
8.
Cancer Res ; 81(7): 1896-1908, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33483374

RESUMO

MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer are a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in MYCN-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in MYCN-amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway. SIGNIFICANCE: This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of MYCN-amplified neuroblastoma.


Assuntos
Ferro/farmacologia , Neuroblastoma/tratamento farmacológico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Auranofina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Criança , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Amplificação de Genes , Regulação Enzimológica da Expressão Gênica/fisiologia , Glutationa/metabolismo , Humanos , Ferro/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Oxazóis/farmacologia , Oxazóis/uso terapêutico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Sulfassalazina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Ethnopharmacol ; 269: 113716, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33352238

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Jiaolong capsule (JLC) was approved for the therapy of gastrointestinal diseases by the State Food and Drug Administration (SFDA) of China. It has a satisfactory curative effect in the treatment of patients with inflammatory bowel disease, however, the mechanism remains to be elucidated. AIM OF THE STUDY: In current study, the effects and possible mechanisms of JLC on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis were investigated. MATERIALS AND METHODS: Sulfasalazine and JLC were administrated orally and initialized 6 h after TNBS enema, once a day for seven consecutive days. The effect of JLC on intestinal microbial populations and LPS/TLR-4/NF-κB pathway was observed and assessed. Thirty female SD rats were distributed into six groups randomly and equally, namely, control, TNBS, TNBS + sulfasalazine (625 mg/kg), and TNBS + three different doses of JLC (25, 50, and 100 mg/kg) groups. RESULTS: The effect of JLC on restoring normal structures of colorectum and repairing colonic damage were superior to that of sulfasalazine. JLC showed a positive effect in re-balancing intestinal bacteria population of colitis, and suppressed the activation of LPS/TLR-4/NF-κB pathway. CONCLUSION: The results suggest that JLC demonstrated a beneficial effect on treating colitis in a rat model. The possible mechanisms may be through the regulatory effect of intestinal commensal bacteria and down-regulation of LPS/TLR-4/NF-κB pathway.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Fármacos Gastrointestinais/farmacologia , Substâncias Protetoras/farmacologia , Ácido Acético/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Colite Ulcerativa/induzido quimicamente , Colo/efeitos dos fármacos , Colo/patologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Fármacos Gastrointestinais/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos Endogâmicos ICR , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Dor/induzido quimicamente , Dor/tratamento farmacológico , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêutico , Receptor 4 Toll-Like/biossíntese , Receptor 4 Toll-Like/efeitos dos fármacos , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Ácido Trinitrobenzenossulfônico/toxicidade
10.
Med Sci Monit ; 26: e926550, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32925871

RESUMO

BACKGROUND The anti-inflammatory drug sulfasalazine (SAS) has been confirmed to inhibit the growth of triple-negative breast cancer (TNBC), but the mechanism is not clear. The aim of this study was to use network pharmacology to find relevant pathways of SAS in TNBC patients. MATERIAL AND METHODS Through screening of the GeneCards, CTD, and ParmMapper databases, potential genes related to SAS and TNBC were identified. In addition, gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed using the R programming language. Protein-protein interaction networks were constructed using Cytoscape. The Kaplan-Meier plotter screened genes related to TNBC prognosis. TNBC patient gene expression profiles and clinical data were downloaded from The Cancer Genome Atlas database. A heatmap was generated using the R programming language that presents the expression of potential target genes in patients with TNBC. RESULTS Eighty potential target genes were identified through multiple databases. The bioinformatical analyses predicted the interrelationships, potential pathways, and molecular functions of the genes from multiple aspects, which are associated with physiological processes such as the inflammatory response, metabolism of reactive oxygen species (ROS), and regulation of proteins in the matrix metalloproteinase (MMP) family. Survival analysis showed that 12 genes were correlated with TNBC prognosis. Heatmapping showed that genes such as those encoding members of the MMP family were differentially expressed in TNBC tissues and normal tissues. CONCLUSIONS Our analysis revealed that the main reasons for the inhibitory effect of SAS on TNBC cells may be inhibition of the inflammatory response and MMP family members and activation of ROS.


