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1.
Life Sci ; 245: 117365, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32001267

RESUMO

AIMS: Hyperglycemia in combination with oxidative stress plays a significant pathophysiological role in diabetic testicular dysfunction, often leading to infertility. Activation of Toll-like receptor 4 (TLR4) has been reported to mediate oxidative stress during diabetes. However, engagement of the TLR4 signaling pathway in diabetic testicular dysfunction has not been previously explored. Herein, we investigated the role of TLR4 in reactive oxygen species (ROS) production and in the phosphorylation status of ERK1/2 in primary Leydig cells exposed to high glucose and in testis isolated from diabetic rats. MAIN METHODS: Testicular levels of TLR4 and phospho-ERK1/2 were determined by Western blotting. ROS production was detected with a fluorescent probe. Additionally, primary Leydig cells were exposed to normal (5.5 mmol/l) or elevated (33 mmol/l) glucose concentrations and treated with or without a TLR4 inhibitor, CLI095 (10-5 mol/l) for 24 h, followed by evaluation of TLR4 and phospho-ERK1/2 expression levels by Western blotting and immunofluorescence staining, respectively. KEY FINDINGS: We show that high glucose induces the expression of TLR4 in Leydig cells. Additionally, we demonstrate that blockade of this receptor in this cell population reduces oxidative stress and restores the levels of phospho-ERK1/2. SIGNIFICANCE: Our findings provide new insight into TLR4 interaction with ROS and MEK/ERK pathway in Leydig cells exposed to high glucose and present a rationale for the development of new therapeutics for diabetic testicular dysfunction.


Assuntos
Hiperglicemia/metabolismo , Células Intersticiais do Testículo/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estresse Oxidativo , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Western Blotting , Diabetes Mellitus Experimental/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo
2.
Acta Neurochir Suppl ; 127: 77-81, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407067

RESUMO

BACKGROUND: Brain edema is a common and critical pathology following subarachnoid hemorrhage (SAH). Toll-like receptor 4 (TLR4) activation may exacerbate brain edema. The purpose of this study was to clarify if TAK-242, a TLR4 antagonist, suppresses brain edema formation and neurological impairments after SAH in mice. METHODS: A total of 46 mice underwent endovascular perforation to induce SAH or sham operation and were classified as Sham+TAK-242, SAH+ phosphate-buffered saline (PBS), and SAH + TAK-242 groups. The PBS or TAK-242 was administered intracerebroventricularly to mice at 30 min from the operation. Neurobehavioral tests, SAH severity, and brain water content were evaluated at 24 h from the operation. RESULTS: The SAH + PBS group was significantly worse in neurological tests (P < 0.001) and brain water content of the cerebral hemisphere in the bleeding side (p = 0.005) compared with the Sham+PBS group, while there were no differences between the SAH + TAK-242 and Sham+PBS groups. SAH severity in the SAH + PBS group was similar to that in the SAH + TAK-242 group. CONCLUSIONS: Intracerebroventricular administration of TAK-242 possibly prevents neurological impairments at least via suppression of brain edema.


Assuntos
Edema Encefálico , Hemorragia Subaracnóidea , Sulfonamidas , Receptor 4 Toll-Like , Animais , Edema Encefálico/tratamento farmacológico , Camundongos , Hemorragia Subaracnóidea/tratamento farmacológico , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores
3.
Life Sci ; 239: 117000, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31654747

RESUMO

AIMS: ß2-glycoprotein I/anti-ß2-glycoprotein I antibody complex (ß2/aß2) could promote oxLDL-induced endothelial inflammation through Toll-like receptor 4 (TLR4), therefore accelerates atherosclerosis in patients with anti-phospholipid syndrome (APS). However, effects of ß2/aß2 and TLR4 on oxLDL-induced CD36 activation in macrophages remain to be elucidated and are currently under investigation. MATERIALS AND METHODS: THP-1 macrophages with or without the pre-treatment of TAK-242, a TLR4 inhibitor, were treated with RPMI 1640, oxLDL, oxLDL+ß2/aß2 or oxLDL + LPS.CD36 expression and subsequent intracellular lipid accumulation, cholesterol-transportation-related proteins (ACAT1, ABCG1 and ABCA1) expression, inflammatory cytokines (IL-1ß, TNF-α and IL-6) secretion, focal adhesion kinases (FAK) activation and matrix metalloproteinases (MMP-2 and MMP-9) expression by these THP-1 macrophages were evaluated. Moreover, effects of TLR4 on oxLDL+ß2/aß2-induced peroxisome proliferators-activated receptor-γ (PPAR-γ) expression and CD36 translocation have also been observed. KEY FINDINGS: Compared with oxLDL-treated ones, CD36 expression, intracellular lipid accumulation and FAK activation were inhibited, whereas the levels of inflammatory cytokines and MMPs were upregulated in THP-1 macrophages treated with oxLDL+ß2/aß2 (p < 0.05). Moreover, observed differences between oxLDL-treated and oxLDL+ß2/aß2-treated THP-1 macrophages could be reversed by TAK-242 pre-treatment (p < 0.05). Furthermore, oxLDL+ß2/aß2 promoted PPAR-γ expression and CD36 cytoplasmic translocation in THP-1 macrophages, these effects could also be attenuated by TAK-242 (p < 0.05). SIGNIFICANCE: Through a TLR4 dependent manner, ß2/aß2 inhibited oxLDL-induced CD36 expression, lipid accumulation and FAK activation, while promoted inflammatory cytokines and MMPs expression in THP-1 macrophages, indicating the novel dual roles played by ß2/aß2 in APS-related atherosclerosis.


