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1.
Nat Mater ; 18(12): 1376-1383, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31636420

RESUMO

Among the strategies used for enhancement of tumour retention of imaging agents or anticancer drugs is the rational design of probes that undergo a tumour-specific enzymatic reaction preventing them from being pumped out of the cell. Here, the anticancer agent olsalazine (Olsa) was conjugated to the cell-penetrating peptide RVRR. Taking advantage of a biologically compatible condensation reaction, single Olsa-RVRR molecules were self-assembled into large intracellular nanoparticles by the tumour-associated enzyme furin. Both Olsa-RVRR and Olsa nanoparticles were readily detected with chemical exchange saturation transfer magnetic resonance imaging by virtue of exchangeable Olsa hydroxyl protons. In vivo studies using HCT116 and LoVo murine xenografts showed that the OlsaCEST signal and anti-tumour therapeutic effect were 6.5- and 5.2-fold increased, respectively, compared to Olsa without RVRR, with an excellent 'theranostic correlation' (R2 = 0.97) between the imaging signal and therapeutic response (normalized tumour size). This furin-targeted, magnetic resonance imaging-detectable platform has potential for imaging tumour aggressiveness, drug accumulation and therapeutic response.


Assuntos
Ácidos Aminossalicílicos/metabolismo , Antineoplásicos/metabolismo , Furina/metabolismo , Espaço Intracelular/metabolismo , Imagem por Ressonância Magnética/métodos , Nanopartículas , Ácidos Aminossalicílicos/química , Animais , Antineoplásicos/química , Catálise , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Células HCT116 , Humanos , Camundongos
2.
United European Gastroenterol J ; 7(8): 1042-1050, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31662861

RESUMO

Background: Knowing patients' ulcerative colitis history is essential to selecting the appropriate therapy according to risk stratification. Objective: To evaluate and identify predictive factors of non-response to aminosalicylates judged as the need for a step-up approach over time. Methods: A case-control study of ulcerative colitis patients treated with aminosalicylates after the diagnosis of disease flare included in the ENEIDA single-centre registry from 1997 to 2017. Long-term treatment maintenance with aminosalicylates and higher therapeutic requirements were recorded. The cumulative incidence of treatment escalation was estimated using Kaplan-Meier curves and compared by the log-rank test. Cox regression analysis was performed to identify predictive factors of treatment with immunomodulators, biological agents or surgery. Results: A total of 457 patients were included, of whom 28% (n = 126) were non-responders to aminosalicylates. The cumulative probability for a step-up approach within 20 years of follow up was 35%, mainly due to steroid-dependent colitis. Risk factors for treatment escalation were age ≤27 years (hazard ratio 2.31, 95% confidence interval 1.36-3.92), extensive colitis (hazard ratio 1.65, 95% confidence interval 1.04-2.60), Mayo endoscopic subscore ≥2 (hazard ratio 1.45, 95% confidence interval 1.02-2.06) and extraintestinal manifestations (hazard ratio 2.04, 95% confidence interval 1.03-4.05). Conclusions: Aminosalicylates represent an effective maintenance therapy. Younger age, extensive colitis, endoscopic disease severity and extraintestinal manifestations are risk factors for higher therapeutic requirements.


Assuntos
Ácidos Aminossalicílicos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/epidemiologia , Adulto , Fatores Biológicos/uso terapêutico , Estudos de Casos e Controles , Regras de Decisão Clínica , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/cirurgia , Feminino , Seguimentos , Humanos , Fatores Imunológicos/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
3.
Oncol Rep ; 42(3): 1205-1213, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322250

RESUMO

Signal transducer and activator of transcription 3 (STAT3) plays a key role in the transformation of normal cells to cancerous cells. Although inhibitors of STAT3 have been shown to suppress the growth of multiple cancer types in vitro and in vivo, such agents are of particular interest for the prevention of breast cancer, which affects over 200,000 women and claims more than 40,000 lives in the United States each year. In the present study, we employed the MMTV/Neu transgenic mouse model, which develops estrogen receptor (ER)­negative, Neu­overexpressing tumors, and the Sprague­Dawley (SD) rat model, which develops ER­positive tumors upon exposure to the carcinogen 7,12­dimethylbenz[a]anthracene (DMBA), to test the efficacy of the STAT3 inhibitor GLG­302 in the prevention of mammary cancer. Orally administered GLG­302 and its trizma salt derivative reduced mammary cancer incidence, multiplicity, and tumor weights in female MMTV/Neu mice, and GLG­302 reduced tumor multiplicity and weights in female DMBA­treated rats. Consistent with the mechanism of action of STAT3 inhibitors, the reductions in mammary tumors were correlated with decreases in STAT3 phosphorylation and cell proliferation. These data suggest that GLG­302 is a novel agent with potential for prevention of mammary cancer and support the further development of STAT3 inhibitors for this cause.