Assuntos
Farmacologia Clínica/métodos , Sulfassalazina/farmacologia , Neoplasias de Mama Triplo Negativas , Anti-Inflamatórios não Esteroides/farmacologia , Biologia Computacional/métodos , Feminino , Redes Reguladoras de Genes , Humanos , Inflamação , Metaloproteinases da Matriz , Mapas de Interação de Proteínas , Espécies Reativas de Oxigênio
12.
Cells ; 9(7)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32630312

RESUMO

xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes cell death. Further understanding the mechanism of glucose deprivation-induced cell death is important for developing anticancer treatments targeting the glucose metabolism. In this study, we found that breast cancer cells with a high expression of xCT demonstrated increased levels of reactive oxygen species (ROS) and were more sensitive to glucose deprivation than the cells with a low expression of xCT. However, AMP-activated protein kinase (AMPK) did not significantly affect glucose-deprivation-induced cell death. The antioxidant N-acetyl-cysteine prevented glucose-deprivation-induced cell death, and the glutathione biosynthesis inhibitor L-buthionine-S, R-sulfoximine enhanced glucose-deprivation-induced cell death. The inhibition of xCT by sulfasalazine or a knockdown of xCT reduced the glucose-deprivation-increased ROS levels and glucose-deprivation-induced cell death. Glucose deprivation reduced the intracellular glutamate, and supplementation with α-ketoglutarate prevented the glucose-deprivation-increased ROS levels and rescued cell death. The knockdown of sirtuin-3 (SIRT3) further enhanced the ROS levels, and promoted xCT-related cell death after glucose deprivation. In conclusion, our results suggested that ROS play a critical role in xCT-dependent cell death in breast cancer cells under glucose deprivation.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Neoplasias da Mama/metabolismo , Morte Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucose/deficiência , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Sistema y+ de Transporte de Aminoácidos/genética , Neoplasias da Mama/genética , Morte Celular/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Ácido Glutâmico/metabolismo , Glutationa/metabolismo , Humanos , Ácidos Cetoglutáricos/farmacologia , Proteínas Quinases/metabolismo , RNA Interferente Pequeno , Sirtuína 3/genética , Sirtuína 3/metabolismo , Sulfassalazina/farmacologia , Regulação para Cima
13.
Int J Mol Sci ; 21(14)2020 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-32664576

RESUMO

Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and redox imbalance. Ferroptosis shows specific biological and morphological features when compared to the other cell death patterns. The loss of lipid peroxide repair activity by glutathione peroxidase 4 (GPX4), the presence of redox-active iron and the oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are considered as distinct fingerprints of ferroptosis. Several pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion, p53, Keap1/Nrf2 and phospholipid biosynthesis, can modify susceptibility to ferroptosis. Through the decades, various diseases, including acute kidney injury; cancer; ischemia-reperfusion injury; and cardiovascular, neurodegenerative and hepatic disorders, have been associated with ferroptosis. In this review, we provide a comprehensive analysis of the main biological and biochemical mechanisms of ferroptosis and an overview of chemicals used as inducers and inhibitors. Then, we report the contribution of ferroptosis to the spectrum of liver diseases, acute or chronic. Finally, we discuss the use of ferroptosis as a therapeutic approach against hepatocellular carcinoma, the most common form of primary liver cancer.


Assuntos
Ferroptose , Hepatopatias/patologia , Animais , Autofagia/fisiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cicloexilaminas/farmacologia , Cisteína/metabolismo , Ferroptose/efeitos dos fármacos , Glutationa/biossíntese , Heme/metabolismo , Humanos , Ferro/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoxigenase/fisiologia , Neoplasias Hepáticas/patologia , Estresse Oxidativo , Fenilenodiaminas/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/fisiologia , Piperazinas/farmacologia , Quinoxalinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Sorafenibe/farmacologia , Compostos de Espiro/farmacologia , Sulfassalazina/farmacologia , Proteína Supressora de Tumor p53/metabolismo , alfa-Tocoferol/farmacologia
14.
Theranostics ; 10(17): 7775-7786, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32685019

RESUMO

Rationale: Loss of iron-sulfur cluster function predisposes cancer cells to ferroptosis by upregulating iron-starvation response, but the role of glutaredoxin 5 (GLRX5) silencing in ferroptosis remains unknown. We examined the role of GLRX5 functional loss in promoting ferroptosis in cisplatin-resistant head and neck cancer (HNC) cells. Methods: The effects of sulfasalazine treatment and GLRX5 gene silencing were tested on HNC cell lines and mouse tumor xenograft models. These effects were analyzed concerning cell viability and death, lipid reactive oxygen species (ROS) and mitochondrial iron production, labile iron pool, mRNA/protein expression, and malondialdehyde assays. Results: Cyst(e)ine deprivation, erastin, or sulfasalazine induced ferroptosis in HNC cells, which was relatively less sensitive in cisplatin-resistant HNC cells. Sulfasalazine or cyst(e)ine deprivation-induced ferroptosis resulted from increased lipid peroxidation and intracellular free iron, which were significantly promoted by short-interfering RNA or short hairpin RNA (shRNA) targeting GLRX5 (P<0.05). GLRX5 silencing activated iron-starvation response and boosted up intracellular free iron through the iron-responsive element-binding activity of increased iron regulatory protein (increased transferrin receptor and decreased ferritin). These effects were rescued by resistant GLRX5 cDNA but not by catalytically inactive mutant GLRX5 K101Q. The same results were noted in an in vivo mouse model transplanted with vector or shGLRX5-transduced HNC cells and treated with sulfasalazine. Conclusion: Our data suggest that inhibition of GLRX5 predisposes therapy-resistant HNC cells to ferroptosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Glutarredoxinas/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Ferro/metabolismo , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mutação , Interferência de RNA , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Ethnopharmacol ; 260: 112991, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32442592

