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1.
Braz. J. Pharm. Sci. (Online) ; 58: e191142, 2022. tab, graf
Article in English | LILACS | ID: biblio-1394056

ABSTRACT

A series of N-(benzoylphenyl)-carboxamide derivatives (2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a and 6b) was prepared with good yields by reacting the corresponding carbonyl chlorides with aminobenzophenones at room temperature. This was followed by evaluating the hypotriglyceridemic and hypocholesterolemic effects of 3b, 5a and 5b. Triton WR-1339 (300 mg/kg) was intraperitoneally administered to overnight-fasted rats to induce hyperlipidemia. Rats were divided into six groups: control, hyperlipidemic, hyperlipidemic plus compounds 3b, 5a and 5b and hyperlipidemic plus bezafibrate. Results showed that after 18 h of treatment at a dose of 15 mg/kg body weight of each of the test compounds, the elevated plasma levels of triglycerides (TG) and total cholesterol (TC) were significantly lowered by compounds 5b and 3b (p < 0.001) and by 5a (p < 0.0001), compared to the hyperlipidemic control group. Compounds 3b and 5a significantly increased levels of high-density lipoprotein cholesterol (HDL-C) by 58 and 71%, respectively. In addition, compounds 3b and 5a caused significant reduction (p < 0.0001) of low-density lipoprotein cholesterol (LDL-C) levels compared to the control group. These results suggest a promising potential for compounds 3b, 5a and 5b as lipid-lowering agents, which may contribute to reducing the risk of atherosclerosis and cardiovascular disease


Subject(s)
Animals , Male , Rats , Pyridines/pharmacology , Hyperlipidemias/chemically induced , Lipids/blood , Hypolipidemic Agents/pharmacology , Polyethylene Glycols , Pyridines/chemical synthesis , Triglycerides/blood , Cholesterol/blood , Rats, Wistar , Disease Models, Animal , Lipoproteins, HDL/drug effects , Lipoproteins, LDL/drug effects , Hypolipidemic Agents/chemical synthesis
2.
Frontiers of Medicine ; (4): 467-482, 2022.
Article in English | WPRIM | ID: wpr-939878

ABSTRACT

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.


Subject(s)
Animals , Humans , Anilides/pharmacology , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Cell Proliferation , Endothelial Cells/metabolism , Liver Neoplasms/drug therapy , Pyridines/pharmacology , Sirolimus/pharmacology , Xenograft Model Antitumor Assays
3.
Rev. Soc. Bras. Med. Trop ; 53: e20190489, 2020. tab, graf
Article in English | LILACS | ID: biblio-1057274

ABSTRACT

Abstract INTRODUCTION: In Brasilia, pyriproxyfen (PPF; 0.01 mg/L) has been used for the larval control of Aedes aegypti mosquitoes since 2016. Information on the susceptibility of Ae. aegypti to PPF, and the development of resistance in populations from the Federal District of Brazil (FD) is limited. It is essential to monitor the susceptibility of Ae. aegypti to insecticides in order to improve vector control strategies. This study aimed to evaluate the susceptibility of Ae. aegypti populations from five areas of Brasilia to PPF. METHODS: We performed dose-response tests to estimate the emergence inhibition and resistance ratio of each field population, including the Rockefeller reference population. We also analyzed egg positivity, and the density and mortality of larvae and pupae. RESULTS: Populations from Vila Planalto (RR50=1.7), Regiment Guards Cavalry (RR50=2.5), and Sub-secretary of Justice Complex (RR50=3.7) presented high susceptibility to PPF, while the RR values of populations from Lago Norte (RR50=7.7) and Varjão (RR50=5.9) were moderately high, suggesting the emergence of insipient resistance to PPF in Brasilia. At 30 ng/mL, the highest larvae mortality rate was 2.7% for the population from Lago Norte, while that of pupae was 92.1% for Varjão and Vila Planalto. CONCLUSIONS: The five populations of Ae. aegypti from the FD are susceptible to PPF and there is a need to monitor the susceptibility of Ae. aegypti in new areas of the FD.


Subject(s)
Animals , Pyridines/pharmacology , Insecticide Resistance , Aedes/drug effects , Mosquito Vectors/drug effects , Insecticides/pharmacology , Brazil , Larva/drug effects
4.
Journal of Southern Medical University ; (12): 1784-1792, 2020.
Article in Chinese | WPRIM | ID: wpr-880803

ABSTRACT

OBJECTIVE@#To investigate the effect of palbociclib on cell cycle progression and proliferation of human renal tubular epithelial cells.@*METHODS@#Human renal tubular epithelial cell line HK-2 was treated with 1, 5, 10, and 20 μmol/L of palbociclib, and the changes in cell proliferation and viability were examined by cell counting and CCK8 assay. EDU staining was used to assess the proliferation of HK-2 cells following palbiciclib treatment at different concentrations for 5 days. The effect of palbociclib on cell cycle distribution of HK-2 cells was evaluated using flow cytometry. SA-β-Gal staining and C12FDG senescence staining were used to detect senescence phenotypes of HK-2 cells after palbociclib treatment at different concentrations for 5 days. The relative mRNA expression levels of P16, P21, and P53 and the genes associated with senescence-related secretion phenotypes were detected by RT-PCR, and the protein expressions of P16, P21 and P53 were detected by Western blotting.@*RESULTS@#Palbociclib inhibited HK-2 cell proliferation and induced cell cycle arrest in G1 phase. Compared with the control cells, HK-2 cells treated with high-dose (10 μmol/L) palbociclib exhibited significantly suppressed cell proliferation activity, and the inhibitory effect was the most obvious on day 5 (@*CONCLUSIONS@#Palbociclib induces HK-2 cell senescence by causing cell growth arrest and delaying cell cycle progression.


Subject(s)
Humans , Cell Cycle , Cell Cycle Checkpoints , Cellular Senescence , Epithelial Cells , Piperazines/pharmacology , Pyridines/pharmacology , Tumor Suppressor Protein p53/genetics
5.
Mem. Inst. Oswaldo Cruz ; 115: e200271, 2020. tab, graf
Article in English | LILACS, SES-SP | ID: biblio-1135271

ABSTRACT

BACKGROUND Aedes aegypti is the primary transmitter of several arbovirus with great impact in human health. Controlling vector mosquitoes is an essential and complex task. One promising control method is to use mosquitoes as a vehicle to disseminate tiny particles of juvenile-killing insecticides, such as pyriproxyfen (PPF), to breeding sites. OBJECTIVES We aimed to investigate the capacity of Ae. aegypti to disseminate two new formulations of PPF in two sites of Rio de Janeiro city for assessment of the efficacy of these products. METHODS Dissemination stations impregnated with powder and liquid new formulations of PPF were installed in two test sites. Ovitraps were used in the test sites and in a control site for monitoring the presence of Ae. aegypti throughout eggs collection. FINDINGS Entomological indices indicated that the new formulations of PPF were efficient in reducing eggs abundance. Liquid formulation performed better than powder formulation. Ready-to-use formulations of PPF can be quickly applied in the field and can be replaced after a few months. MAIN CONCLUSIONS New formulations of PPF associated with mosquito dissemination approach make a valuable vector control strategy, managing to cover places of difficult access for whatever reason. New formulations application requires less labour, being economically attractive.


Subject(s)
Humans , Animals , Adolescent , Pyridines/pharmacology , Mosquito Control/methods , Aedes/drug effects , Insecticides/pharmacology , Larva/drug effects , Cities , Mosquito Vectors/growth & development , Mosquito Vectors/drug effects , Larva/growth & development
6.
Braz. oral res. (Online) ; 30(1): e125, 2016. graf
Article in English | LILACS | ID: biblio-951959

ABSTRACT

Abstract The aim of this study was to assess the in vitro antimicrobial effects of chlorhexidine digluconate (CHX), polyhexamethylene biguanide (PHBM), and octenidine dihydrochloride (OCT) on cariogenic microorganisms by using their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). CHX, PHBM, and OCT were diluted in distilled water to the final test concentrations. Using the in-tube dilution method, Streptococcus mutans, Lactobacillus acidophilus, Lactobacillus rhamnosus, and Actinomyces viscosus were cultivated on blood agar and Mueller-Hinton broth (MHB) at 37°C for 48 h. They were read using a spectrophotometer to detect MIC. To determine MBC, samples in the range of the turbidity threshold after 24 h were transferred onto blood agar and evaluated for growth after 24 h. Different MICs and MBCs were observed in all disinfectants against each microorganism. The lowest MIC and MBC against S. mutans (60 mg/L) were obtained from PHBM. The lowest values against L. rhamnosus (15 mg/L, 30 mg/L), A. viscosus (30 mg/L), and L. acidophilus (15 mg/L, 30 mg/L) were determined by OCT. PHBM and OCT have the potential to be replaced with CHX because they were effective against cariogenic microorganisms.


Subject(s)
Pyridines/pharmacology , Biguanides/pharmacology , Chlorhexidine/analogs & derivatives , Gram-Positive Bacteria/drug effects , Anti-Infective Agents, Local/pharmacology , Anti-Bacterial Agents/pharmacology , Spectrophotometry , Time Factors , Microbial Sensitivity Tests , Chlorhexidine/pharmacology , Reproducibility of Results , Agar , Dental Caries/microbiology , Gram-Positive Bacteria/growth & development
7.
Rev. paul. pediatr ; 33(1): 19-27, Jan-Mar/2015. tab, graf
Article in English | LILACS | ID: lil-744705

ABSTRACT

OBJECTIVE: To analyze the neonatal screening program for hemoglobinopathies in São Carlos, Southeast Brazil, by investigating a series of cases in which the screening test was abnormal. More specifically, it was aimed to know the information regarding the neonatal screening received by mothers at the hospital and at primary health care, in addition to information related to genetic counseling. METHODS: A descriptive study that enrolled 119 mothers, accounting for 73% of all children born between 2010 and 2011 with abnormal results of neonatal screening for hemoglobinopathies. The mothers completed a questionnaire that assessed the information received at hospital and primary health care, and issues related to genetic counseling. Descriptive statistics was performed. RESULTS: Of the 119 participating mothers, 69 (58%) had children with sickle cell trait, 22 (18.5%) with hemoglobin C trait, 18 (15.1%) with alpha thalassemia trait and, in 10 cases (8.4%), the result was inconclusive. At the hospital, 118 mothers (99.2%) received information about where to go to collect the test and 115 (96.6%) were informed about the correct time to collect the test. Only 4 mothers (3.4%) were informed about which diseases are investigated and the risks of not performing the screening. Seventeen mothers (14.3%) recognized the difference between trait and disease, and 42 (35.3%) considered that a positive screening test could have implications for future pregnancies. In 70 cases (58.8%), the child's physician was not informed about the screening test results. CONCLUSIONS: The neonatal screening program needs further improvement. In both scenarios investigated, health professionals demonstrated a lack of training in providing information to mothers and families. .


OBJETIVO: Fazer uma análise do programa de triagem neonatal de hemoglobinopatias no município de São Carlos, São Paulo, Brasil, por meio da investigação de série de casos cujo resultado do teste de rastreio foi alterado. Objetivou-se conhecer as informações a respeito da triagem neonatal recebidas pelas mães na maternidade e na atenção primária à saúde, além das informações relacionadas à orientação genética. MÉTODOS: Estudo descritivo, no qual participaram 119 mães cujos filhos apresentaram teste de triagem de hemoglobinopatia alterado, o que correspondeu a 73% das crianças nascidas entre 2010 e 2011 com resultado de triagem neonatal para hemoglobinopatia anormal. As mães responderam um questionário que avaliou informações recebidas na maternidade e na atenção primária à saúde, além de aspectos relacionados à orientação genética. Foi feita estatística descritiva dos dados. RESULTADOS: Das 119 mães participantes, 69 (58%) tinham filhos com traço falciforme, 22 (18,5%) traço C, 18 (15,1%) traço alfatalassêmico e 10 (8,4%) resultado inconclusivo. Na maternidade, 118 mães (99,2%) receberam informação sobre onde ir e 115 (96,6%) foram orientadas sobre o momento correto para coleta do teste. Somente quatro mães (3,4%) foram informadas sobre quais doenças seriam investigadas e os riscos de não fazer o rastreio. Das 119 mães participantes, 17 (14,3%) reconheceram a diferença entre traço e doença e 42 (35,3%) consideraram que um teste alterado poderia ter implicações para futuras gestações. Em 70 casos (58,8%), o médico da criança não foi informado sobre o resultado da triagem. CONCLUSÕES: O programa de triagem neonatal necessita de aperfeiçoamento. Nos dois cenários investigados, os profissionais de saúde carecem de treinamento para orientar mães e famílias. .


Subject(s)
Antimalarials/pharmacology , Oxazines/pharmacology , Plasmodium falciparum/drug effects , Pyridines/pharmacology , Antimalarials/chemical synthesis , Antimalarials/metabolism , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Oxazines/chemical synthesis , Oxazines/metabolism , Parasitic Sensitivity Tests , Pyridines/chemical synthesis , Pyridines/metabolism , Structure-Activity Relationship
8.
Rev. bras. epidemiol ; 18(1): 234-247, Jan-Mar/2015. tab
Article in Portuguese | LILACS | ID: lil-736431

ABSTRACT

OBJETIVO: Estimar a prevalência de dor crônica e sua associação com a situação socioeconômica, demográfica e atividade física no lazer em idosos. MÉTODOS: Este estudo é parte do inquérito epidemiológico e transversal de base populacional e domiciliar EpiFloripa Idoso 2009-2010 realizado com 1.705 idosos (≥ 60 anos), residentes em Florianópolis, Santa Catarina. A partir da resposta afirmativa de dor crônica, foram investigadas as associações com as variáveis obtidas por meio de entrevista estruturada. Realizou-se a estatística descritiva, incluindo cálculos de proporções e intervalos de confiança 95% (IC95%). Na análise bruta e ajustada, empregou-se regressão de Poisson, estimando-se as razões de prevalência, com intervalos de confiança de 95% e valores p ≤ 0,05. RESULTADOS: Dentre os idosos investigados, 29,3% (IC95% 26,5 - 32,2) relataram dor crônica. Na análise ajustada, observou-se que as variáveis sexo feminino, menor escolaridade e pior situação econômica ficaram associadas significativamente com maior prevalência de dor crônica; ser fisicamente ativo no lazer ficou associado significativamente com menor prevalência do desfecho. CONCLUSÕES: Percebe-se que a dor crônica é um agravo que acomete considerável parcela de idosos, havendo desigualdades sociais na sua frequência e sendo beneficamente afetada pela atividade física no lazer. É necessário que políticas públicas de saúde subsidiem programas multidisciplinares de controle da dor incluindo a prática regular de atividade física, voltada especificamente à promoção da saúde do idoso, evitando assim que a dor crônica comprometa a qualidade de vida desta população. .