Assuntos
Benzenossulfonatos/farmacologia , Neoplasias Mamárias Experimentais/prevenção & controle , Receptor ErbB-2/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Ácidos Aminossalicílicos/farmacologia , Animais , Antracenos/toxicidade , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Neoplasias Mamárias Experimentais/etiologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Transgênicos , Piperidinas/toxicidade , Ratos , Ratos Sprague-Dawley , Células Tumorais Cultivadas
4.
J Endocrinol ; 242(3): 199-210, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31277074

RESUMO

Emerging evidence implicates elevated activity of STAT3 transcription factor in driving the development and progression of diabetic cardiomyopathy (DCM). We hypothesized that the fibrosis-promoting and hypertrophic actions of STAT3 are linked to the activation by epidermal growth factor receptor (EGFR). We tested this hypothesis by challenging cultured cardiomyocytes to high-concentration glucose and heart tissues of streptozotocin (STZ)-induced type 1 diabetic mice. Our results indicated that, in diabetic mice, the blockade of STAT3 or EGFR using selective inhibitors S3I-201 and erlotinib, respectively, abrogated the increased activating STAT3 phosphorylation and the induction of genes regulating fibrosis and hypertrophy in myocardial tissue. S3I-201 and erlotinib significantly reduced myocardial structural and functional deficits in diabetic mice. In cultured cardiomyocytes, high-concentration glucose induced EGFR-mediated STAT3 phosphorylation. We further showed that blockade of STAT3 or EGFR using selective inhibitors and siRNAs significantly reduced the increased expression of genes known to promote fibrosis and hypertrophy in cardiomyocytes. These results provide novel evidence that the EGFR-STAT3 signaling axis likely plays a crucial role in the development and progression of DCM.


Assuntos
Benzenossulfonatos/farmacologia , Cardiomiopatias Diabéticas/prevenção & controle , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Ácidos Aminossalicílicos/farmacologia , Animais , Linhagem Celular , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Cardiomiopatias Diabéticas/complicações , Cardiomiopatias Diabéticas/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
5.
Gene ; 710: 193-201, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31176734

RESUMO

Accumulative researches have demonstrated the critical functions of long non-coding RNAs (lncRNAs) in the progression of malignant tumors, including bladder cancer (BC). Our previous studies showed that lnc-DILC was an important tumor suppressor gene in both liver cancer and colorectal cancer. However, the role of lnc-DILC in BC remains to be elucidated. In the present study, we for first found that lnc-DILC was downregulated in human bladder cancer tissues. Lnc-DILC overexpression suppressed the proliferation, metastasis and expansion of bladder cancer stem cells (CSCs). Mechanically, lnc-DILC suppressed BC cells progression via STAT3 pathway. Special STAT3 inhibitor S3I-201 diminished the discrepancy of growth, metastasis and self-renewal ability between lnc-DILC-overexpression BC cells and their control cells, which further confirmed that STAT3 was acquired for lnc-DILC-disrupted BC cell growth, metastasis and self-renewal. Taken together, our results suggest that lnc-DILC is a novel bladder tumor suppressor and indicate that lnc-DILC inhibits BC progression via inactivating STAT3 signaling.


Assuntos
Regulação para Baixo , RNA Longo não Codificante/genética , Transdução de Sinais , Neoplasias da Bexiga Urinária/genética , Ácidos Aminossalicílicos/farmacologia , Benzenossulfonatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Autorrenovação Celular/efeitos dos fármacos , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos
6.
Mol Carcinog ; 58(8): 1389-1399, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30997702

RESUMO

Hepatocellular carcinoma (HCC) is a fatal disease with increasing morbidity and poor prognosis due to surgical recurrence and metastasis. Moreover, the molecular mechanism of HCC progression remains unclear. Although the role of p120-catenin (p120ctn) in liver cancer is well studied, the effects of secreted p120ctn transported by exosomes are less understood. Here, we show that p120ctn in exosomes secreted from liver cancer cells suppresses HCC cell proliferation and metastasis and expansion of liver cancer stem cells (CSCs). Mechanically, exosome p120ctn inhibits HCC cell progression via the STAT3 pathway, and the STAT3 inhibitor S3I-201 abolishes the observed effects on growth, metastasis, and self-renewal ability between exosome p120ctn-treated HCC cells and control cells. Taken together, we propose that p120ctn-containing exosomes derived from cancer cells inhibit the progression of liver cancer and may offer a new therapeutic strategy.


Assuntos
Carcinoma Hepatocelular/patologia , Cateninas/metabolismo , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/patologia , Fator de Transcrição STAT3/metabolismo , Ácidos Aminossalicílicos/farmacologia , Benzenossulfonatos/farmacologia , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Exossomos/patologia , Humanos , Neoplasias Hepáticas/genética , Metástase Neoplásica/patologia , Fator de Transcrição STAT3/antagonistas & inibidores
7.
Spectrochim Acta A Mol Biomol Spectrosc ; 214: 531-536, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30818152

RESUMO

In this work, the supramolecular host-guest interaction of the prodrug Olsalazine (OLZ) and ß-Cyclodextrin (ß-CD) was examined experimentally and computationally. Experimentally, employing the UV-Vis spectroscopic method in aqueous media at various pH's, results obtained using the Benesi-Hilderbrand approach demonstrated that OLZ can form supramolecular inclusion complex with ß-CD with stoichiometric ratio of 1:1. Furthermore, these results revealed that the formation of OLZ: ß-CD complexes exhibited insignificant pH dependency in the range 5-8 with an average binding constant (Kb) of approximately 1×103M-1. Computationally, geometry optimization of 1:1 OLZ: ß-CD complexes was performed employing the ONIOM (DFT((ωB97XB)/6-31+G(d)),SQM(PM3)) approach. Obtained results demonstrated that OLZ: ß-CD complex is stabilized by the formation of intermolecular hydrogen bonds with an average length of approximately 1.8Å. Additionally, the stability of OLZ: ß-CD complex was demonstrated employing ADMP molecular dynamic simulations over a timeframe of 500fs. The molecularity of the supramolecular host-guest interaction between OLZ and ß-CD is presented and interpreted in the essence of TD-DFT and molecular orbitals analyses.


Assuntos
Ácidos Aminossalicílicos/química , Simulação de Dinâmica Molecular , beta-Ciclodextrinas/química
8.
Mol Med Rep ; 19(4): 2698-2706, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720080

RESUMO

BP­1­102, a novel inhibitor of signal transducer and activator of transcription 3 (STAT3), exhibits significant antitumor effects in several malignancies in vitro and in vivo. However, its role in gastric cancer (GC) remains to be elucidated. In the present study, the effect and potential molecular mechanisms of BP­102 in human GC cell lines were investigated. The results showed that BP­1­02 dose­dependently inhibited the proliferation of AGS cells, whereas it had little effect on HGC­27 cells. Flow cytometric analysis indicated that BP­1­102 induced apoptosis, but had minimal effect on cell cycle distribution. In addition, cells treated with BP­1­102 demonstrated markedly suppressed migration and invasion capacities. Western blot analysis revealed that BP­1­102 inhibited the phosphorylation of STAT3 and its target genes, including c­Myc, cyclin D1 and survivin, in a time­ and dose­dependent manner. Furthermore, it was found that BP­1­102 induced the phosphorylation of c­Jun N­terminal kinase and p38 mitogen­activated protein kinase (MAPK) and inhibited the activation of extracellular signal­related kinases. Taken together, these results demonstrated that BP­1­102 may be a potent antitumor agent that acts through modulating the STAT3 and MAPK signaling pathways in GC cells.


Assuntos
Ácidos Aminossalicílicos/farmacologia , Antineoplásicos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Fator de Transcrição STAT3/antagonistas & inibidores
9.
J Surg Res ; 236: 172-183, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30694753

RESUMO

BACKGROUND: Acute liver failure (ALF) from severe acute liver injury is a critical condition associated with high mortality. The purpose of this study was to investigate the impact of preemptive administration of γ-aminobutyric acid (GABA) on hepatic injury and survival outcomes in mice with experimentally induced ALF. MATERIALS AND METHODS: To induce ALF, C57BL/6NHsd mice were administered GABA, saline, or nothing for 7 d, followed by intraperitoneal administration of 500 µg of tumor necrosis factor α and 20 mg of D-galactosamine. The study mice were humanely euthanized 4-5 h after ALF was induced or observed for survival. Proteins present in the blood samples and liver tissue from the euthanized mice were analyzed using Western blot and immunohistochemical and histopathologic analyses. For inhibition studies, we administered the STAT3-specific inhibitor, NSC74859, 90 min before ALF induction. RESULTS: We found that GABA-treated mice had substantial attenuation of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive hepatocytes and hepatocellular necrosis, decreased caspase-3, H2AX, and p38 MAPK protein levels and increased expressions of Jak2, STAT3, Bcl-2, and Mn-SOD, with improved mitochondrial integrity. The reduced apoptotic proteins led to a significantly prolonged survival after ALF induction in GABA-treated mice. The STAT3-specific inhibitor NSC74859 eliminated the survival advantage in GABA-treated mice with ALF, indicating the involvement of the STAT3 pathway in GABA-induced reduction in apoptosis. CONCLUSIONS: Our results showed that preemptive treatment with GABA protected against severe acute liver injury in mice via GABA-mediated STAT3 signaling. Preemptive administration of GABA may be a useful approach to optimize marginal donor livers before transplantation.


Assuntos
Falência Hepática Aguda/prevenção & controle , Fígado/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Ácido gama-Aminobutírico/administração & dosagem , Ácidos Aminossalicílicos/administração & dosagem , Animais , Benzenossulfonatos/administração & dosagem , Modelos Animais de Doenças , Galactosamina/toxicidade , Humanos , Injeções Intraperitoneais , Fígado/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose/induzido quimicamente , Necrose/patologia , Necrose/prevenção & controle , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/toxicidade
10.
Photochem Photobiol Sci ; 18(1): 166-176, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30397697

RESUMO

A novel multiple target sensor, (E)-5-((4-(diethylamino)-2-hydroxybenzyldene)amino)-1H-imidazole-4-carboxamide (DHIC), was synthesized for fluorescence detection of Zn2+ and S2- and colorimetric detection of Fe3+/2+ in aqueous media. DHIC can operate as a turn "on-off" sequential fluorescent sensor for Zn2+ and S2-. Detection limits (1.59 µM and 8.03 µM) for Zn2+ and S2- are below the WHO standards (76.0 µM and 14.7 µM). The DHIC-Zn2+ complex could be reversibly reused with ethylenediaminetetraacetic acid. Importantly, DHIC could image sequentially Zn2+ and S2- in living cells. Moreover, DHIC displayed a discriminatory color change from pale yellow to orange yellow to Fe3+/2+. The detection limit of DHIC for Fe3+/2+ (0.73 µM and 1.11 µM) is far below the EPA drinking water standard (5.37 µM). The sensor DHIC could be applied to analyze Fe3+ in real samples.


Assuntos
Técnicas Biossensoriais , Ferro/análise , Enxofre/análise , Zinco/análise , Ácidos Aminossalicílicos/química , Ácido Edético/química , Etilaminas/química , Fluorescência , Células HeLa , Humanos , Imidazóis/química , Ferro/química , Limite de Detecção , Metanol/química , Enxofre/química , Água/química , Zinco/química
11.
Aliment Pharmacol Ther ; 49(4): 364-374, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30569460

RESUMO

BACKGROUND: Aminosalicylates are the most frequently prescribed treatment for ulcerative colitis (UC). In the absence of empirical evidence, clinicians are uncertain whether to continue aminosalicylates in patients with UC after escalating therapy. AIMS: To quantify concomitant aminosalicylate use in UC randomised clinical trials (RCTs), identify factors associated with their use, and estimate treatment costs of concomitant aminosalicylate therapy. METHODS: MEDLINE, Embase, and CENTRAL were searched from inception to 1 March 2017 for placebo-controlled RCTs of immunosuppressants, biologics, or oral small molecules in adults with UC. The proportion of patients prescribed concomitant aminosalicylates at trial entry was pooled using a random-effects model. Meta-regression was performed to assess trial-level factors associated with aminosalicylate use. Treatment costs were estimated using 2018 formulary data from five Canadian provinces. RESULTS: Thirty-two trials were included (23 induction only, nine induction, and maintenance trials). The pooled proportion of patients co-prescribed aminosalicylates was 80.7% (95% CI 75.5%-85.1%), with considerable observed heterogeneity (I2  = 95%). In univariable meta-regression, aminosalicylate use was not associated with trial design, setting, year of publication, disease severity, disease duration, or drug class. The estimated direct annual treatment cost of concomitant aminosalicylates is ~$20 million for the Canadian UC population, assuming conservative estimates of UC prevalence, aminosalicylate use and dose, and the lowest cost formulation. CONCLUSIONS: Approximately 80% of UC patients entering clinical trials of immunosuppressants, biologics, or oral small molecules continue to use aminosalicylates. An RCT is needed to inform the benefits and harms of continuing vs stopping aminosalicylates in patients escalating therapy.


Assuntos
Ácidos Aminossalicílicos/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Imunossupressores/uso terapêutico , Adulto , Produtos Biológicos/uso terapêutico , Terapia Biológica , Canadá , Humanos , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
J Pharm Pharm Sci ; 21(1s): 325s-334s, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30465708

RESUMO

Interleukin (IL)-6 decreases hepatic expression of numerous transporters. Although IL-6 signaling occurs through STAT3, the extent of the involvement of the STAT3 signaling pathway has not been elucidated. PURPOSE: Our objective was to investigate whether IL-6-mediated effects occur through STAT3, and whether PXR plays a role in this regulation. METHOD: PXR null (-/-) or wild-type (+/+) male mice were pre-dosed with a selective STAT3 inhibitor S3I-201 (7.5 mg/kg ip) or vehicle (n=5-8/group) 30 minutes before receiving a single dose of IL-6 (1 µg ip) or saline. Animals were sacrificed after 6 hours and liver samples were analyzed using qRT-PCR and western blotting. RESULTS: As compared to saline controls, IL-6 decreased the expression of Cyp3a, Abcb1a, Abcc3, and Slco1a4 20-70% similarly in PXR (+/+) and (-/-) mice at 6 hr, while downregulation of Abcb11, Abcc2, Slc10a1and Slco2b1 was only seen in PXR (+/+). Pre-administration of S3I-201 attenuated IL-6-mediated changes of most transporters in PXR (+/+) and PXR (-/-) mice. At early times after IL-6 administration (10-120 minutes), transcript levels of Socs3, PXR, Abcb1a, Abcc3, Abcb11, Slco1a4 and Slco2b1were increased in PXR (+/+) mice. CONCLUSIONS: Our findings demonstrate that IL-6 imposes a significant downregulation of numerous ABC and SLC transporters in liver primarily through activation of the STAT3 signaling pathway. Based on time-dependent changes in transporter expression, downregulation likely occurs downstream of STAT3 activation.  As IL-6 is elevated in many diseases, understanding the underlying mechanism(s) involved in transporter dysregulation will allow us to predict potential drug-disease interactions.


Assuntos
Regulação para Baixo , Interleucina-6/metabolismo , Receptor de Pregnano X/metabolismo , Fator de Transcrição STAT3/metabolismo , Ácidos Aminossalicílicos/administração & dosagem , Ácidos Aminossalicílicos/farmacologia , Animais , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Injeções Intraperitoneais , Interleucina-6/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Pregnano X/deficiência , Receptor de Pregnano X/genética , Fator de Transcrição STAT3/antagonistas & inibidores
13.
Biofactors ; 44(6): 570-576, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30375073

RESUMO

BACKGROUND/AIM: High mobility group box 1 protein (HMGB1) is functionally dynamic and pleiotropic molecule, it has the potential to promote both cell survival and death by regulating multiple signaling pathways, including inflammation and apoptosis. This study aimed at investigating the role of silencing HMGB1 on tumor cells apoptosis and pro-inflammatory proteins expression in hepatocellular HepG2 cancer cells. METHODS: HepG2 cells was transfected with si-RNA HMGB1, and the effect on pro-apoptotic proteins expressions like Bax, Bcl2, and pro-inflammatory cytokines like, p65-NFκB, and Cyclooxygenase-2 (Cox2) was assessed using western blot, and also cells apoptosis and proliferation was assessed using annexin V FITC and Calcien AM expression in flow cytometry and fluorescence. RESULTS: HMGB1 silencing was found significantly increase tumor cells viability with significant decrease of pro-apoptotic proteins, also antiapoptotic protein Bcl2 was significantly up-regulated, which suggests a possible role in restricting apoptosis. Furthermore, HMGB1 knocked down found to inhibit Stat3 phosphorylation and significantly affect NFkB p65/Cox2 expression which suggests a link between HMGB1 and Stat3 activation. Our results revealed that HMGB1 knocked down may suppress cells apoptosis and enhance HepG2 cells viability via NFkB/Cox2 and Stat3. © 2018 BioFactors, 44(6):570-576, 2018.