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Guchang Zhixie Wan (GC) is a traditional Chinese patent medicine used in the treatment of colitis in clinical trials. Though the notable effect of GC on colitis, the concrete mechanism of GC remain elusive. Emerging evidence showed that the imbalances of inflammatory cytokines and gut microbiota were both closely related to the initiation and progression of colitis. AIM OF THE STUDY: To elucidate the relationship between the protective effects of GC on colitis and gut microbiota. MATERIALS AND METHODS: Male Kunming (KM) mice were enrolled in our work to establish colitis model induced by dextran sulfate sodium (DSS). The colitis mice were randomly divided into different groups and treated orally with 125 mg/kg of sulfasalazine (positive control) and 25, 50, 100 mg/kg of GC for 7 days, respectively. Inflammation cytokines of IL-1ß, IL-4, IL-6, IL-8, IL-11, IL-12 and TNF-α were detected by ELISA analysis and the histological changes were detected by H&E staining. Gut microbiota diversity was analyzed by 16S rDNA sequencing. Metagenomes analysis were also conducted to reflect the protective effects of GC on colitis. RESULTS: The results of CAS (Clinical Activity Score) confirmed the protective effects of GC on colitis. After administration of GC, the levels of pro-inflammatory cytokines IL-1ß, IL-6, IL-8, IL-11, IL-12 and TNF-α were all decreased while the anti-inflammatory cytokines IL-4 was slightly increased, indicating that GC could down regulate pro-inflammatory cytokines. H&E staining revealed that GC could improve the histopathological structure of the colon tissue. The results of 16S rDNA sequences analysis showed that GC could decrease the relative abundance of Turicibacter and increase the relative abundance of Ruminococcaceae_UCG-005. CONCLUSION: GC greatly improve the health condition of colitis mice induced by DSS through improving the imbalances of inflammatory cytokines and gut microbiota.


Assuntos
Colite/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Colo/efeitos dos fármacos , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Camundongos , Sulfassalazina/farmacologia
16.
Placenta ; 95: 78-83, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32452405

RESUMO

INTRODUCTION: The antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are elevated in preeclampsia and have been implicated in its pathogenesis. We have previously demonstrated metformin and sulfasalazine independently reduce antiangiogenic factor secretion. Here we examined whether combining metformin and sulfasalazine may be more effective than either alone in reducing placental expression and secretion of antiangiogenic and angiogenic factors and the expression of markers of endothelial dysfunction. METHODS: We performed functional experiments using primary human placenta to explore the effect of metformin and sulfasalazine, at lower doses than previously explored, individually and in combination, on sFlt-1 and sENG secretion and placental growth factor (PlGF) and vascular endothelial growth factor (VEGFα) expression. Using primary endothelial cells we induced dysfunction using cytokine tumor necrosis factor-α (TNF-α) and assessed the effect of low dose combination treatment on the expression of vascular cell adhesion molecule-1 (VCAM-1) and Endothelin-1 (a potent vasoconstrictor). RESULTS: We demonstrated combination metformin and sulfasalazine was additive in reducing sFlt-1 secretion from cytotrophoblasts and placental explants. Combination treatment was also additive in reducing sENG secretion from placental explants. Furthermore, combination treatment increased cytotrophoblast VEGFα mRNA expression. Whilst combination treatment increased PlGF mRNA expression this was similar to treatment with sulfasalazine alone. Combination therapy reduced TNFα induced endothelin-1 mRNA expression however did not change VCAM expression. DISCUSSION: Low dose combination metformin and sulfasalazine reduced cytotrophoblast sFlt-1 and sENG secretion, increased VEGFα expression and reduced TNFα induced endothelin-1 expression in primary endothelial cells. Combination therapy has potential to treat preeclampsia.