Assuntos
Antígenos CD36/genética , Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , beta 2-Glicoproteína I/antagonistas & inibidores , beta 2-Glicoproteína I/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Colesterol/metabolismo , Citocinas/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Humanos , Macrófagos/metabolismo , Metaloproteinases da Matriz/metabolismo , PPAR gama/biossíntese , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , beta 2-Glicoproteína I/imunologia
4.
Immunology ; 158(2): 136-149, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31515801

RESUMO

Immune-checkpoint blockade antibodies have been approved for the treatment of cancer. However, poorly immunogenic tumours are less responsive to such therapies. Agonistic anti-Toll-like receptor 4 (TLR4) monoclonal antibodies (mAbs) activate only cell-surface TLR4; in contrast, lipopolysaccharide (LPS) activates both TLR4 and intracellular inflammatory caspases. In this study, we investigated the adjuvant activity of an anti-TLR4 mAb in T-cell-mediated antitumour immunity. The anti-TLR4 mAb induced the activation of antigen-specific T-cells in adoptive transfer studies. The growth of ovalbumin (OVA)-expressing tumours was significantly suppressed by administration of OVA and the anti-TLR4 mAb in combination, but not individually. The antitumour effect of anti-PD-1 mAb was enhanced in mice administered with OVA plus the anti-TLR4 mAb. The OVA-specific IFN-γ-producing CD8 T-cells were induced by administration of OVA and the anti-TLR4 mAb. The suppression of tumour growth was diminished by depletion of CD8, but not CD4, T-cells. The inflammatory response to the anti-TLR4 mAb was of significantly lesser magnitude than that to LPS, as assessed by NF-κB activation and production of TNF-α, IL-6 and IL-1ß. Administration of LPS (at a dose that elicited levels of proinflammatory cytokines comparable to those by the anti-TLR4 mAb) plus OVA induced no or less-marked activation of OVA-specific T-cells and failed to suppress tumour growth in mice. In conclusion, the agonistic anti-TLR4 mAb induces potent CD8 T-cell-dependent antitumour immunity and an inflammatory response of lesser magnitude than does LPS. The agonistic anti-TLR4 mAb has potential as an adjuvant for use in vaccines against cancer.


Assuntos
Adjuvantes Imunológicos/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Melanoma Experimental/terapia , Neoplasias Cutâneas/terapia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Imunização , Imunoterapia/métodos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/imunologia , Ovalbumina/administração & dosagem , Cultura Primária de Células , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/patologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
5.
Endocrinology ; 160(11): 2646-2662, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504393

RESUMO

Inflammation elicited by infection or noninfectious insults during gestation induces proinflammatory cytokines that can shift the trajectory of development to alter offspring phenotype, promote adiposity, and increase susceptibility to metabolic disease in later life. In this study, we use mice to investigate the utility of a small molecule Toll-like receptor (TLR)4 antagonist (+)-naloxone, the nonopioid isomer of the opioid receptor antagonist (-)-naloxone, for mitigating altered fetal metabolic programming induced by a modest systemic inflammatory challenge in late gestation. In adult progeny exposed to lipopolysaccharide (LPS) challenge in utero, male but not female offspring exhibited elevated adipose tissue, reduced muscle mass, and elevated plasma leptin at 20 weeks of age. Effects were largely reversed by coadministration of (+)-naloxone following LPS. When given alone without LPS, (+)-naloxone elicited accelerated postweaning growth and elevated muscle and fat mass in adult male but not female offspring. LPS induced expression of inflammatory cytokines Il1a, Il1b, Il6, Tnf, and Il10 in fetal brain, placental, and uterine tissues, and (+)-naloxone suppressed LPS-induced cytokine expression. Fetal sex-specific regulation of cytokine expression was evident, with higher Il1a, Il1b, Il6, and Il10 induced by LPS in tissues associated with male fetuses, and greater suppression by (+)-naloxone of Il6 in females. These data demonstrate that modulating TLR4 signaling with (+)-naloxone provides protection from inflammatory diversion of fetal developmental programming in utero, associated with attenuation of gestational tissue cytokine expression in a fetal sex-specific manner. The results suggest that pharmacologic interventions targeting TLR4 warrant evaluation for attenuating developmental programming effects of fetal exposure to maternal inflammatory mediators.


Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Naloxona/uso terapêutico , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Receptor 4 Toll-Like/antagonistas & inibidores , Adipocinas/sangue , Animais , Citocinas/sangue , Feminino , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Naloxona/farmacologia , Gravidez , Caracteres Sexuais
6.
Hypertension ; 74(4): 843-853, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476902

RESUMO

Preterm birth is associated with proinflammatory conditions and alterations in adult cardiac shape and function. Neonatal exposure to high oxygen, a rat model of prematurity-related conditions, leads to cardiac remodeling, fibrosis, and dysfunction. TLR (Toll-like receptor) 4 signaling is a critical link between oxidative stress, inflammation, and the pathogenesis of cardiovascular diseases. The current study sought to investigate the role of TLR4 signaling in neonatal oxygen-induced cardiomyopathy. Male Sprague-Dawley pups were kept in 80% oxygen or room air from day 3 to 10 of life and treated with TLR4 antagonist lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides(LPS-RS) or saline. Echocardiography was performed at 4, 7, and 12 weeks. At 12 weeks, intraarterial blood pressure was measured before euthanization for histological and biochemical analyses. At day 10, cardiac TLR4, Il (interleukin) 18, and Il1ß expression were increased in oxygen-exposed compared with room air controls. At 4 weeks, compared with room air-saline, saline-, but not LPS-RS treated-, oxygen-exposed animals, exhibited increased left ventricle mass index, reduced ejection fraction, and cardiac output index. Findings were similar at 7 and 12 weeks. LPS-RS did not influence echocardiography in 12 weeks room air animals. Systolic blood pressure was higher in saline- but not LPS-RS treated-oxygen-exposed animals compared with room air-saline and -LPS-RS controls. LPS-RS prevented cardiac fibrosis and cardiomyocytes hypertrophy, the increased TLR4, Myd88, and Il18 gene expression, TRIF expression, and CD68+ macrophages infiltration associated with neonatal oxygen exposure, without impact in room air rats. This study indicates that neonatal exposure to high oxygen programs TLR4 activation, which contributes to cardiac remodeling and dysfunction.


Assuntos
Hiperóxia/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Lipopolissacarídeos/uso terapêutico , Receptor 4 Toll-Like/antagonistas & inibidores , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Animais Recém-Nascidos , Citocinas/metabolismo , Modelos Animais de Doenças , Hiperóxia/complicações , Hiperóxia/metabolismo , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/prevenção & controle
7.
Inflammation ; 42(5): 1869-1877, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376096

RESUMO

The Toll-like receptor 4 (TLR4)-mediated neuroinflammation plays a key role in inducing secondary brain injury after intracerebral hemorrhage (ICH). However, how TLR4 is regulated during this pathological process is not well understood. In the present study, by taking advantage of a rat ICH model, we show that miR-140-5p is reversely correlated with TLR4 expression in the peri-hematomal striatum following ICH. In vitro, miR-140-5p directly targets TLR4 and suppresses its expression in a rat neuronal PC12 cell line. Moreover, an intracerebral ventricular injection of miR-140-5p mimics improves neurological function and reduces apoptotic cell death and limits the production of inflammatory cytokines following ICH, indicating that miR-140-5p attenuates brain injury and neuroinflammation in vivo. Furthermore, miR-140-5p suppresses TLR4 expression and inhibits the downstream MyD88/TRIF inflammatory pathway and NF-κB activity following ICH, suggesting that the inhibition of TLR4-mediated neuroinflammation at least in part accounts for the neuroprotective role of miR-140-5 against ICH-induced brain injury in rats. Collectively, these results identify miR-140-5 as a negative regulator of TLR4 and downstream inflammatory pathway following ICH, implicating that miR-140-5 might represent as a potential therapeutic target for alleviating ICH-induced brain injury.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Hemorragia Cerebral/tratamento farmacológico , Inflamação/tratamento farmacológico , MicroRNAs/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Lesões Encefálicas/patologia , Hemorragia Cerebral/patologia , MicroRNAs/uso terapêutico , NF-kappa B/metabolismo , Neuroproteção , Ratos
8.
Prostate ; 79(13): 1498-1504, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31376214