OBJECTIVE: To estimate the prevalence of chronic pain and its association with socioeconomic and demographic status, and leisure physical activity in the elderly population. METHODS: This study is part of an epidemiological cross-sectional population-based household survey called EpiFloripa Elderly 2009-2010, which was conducted with 1,705 elderly individuals (≥ 60 years) residents of Florianópolis, Santa Catarina. From the positive response to chronic pain, the associations with the variables were investigated through a structured interview. Descriptive statistics were conducted, including ratio calculation and 95% confidence intervals. In crude and adjusted analysis, Poisson regression was utilized, estimating prevalence ratios, with 95% confidence intervals and ≤ 0.05 p-values. RESULTS: Among the subjects, 29.3% (IC95% 26.5 - 32.2) reported chronic pain. Adjusted analysis showed that being female, having less years of schooling, and being in worse economic situation were significantly associated with a higher prevalence of chronic pain. Being physically active during leisure time was significantly associated with lower prevalence of the outcome. CONCLUSIONS: Therefore, it is clear that chronic pain affects a considerable amount of elderly individuals. Social inequalities are a harmful influence in these individuals' quality of life, inasmuch as those inequalities increase the frequency with which chronic pain afflicts them. At the same time, physical activity during leisure time decreases chronic pain frequency. It is fundamental that public health policies subsidize multidisciplinary pain management programs, which should include health targeted physical activity for the elderly, thus preventing the decrease in quality of life that chronic pain brings to this population. .


Subject(s)
Animals , Humans , Early Growth Response Protein 1/genetics , Epithelial Cells/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , /metabolism , Sulindac/analogs & derivatives , Apoptosis/drug effects , Blotting, Western , Butadienes/pharmacology , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Early Growth Response Protein 1/metabolism , Epithelial Cells/cytology , Epithelial Cells/metabolism , Imidazoles/pharmacology , Intestines/cytology , Intestines/drug effects , Intestines/metabolism , Luciferases/genetics , Luciferases/metabolism , Microscopy, Confocal , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , /antagonists & inhibitors , Nitriles/pharmacology , Pyridines/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction/drug effects , Sulindac/pharmacology , Transfection , Up-Regulation/drug effects , ets-Domain Protein Elk-1/genetics , ets-Domain Protein Elk-1/metabolism
9.
Indian J Biochem Biophys ; 2015 Feb; 52 (1): 23-28
Article in English | IMSEAR | ID: sea-157951

ABSTRACT

Crizotinib is the potential anticancer drug used for the treatment of non-small cell lung cancer (NSCLC) approved by FDA in 2011. The main target for the crizotinib is anaplastic lymphoma kinase (ALK). Evidences available indicate that double mutant ALK (L1196M and G1269A) confers resistance to crizotinib. However, how mutation confers drug resistance is not well-understood. Hence, in the present study, molecular dynamic (MD) simulation approach was employed to study the impact of crizotinib binding efficacy with ALK structures at a molecular level. Docking results indicated that ALK double mutant (L1196M and G1269A) significantly affected the binding affinity for crizotinib. Furthermore, MD studies revealed that mutant ALK-crizotinib complex showed higher deviation, higher fluctuation and decreased number of intermolecular H-bonds, when compared to the native ALK-crizotinib complex. These results may be immense importance for the molecular level understanding of the crizotinib resistance pattern and also for designing potential drug molecule for the treatment of lung cancer.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/etiology , Molecular Dynamics Simulation/statistics & numerical data , Pyrazoles/pharmacology , Pyridines/pharmacology
10.
Experimental & Molecular Medicine ; : e143-2015.
Article in English | WPRIM | ID: wpr-42472

ABSTRACT

An F-box protein, beta-TrCP recognizes substrate proteins and destabilizes them through ubiquitin-dependent proteolysis. It regulates the stability of diverse proteins and functions as either a tumor suppressor or an oncogene. Although the regulation by beta-TrCP has been widely studied, the regulation of beta-TrCP itself is not well understood yet. In this study, we found that the level of beta-TrCP1 is downregulated by various protein kinase inhibitors in triple-negative breast cancer (TNBC) cells. A PI3K/mTOR inhibitor PI-103 reduced the level of beta-TrCP1 in a wide range of TNBC cells in a proteasome-dependent manner. Concomitantly, the levels of c-Myc and cyclin E were also downregulated by PI-103. PI-103 reduced the phosphorylation of beta-TrCP1 prior to its degradation. In addition, knockdown of beta-TrCP1 inhibited the proliferation of TNBC cells. We further identified that pharmacological inhibition of mTORC2 was sufficient to reduce the beta-TrCP1 and c-Myc levels. These results suggest that mTORC2 regulates the stability of beta-TrCP1 in TNBC cells and targeting beta-TrCP1 is a potential approach to treat human TNBC.


Subject(s)
Female , Humans , Cell Line, Tumor , Cell Proliferation , Cell Survival/drug effects , Cyclin E/genetics , Dose-Response Relationship, Drug , Furans/pharmacology , Gene Knockdown Techniques , Models, Biological , Multiprotein Complexes/antagonists & inhibitors , Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Proteolysis/drug effects , Proto-Oncogene Proteins c-myc/genetics , Pyridines/pharmacology , Pyrimidines/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Triple Negative Breast Neoplasms/genetics , beta-Transducin Repeat-Containing Proteins/genetics
11.
The Korean Journal of Parasitology ; : 255-258, 2013.
Article in English | WPRIM | ID: wpr-103944

ABSTRACT

Spillage of cyst contents during surgical operation is the major cause of recurrence after hydatid cyst surgery. Instillation of a scolicidal agent into a hepatic hydatid cyst is the most commonly employed measure to prevent this complication. SB202190 is a pyridinyl imidazole derivative and is known to be a specific inhibitor of p38 MAPK. In the present study, the scolicidal effect of SB202190 was investigated. Freshly isolated Echinococcus granulosus protoscolices were subjected to SB202190 treatment (10, 20, 40, and 80 microM), and the effects on parasite viability were monitored by trypan blue staining. Corresponding effects were visualized by scanning and transmission electron microscopy. Dose-dependent protoscolex death within a few days of SB202190 treatment was observed. Although the in vitro scolicidal effect of SB202190 was satisfactory, the in vivo efficacy of this drug and also possible side effects remain to be further investigated.


Subject(s)
Animals , Anthelmintics/pharmacology , Dose-Response Relationship, Drug , Echinococcus granulosus/drug effects , Imidazoles/pharmacology , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Parasitic Sensitivity Tests , Pyridines/pharmacology , Survival Analysis
12.
Experimental & Molecular Medicine ; : 159-166, 2012.
Article in English | WPRIM | ID: wpr-93414

ABSTRACT

Sphingosylphosphorylcholine (SPC) induces differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) into smooth muscle-like cells expressing alpha-smooth muscle actin (alpha-SMA) via transforming growth factor-beta1/Smad2- and RhoA/Rho kinase-dependent mechanisms. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have been known to have beneficial effects in the treatment of cardiovascular diseases. In the present study, we examined the effects of simvastatin on the SPC-induced alpha-SMA expression and Smad2 phosphorylation in hASCs. Simvastatin inhibited the SPC-induced alpha-SMA expression and sustained phosphorylation of Smad2 in hASCs. SPC treatment caused RhoA activation via a simvastatin-sensitive mechanism. The SPC-induced alpha-SMA expression and Smad2 phosphorylation were abrogated by pretreatment of the cells with the Rho kinase inhibitor Y27632 or overexpression of a dominant negative RhoA mutant. Furthermore, SPC induced secretion of TGF-beta1 and pretreatment with either Y27632 or simvastatin inhibited the SPC-induced TGF-beta1 secretion. These results suggest that simvastatin inhibits SPC-induced differentiation of hASCs into smooth muscle cells by attenuating the RhoA/Rho kinase-dependent activation of autocrine TGF-beta1/Smad2 signaling pathway.


Subject(s)
Humans , Amides/pharmacology , Blotting, Western , Cell Differentiation/drug effects , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Immunohistochemistry , Mesenchymal Stem Cells/cytology , Myocytes, Smooth Muscle/cytology , Phosphorylcholine/analogs & derivatives , Pyridines/pharmacology , Simvastatin/pharmacology , Sphingosine/analogs & derivatives , rhoA GTP-Binding Protein/antagonists & inhibitors
13.
Journal of Korean Medical Science ; : 1563-1568, 2011.
Article in English | WPRIM | ID: wpr-227749

ABSTRACT

Epidermal growth factor receptor (EGFR)-targeted therapies have been effective in some cancers, but not in hepatocellular carcinoma (HCC). The aim of this study was to investigate the drug potential to overcome multi-drug resistance in HCC cells. Thirteen drug-sensitive HCC cells were assessed using the CCK-8 assay. G0-G1 arrest was measured by FACS. Western blot analysis was used to detect the key enzymes in both the Ras/Raf and PI3K pathways. When establishing the IC50 of HCC to several drugs, including EKB-569, sorafenib, erlotinib, gefitinib, pazopanib, and brivanib, SK-Hep1 cells treated with EKB-569 have shown the highest (72.8%-86.4%) G0-G1 arrest and decreased the phosphorylation of AKT and ERK at the protein level. We found that EKB-569 had higher efficacy in HCC, compared to first generation, reversible EGFR-TK inhibitors. Furthermore, the combination of sorafenib and EKB-569 showed a synergistic effect to inhibit proliferation of SNU-475, previously the most resistant cell to EGFR-TKIs. Therefore, novel EKB-569 in combination with sorafenib may be able to overcome HCC resistance to EGFR-TK inhibitors.


Subject(s)
Humans , Aminoquinolines/pharmacology , Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Benzenesulfonates/pharmacology , Carcinoma, Hepatocellular/drug therapy , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm , Drug Synergism , Liver Neoplasms/drug therapy , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Pyridines/pharmacology , ErbB Receptors/antagonists & inhibitors
14.
Yonsei Medical Journal ; : 420-428, 2011.
Article in English | WPRIM | ID: wpr-95678

ABSTRACT

PURPOSE: Dexmedetomidine, a full agonist of alpha2B-adrenoceptors, is used for analgesia and sedation in the intensive care units. Dexmedetomidine produces an initial transient hypertension due to the activation of post-junctional alpha2B-adrenoceptors on vascular smooth muscle cells (SMCs). The aims of this in vitro study were to identify mitogen-activated protein kinase (MAPK) isoforms that are primarily involved in full, alpha2B-adrenoceptor agonist, dexmedetomidine-induced contraction of isolated rat aortic SMCs. MATERIALS AND METHODS: Rat thoracic aortic rings without endothelium were isolated and suspended for isometric tension recording. Cumulative dexmedetomidine (10(-9) to 10(-6) M) dose-response curves were generated in the presence or absence of extracellular signal-regulated kinase (ERK) inhibitor PD 98059, p38 MAPK inhibitor SB 203580, c-Jun NH2-terminal kinase (JNK) inhibitor SP 600125, L-type calcium channel blocker (verapamil and nifedipine), and alpha2-adrenoceptor inhibitor atipamezole. Dexmedetomidine-induced phosphorylation of ERK, JNK, and p38 MAPK in rat aortic SMCs was detected using Western blotting. RESULTS: SP 600125 (10(-6) to 10(-5) M) attenuated dexmedetomidine-evoked contraction in a concentration-dependent manner, whereas PD 98059 had no effect on dexmedetomidine-induced contraction. SB 203580 (10(-5) M) attenuated dexmedetomidine-induced contraction. Dexmedetomidine-evoked contractions were both abolished by atipamezole and attenuated by verapamil and nifedipine. Dexmedetomidine induced phosphorylation of JNK and p38 MAPK in rat aortic SMCs, but did not induce phosphorylation of ERK. CONCLUSION: Dexmedetomidine-induced contraction involves a JNK- and p38 MAPK-mediated pathway downstream of alpha2-adrenoceptor stimulation in rat aortic SMCs. In addition, dexmedetomidine-induced contractions are primarily dependent on calcium influx via L-type calcium channels.


Subject(s)
Animals , Male , Rats , Adrenergic alpha-2 Receptor Agonists/pharmacology , Anthracenes/pharmacology , Aorta/cytology , Dexmedetomidine/pharmacology , Enzyme Inhibitors/pharmacology , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Flavonoids/pharmacology , Imidazoles/pharmacology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Muscle Contraction , Muscle, Smooth, Vascular/drug effects , Protein Isoforms/antagonists & inhibitors , Pyridines/pharmacology , Rats, Sprague-Dawley , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
15.
J. appl. oral sci ; 18(6): 630-634, Nov.-Dec. 2010. ilus, graf
Article in English | LILACS | ID: lil-573735

ABSTRACT

Prostaglandins control osteoblastic and osteoclastic function under physiological or pathological conditions and are important modulators of the bone healing process. The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and consequently prostaglandins synthesis. Experimental and clinical evidence has indicated a risk for reparative bone formation related to the use of non-selective (COX-1 and COX-2) and COX-2 selective NSAIDs. Ketorolac is a non-selective NSAID which, at low doses, has a preferential COX-1 inhibitory effect and etoricoxib is a new selective COX-2 inhibitor. Although literature data have suggested that ketorolac can interfere negatively with long bone fracture healing, there seems to be no study associating etoricoxib with reparative bone formation. Paracetamol/acetaminophen, one of the first choices for pain control in clinical dentistry, has been considered a weak anti-inflammatory drug, although supposedly capable of inhibiting COX-2 activity in inflammatory sites. OBJECTIVE: The purpose of the present study was to investigate whether paracetamol, ketorolac and etoricoxib can hinder alveolar bone formation, taking the filling of rat extraction socket with newly formed bone as experimental model. MATERIAL AND METHODS: The degree of new bone formation inside the alveolar socket was estimated two weeks after tooth extraction by a differential point-counting method, using an optical microscopy with a digital camera for image capture and histometry software. Differences between groups were analyzed by ANOVA after confirming a normal distribution of sample data. RESULTS AND CONCLUSIONS: Histometric results confirmed that none of the tested drugs had a detrimental effect in the volume fraction of bone trabeculae formed inside the alveolar socket.


Subject(s)
Animals , Male , Rats , Acetaminophen/adverse effects , Analgesics, Non-Narcotic/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Bone Regeneration/drug effects , /adverse effects , Ketorolac/adverse effects , Pyridines/adverse effects , Sulfones/adverse effects , Analysis of Variance , Acetaminophen/pharmacology , Analgesics, Non-Narcotic/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 1/adverse effects , Cyclooxygenase 1/pharmacology , /pharmacology , Disease Models, Animal , Fracture Healing/drug effects , Ketorolac/pharmacology , Pyridines/pharmacology , Rats, Wistar , Sulfones/pharmacology , Time Factors
16.
Experimental & Molecular Medicine ; : 731-738, 2010.
Article in English | WPRIM | ID: wpr-158015

ABSTRACT

The nuclear receptors, steroid and xenobiotic receptor (SXR) and constitutive androstane receptor (CAR) play important functions in mediating lipid and drug metabolism in the liver. The present study demonstrates modulatory actions of estrogen in transactivations of SXR-mediated liver X receptor response element (LXRE) and CAR-mediated phenobarbital response element (PBRU). When human estrogen receptor (hERalpha) and SXR were exogenously expressed, treatment with either rifampicin or corticosterone promoted significantly the SXR-mediated transactivation of LXRE reporter gene in HepG2. However, combined treatment with estrogen plus either rifampicin or corticosterone resulted in less than 50% of the mean values of the transactivation by rifampicin or corticosterone alone. Thus, it is suggested that estrogen may repress the SXR-mediated transactivation of LXRE via functional cross-talk between ER and SXR. The CAR-mediated transactivation of PBRU was stimulated by hERalpha in the absence of estrogen. However, the potentiation by CAR agonist, TCPOBOP, was significantly repressed by moxestrol in the presence of ER. Thus, ER may play both stimulatory and inhibitory roles in modulating CAR-mediated transactivation of PBRU depending on the presence of their ligands. In summary, this study demonstrates that estrogen modulates transcriptional activity of SXR and CAR in mediating transactivation of LXRE and PBRU, respectively, of the nuclear receptor target genes through functional cross-talk between ER and the corresponding nuclear receptors.


Subject(s)
Humans , Corticosterone/pharmacology , Estrogens/metabolism , Ethinyl Estradiol/analogs & derivatives , Hep G2 Cells , Liver/metabolism , Orphan Nuclear Receptors/metabolism , Phenobarbital/metabolism , Pyridines/pharmacology , Receptor Cross-Talk , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Steroid/metabolism , Response Elements , Rifampin/pharmacology , Transcriptional Activation/drug effects
17.
Journal of the Egyptian Society of Parasitology. 2010; 40 (3): 565-574
in English | IMEMR | ID: emr-182208

ABSTRACT

The biological effects of two insect growth regulators [IGRs], pyriproxyfen and diflubenzuron against larvae of the mosquito Aedes aegypti [L.] have been evaluated. Mosquitoes were collected from Jeddah governorate, west of the Kingdom of Saudi Arabia and maintained in the laboratory. According to IC[50] values obtained [concentrations which inhibit the emergence of 50% of adults], diflubenzuron [0.00036 ppm] proved to be more effective by 11.4 fold of pyriproxyfen [0.0041ppm]. In addition to the delayed lethal action, larval treatment with the two IGRs, pyriproxyfen and diflubenzuron led to pronounced reduction in the reproductive potential of mosquito adults that emerged from these treatments. Pyriproxyfen caused a 33.2% decrease in egg production compared to 25.5% for diflubenzuron. The reduction in egg hatchability was by 40.6 and 36.2 % for pyriproxyfen and diflubenzuron, respectively, with up to 4 fold higher reduction rates than in the control tests. These results shed light on the extended biological effects of IGRs on mosquitoes and encourage further testing of IGRs for wider use in the control of Ae. aegypti and other important disease vectors in Arabia and the world


Subject(s)
Insecta , Juvenile Hormones , Pyridines/pharmacology , Diflubenzuron/pharmacology , Pest Control, Biological
18.
Experimental & Molecular Medicine ; : 180-188, 2009.
Article in English | WPRIM | ID: wpr-76612

ABSTRACT

Tumor cells are known to produce larger amounts of reactive oxygen species (ROS) than normal cells. Although numerous reports have indicated the importance of ROS in urokinase plasminogen activator (uPA) production, the precise mechanisms remain controversial. In our study, we investigated the effect of ROS on uPA generation in human hepatoma cells, HepG2 and Hep 3B. We determined the effects of hepatocyte growth factor (HGF) on the regulation of ROS, which resulted in suppression of ROS production, as measured with the fluorescent probe, 2'-7'-dichlorofluorescein diacetate. The role of HGF in modulating ROS production, particularly that regulated by Rac-1, was determined. HGF suppressed the increment in Rac-1-regulated ROS in both cell lines. Treatment with 200 microM of H2O2 showed a 1.6-2.1 fold increment in HGF, but a little increment occurred at 500 microM of H2O2. It looks no dose dependent manner. Combined treatment with H2O2 and HGF, resulted in a slightly increased production of HGF compared to no treatment (control). Also, H2O2 upregulated uPA expression in both hepatoma cell lines. To identify the downstream pathways regulated by ROS, we treated cells with PD 98059, an MEK inhibitor, and SB 203580, a p38 inhibitor, after treatment with H2O2, and showed negative control between ERK and p38 kinase activities for uPA regulation. We found that HGF modulate Rac-1-regulated ROS production through activation of Akt and ROS regulates uPA production via MAP kinase, which provides a novel clue to clarify the mechanism underlying hepatoma progression.


Subject(s)
Humans , Cell Line, Tumor , Fluorescent Dyes/chemistry , Hepatocyte Growth Factor/pharmacology , Hydrogen Peroxide/pharmacology , Imidazoles/pharmacology , Liver Neoplasms/drug therapy , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Pyridines/pharmacology , Reactive Oxygen Species/metabolism , Recombinant Proteins/pharmacology , Urokinase-Type Plasminogen Activator/biosynthesis , rac1 GTP-Binding Protein/metabolism
19.
Indian J Exp Biol ; 2007 Jul; 45(7): 654-6
Article in English | IMSEAR | ID: sea-59884

ABSTRACT

Experimental diabetes induced by streptozotocin (200 mg/kg, ip) markedly decreased the antinociceptive effect of morphine and significantly increased the urinary nitrite concentration. Administration of FR-167653 (a selective p38MAPKinase inhibitor) in a dose of 4 mg/kg improved the antinociceptive effect of morphine and attenuated the increase in urinary nitrite concentration in diabetic mice. It may be concluded that diabetes-induced decrease in antinociceptive effect of morphine may be due to induction of p38 MAPKinase activity.


Subject(s)
Analgesics/pharmacology , Analgesics, Opioid/pharmacology , Animals , Blood Glucose/metabolism , Cyclooxygenase Inhibitors/chemistry , Drug Design , Female , Male , Mice , Models, Statistical , Morphine/pharmacology , Nitrites/chemistry , Pyrazoles/pharmacology , Pyridines/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
20.
Braz. j. med. biol. res ; 40(6): 825-830, June 2007. graf, tab
Article in English | LILACS | ID: lil-452681

ABSTRACT

Serotonin (5-HT1B) receptors play an essential role in the inhibition of aggressive behavior in rodents. CP-94,253, a 5-HT1B receptor agonist, can reduce aggression in male mice when administered directly into the ventro-orbitofrontal (VO) prefrontal cortex (PFC). The objective of the current study was to assess the effects of two selective 5-HT1B receptor agonists (CP-94,253 and CP-93,129), microinjected into the VO PFC, on maternal aggressive behavior after social instigation in rats. CP-94,253 (0.56 µg/0.2 µL, N = 8, and 1.0 µg/0.2 µL, N = 8) or CP-93,129 (1.0 µg/0.2 µL, N = 9) was microinjected into the VO PFC of Wistar rats on the 9th day postpartum and 15 min thereafter the aggressive behavior by the resident female against a male intruder was recorded for 10 min. The frequency and duration of aggressive and non-aggressive behaviors were analyzed using ANOVA and post hoc tests. CP-93,129 significantly decreased maternal aggression. The frequency of lateral attacks, bites and pinnings was reduced compared to control, while the non-aggressive behaviors and maternal care were largely unaffected by this treatment. CP-94,253 had no significant effects on aggressive or non-aggressive behaviors when microinjected into the same area of female rats. CP-93,129, a specific 5-HT1B receptor agonist, administered into the VO PFC reduced maternal aggressive behavior, while the CP-94,253 agonist did not significantly affect this behavior after social instigation in female rats. We conclude that only the 5-HT1B receptor agonist CP-93,129 administered into the VO PFC decreased aggression in female rats postpartum after social instigation.


Subject(s)
Animals , Female , Male , Rats , Aggression/drug effects , Maternal Behavior/drug effects , Pyridines/administration & dosage , Pyrroles/administration & dosage , /drug effects , Serotonin Receptor Agonists/administration & dosage , Behavior, Animal/drug effects , Microinjections , Prefrontal Cortex/drug effects , Pyridines/pharmacology , Pyrroles/pharmacology , Rats, Wistar , Serotonin Receptor Agonists/pharmacology
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