Assuntos
Endoglina/metabolismo , Metformina/uso terapêutico , Placenta/efeitos dos fármacos , Pré-Eclâmpsia/tratamento farmacológico , Sulfassalazina/uso terapêutico , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Quimioterapia Combinada , Endotelina-1/metabolismo , Feminino , Humanos , Metformina/farmacologia , Placenta/metabolismo , Fator de Crescimento Placentário/metabolismo , Pré-Eclâmpsia/metabolismo , Gravidez , Sulfassalazina/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Nat Cell Biol ; 22(4): 476-486, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231310

RESUMO

SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11high) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11high cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11high cancers.


Assuntos
Sistema y+ de Transporte de Aminoácidos/genética , Carcinoma de Células Renais/genética , Cistina/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Via de Pentose Fosfato/genética , Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dissulfetos/metabolismo , Fármacos Gastrointestinais/farmacologia , Glucose/deficiência , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 3/antagonistas & inibidores , Transportador de Glucose Tipo 3/genética , Transportador de Glucose Tipo 3/metabolismo , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Camundongos , Camundongos Nus , Fosfogluconato Desidrogenase/genética , Fosfogluconato Desidrogenase/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Estresse Fisiológico , Sulfassalazina/farmacologia , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
18.
BMB Rep ; 53(5): 284-289, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32317086

RESUMO

Tamoxifen, a nonsteroidal estrogen receptor (ER) antagonist, is used routinely as a chemotherapeutic agent for ER-positive breast cancer. However, it is also causes side effects, including retinotoxicity. The retinal pigment epithelium (RPE) has been recognized as the primary target of tamoxifen-induced retinotoxicity. The RPE plays an essential physiological role in the normal functioning of the retina. Nonetheless, potential therapeutic agents to prevent tamoxifen-induced retinotoxicity in breast cancer patients have not been investigated. Here, we evaluated the action mechanisms of sulfasalazine against tamoxifen- induced RPE cell death. Tamoxifen induced reactive oxygen species (ROS)-mediated autophagic cell death and caspase-1-mediated pyroptosis in RPE cells. However, sulfasalazine reduced tamoxifen-induced total ROS and ROS-mediated autophagic RPE cell death. Also, mRNA levels of tamoxifen-induced pyroptosis-related genes, IL-1ß, NLRP3, and procaspase-1, also decreased in the presence of sulfasalazine in RPE cells. Additionally, the mRNA levels of tamoxifen-induced AMD-related genes, such as complement factor I (CFI), complement factor H (CFH), apolipoprotein E (APOE), apolipoprotein J (APOJ), toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4), were downregulated in RPE cells. Together, these data provide novel insight into the therapeutic effects of sulfasalazine against tamoxifen-induced RPE cell death. [BMB Reports 2020; 53(5): 284-289].


Assuntos
Epitélio Pigmentado da Retina/efeitos dos fármacos , Sulfassalazina/farmacologia , Tamoxifeno/antagonistas & inibidores , Morte Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Relação Estrutura-Atividade , Tamoxifeno/farmacologia
19.
Development ; 147(10)2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32291273

RESUMO

Retinal regeneration is robust in some cold-blooded vertebrates, but this process is ineffective in warm-blooded vertebrates. Understanding the mechanisms that suppress the reprogramming of Müller glia into neurogenic progenitors is key to harnessing the regenerative potential of the retina. Inflammation and reactive microglia are known to influence the formation of Müller glia-derived progenitor cells (MGPCs), but the mechanisms underlying this interaction are unknown. We used a chick in vivo model to investigate nuclear factor kappa B (NF-κB) signaling, a critical regulator of inflammation, during the reprogramming of Müller glia into proliferating progenitors. We find that components of the NF-κB pathway are dynamically regulated by Müller glia after neuronal damage or treatment with growth factors. Inhibition of NF-κB enhances, whereas activation suppresses, the formation of proliferating MGPCs. Following microglia ablation, the effects of NF-κB-agonists on MGPC-formation are reversed, suggesting that signals provided by reactive microglia influence how NF-κB impacts Müller glia reprogramming. We propose that NF-κB is an important signaling 'hub' that suppresses the reprogramming of Müller glia into proliferating MGPCs and this 'hub' coordinates signals provided by reactive microglia.


Assuntos
Proliferação de Células/genética , Galinhas/crescimento & desenvolvimento , Células Ependimogliais/metabolismo , NF-kappa B/metabolismo , Retina/metabolismo , Transdução de Sinais/genética , Células-Tronco/metabolismo , Animais , Reprogramação Celular/genética , Galinhas/genética , Inativação Gênica , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Microglia/metabolismo , NF-kappa B/agonistas , NF-kappa B/antagonistas & inibidores , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/genética , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Retina/crescimento & desenvolvimento , Sulfassalazina/farmacologia
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