RESUMO

BACKGROUND: This study aims to evaluate the effect of extracorporeal shock wave therapy (ESWT) on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and to explore the mechanism. METHODS: RWPE-2 cells were randomly divided into three groups: (a) RWPE-2 group (normal control), (b) LPS groups (lipopolysaccharide inducing inflammation) and (c) ESWT groups (LPS induced RWPE-2 treated by ESWT). After ESWT was administered, cells and supernatant were collected for enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. In vivo, Sprague-Dawley rats (n = 30) were randomly divided into three groups: (a) normal control group, (b) prostatitis groups, and (c) ESWT groups. Prostatitis rats were induced by 17 ß-estradiol and dihydrotestosterone for 4 weeks. After ESWT, prostates of each group were collected for immunohistochemistry, Western blot analysis, and ELISA. RESULTS: ESWT improved prostatitis by attenuating inflammation (P < .01). ESWT downregulated the expression of cyclooxygenase 2 (COX-2) through inhibiting TLR4-NFκB pathway compared with the LPS group in vitro or prostatitis group in vivo (P < .05). TRAF2 mediates ERK1/2-COX2 pathway. ESWT promotes prostate tissue recovery by stimulating vascular endothelial growth factor expression (P < .01). ESWT could suppress apoptosis in the prostate. CONCLUSIONS: ESWT improved CP/CPPS and reduced inflammation by degrading COX-2 in microenvironment through TLR4-NFκB-inhibiting pathway. TRAF2 regulator in ERK1/2-COX-2 inhibition significantly reduced inflammation, thus suggesting ESWT may be a potential and promising treatment for CP/CPPS.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Tratamento por Ondas de Choque Extracorpóreas , NF-kappa B/metabolismo , Prostatite/terapia , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose/fisiologia , Linhagem Celular , Doença Crônica , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , NF-kappa B/antagonistas & inibidores , Dor Pélvica/metabolismo , Dor Pélvica/patologia , Dor Pélvica/terapia , Prostatite/metabolismo , Prostatite/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/biossíntese
9.
Biomed Pharmacother ; 118: 109152, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376652

RESUMO

Antimicrobial peptides (AMPs) are small molecules with microbicidal and immunoregulatory activities. In this study we evaluated the anti-inflammatory and antimicrobial activities of peptides ToAP3 and ToAP4, AMPs from the venom of the Brazilian scorpion Tityus obscurus. To test the peptides' activity, murine bone marrow-derived macrophages (BMDMs) or dendritic cells (BMDCs) were stimulated with peptides plus LPS to analyze their ability to modulate cytokine release as well as phenotypic markers. For antimicrobial analysis, we evaluated the indirect activity against macrophage-internalized Cryptococcus neoformans and direct activity against Mycobacterium massiliense. Our data demonstrate that they were able to reduce TNF-α and IL-1ß transcript levels and protein levels for BMDM and BMDC. Furthermore, the reduction of TNF-α secretion, before LPS- inflammatory stimuli, is associated with peptide interaction with TLR-4. ToAP4 increased MHC-II expression in BMDC, while ToAP3 decreased co-stimulatory molecules such as CD80 and CD86. Although these peptides were able to modulate the production of cytokines and molecules associated with antigen presentation, they did not increase the ability of clearance of C. neoformans by macrophages. In antimicrobial analysis, only ToAP3 showed potent action against bacteria. Altogether, these results demonstrate a promising target for the development of new immunomodulatory and anti-bacterial therapies.


Assuntos
Anti-Infecciosos/farmacologia , Citocinas/metabolismo , Peptídeos/farmacologia , Venenos de Escorpião/química , Escorpiões , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Anti-Infecciosos/isolamento & purificação , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular , Cryptococcus neoformans/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Imunidade Inata/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Testes de Sensibilidade Microbiana , Mycobacterium abscessus/efeitos dos fármacos , Peptídeos/isolamento & purificação , Receptor 4 Toll-Like/genética
10.
Exp Neurol ; 321: 113039, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31442443