Assuntos
Ciclo-Oxigenase 2/genética , Regulação Neoplásica da Expressão Gênica , Proteína HMGB1/genética , NF-kappa B/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição RelA/genética , Acetilcisteína/farmacologia , Ácidos Aminossalicílicos/farmacologia , Benzenossulfonatos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/metabolismo , Células Hep G2 , Humanos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT3/agonistas , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
14.
Neuropharmacology ; 141: 238-248, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30193808

RESUMO

Hemorrhages occurring within the thalamus lead to a pain syndrome. Clinical treatment of thalamic pain is ineffective, at least in part, due to the elusive mechanisms that underlie the induction and maintenance of thalamic pain. The present study investigated the possible contribution of a protein-protein interaction between postsynaptic density protein 95 (PSD-95) and neuronal nitric oxide synthase (nNOS) to thalamic pain in mice. Thalamic hemorrhage was induced by microinjection of type IV collagenase into unilateral ventral posterior medial/lateral nuclei of the thalamus. Pain hypersensitivities, including mechanical allodynia, heat hyperalgesia, and cold allodynia, appeared at day 1 post-microinjection, reached a peak 5-7 days post-microinjection, and persisted for at least 28 days post-microinjection on the contralateral side. Systemic pre-treatment (but not post-treatment) of ZL006, a small molecule that disrupts PSD-95-nNOS interaction, alleviated these pain hypersensitivities. This effect is dose-dependent. Mechanistically, ZL006 blocked the hemorrhage-induced increase of binding of PSD-95 with nNOS and membrane translocation of nNOS in thalamic neurons. Our findings suggest that the protein-protein interaction between PSD-95 and nNOS in the thalamus plays a significant role in the induction of thalamic pain. This interaction may be a promising therapeutic target in the clinical management of hemorrhage-induced thalamic pain.


Assuntos
Hemorragia Cerebral/prevenção & controle , Proteína 4 Homóloga a Disks-Large/metabolismo , Neuralgia/prevenção & controle , Óxido Nítrico Sintase Tipo I/metabolismo , Tálamo/patologia , Ácidos Aminossalicílicos/farmacologia , Animais , Benzilaminas/farmacologia , Hemorragia Cerebral/induzido quimicamente , Colágeno Tipo IV/administração & dosagem , Relação Dose-Resposta a Droga , Masculino , Camundongos , Microinjeções , Medição da Dor/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Tálamo/irrigação sanguínea
15.
Cell Signal ; 52: 127-136, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30213685

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose symptoms include communication deficits, a lack of social skills, and stereotyped repetitive behaviors. We used BTBR T+ Itpr3tf/J (BTBR) mice, a model that demonstrates most of the core behavioral features of ASD, such as decreased sociability and high levels of repetitive behaviors. Currently, there is no treatment available that is able to improve most of the ASD disorder symptoms; thus, finding novel therapies is immediately required. Stat3 inhibitors are potential targets in the treatment of several immune disorders. The aim of the present study was to investigate the effects of S3I-201, a selective Stat3 inhibitor, to determine its potential mechanism in BTBR mice. In this study, we first examined the effects of S3I-201 on repetitive behavior and marble burying. We also examined the treatment of S3I-201 on Th1 (IFN-γ and T-bet), Th17 (IL-17A, RORγt, Stat3, IL-21, and IL-22), and T regulatory (Treg, Foxp3 and Helios) production in spleen CD4+ T cells. We further assessed Th1, Th17, and Treg mRNA and protein expression levels in brain tissues. S3I-201 treatment in BTBR mice significantly prevents marble burying and repetitive behavior. Furthermore, S3I-201 administration causes a considerable decrease in IFN-γ, T-bet, IL-17A, RORγt, Stat3, IL-21, and IL-22 levels, and increases in Foxp3 and Helios production CD4+ T cells in BTBR mice. Additionally, S3I-201 treatment also significantly decreases Th1 and Th17 levels, and increases Treg mRNA and protein expression levels. Therefore, these results suggest that S3I-201 could be considered as a therapeutic option for ASD.


Assuntos
Transtorno do Espectro Autista , Benzenossulfonatos/farmacologia , Encéfalo , Linfócitos T CD4-Positivos , Fator de Transcrição STAT3/antagonistas & inibidores , Baço , Ácidos Aminossalicílicos/farmacologia , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/imunologia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
16.
Lab Invest ; 98(12): 1600-1613, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30206312

RESUMO

Liver fibrosis is a common pathological response to chronic hepatic injury. STAT3 is actively involved in the fibrogenesis and angiogenesis seen in liver fibrosis. S3I-201 (NSC 74859) is a chemical inhibitor of STAT3 activity, which blocks the dimerization of STAT3, STAT3-DNA binding and transcription activity. This study evaluated the effects of S3I-201 against liver fibrosis. S3I-201 inhibited the proliferation, migration, and actin filament formation in primary human hepatic stellate cells (HSCs), as well as the expression of α-SMA, collagen I and TIMP1 in both primary HSC and in a CCl4-induced fibrosis mouse model. S3I-201 induced both apoptosis and cell cycle arrest in the HSC cell line (LX-2). S3I-201 inhibited the expression of fibrogenesis factors TGFß1 and TGFßRII, as well as the downstream phosphorylation of Smad2, Smad3, Akt and ERK induced by TGFß1. In addition to fibrogenesis, both in vitro and in vivo assays showed that S3I-201 inhibited angiogenesis through expression suppression of VEGF and VEGFR2. Moreover, S3I-201 also had a synergistic effect with sorafenib, an FDA approved liver cancer drug, in the proliferation, apoptosis, angiogenesis and fibrogenesis of HSC. S3I-201 suppressed liver fibrosis through multiple mechanisms, and combined with sorafenib, S3I-201 could be a potentially effective antifibrotic agent.


Assuntos
Benzenossulfonatos/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Neovascularização Fisiológica/efeitos dos fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Ácidos Aminossalicílicos/farmacologia , Ácidos Aminossalicílicos/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzenossulfonatos/farmacologia , Linhagem Celular , Sinergismo Farmacológico , Humanos , Masculino , Camundongos Endogâmicos BALB C , Cultura Primária de Células , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Sorafenibe/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Transl Psychiatry ; 8(1): 155, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30108200

RESUMO

Stimulation of N-methyl-D-aspartic acid receptors (NMDARs) and the resulting increase of nitric oxide (NO) production are critical for fear memory formation. Following NMDAR activation, efficient production of NO requires linking the 95 kDa postsynaptic density protein (PSD95), a scaffolding protein to neuronal nitric oxide synthase (nNOS). A variety of previously studied NMDAR antagonists and NOS inhibitors can disrupt fear conditioning, but they also affect many other CNS functions such as motor activity, anxiety, and learning. We hypothesized that disrupting nNOS and PSD95 interaction in the amygdala, a critical site for fear memory formation, will reduce conditioned fear. Our results show that systemic treatment with ZL006, a compound that disrupts PSD95/nNOS binding, attenuates fear memory compared to its inactive isomer ZL007. Co-immunoprecipitation after fear conditioning showed a robust increase in the amygdala PSD95/nNOS binding, which was blocked by systemic pre-administration of ZL006. Treatment of amygdala slices with ZL006 also impaired long-term potentiation (LTP), a cellular signature of synaptic plasticity. Direct intra-amygdala infusion of ZL006 also attenuated conditioned fear. Finally, unlike NMDAR antagonist MK-801, ZL006 does not affect locomotion, social interaction, object recognition memory, and spatial memory. These findings support the hypothesis that disrupting the PSD95/nNOS interaction downstream of NMDARs selectively reduces fear memory, and highlights PSD95/nNOS interaction as a novel target for fear-related disorders, such as posttraumatic stress disorder.


Assuntos
Ácidos Aminossalicílicos/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Benzilaminas/farmacologia , Proteína 4 Homóloga a Disks-Large/metabolismo , Medo/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I/metabolismo , Animais , Maleato de Dizocilpina/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Transtornos de Estresse Pós-Traumáticos/psicologia
18.
Molecules ; 23(7)2018 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973523

RESUMO

The antibacterial effects against Staphylococcus epidermidis of five silver carboxylate complexes with anti-inflammatory ligands were studied in order to analyze and compare them in terms of stability (in solution and after exposure to UV light), and their antibacterial and morphological differences. Four effects of the Ag-complexes were evidenced by transmission electronic microscopy (TEM) and scanning electronic microscopy (SEM): DNA condensation, membrane disruption, shedding of cytoplasmic material and silver compound microcrystal penetration of bacteria. 5-Chlorosalicylic acid (5Cl) and sodium 4-aminosalicylate (4A) were the most effective ligands for synthesizing silver complexes with high levels of antibacterial activity. However, Ag-5Cl was the most stable against exposure UV light (365 nm). Cytotoxic effects were tested against two kinds of eukaryotic cells: murine fibroblast cells (T10 1/2) and human epithelial ovarian cancer cells (A2780). The main objective was to identify changes in their antibacterial properties associated with potential decomposition and the implications for clinical applications.


Assuntos
Antibacterianos/síntese química , Complexos de Coordenação/síntese química , Prata/química , Staphylococcus epidermidis/efeitos dos fármacos , Ácidos Aminossalicílicos/química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Linhagem Celular , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Estabilidade de Medicamentos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Salicilatos/química
19.
Am J Manag Care ; 24(8 Spec No.): SP303-SP308, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30020742

RESUMO

OBJECTIVES: To switch patients with ulcerative colitis (UC) from costlier 5-aminosalicylic acid compounds to sulfasalazine and assess (1) the cost savings, (2) the barriers to switching, and (3) adverse events (AEs) and adherence at 3 months after the drug switch. STUDY DESIGN: An open-label, pharmacist-administered drug switch program coordinated at an academic inflammatory bowel disease center. METHODS: A clinical pharmacist contacted patients with UC who were prescreened by physicians and covered by specific insurers to enroll them in the drug switch program. Enrolled patients were followed for 3 months to assess AEs and medication adherence. Reasons for declining to participate were recorded. RESULTS: A total of 205 eligible patients were identified; only 14 enrolled, and 10 remained on sulfasalazine for the entire 3-month follow-up period. The enrollment rate was only 4.9%, yet a net cost savings of $22,828/3-month to the insurer was achieved (including program administration costs but excluding AE costs), with co-pays reduced by approximately $25 per month per patient. The rate of AEs on sulfasalazine (28.6%) was similar to that found in previous reports. Significant unanticipated barriers to switching were encountered, namely patient desire to not alter an existing effective drug regimen. CONCLUSIONS: A pharmacist-administered drug switch program in patients with UC was significantly more difficult than anticipated, with questionable achievement of cost savings. This experience suggests that future drug switches and studies should focus on patient preferences for drug switching, as this may have implications for switching from brand name to biosimilar drugs.


Assuntos
Ácidos Aminossalicílicos/economia , Colite Ulcerativa/tratamento farmacológico , Redução de Custos , Substituição de Medicamentos/economia , Sulfassalazina/economia , Sulfassalazina/uso terapêutico , Administração Oral , Adolescente , Adulto , Ácidos Aminossalicílicos/uso terapêutico , Estudos de Coortes , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/economia , Feminino , Humanos , Masculino , Avaliação de Programas e Projetos de Saúde , Estudos Retrospectivos , Estados Unidos , Adulto Jovem
20.
Biochem Biophys Res Commun ; 503(1): 177-180, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-29885836

RESUMO

It is high incidence of tubulointerstitial lesion (TIL) in lupus nephritis (LN) and TIL can affect the prognosis of patients with LN. Signal transducer and activator of transcription (STAT) 3 was activated in LN and STAT3 inhibition could delay the onset of LN. Here, we evaluated the role of a well-known STAT3 inhibitor, S3I-201, on TIL in lupus nephritis. STAT3 was activated in MRL/lpr mice (a mouse model of lupus nephritis), and treatment with S3I-201 inhibited the activation of it. The level of 24-h urine protein and nitrogen urea increased in MRL/lpr mice and adminstration of S3I-201 reduced the level of urinary protein. In addition, S3I-201 attenuated the expression of α-smooth muscle actin (α-SMA), Fibronectin (FN) proteins, as well as the expression of monocyte chemotactic factor-1 (MCP-1) and intercellular adhesion molecule (ICAM-1). However, the expression of E-cadherin improved when treatment with S3I-201. These results revealed that the activation of STAT3 mediates tubulointerstitial lesion in mice with LN. S3I-201, by suppressing STAT3 activity, has therapeutic effect in lupus nephritis.


Assuntos
Benzenossulfonatos/farmacologia , Rim/efeitos dos fármacos , Nefrite Lúpica/tratamento farmacológico , Nefrite Intersticial/tratamento farmacológico , Ácidos Aminossalicílicos/farmacologia , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Modelos Animais de Doenças , Feminino , Rim/patologia , Rim/fisiopatologia , Nefrite Lúpica/patologia , Nefrite Lúpica/fisiopatologia , Camundongos , Camundongos Endogâmicos MRL lpr , Nefrite Intersticial/patologia , Nefrite Intersticial/fisiopatologia , Proteinúria/tratamento farmacológico , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
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