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1.
Life Sci ; 260: 118410, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32926927

RESUMO

AIMS: Methylsulfonylmethane (MSM), is an organosulfur compound, has many health benefits. Bisphenol-A (BPA) and γ-radiation (R) are two risky environmental contaminants that human beings are exposed to in everyday life. This work aims at unveiling the modulatory role of MSM in combating BPA and R co-exposure induced neurodegenerative disorder (Alzheimer's (AD)-mimic neurotoxicity). MAIN METHODS: Female rats were randomly divided into five groups. One group was normal control and the other four groups were subjected to subacute BPA intoxication and/or exposed to fractionated weekly doses of R for 4 weeks and either untreated or treated with MSM concomitantly. KEY FINDINGS: BPA and R co-exposure induced typical hallmarks of neurodegenerative disorders as revealed by tremendously elevated oxidative stress, extensive neuroinflammation (tumor necrosis factor -α and interleukin-1ß), elevated AD markers (amyloid-beta (Aß42), acetylcholinesterase (AchE) activity and tau-phosphorylation) in cortex and hippocampus as well as up-regulation of microglial pro-inflammatory triggering receptor expressed on myeloid cell-2(TREM-2)/DNAX-activating protein of 12 kDa (DAP-12)/spleen-tyrosine kinase (Syk) pathway and its downstream targets (PLC-γ/DAG/p38-MAPK) in hippocampus. Also, neurodegenerative lesions were revealed in histopathological examination of cortex and hippocampus coupled with marked Aß deposition in hippocampus. Whereas, MSM treatment improved histopathological insults and ameliorated level of oxidative stress, neuroinflammation and AD markers as well as modulated TREM-2/DAP-12/Syk pathway. SIGNIFICANCE: Our data suggest that MSM afforded neuroprotection against BPA and R; supporting its potential application in the associated neurodegenerative disorders.


Assuntos
Compostos Benzidrílicos/toxicidade , Dimetil Sulfóxido/farmacologia , Raios gama/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Fenóis/toxicidade , Receptores Imunológicos/metabolismo , Sulfonas/farmacologia , Quinase Syk/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Estrogênios não Esteroides/toxicidade , Feminino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Ratos , Ratos Wistar , Receptores Imunológicos/genética , Quinase Syk/genética
2.
Pestic Biochem Physiol ; 170: 104695, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980058

RESUMO

In this study, thirty 1,3,4-oxadiazole sulfone derivatives containing 3,4-dichloroisothiazolamide moiety were designed and synthesized, and their antibacterial activities were evaluated. Bioassay results showed that some compounds exhibited excellent antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas oryzae pv. oryzicola (Xoc) in vitro and in vivo. Notably, the EC50 values of compounds 2 and 3 against Xoo were 0.79 and 0.85 µg/mL, respectively, which were superior to those of the control agents isotianil, bismerthiazol, and thiodiazole copper. In addition, in vivo antibacterial activities revealed that the compound 2 at 50 µg/mL possessed protective and curative activities of 43.99% and 41.06% against Xoo, respectively, which were better than positive controls. Furthermore, the preliminary mechanism study disclosed that compound 2 exhibited effective antibacterial activity against Xoo by inhibiting the formation of extracellular polysaccharides from Xoo, increasing cell permeability, and changing the shape of cells. This study suggested that 1,3,4-oxadiazole sulfone derivatives containing 3,4-dichloroisothiazolamide moiety displayed excellent antibacterial activity and could be further explored and developed as commercial pesticides.


Assuntos
Oryza , Xanthomonas , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Oxidiazóis , Doenças das Plantas , Sulfonas/farmacologia
3.
Anticancer Res ; 40(9): 5191-5200, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878807

RESUMO

BACKGROUND/AIM: Colorectal cancer is one of the most common malignancies worldwide. Small molecule-based chemotherapy is an attractive approach for the chemoprevention and treatment of colorectal cancer. Methylsulfonylmethane (MSM) is a natural organosulfur compound with anticancer properties, as revealed by studies on in vitro models of gingival, prostate, lung, hepatic, and breast cancer. However, the molecular mechanisms underlying the effects of MSM in colon cancer cells remain unclear. MATERIALS AND METHODS: Here, we investigated the effects of MSM, especially on the cell cycle arrest and apoptosis, in HT-29 cells. RESULTS: MSM suppressed the viability of HT-29 cells by inducing apoptosis and cell cycle arrest at the G0/G1 phase. MSM suppressed the sphere-forming ability and expression of stemness markers in HT-29 cells. CONCLUSION: MSM has anti-cancer effects on HT-29 cells, and induces cell cycle arrest and apoptosis, while suppressing the stemness potential.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Dimetil Sulfóxido/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Sulfonas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HT29 , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Esferoides Celulares , Células Tumorais Cultivadas
4.
J Cancer Res Clin Oncol ; 146(11): 2871-2883, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32770382

RESUMO

PURPOSE: Polo-like kinase 4 (PLK4) inhibitors, such as CFI-400945 and centrinone, are emerging as promising antineoplastic agents. However, their effectiveness against Ewing's sarcoma, a highly aggressive childhood cancer, remains to be established. METHODS: CFI-400945 and centrinone were tested in three Ewing's sarcoma cell lines with different TP53 status. Effects were assessed by flow-cytometric analyses of cell death, dissipation of the mitochondrial transmembrane potential and cell cycle distribution, by cell viability assay as well as by caspase 3/7 activity measurement, by immunoblotting and by immunofluorescence microscopy. RESULTS: CFI-400945 and centrinone elicited cell death in p53 wild-type and mutant Ewing's sarcoma cells. Both agents induced mitochondrial membrane depolarisation, caspase 3/7 activation, PARP1 cleavage and DNA fragmentation, indicating an apoptotic form of cell death. In addition, the PLK4 inhibitors induced a G2/M cell cycle arrest, particularly when cell killing was attenuated by the pan-caspase inhibitor z-VAD-fmk. Moreover, CFI-400945 treatment produced polyploidy. CONCLUSION: Our findings show that PLK4 inhibitors were effective against Ewing's sarcoma cells in vitro and thus provide a rationale for their evaluation in vivo.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Sarcoma de Ewing/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Indazóis/farmacologia , Indóis/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pirimidinas/farmacologia , Sulfonas/farmacologia
5.
Mol Cell ; 79(1): 191-198.e3, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32619469

RESUMO

We recently used CRISPRi/a-based chemical-genetic screens and cell biological, biochemical, and structural assays to determine that rigosertib, an anti-cancer agent in phase III clinical trials, kills cancer cells by destabilizing microtubules. Reddy and co-workers (Baker et al., 2020, this issue of Molecular Cell) suggest that a contaminating degradation product in commercial formulations of rigosertib is responsible for the microtubule-destabilizing activity. Here, we demonstrate that cells treated with pharmaceutical-grade rigosertib (>99.9% purity) or commercially obtained rigosertib have qualitatively indistinguishable phenotypes across multiple assays. The two formulations have indistinguishable chemical-genetic interactions with genes that modulate microtubule stability, both destabilize microtubules in cells and in vitro, and expression of a rationally designed tubulin mutant with a mutation in the rigosertib binding site (L240F TUBB) allows cells to proliferate in the presence of either formulation. Importantly, the specificity of the L240F TUBB mutant for microtubule-destabilizing agents has been confirmed independently. Thus, rigosertib kills cancer cells by destabilizing microtubules, in agreement with our original findings.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células , Glicina/análogos & derivados , Microtúbulos/efeitos dos fármacos , Neoplasias/patologia , Preparações Farmacêuticas/metabolismo , Sulfonas/farmacologia , Tubulina (Proteína)/metabolismo , Células Cultivadas , Cristalografia por Raios X , Contaminação de Medicamentos , Glicina/farmacologia , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Preparações Farmacêuticas/química , Conformação Proteica , Tubulina (Proteína)/química , Tubulina (Proteína)/genética
6.
J Biol Regul Homeost Agents ; 34(3): 785-794, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723437

RESUMO

Previous reports indicated that specific cyclooxygenase-2 (COX-2) inhibitor suppresses osteoarthritis (OA). This study aimed to further explore the possible mechanism of Rofecoxib as a COX-2 inhibitor on the inhibition of chondrocyte (CH) hypertrophic development and tested the optimal treatment of Rofecoxib on CH. Basically, IL-1ß was used as a stimulus to establish a degenerated CH model. Immunofluorescence, Western blot, and RT-PCR were performed to determine the gene expression of Axin2, ß-catenin, GSK3ß, collagen X, collagen II, COX-2, PGE-2, SOX-9, Runx-2, and MMP- 13 expression. Cell Counting Kit (CCK-8) assay was used to analyze the viability of CHs. The data indicated that Rofecoxib significantly inhibited COX-2 expression and had less harmful effects on CH viability. Rofecoxib reversed the IL-1ß-induced upregulation of collagen X, COX-2, PGE-2, Runx-2, and MMP-13 expression, and promoted the viability of collagen II, SOX-9 expression of CHs. Furthermore, Rofecoxib suppressed Axin2, ß-catenin, and GSK3ß expression of the Wnt pathway, which was activated by IL-1ß or human recombinant Wnt-1 protein treatment. Therefore, Rofecoxib is an effective COX-2 inhibitor that protects CHs from hypertrophy by suppression of the Wnt/ß-catenin pathway.