RESUMO

Neonatal hypoxic-ischemic brain damage (HIBD) survivors present with long-term neurological disorders affecting their quality of life, and there remains a lack of effective treatment. Toll-like receptor 4 (TLR4) is widely distributed in nerve cells and its inhibition has a neuroprotective effect against brain injury. The present study aimed to evaluate the long-term neuroprotective effects of early inhibition of TLR4 during HIBD. Seven-day-old rat pups were subjected to left carotid artery ligation followed by 2 h of hypoxia (8.0% O2). A single dose of TAK-242 (0.5 mg/kg), a TLR4-specific antagonist, was intraperitoneally injected half an hour prior to hypoxic ischemia (HI). The long-term effects of TAK-242 inhibition on the induced hippocampal injury were investigated by assessing behaviour at P28, and then using a variety of methods to exploring the mechanism, including immunofluorescence, Golgi silver staining, Western blotting and real-time polymerase chain reaction (RT-PCR). TAK-242 treatment significantly reduced the expression levels of TLR4 and its downstream signalling molecules in the ipsilateral lesion of the hippocampus 24 h after HIBD. The Morris water maze (MWM) test demonstrated that TAK-242 treatment reduced the loss of HI-induced learning and memory functions. Immunofluorescence experiments showed that TAK-242 administration attenuated HI-induced loss of neurons, prevented the activation of microglia and astrocytes, and increased the expression of the glutamate receptor subtype, N-methyl d-aspartate 2A (NR2A) in the ipsilateral hippocampus region. Golgi silver staining revealed that TAK-242 prevented an HI-induced decline in spine density in the ipsilateral hippocampus. Western blot and RT-PCR results indicated that the expression of NR2A protein and mRNA in the ipsilateral hippocampi of adolescent rats decreased after neonatal HIBD; early TAK-242 administration may reverse these effects. In conclusion, our findings indicate that early inhibition of TLR4 signalling may improve the long-term prognosis of neonatal HIBD. The mechanisms contributing to this improvement involve reductions in neuronal loss, a decrease in glial cell activation, and an improvement in synaptic plasticity.


Assuntos
Hipocampo/patologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Plasticidade Neuronal/fisiologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Hipóxia-Isquemia Encefálica/complicações , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/efeitos dos fármacos , Sulfonamidas/farmacologia
11.
Mol Med Rep ; 20(4): 3043-3054, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432179

RESUMO

The present study was designed to investigate the role of microRNA­451 (miRNA­451) on cerebral ischemia­reperfusion and to explore its possible mechanism. The expression of miRNA­451 was downregulated in rats with cerebral ischemia­reperfusion. In an in vitro model of cerebral ischemia­reperfusion, the downregulation of miRNA­451 increased inflammation, demonstrated by increased levels of tumor necrosis factor α, interleukin (IL)­1b, IL­6 and IL­18. However, the upregulation of miRNA­451 expression decreased inflammation in the same in vitro model of cerebral ischemia­reperfusion. In addition, it was found that the downregulation of miRNA­451 induced the expression of Toll­like receptor 4 (TLR4), myeloid differentiation primary response protein MyD88 (MyD88) and nuclear factor­κB (NF­κB)/p65. Moreover, the administration of a MyD88 inhibitor, ST 2825, reduced the expression of MyD88 and NF­κB/p65 in the in vitro model of cerebral ischemia­reperfusion, inhibiting the effects of miRNA­451 upregulation on inflammation. A TLR4 inhibitor, TAK­242, was used to reduce the expression of TLR4 in the in vitro model of cerebral ischemia­reperfusion. TAK­242 suppressed the effects of miRNA­451 downregulation on inflammation. The present study suggested that miRNA­451 regulated cerebral ischemia­reperfusion­induced inflammation, which is mediated through the TLR4/MyD88/NF­κB signaling pathway.


Assuntos
Lesões Encefálicas/metabolismo , MicroRNAs/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Lesões Encefálicas/patologia , Citocinas/metabolismo , Compostos Heterocíclicos com 2 Anéis/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Traumatismo por Reperfusão/patologia , Compostos de Espiro/farmacologia , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores
12.
Immunopharmacol Immunotoxicol ; 41(4): 513-520, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31397191

RESUMO

Exposure to environmentally relevant doses of arsenic has several harmful effects on the human immune system. In traditional Eastern medicines, nettle has been used as an anti-inflammatory agent to treat rheumatism and osteoarthritis. Fumaric acid (FA) as a major effective compound in nettle was chosen based on very accurate virtual screening to find antagonist for TLR4/MD structure. In this study, the in vitro therapeutic effects of FA on arsenic-exposed monocytes-derived dendritic cells (MDDCs) were evaluated. All the canonical functions of dendritic cells in bridging innate and adaptive immune system including phagocytosis and antigen-presenting capacity, and also cytokines secretion, were evaluated after exposure to arsenic/FA. FA profoundly over-expressed antigen-presenting capacity of MDDCs after exposure to arsenic through the upregulation of MHCιι. However, phagocytosis capacity of arsenic-exposed MDDCs is not compensated for, by treatment with FA. