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1.
J Med Life ; 12(2): 150-155, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31406516

RESUMO

Pain control during and after any surgical procedure, is extremely essential for the comfort of patients. Pain killers used routinely act by inhibiting cyclooxygenase to control pain and inflammation. Cox-1 is constitutively expressed in most cell types, including platelets, whereas Cox-2 is absent from most healthy tissues but is induced by pro-inflammatory or proliferative stimuli. Cox-1 plays a role in the production of prostaglandins involved in protection of the gastric mucosal layer and thromboxanes (TX) in platelets. Cox-2 generally mediates elevations of prostaglandins associated with inflammation, pain, and pyresis. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen are generally nonselective inhibitors of Coxs. This lack of selectivity has been linked to their propensity to cause gastrointestinal side effects. The new Cox-2 selective inhibitors, or coxibs, show the same anti-inflammatory, analgesic, and antipyretic effects as nonselective NSAIDs but are supposed to have reduced side-effect profiles. This study evaluates whether rofecoxib (50 mg) given one hour pre-operatively or the same drug given one hour post-operatively is more effective in controlling the pain and swelling in mandibular third molar surgery.


Assuntos
Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Mandíbula/cirurgia , Dente Serotino/cirurgia , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Proteína C-Reativa/metabolismo , Feminino , Humanos , Lactonas/farmacologia , Masculino , Cuidados Pós-Operatórios , Sulfonas/farmacologia , Adulto Jovem
2.
Ann Hematol ; 98(9): 2063-2072, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31312928

RESUMO

Rigosertib is a novel multi-kinase inhibitor, which has clinical activity towards leukemic progenitor cells of patients with high-risk myelodysplastic syndromes (MDS) after failure or progression on hypomethylating agents. Since the bone marrow microenvironment plays an important role in MDS pathogenesis, we investigated the impact of rigosertib on cellular compartments within the osteo-hematopoietic niche. Healthy C57BL/6J mice treated with rigosertib for 3 weeks showed a mild suppression of hematopoiesis (hemoglobin and red blood cells, both - 16%, p < 0.01; white blood cells, - 34%, p < 0.05; platelets, - 38%, p < 0.05), whereas there was no difference in the number of hematopoietic stem cells in the bone marrow. Trabecular bone mass of the spine was reduced by rigosertib (- 16%, p = 0.05). This was accompanied by a lower trabecular number and thickness (- 6% and - 10%, respectively, p < 0.05), partly explained by the increase in osteoclast number and surface (p < 0.01). Milder effects of rigosertib on bone mass were detected in an MDS mouse model system (NHD13). However, rigosertib did not further aggravate MDS-associated cytopenia in NHD13 mice. Finally, we tested the effects of rigosertib on human mesenchymal stromal cells (MSC) in vitro and demonstrated reduced cell viability at nanomolar concentrations. Deterioration of the hematopoietic supportive capacity of MDS-MSC after rigosertib pretreatment demonstrated by decreased number of colony-forming units, especially in the monocytic lineage, further supports the idea of disturbed crosstalk within the osteo-hematopoietic niche mediated by rigosertib. Thus, rigosertib exerts inhibitory effects on the stromal components of the osteo-hematopoietic niche which may explain the dissociation between anti-leukemic activity and the absence of hematological improvement.


Assuntos
Glicina/análogos & derivados , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Síndromes Mielodisplásicas , Nicho de Células-Tronco/efeitos dos fármacos , Sulfonas/farmacologia , Animais , Glicina/farmacologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Transgênicos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia
3.
Chem Pharm Bull (Tokyo) ; 67(6): 599-603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155566

RESUMO

The PF-543 is known as a potent and selective inhibitor of sphingosine kinase (SK) 1 amongst all the SK inhibitors known to date. In a recently reported study by Pfizer on the synthesis of PF-543 derivatives and the SK inhibitory effects, the introduction of propyl moiety into sulfonyl group of PF-543 in the case of 26b revealed an excellent result of 1.7 nM of IC50 of SK1, suggesting the potential substitution of chain structure for benzenesulfonyl structure. In the present work, we aimed for identification of antitumor activity and inhibitory effects of PF-543 derivative containing aliphatic long chain (similar to known SK inhibitors) on SK1. The synthesized compound 2 exhibited an inhibitory effect on SK1 in a manner similar to that of PF-543; the PF-543 derivative manifested similar antitumor activity on HT29, HCT116 (colorectal cancer cell line), and AGS (gastric cancer cell line) cells. Also, from the docking study conducted with PF-543 and compound 2, it was apparent that the aliphatic chain in compound 2 could probably replace benzenesulfonyl structure of PF-543.


Assuntos
Antineoplásicos/síntese química , Pirrolidinas/química , Sulfonas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologia
4.
Nat Chem Biol ; 15(6): 556-559, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31086327

RESUMO

Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and specific small-molecule inhibitor of the NLRP3 pathway, but its molecular target is not defined. Here, we show that MCC950 directly interacts with the Walker B motif within the NLRP3 NACHT domain, thereby blocking ATP hydrolysis and inhibiting NLRP3 activation and inflammasome formation.


Assuntos
Trifosfato de Adenosina/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonas/farmacologia , Trifosfato de Adenosina/metabolismo , Sítios de Ligação/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Hidrólise/efeitos dos fármacos , Inflamassomos/biossíntese , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfonas/química
5.
Nat Chem Biol ; 15(6): 560-564, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31086329

RESUMO

NLRP3 (NOD-like receptor pyrin domain-containing protein 3) is an innate immune sensor that contributes to the development of different diseases, including monogenic autoinflammatory syndromes, gout, atherosclerosis, and Alzheimer's disease. The molecule sulfonylurea MCC950 is a NLRP3 inflammasome inhibitor with potential clinical utility. However, the mechanism of action of MCC950 remains unknown. Here, we characterize the mechanism of action of MCC950 in both wild-type and autoinflammatory-related NLRP3 mutants, and demonstrate that MCC950 closes the 'open' conformation of active NLRP3.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Células HEK293 , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Conformação Proteica , Sulfonas/química
6.
Molecules ; 24(9)2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31052354

RESUMO

TW-37 is a small-molecule inhibitor of Bcl-2 family proteins, which can induce anti-cancer activities in various types of cancer. In the current study, we investigated the potential molecular mechanism underlying the differential response to TW-37-induced apoptosis in two human mucoepidermoid carcinoma (MEC) cell lines. The differential response and underlying molecular mechanism of human MEC cells to TW-37 was evaluated by trypan blue exclusion assay, western blotting, 4', 6-diamidino-2-phenylindole staining, annexin V/propidium iodide double staining, analysis of the sub-G1 population, human apoptosis array, and measurements of intracellular reactive oxygen species (ROS). TW-37 decreased cell viability and induced apoptosis in YD-15 cells, but not in MC3 cells. Proteome profiling using a human apoptosis array revealed four candidate proteins and of these, heme oxygenase-1 (HO-1) was mainly related to the differential response to TW-37 of YD-15 and MC3 cells. TW-37 also led to a significant increase in intracellular levels of ROS in YD-15 cells, which is associated with apoptosis induction. The ectopic expression of HO-1 recovered YD-15 cells from TW-37-induced apoptosis by reducing intracellular levels of ROS. The expression of HO-1 was reduced through both transcriptional and post-translational modification during TW-37-mediated apoptosis. We conclude that HO-1 is a potential indicator to estimate response to TW37-induced apoptosis in human MEC.


Assuntos
Benzamidas/farmacologia , Carcinoma Mucoepidermoide/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Sulfonas/farmacologia , Carcinoma Mucoepidermoide/tratamento farmacológico , Carcinoma Mucoepidermoide/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteômica/métodos , Espécies Reativas de Oxigênio/metabolismo
7.
Anticancer Res ; 39(5): 2429-2435, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092435

RESUMO

BACKGROUND/AIM: Perfluorooctanoic acid (PFOA) is one of the most common perfluorinated compounds widely used in several applications. Due to its persistence in the environment, PFOA has been associated with various diseases, including cancer. This study explored the effects of PFOA on follicular thyroid carcinoma cells (FTC133). MATERIALS AND METHODS: Cell invasion, migration, adhesion and activity of matrix metalloproteinase-2 (MMP-2) were investigated using Transwell assays, adhesion assay and gelatin zymography, respectively. The underlying mechanism involved in the effects observed was evaluated by immunoblot analyses. RESULTS: Treatment with PFOA did not affect cell migration, but enhanced cell invasion, adhesion and activity of MMP-2 in FTC133 cells. PFOA selectively enhanced the phosphorylation of nuclear factor kappa B (NF-κB) p65, as well as induced NF-κB nuclear translocation. Treatment with a NF-κB inhibitor (BAY 11-7085) was able to reverse PFOA-induced cell invasiveness. CONCLUSION: PFOA promotes invasiveness of FTC133 cells mediated through the activation of NF-κB signaling.


Assuntos
Adenocarcinoma Folicular/tratamento farmacológico , Caprilatos/farmacologia , Fluorcarbonetos/farmacologia , Metaloproteinase 2 da Matriz/genética , Fator de Transcrição RelA/genética , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Nitrilos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia , Fator de Transcrição RelA/antagonistas & inibidores , Ativação Transcricional/efeitos dos fármacos
8.
Gene ; 710: 91-97, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31002892

RESUMO

BACKGROUND: Chronic inflammatory microenvironment has been shown to play a key role in initiating tumorigenesis and facilitating malignant progression. Primary tumors surrounded with and infiltrated by tumor-associated macrophages (TAMs) significantly promote the epithelial-to-mesenchymal transition (EMT) and distant metastasis in urothelial bladder cancer. METHODS: In this study, we aimed to explore the potential of targeting TAMs for the treatment of malignant bladder cancer. RESULTS: First, we found a higher number of TAMs, CD68 (pan-macrophage marker), and clever-1 (M2 macrophage marker) was associated with a higher pT category and grade in a cohort of 108 patients. In vitro assays showed that the co-culture of TAMs promoted the metastatic potential in HTB-1 and T24 by up-regulating EMT markers including Snail, VEGF and Vimentin, as well as oncogenic markers such as ß-catenin and NF-κB. More importantly, M2 co-cultured HTB-1 and T24 showed an increased level of metastatic microRNA, miR-30. Silencing of miR-30 resulted in the reduced metastatic potential, migration/invasion, in association with the decreased expression of Twist1 and Vimentin. The addition of BAY11-7082 into the TAM/cancer co-culture system significantly reduced the M2 phenotype and tumorigenic properties. Coincidentally, miR-30a level was significantly lowered in the presence of BAY11-7082. CONCLUSION: Our study demonstrated that AMs promoted metastatic potential of bladder cancer cells via promoting EMT through the increase of miR-30a. BAY11-7082 treatment suppressed both oncogenic and metastatic potential in bladder cancer cells while preventing the M2 polarization of TAMs.


Assuntos
Macrófagos/citologia , Nitrilos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia , Neoplasias da Bexiga Urinária/genética , Linhagem Celular Tumoral , Polaridade Celular/efeitos dos fármacos , Técnicas de Cocultura , Regulação para Baixo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , MicroRNAs/genética , NF-kappa B/metabolismo , Metástase Neoplásica , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo
9.
Reprod Biol ; 19(1): 100-111, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30929911

RESUMO

Prostaglandins (PGs) are important regulators of the early corpus luteum (CL) in the dog. Whereas, initially, CL is gonadotropin independent, in the second half of its lifespan, hypophyseal support is required. The transition period is marked by decreased availability of PGs, in particular of PGE2. We previously reported that inhibition of COX2/PTGS2 in vivo suppressed luteal production of PGE2, lowered circulating progesterone and negatively affected luteal development. Therefore, bitches were treated with a COX2-specific blocker, firocoxib, for 5, 10, 20 and 30 days after ovulation, leading to suppression of the steroidogenic machinery. Control groups received a placebo for the same periods. Considering the wide range of possible modulatory roles of PGs shown in different organ systems, this follow-up project aimed to understand further possible PG-mediated effects in early canine CL. Thirty-four (34) factors related predominantly to vascularization and immune response were screened (mRNAs and proteins) on samples from the above described in vivo study. Most of the effects were observed during the transitional period (days 20 and 30). The inhibition of COX2 diminished the expression of angiopoietin family members ANGPT1, -2, Tie1 and -2 receptors. The expression of endothelin (ET)-1 was increased. Concerning the immune system, increased expression of the pro-inflammatory cytokines, IL1ß, IL6 and IL12a, and elevated expression levels of CD4, was observed. Cumulatively, besides its involvement in regulating steroidogenesis, our results indicate a broader role of PGs in the canine CL, including modulation of angiogenesis, vascular stabilization and local immunomodulation. Possible cross-species translational effects are strongly implied.


Assuntos
4-Butirolactona/análogos & derivados , Corpo Lúteo/efeitos dos fármacos , Corpo Lúteo/metabolismo , Fatores Imunológicos/metabolismo , Prostaglandinas/farmacologia , Sulfonas/farmacologia , 4-Butirolactona/farmacologia , Animais , Inibidores de Ciclo-Oxigenase 2/farmacologia , Cães , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/genética , RNA Mensageiro/metabolismo , Receptores Estrogênicos/metabolismo , Transcriptoma
10.
Nat Commun ; 10(1): 1810, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31000710

RESUMO

During centriole duplication, a single daughter centriole is formed next to the mother centriole. The molecular mechanism that determines a single duplication site remains a long-standing question. Here, we show that intrinsic self-organization of Plk4 is implicated in symmetry breaking in the process of centriole duplication. We demonstrate that Plk4 has an ability to phase-separate into condensates via an intrinsically disordered linker and that the condensation properties of Plk4 are regulated by autophosphorylation. Consistently, the dissociation dynamics of centriolar Plk4 are controlled by autophosphorylation. We further found that autophosphorylated Plk4 is already distributed as a single focus around the mother centriole before the initiation of procentriole formation, and is subsequently targeted for STIL-HsSAS6 loading. Perturbation of Plk4 self-organization affects the asymmetry of centriolar Plk4 distribution and proper centriole duplication. Overall, we propose that the spatial pattern formation of Plk4 is a determinant of a single duplication site per mother centriole.


Assuntos
Ciclo Celular/fisiologia , Centríolos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Microscopia Intravital/métodos , Microscopia Confocal/métodos , Fosforilação/efeitos dos fármacos , Agregados Proteicos/fisiologia , Domínios Proteicos/fisiologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/isolamento & purificação , Pirimidinas/farmacologia , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Sulfonas/farmacologia
11.
Life Sci ; 227: 101-113, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31002919

RESUMO

AIMS: NLRP3 inflammasome has been reported associated with some inflammatory and autoimmune diseases. We previously researches showed that interleukin-23 (IL-23) and interleukin-17 (IL-17) aggravates the ischaemic injury of the brain tissue. However, it is poorly understood whether the NLPR3 inflammasome was involved in regulating and activating the IL-23/IL-17 axis in ischaemic stroke. We aimed to delineate whether the NLRP3 inflammasome signalling provokes the IL-23/IL-17 axis and interleukin-23 receptor (IL-23R) inducing the ischaemia-reperfusion injury of the brain in mice. MAIN METHODS: The male C57/BL6 mice with experimental transient middle cerebral artery occlusion (tMCAO) were established for cerebral ischaemia-reperfusion injury. MCC950 was utilized as a selective NLRP3 inflammasome inhibitor. NLRP3 inflammasome associated protein, IL-23/IL-17 and IL-23R were detected to investigate their changes in the brain tissue after tMCAO. KEY FINDINGS: MCC950 inhibited the NLRP3 inflammasome, which alleviated the neurological ischaemia-reperfusion injury. Inhibition the NLRP3 inflammasome signalling by treatment with MCC950 decreased the activation of IL-23/IL-17 axis and the expression of IL-23R. SIGNIFICANCE: The NLRP3 inflammasome facilitated the injury effect of the IL-23/IL-17 axis, which contributed to the cerebral ischaemia-reperfusion injury. This process was associated with IL-23R. Furthermore, this indicated that the NLRP3 inflammasome, as an important therapeutic target for ischaemic stroke, involves multiple mechanisms in ischaemia-reperfusion injury, and MCC950 is a promising way for clinical treatment.


Assuntos
Isquemia Encefálica/fisiopatologia , Inflamassomos/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Animais , Modelos Animais de Doenças , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/metabolismo , Interleucina-17/fisiologia , Interleucina-23/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Artéria Cerebral Média/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de Interleucina/fisiologia , Traumatismo por Reperfusão/fisiopatologia , Acidente Vascular Cerebral/metabolismo , Sulfonas/farmacologia
12.
BMC Cancer ; 19(1): 243, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885150

RESUMO

BACKGROUND: High-risk neuroblastoma with N-Myc amplification remains a therapeutic challenge in paediatric oncology. Antagonism of pro-death Bcl-2 homology (BH) proteins to pro-survival BH members such as Mcl-1 and Bcl-2 has become a treatment approach, but previous studies suggest that a combined inhibition of Bcl-2 and Mcl-1 is necessary. TW-37 inhibits Mcl-1 and Bcl-2 with almost the same affinity. However, single-agent cytotoxicity of TW-37 in neuroblastoma cell lines has not been investigated. METHODS: Cell viability, apoptosis, proliferation and changes in growth properties were determined in SKNAS, IMR-5, SY5Y and Kelly cells after treatment with TW-37. After transfection with Mcl-1 or Bcl-2 siRNA, apoptosis and proliferation were investigated in Kelly cells. Mice with Kelly cell line xenografts were treated with TW-37 and tumor growth, survival and apoptosis were determined. RESULTS: Cell lines with N-Myc amplification were more sensitive to TW-37 treatment, IC50 values for IMR-5 and Kelly cells being 0.28 µM and 0.22 µM, compared to SY5Y cells and SKNAS cells (IC50 0.96 µM and 0.83 µM). Treatment with TW-37 resulted in increased apoptosis and reduced proliferation rates, especially in IMR5 and Kelly cells. Bcl-2 as well as Mcl-1 knockdown induced apoptosis in Kelly cells. TW-37 led to a decrease in tumor growth and a favorable survival (p = 0.0379) in a Kelly neuroblastoma xenografts mouse model. CONCLUSION: TW-37 has strong single-agent cytotoxicity in vitro and in vivo. Therefore, combined inhibition of Bcl-2/Mcl-1 by TW-37 in N-Myc amplified neuroblastoma may represent an interesting therapeutic strategy.


Assuntos
Benzamidas/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neuroblastoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Amplificação de Genes , Técnicas de Silenciamento de Genes , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Neuroblastoma/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonas/uso terapêutico , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Artigo em Inglês | MEDLINE | ID: mdl-30857466

RESUMO

The current research article involves one pot synthesis of novel substituted 1-nitro-10H-phenothiazines via Smiles rearrangement. These substituted phenothiazines undergo oxidation to yield 10H-phenothiazine-5,5-dioxides (sulfones) while on treatment with ß-D-ribofuranose-1-acetate-2,3,5-tribenzoate yield ribofuranosides. These compounds were screened for their antimicrobial vitalities (in vitro) against selected strains of bacteria and fungi. The characterization of synthesized compounds was done by elemental and spectral studies.


Assuntos
Anti-Infecciosos/síntese química , Nitrocompostos/síntese química , Nucleosídeos/química , Fenotiazinas/síntese química , Sulfonas/química , Anti-Infecciosos/farmacologia , Proteínas de Bactérias/química , Benzoatos/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Nitrocompostos/farmacologia , Oxirredução , Fenotiazinas/farmacologia , Relação Estrutura-Atividade , Sulfonas/farmacologia
14.
Biomed Pharmacother ; 111: 1458-1466, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841461

RESUMO

INTRODUCTION: Prostaglandins (PGs) play an important role in corpus cavernosum relaxation, as evidenced by alprostadil being used as a drug for erectile dysfunction. Reports about the effect of cyclooxygenase (COX) inhibitors on erectile function are highly contradictory. AIM: To compare the potential effects of some COX inhibitors with varying COX-1/COX-2 selectivities (indomethacin, ketoprofen and diclofenac) with that of the selective COX-2 inhibitor (DFU) on corpus cavernosal tone in-vitro. The role played by PGE1, PGI2-analogue and PGE4 receptor (EP4)-agonist in controlling corpus cavernosum function and the modulation of their action by sildenafil is also studied. METHODS: Organ bath experiments were performed using isolated rat corpus cavernosum. Direct relaxations and changes to electric field stimulation (EFS, 2-16 Hz, 60 V, 0.8 ms, 10 s train)-induced relaxation by the effect of the selected drugs were studied. Strips were precontracted using phenylephrine (PE, 10-5 M). Results are expressed as mean ± SEM of 5-9 rats. RESULTS: Alprostadil, iloprost and L902688 (selective EP4 agonist) induced direct relaxation where L902688 showed greater relaxant effect. Sildenafil potentiated the Emax of alprostadil and iloprost but not L902688. EFS and acetylcholine (ACh)-induced relaxations were significantly potentiated in presence of indomethacin, ketoprofen and diclofenac (20, 100 µM) but not in presence of selective COX-2 inhibitor (DFU, 1 µM). GR32191B (Thromboxane A2 receptor antagonist, 10-6 M) significantly reduced the potentiatory effect of indomethacin. Only diclofenac succeeded to potentiate sodium nitroprusside (SNP)-induced relaxation. CONCLUSIONS: EP4 receptors may play an important nitric oxide (NO)/cGMP-independent role in corpus cavernosal relaxation. Nonselective COX inhibitors seem of no harm concerning cavernosal tissue relaxation, possibly because they inhibit the synthesis of the highly contracting mediator thromboxane A2.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Pênis/efeitos dos fármacos , Prostaglandinas/metabolismo , Alprostadil/farmacologia , Animais , GMP Cíclico/metabolismo , Diclofenaco/farmacologia , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/metabolismo , Iloprosta/farmacologia , Indometacina/farmacologia , Cetoprofeno/farmacologia , Masculino , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Ereção Peniana/efeitos dos fármacos , Pênis/metabolismo , Piperazinas/farmacologia , Ratos , Citrato de Sildenafila/farmacologia , Sulfonas/farmacologia
15.
BMC Cancer ; 19(1): 211, 2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30849956

RESUMO

BACKGROUND: The Na+/H+ exchanger (NHE1) plays a crucial role in cancer cell proliferation and metastasis. However, the mechanism underlying chemotherapeutic resistance in cancer cells has not been completely elucidated. The NHE1 inhibitor cariporide has been demonstrated to inhibit human cancer cell lines. The goal of this study was to provide new sights into improved cancer cell chemosensitivity mediated by cariporide with activation of the apoptosis pathway. METHODS: The NHE1 expression levels were first evaluated using the online database Oncomine and were determined by RT-PCR and western blot in vitro and in vivo. Cell proliferation was assessed In vitro through a CCK-8 assay, and apoptosis was analyzed by flow cytometry. An in vivo analysis was performed in BALB/c nude mice, which were intraperitoneally injected with MCF-7/ADR cells. RESULTS: NHE1 levels were significantly higher in breast cancer tissue than adjacent tissue, as well as in resistant cancer cells compared to sensitive cells. Cariporide induced the apoptosis of MCF-7/ADR cells and was associated with the intracellular accumulation of doxorubicin and G0/G1 cell cycle arrest. Moreover, cariporide decreased MDR1 expression and activated cleaved caspase-3 and caspase-9, promoting caspase-independent apoptosis in vitro. In vivo, cariporide significantly improved doxorubicin sensitivity in a xenograft model, enhancing tumor growth attenuation and diminishing tumor volume. CONCLUSIONS: Our results demonstrate that cariporide significantly facilitates the sensitivity of breast cancer to doxorubicin both in vitro and in vivo. This finding suggests that NHE1 may be a novel adjuvant therapeutic candidate for the treatment of resistant breast cancer.


Assuntos
Neoplasias da Mama/genética , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Guanidinas/farmacologia , Trocador 1 de Sódio-Hidrogênio/genética , Sulfonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/genética , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Camundongos
16.
Toxicon ; 162: 9-14, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30849454

RESUMO

The hepatocyte growth factor (HGF)/c-met pathway, which mainly consists of HGF activator (HGFA) and its substrate HGF, protects various types of cells via anti-apoptotic and anti-inflammatory signals. Thrombin is the main physiological activator of such plasmatic pathway, and increased plasma concentrations of HGF have been considered as a molecular marker for some pathological conditions, such as disseminated intravascular coagulation. Since thrombin generation is often linked to tissue injury, and these events are common during snake venom-induced consumption coagulopathies (VICC), our goals were to examine whether Bothrops jararaca venom (Bjv), which induces VICC in vivo: (i) activates the HGF/c-met pathway in vivo and (ii) cleaves zymogen forms of HGFA and HGF (proHGFA and proHGF, respectively) in vitro. Two experimental groups (n = 6, each) of male adult Wistar rats were subcutaneously injected with 500 µL of 0.9% NaCl solution (control) or sub-lethal doses (1.6 mg/kg) of Bjv. Three hours after envenomation, whole blood samples were collected from the carotid arteries to evaluate relevant coagulation parameters using rotational thromboelastometry and fibrinogen level (colorimetric assay). Additionally, the plasma concentration of HGF was assayed (ELISA). Thromboelastometric assays showed that blood clotting and fibrin polymerization were severely impaired 3 h after Bjv injection. Total plasma HGF concentrations were almost 6-fold higher in the Bjv-injected group (410.0 ±â€¯91) compared with control values (68 ±â€¯18 pg/mL, p < 0.05). Western blotting assay showed that Bjv processed proHGFA and proHGF, generating bands resembling those generated by thrombin and kallikrein, respectively. In contrast to the serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF), the metalloprotease inhibitor ethylenediaminetetraacetic acid disodium salt (Na2-EDTA) strongly reduced the ability of Bjv to process proHGFA and generated one active band similar to that of thrombin. Since Bjv contains prothrombin and factor X activators, increased intravascular thrombin formation might partly explain the increased HGF levels after bothropic envenomation. In conclusion, these findings suggest that snake venom metalloproteases may be determinant for elevation of plasma levels of HGF in rats experimentally envenomated with Bjv.


Assuntos
Bothrops , Venenos de Crotalídeos/toxicidade , Fator de Crescimento de Hepatócito/sangue , Metaloproteases/metabolismo , Precursores de Proteínas/sangue , Animais , Coagulação Sanguínea , Venenos de Crotalídeos/enzimologia , Feminino , Fibrina/análise , Fator de Crescimento de Hepatócito/metabolismo , Masculino , Precursores de Proteínas/metabolismo , Ratos Wistar , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/farmacologia , Sulfonas/farmacologia
17.
Biomed Res Int ; 2019: 3702783, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30834261

RESUMO

Increased metabolism accelerates local acid production in cancer tissue. The mechanisms eliminating acidic waste products from human colon cancer tissue represent promising therapeutic targets for pharmacological manipulation in order to improve prognosis for the increasing number of patients with colon cancer. We sampled biopsies of human colonic adenocarcinomas and matched normal colon tissue from patients undergoing colon cancer surgery. We measured steady-state intracellular pH and rates of net acid extrusion in freshly isolated human colonic crypts based on fluorescence microscopy. Net acid extrusion was almost entirely (>95%) Na+-dependent. The capacity for net acid extrusion was increased and steady-state intracellular pH elevated around 0.5 in crypts from colon cancer tissue compared with normal colon tissue irrespective of whether they were investigated in the presence or absence of CO2/HCO3 -. The accelerated net acid extrusion from the human colon cancer tissue was sensitive to the Na+/H+-exchange inhibitor cariporide. We conclude that enhanced net acid extrusion via Na+/H+-exchange elevates intracellular pH in human colon cancer tissue.


Assuntos
Ácidos/metabolismo , Neoplasias do Colo/genética , Trocadores de Sódio-Hidrogênio/genética , Ácidos/química , Bicarbonatos/metabolismo , Dióxido de Carbono/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias do Colo/ultraestrutura , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Guanidinas/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Íons/química , Íons/metabolismo , Masculino , Microscopia de Fluorescência , Trocadores de Sódio-Hidrogênio/metabolismo , Sulfonas/farmacologia , Ativação Transcricional/genética
18.
Int Immunopharmacol ; 70: 147-155, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30802677

RESUMO

Cholestasis occurs in many clinical circumstances and leads to severe liver disorders. MCC950, a small-molecule NLRP3 inhibitor, was previously shown to have anti-inflammatory effects. However, these effects have not yet been examined in cholestatic liver injury. This study aimed to investigate the role of NLRP3 inflammasome and test the therapeutic efficacy and molecular mechanisms of MCC950 in cholestatic liver injury through the common bile duct ligation (BDL) model in mice. The influence of MCC950 on histological changes, levels of liver damage, neutrophil infiltration, liver cell death, inflammatory cytokine levels, and NLRP3 inflammasome expression were examined. The results of the current study confirmed that NLRP3 components were up-regulated during bile duct obstruction. MCC950 treatment significantly alleviated BDL-induced liver injury by reducing production of the pro-inflammatory cytokines IL-1ß and IL-18 and inhibiting neutrophil infiltration and hepatic cell death. Moreover, MCC950 significantly inhibited NLRP3 activation during cholestatic liver injury. In addition, transcriptome analysis indicated that Toll-like receptor signaling may be involved in the protective effects of MCC950 in cholestatic liver injury. In conclusion, experimental findings demonstrate that MCC950 exerted protective effects in cholestatic liver injury and liver fibrosis by blocking NLRP3 inflammasome activation and the mechanism was partially attributed to inhibition of Toll-like receptor signaling. The present study indicates MCC950 could potentially be an effective therapeutic strategy for the treatment of cholestatic liver injury.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colestase/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Inflamassomos/antagonistas & inibidores , Fígado/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonas/uso terapêutico , Animais , Ductos Biliares/cirurgia , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Fígado/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Transdução de Sinais , Sulfonas/farmacologia , Receptores Toll-Like/metabolismo
19.
Biomed Res Int ; 2019: 3104057, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809537

RESUMO

Aurantiochytrium limacinum 4W-1b (AL4W-1b) is a newly discovered microalgal strain with unique features. In the present study, we investigated the effects of ethanol extracts of AL4W-1b on lipopolysaccharide- (LPS-) induced inflammatory responses in RAW264 murine macrophage cells. Pretreatment of RAW264 cells with the AL4W-1b extract significantly reduced the production of LPS-induced nitric oxide (NO) and the expression of proinflammatory cytokine genes, including tumor necrosis factor α, interleukin- (IL-) 1ß, and IL-6. Treatment with the AL4W-1b extract also decreased the production of IL-1ß and IL-6. These results suggest that AL4W-1b might have anti-inflammatory effects in RAW264 cells. The NF-κB inhibitor, BAY 11-7082, synergistically prevented LPS-induced NO production after pretreatment with the AL4W-1b extract. Thus, the AL4W-1b extract may affect not only the NF-κB pathway but also other inflammatory pathways. To the best of our knowledge, this is the first study to report the anti-inflammatory effects of AL4W-1b extract and its mechanism of action in LPS-stimulated murine macrophage cells.


Assuntos
Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Estramenópilas/química , Animais , Etanol/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-6/genética , Lipopolissacarídeos/toxicidade , Camundongos , NF-kappa B/genética , Óxido Nítrico/genética , Nitrilos/farmacologia , Extratos Vegetais/química , Células RAW 264.7 , Sulfonas/farmacologia
20.
J Colloid Interface Sci ; 540: 295-305, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30660082

RESUMO

Mixed matrix membranes blended with graphene-based nanomaterials have great potential in water and wastewater treatment on account of their multiple functionalities. To solve the complicated biofouling problem and diversify the applications of membranes, novel synergistic antibacterial guanidyl-functionalized graphene/polysulfone (GFG/PSF) mixed matrix ultrafiltration membranes were prepared by a non-solvent induced phase separation method. The guanidyl-functionalized graphene nanosheets were achieved by a two-step grafting process consisting of amination and guanidination and exhibited high dispersibility in the casting solution, which showed good compatibility with the polymer matrix. Besides the advantages of partially reduced graphene oxide (GO) nanosheets in creating a stronger interaction with the bacterial cell membrane to destroy the bacteria, the induced bidendate binding between guanidyl groups and phosphate groups on the cell wall can make high sterilization rate even at low concentrations. Different techniques including XRD, FTIR, XPS, SEM, TEM, EDX, contact angle meter, filtration and antibacterial experiments were employed to characterize and investigate the performance of nanosheets and membranes. Compared with pure PSF membrane, the GFG/PSF mixed matrix membranes not only exhibited superior permeability and prominent antifouling property performance toward bovine serum albumin (BSA), but also displayed excellent antimicrobial activity and long-term duration toward Escherichia coli and Staphylococcus aureus.


Assuntos
Antibacterianos/química , Grafite/química , Guanina/química , Membranas Artificiais , Polímeros/química , Sulfonas/química , Ultrafiltração/instrumentação , Purificação da Água/instrumentação , Antibacterianos/farmacologia , Infecções Bacterianas/prevenção & controle , Incrustação Biológica/prevenção & controle , Escherichia coli/efeitos dos fármacos , Grafite/farmacologia , Guanina/farmacologia , Humanos , Nanoestruturas/química , Permeabilidade , Polímeros/farmacologia , Porosidade , Staphylococcus aureus/efeitos dos fármacos , Sulfonas/farmacologia , Microbiologia da Água
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