Assuntos
Condrócitos/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Lactonas/farmacologia , Sulfonas/farmacologia , Via de Sinalização Wnt , Células Cultivadas , Condrócitos/citologia , Humanos , Hipertrofia , beta Catenina
7.
Mol Cell ; 79(1): 180-190.e4, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32619468

RESUMO

Rigosertib is a styryl benzyl sulfone that inhibits growth of tumor cells and acts as a RAS mimetic by binding to Ras binding domains of RAS effectors. A recent study attributed rigosertib's mechanism of action to microtubule binding. In that study, rigosertib was obtained from a commercial vendor. We compared the purity of clinical-grade and commercially sourced rigosertib and found that commercially sourced rigosertib contains approximately 5% ON01500, a potent inhibitor of tubulin polymerization. Clinical-grade rigosertib, which is free of this impurity, does not exhibit tubulin-binding activity. Cell lines expressing mutant ß-tubulin have also been reported to be resistant to rigosertib. However, our study showed that these cells failed to proliferate in the presence of rigosertib at concentrations that are lethal to wild-type cells. Rigosertib induced a senescence-like phenotype in the small percentage of surviving cells, which could be incorrectly scored as resistant using short-term cultures.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células , Glicina/análogos & derivados , Neoplasias Pulmonares/patologia , Sulfonas/farmacologia , Tubulina (Proteína)/metabolismo , Contaminação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Glicina/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Mutação , Tubulina (Proteína)/química , Tubulina (Proteína)/genética , Células Tumorais Cultivadas
8.
Front Immunol ; 11: 1518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655582

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. It is an enveloped single-stranded positive-sense RNA virus. Since December of 2019, a global expansion of the infection has occurred with widespread dissemination of coronavirus disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe disease with complications occurs in 15% of cases. Respiratory failure occurs in severe disease that can be accompanied by a systemic inflammatory reaction characterized by inflammatory cytokine release. In severe cases, fatality is caused by the rapid development of severe lung injury characteristic of acute respiratory distress syndrome (ARDS). Although ARDS is a complication of SARS-CoV-2 infection, it is not viral replication or infection that causes tissue injury; rather, it is the result of dysregulated hyperinflammation in response to viral infection. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release of its products including the proinflammatory cytokines IL-6 and IL-1ß. Here we review the literature that describes the pathogenesis of severe COVID-19 and NLRP3 activation and describe an important role in targeting this pathway for the treatment of severe COVID-19.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/metabolismo , Animais , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Imunidade Inata , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Camundongos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Piroptose/efeitos dos fármacos , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Sesquiterpenos de Guaiano/farmacologia , Sesquiterpenos de Guaiano/uso terapêutico , Sulfonas/farmacologia , Sulfonas/uso terapêutico
9.
Chemosphere ; 259: 127499, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32629314

RESUMO

Soybean looper (SBL), Chrysodeixis includens (Walker), is an economically important soybean and cotton pest in Brazil. Here, we selected an SBL strain resistant to teflubenzuron using F2 screening, estimated the resistance allele frequency, characterized the inheritance of resistance, investigated fitness costs, evaluated patterns of cross-resistance, and determined the magnitude of resistance. The teflubenzuron-resistant strain (Teflu-R) was selected from field-collected populations with an estimated allele frequency of 0.1700. Estimated LC50 values were 0.010 and 363.61 µg a.i. cm-2 for the susceptible (Sus) and Teflu-R strains, respectively, representing a 36,361-fold resistance ratio (RR). The LC50 values of reciprocal crosses were 1.02 and 0.59 µg a.i. cm-2, suggesting that resistance is autosomally inherited. The low survival of reciprocal crosses (16 and 20%) on teflubenzuron-sprayed leaves indicates incomplete recessive resistance. The number of segregations influencing resistance was 2.72, suggesting a polygenic effect. The Teflu-R strain showed longer development periods as well as lower survival and population growth than the Sus strain, revealing fitness costs. The Teflu-R strain also showed high cross-resistancesto other chitin inhibitor insecticides, such as novaluron (RR = 6147-fold) and lufenuron (RR = 953-fold), but low cross-resistance to methoxyfenozide, flubendiamide, and indoxacarb (RR < 3.45-fold). On discriminatory concentrations of teflubenzuron and novaluron, populations of SBL showed survival rates from 15 to 52%, indicating field resistance to these insecticides. Our findings indicated that resistance to teflubenzuron in SBL is autosomal, recessive, polygenic, and associated with fitness cost. We also found a high cross-resistance to other benzoylphenylureas and a high frequency of resistance to this mode-of-action in SBL in Brazil.


Assuntos
Quitina/antagonistas & inibidores , Resistência a Inseticidas , Inseticidas , Mariposas/efeitos dos fármacos , Soja/parasitologia , Animais , Benzamidas/farmacologia , Brasil , Quitina/biossíntese , Quitina/farmacologia , Hidrazinas/farmacologia , Inseticidas/farmacologia , Hormônios Juvenis/farmacologia , Larva/efeitos dos fármacos , Lepidópteros/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Doenças das Plantas/parasitologia , Soja/efeitos dos fármacos , Sulfonas/farmacologia
10.
J Cancer Res Clin Oncol ; 146(9): 2219-2229, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32507974

RESUMO

PURPOSE: Pancreatic cancer is a lethal form of cancer that can be triggered by prolonged or acute inflammation of the pancreas. Inflammation have been shown to be regulated by a group of key protein molecules known as the inflammasomes. The NLRP3 inflammasome is the most studied inflammasome and have been strongly implicated to regulate cancer cell proliferation. Therefore, this study aimed to examine the regulation of NLRP3 inflammasome under LPS-induced inflammation and its role in modulating cell proliferation in a panel of pancreatic cancer cells. METHODS: The effects of LPS-induced NLRP3 activation in the presence or absence of MCC950, NLRP3-specific inhibitor, was tested on a panel of three pancreatic cancer cell lines (SW1990, PANC1 and Panc10.05). Western blotting, cell viability kits and ELISA kits were used to examine the effects of LPS-induced NLRP3 activation and inhibition by MCC950 on NLRP3 expression, cell viability, caspase-1 activity and cytokine IL-1ß, respectively. RESULTS: LPS-induced inflammation in the presence of ATP activates NLRP3 that subsequently increases pancreatic cancer cell proliferation by increasing caspase-1 activity leading to overall production of IL-1ß. The inhibition of the NLRP3 inflammasome activation via the specific NLRP3 antagonist MCC950 was able to reduce the cell viability of pancreatic cancer cells. However, the efficacy of MCC950 varies between cell types which is most probably due to the difference in ASC expressions which have a different role in inflammasome activation. CONCLUSION: There is a dynamic interaction between inflammasome that regulates inflammasome-mediated inflammation in pancreatic adenocarcinoma cells.


Assuntos
Adenocarcinoma/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Sulfonas/farmacologia , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Neoplasias Pancreáticas/induzido quimicamente , Neoplasias Pancreáticas/metabolismo
11.
Prostate ; 80(11): 831-849, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32449814

RESUMO

INTRODUCTION: Prostate smooth muscle contraction is critical for etiology and treatment of lower urinary tract symptoms in benign prostatic hyperplasia (BPH). Integrins connect the cytoskeleton to membranes and cells to extracellular matrix, what is essential for force generation in smooth muscle contraction. Integrins are composed of different subunits and may cooperate with integrin-linked kinase (ILK). Here, we examined effects of inhibitors for different integrin heterodimers and ILK on contraction of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Integrins and ILK were detected by Western blot, real-time polymerase chain reaction (RT-PCR), and double fluorescence staining. Smooth muscle contractions of prostate strips were studied in an organ bath. Contractions were compared after application of solvent (controls), the ILK inhibitor Cpd22 (N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide), the integrin α2ß1 inhibitor BTT-3033 (1-(4-fluorophenyl)-N-methyl-N-[4[[(phenylamino)carbonyl]amino]phenyl]-1H-pyrazole-4-sulfonamide), or the integrin α4ß1/α9ß1 inhibitor BOP (N-(benzenesulfonyl)- l-prolyl- l-O-(1-pyrrolidinylcarbonyl)tyrosine sodium salt). RESULTS: Western blot analyses of prostate tissues using antibodies raised against integrins α2b, α4, α9, ß1, and ILK revealed bands matching the expected sizes of corresponding antigens. Expression of integrins and ILK was confirmed by RT-PCR. Individual variations of expression levels occurred independently from divergent degree of BPH, reflected by different contents of prostate-specific antigen. Double fluorescence staining of prostate sections using antibodies raised against integrins α2 and ß1, or against ILK resulted in immunoreactivity colocalizing with calponin, suggesting localization in prostate smooth muscle cells. Electric field stimulation (EFS) induced frequency-dependent contractions, which were inhibited by Cpd22 (3 µM) and BTT-3033 (1 µM) (inhibition around 37% by Cpd22 and 46% by BTT-3033 at 32 Hz). The thromboxane A2 analog U46619-induced concentration-dependent contractions, which were inhibited by Cpd22 and BTT-3033 (around 67% by Cpd22 and 39% by BTT-3033 at 30 µM U46619). Endothelin-1 induced concentration-dependent contractions, which were not affected by Cpd22 or BTT-3033. Noradrenaline and the α1 -adrenergic agonists methoxamine and phenylephrine-induced concentration-dependent contractions, which were not or very slightly inhibited by Cpd22 and BTT-3033. BOP did not change EFS- or agonist-induced contraction. CONCLUSIONS: Integrin α2ß1 and ILK inhibitors inhibit neurogenic and thromboxane A2 -induced prostate smooth muscle contraction in human BPH. A role for these targets for prostate smooth muscle contraction may appear possible.


Assuntos
Integrina alfa2beta1/antagonistas & inibidores , Músculo Liso/efeitos dos fármacos , Próstata/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Dipeptídeos/farmacologia , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/metabolismo , Músculo Liso/fisiologia , Piperazinas/farmacologia , Próstata/metabolismo , Próstata/fisiologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Sulfonas/farmacologia , Tromboxano A2/metabolismo , Vasoconstritores/farmacologia
12.
Arch Biochem Biophys ; 688: 108402, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32418909

RESUMO

A/J mouse is a model of age-related hearing loss (AHL). Mutation in the citrate synthase (Cs) gene of the mouse plays an important role in the hearing loss and degeneration of cochlear cells. To investigate the pathogenesis of cochlear cell damage in A/J mice resulted from Cs mutation, we downregulated the expression level of CS in HEI-OC1, a cell line of mouse cochlea, by shRNA. The results showed that low CS expression led to low ability of cell proliferation. Further study revealed an increase level of reactive oxygen species (ROS), activation of ATF6 mediated endoplasmic reticulum stress (ERS) and high expression levels of caspase12 and Bax in the cells. Moreover, the AEBSF, an ATF6 inhibitor, could reduce the expression levels of caspase-12 and Bax by inhibiting the hydrolysis of ATF6 in the cells. Finally, antioxidant alpha-lipoic acid (ALA) reduced the ROS levels and the apoptotic signals in the cell model with low CS expression. We therefore conclude that the ERS mediated apoptosis, which is triggered by ROS, may be involved in the cell degeneration in the cochleae of A/J mice.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Citrato (si)-Sintase/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/farmacologia , Fator 6 Ativador da Transcrição/antagonistas & inibidores , Animais , Apoptose/fisiologia , Caspase 12/metabolismo , Linhagem Celular , Proliferação de Células/fisiologia , Regulação para Baixo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Modelos Biológicos , Estresse Oxidativo/fisiologia , Presbiacusia/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Sulfonas/farmacologia , Proteína X Associada a bcl-2/metabolismo
13.
Inflamm Res ; 69(7): 697-710, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32350570

RESUMO

OBJECTIVE: Sepsis-associated encephalopathy (SAE) is a major cause of mortality worldwide. Oxidative stress, inflammatory response and apoptosis participate in the pathogenesis of SAE. Nuclear factor erythroid 2-related factor 2 (Nrf2) and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) pathway is involved in oxidative stress and inflammatory response. We reported that hydrogen gas protected against sepsis in wild-type (WT) but not Nrf2 knockout (KO) mice. Therefore, it is vital to identify the underlying cause of hydrogen gas treatment of sepsis-associated encephalopathy. METHODS: SAE was induced in WT and Nrf2 KO mice by cecal ligation and puncture (CLP). As a NLRP3 inflammasome inhibitor, MCC950 (50 mg/kg) was administered by intraperitoneal (i.p.) injection before operation. Hydrogen gas (H2)-rich saline solution (5 mL/kg) was administered by i.p. injection at 1 h and 6 h after sham and CLP operations. Brain tissue was collected to assess the NLRP3 and Nrf2 pathways by western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. RESULTS: SAE increased NLRP3 and Nrf2 expression in microglia. MCC950 inhibited SAE-induced NLRP3 expression, interleukin (IL)-1ß and IL-18 cytokine release, neuronal apoptosis and mitochondrial dysfunction. SAE increased NLRP3 and caspase-1 expression in WT mice compared to Nrf2 KO mice. Hydrogen increased Nrf2 expression and inhibited the SAE-induced expression of NLRP3, caspase-1, cytokines IL-1ß and IL-18, neuronal apoptosis, and mitochondrial dysfunction in WT mice but not Nrf2 KO mice. CONCLUSION: SAE increased NLRP3 and Nrf2 expression in microglia. Hydrogen alleviated inflammation, neuronal apoptosis and mitochondrial dysfunction via inhibiting Nrf2-mediated NLRP3 pathway.


Assuntos
Hidrogênio/administração & dosagem , Fator 2 Relacionado a NF-E2/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Encefalopatia Associada a Sepse/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Química Encefálica , Ceco , Córtex Cerebral/ultraestrutura , Citocinas/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Masculino , Camundongos , Camundongos Knockout , Microglia/fisiologia , Mitocôndrias/fisiologia , Fator 2 Relacionado a NF-E2/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/análise , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Punções , Encefalopatia Associada a Sepse/patologia , Sulfonas/farmacologia
14.
Toxicol Appl Pharmacol ; 400: 115075, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470352

RESUMO

NLRP3, one of the HSP-90 clients, has been defined as a critical component of IBD. In a rat model of DSS-induced colitis, we investigated the anti-inflammatory potential of the combined therapy with CP-456773 (CP), an NLRP3 inhibitor, and celastrol (CSR), an NF-κB inhibitor. Our results revealed that the CSR/CP combined therapy (CCCT) attenuated colon shortening, DAI and MDI in addition to improvement of the colonic histological picture. Moreover, the CCCT increased the antioxidant defense machinery of the colonic tissue and decreased MPO activity. Furthermore, the inflammation markers such as TNF-α and IL-6 were downregulated. These effects might be attributed to the inhibitory effect of CSR on the priming step of the NLRP3 inflammasome activation by interrupting NF-κB signalling and inhibition of HSP-90 (at the protein and mRNA levels) along with inhibitory effect of CP on the expression of the NLRP3. These latter effects resulted in decreased tissue expression and activity of the caspase-1 and repressing the subsequent release of the active forms of IL-1ß and IL-18, hence, the pyroptosis process is restrained. Additionally, the CCCT resulted in inducing autophagy by AMPK/mTOR-dependent mechanisms leading to the accumulation of BECN1 protein and a significant decrease in the levels of p62 SQSTM1. The inhibitory effect on HSP-90 in conjunction with induction of autophagy suggest increased autophagic degradation of NLRP3. This novel approach provides a basis for the clinical application of this combination in IBD treatment and might also be promising for the pharmacological intervention of other NLRP3 inflammasome-dependent inflammatory conditions.


Assuntos
Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Colite/tratamento farmacológico , Proteínas de Choque Térmico HSP90/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonas/farmacologia , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Proteínas de Choque Térmico HSP90/sangue , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Masculino , Ratos Sprague-Dawley , Sulfonas/administração & dosagem , Sulfonas/uso terapêutico , Triterpenos/administração & dosagem , Triterpenos/uso terapêutico
15.
Anticancer Res ; 40(4): 1905-1913, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234879

RESUMO

BACKGROUND/AIM: Methylsulfonylmethane (MSM) is a natural organic compound that displays anti-inflammatory as well as antioxidant properties. MSM reportedly has potential in inhibition of tumor cells. However, molecular mechanisms underlying the effects of MSM on lung cancer remain unclear. MATERIALS AND METHODS: In this study, the effect of MSM on A549 cells was examined. We focused on the mode of apoptosis induced by MSM and investigated alterations in the integrity of the outer membrane of mitochondria. RESULTS: Our results showed that MSM inhibited viability of A549 cells and changed the shape and permeability of nuclei. In addition, MSM induced G2/M arrest. MSM reduced the mitochondrial membrane potential and contributed to release of cytochrome c from mitochondria to cytoplasm. CONCLUSION: MSM is a potential anticancer agent for the treatment of lung cancer.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dimetil Sulfóxido/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Sulfonas/farmacologia , Células A549 , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Transdução de Sinais/efeitos dos fármacos
16.
Parasitol Res ; 119(5): 1675-1681, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32236711

RESUMO

Toxoplasma gondii can infect virtually all warm-blooded animals, including humans. It can differentiate between rapidly replicating tachyzoites that cause acute infection and slowly growing bradyzoites in tissue cysts. Treatment options for toxoplasmosis are challenging because current therapies cannot eradicate the latent T. gondii infection that is mainly caused by the bradyzoite forms. Accordingly, recurrence of infection is a problem for immunocompromised patients and congenitally infected patients. Protein kinases have been widely studied in eukaryotic cells, and while little is known about signaling in Toxoplasma infection, it is likely that protein kinases play a key role in parasite proliferation, differentiation, and probably invasion. To identify optimized new kinase inhibitors for drug development against T. gondii, we screened a library of kinase inhibitor compounds for anti-Toxoplasma activity and host cell cytotoxicity. Pyrimethamine served as a positive control and 0.5% DMSO was used as a negative control. Among the 80 compounds screened, 6 compounds demonstrated ≥ 80% parasite growth inhibition at concentrations at which 5 compounds did not suppress host cell viability, while 3 kinase inhibitors (Bay 11-7082, Tyrphostin AG 1295 and PD-98059) had suppressive effects individually on parasite growth and host cell invasion, but did not strongly induce bradyzoite formation.


Assuntos
Antiprotozoários/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/efeitos dos fármacos , Toxoplasma/crescimento & desenvolvimento , Toxoplasmose/tratamento farmacológico , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Flavonoides/farmacologia , Humanos , Nitrilos/farmacologia , Pirimetamina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia , Toxoplasma/efeitos dos fármacos , Toxoplasma/patogenicidade , Toxoplasmose/patologia , Tirfostinas/farmacologia
17.
Med Sci Monit ; 26: e920684, 2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32283546

RESUMO

BACKGROUND Acute pancreatitis (AP) is a symptom of sudden pancreas inflammation, which causes patients severe suffering. In general, fibroblast growth factor (FGF) levels are increased and amylase and lipase activities are elevated during AP pathogenesis, but protein concentration are low. However, the mechanism through which FGF signaling regulates AP pathogenesis remains elusive. MATERIAL AND METHODS The concentrations of PGE2, TNF-alpha, sCRP, FGF1, and FGF2 in the serum samples of the AP group and healthy control group were detected by enzyme-linked immunosorbent assay. In addition, IkappaBalpha and p-IkappaBalpha levels were analyzed in the serum samples. Subsequently, the AP rat model was established, and FGF1, FGF2, anti-FGF1, and anti-FGF2 antibodies and Bay11-7082 were injected into AP rats. TNF-alpha, PAI-1 JNK, p-JNK, IkappaBalpha, and p-IkappaBalpha levels were also examined. RESULTS Results showed that levels of PGE2, TNF-alpha, sCRP, p-IkappaBalpha, FGF1, and FGF2, as well as amylase and lipase activity were increased in patients with AP compared with those in healthy people. In addition, protein concentrations were lower in patients with AP than in the healthy group. Activation of FGF signaling by injecting FGF1 or FGF2 also inhibited AP-induced inflammation response in the pancreas and increased amylase and lipase activities, as well as protein concentration. However, the injection of FGF1 and FGF2 antibodies accelerated AP-mediated inflammation responses in the serum. In addition, Bay11-7082 injection inhibited AP activation of inflammation response and amylase and lipase activities. Protein concentration were also increased in AP rats. CONCLUSIONS FGF signaling protects against AP-mediated damage by inhibition of AP-activating inflammatory responses.


Assuntos
Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Inflamação/metabolismo , Pancreatite/patologia , Transdução de Sinais , Doença Aguda , Adulto , Amilases/metabolismo , Animais , Proteína C-Reativa/análise , Estudos de Casos e Controles , Dinoprostona/sangue , Feminino , Fator 1 de Crescimento de Fibroblastos/sangue , Fator 2 de Crescimento de Fibroblastos/sangue , Humanos , Inflamação/patologia , Lipase/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidor de NF-kappaB alfa/sangue , Nitrilos/farmacologia , Ratos , Ratos Sprague-Dawley , Sulfonas/farmacologia , Fator de Necrose Tumoral alfa/sangue
18.
J Toxicol Sci ; 45(4): 227-236, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238697

RESUMO

A growing body of experimental evidence strongly suggests that cannabidiolic acid (CBDA), a major component of the fiber-type cannabis plant, exerts a variety of biological activities. We have reported that CBDA can abrogate cyclooxygenase-2 (COX-2) expression and its enzymatic activity. It is established that aberrant expression of COX-2 correlates with the degree of malignancy in breast cancer. Although the reduction of COX-2 expression by CBDA offers an attractive medicinal application, the molecular mechanisms underlying these effects have not fully been established. It has been reported that COX-2 expression is positively controlled by peroxisome proliferator-activated receptor ß/δ (PPARß/δ) in some cancerous cells, although there is "no" modulatory element for PPARß/δ on the COX-2 promoter. No previous studies have examined whether an interaction between PPARß/δ-mediated signaling and COX-2 expression exists in MDA-MB-231 cells. We confirmed, for the first time, that COX-2 expression is positively modulated by PPARß/δ-mediated signaling in MDA-MB-231 cells. CBDA inhibits PPARß/δ-mediated transcriptional activation stimulated by the PPARß/δ-specific agonist, GW501516. Furthermore, the disappearance of cellular actin stress fibers, a hallmark of PPARß/δ and COX-2 pathway activation, as evoked by the GW501516, was effectively reversed by CBDA. Activator protein-1 (AP-1)-driven transcriptional activity directly involved in the regulation of COX-2 was abrogated by the PPARß/δ-specific inverse agonists (GSK0660/ST-247). Thus, it is implicated that there is positive interaction between PPARß/δ and AP-1 in regulation of COX-2. These data support the concept that CBDA is a functional down-regulator of COX-2 through the abrogation of PPARß/δ-related signaling, at least in part, in MDA-MB-231 cells.


Assuntos
Neoplasias da Mama/enzimologia , Canabinoides/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Expressão Gênica/genética , PPAR delta/fisiologia , Feminino , Humanos , PPAR delta/agonistas , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sulfonas/farmacologia , Tiazóis/farmacologia , Tiofenos/farmacologia , Fator de Transcrição AP-1/fisiologia , Células Tumorais Cultivadas
19.
Med Oncol ; 37(5): 47, 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32277292

RESUMO

Pancreatic cancer is a highly progressive malignant tumor for which there is a critical unmet need for novel therapeutic strategies. A previous study of the authors indicated that VE-821, a selective inhibitor of the ataxia-telangiectasia-mutated and rad3-related protein (ATR), has antitumor efficacy. In this study, the effect of programmed death ligand 1 (PD-L1) on the sensitivity to VE-821 was investigated in p53 mutant pancreatic cancer cells. These results show that BxPC-3 cells exhibited higher sensitivity to VE-821 than mesenchymal PANC-1 cells, which were more migratory and had higher expressions of PD-L1 and CD44. When VE-821 was applied to two cells, epithelial-to-mesenchymal transition (EMT) was induced in PANC-1 cells with concomitant upregulation of PD-L1 and CD44, while BxPC-3 cells did not manifest these changes. Attenuation of PD-L1 expression suppressed VE-821-induced EMT, inhibited cell migration, and downregulated CD44 expression. Furthermore, PD-L1 inhibition partially reversed the activation of AKT/ERK, enhanced DNA damage, and increased VE-821 sensitivity in PANC-1 cells. Analysis of GEPIA data showed positive correlation of PD-L1 expression with EMT-related transcription factors. Taken together, these results suggest a novel function of PD-L1 in regulating response to ATR inhibition. These data highlight PD-L1 inhibition as a promising target to enhance sensitivity to ATR inhibitors in mesenchymal pancreatic cancer.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Antígeno B7-H1/genética , Transição Epitelial-Mesenquimal , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Técnicas de Silenciamento de Genes , Humanos , Receptores de Hialuronatos/genética , Neoplasias Pancreáticas/metabolismo , Pirazinas/farmacologia , Sulfonas/farmacologia , Proteína Supressora de Tumor p53/deficiência , Regulação para Cima/efeitos dos fármacos
20.
Sci Rep ; 10(1): 3709, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111888

RESUMO

Mycobacterium tuberculosis infection causes high rates of morbidity and mortality. Host-directed therapy may enhance the immune response, reduce tissue damage and shorten treatment duration. The inflammasome is integral to innate immune responses but over-activation has been described in tuberculosis (TB) pathology and TB-immune reconstitution syndrome. Here we explore how clinical isolates differentially activate the inflammasome and how inflammasome inhibition can lead to enhanced bacterial clearance. Wild-type, Nlrp3-/-/Aim2-/-, Casp1/11-/- and Asc-/- murine bone-marrow derived macrophages (BMDMs) were infected with laboratory strain M. tuberculosis H37Rv or clinical isolates from various lineages. Inflammasome activation and bacterial numbers were measured, and pharmacological inhibition of NLRP3 was achieved using MCC950. Clinical isolates of M. tuberculosis differed in their ability to activate inflammasomes. Beijing isolates had contrasting effects on IL-1ß and caspase-1 activation, but all clinical isolates induced lower IL-1ß release than H37Rv. Our studies suggest the involvement of NLRP3, AIM2 and an additional unknown sensor in IL-1ß maturation. Pharmacological blockade of NLRP3 with MCC950 reduced bacterial survival, and combined treatment with the antimycobacterial drug rifampicin enhanced the effect. Modulating the inflammasome is an attractive adjunct to current anti-mycobacterial therapy that warrants further investigation.


Assuntos
Inflamassomos/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tuberculose/imunologia , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Sulfonas/farmacologia , Tuberculose/genética , Tuberculose/microbiologia
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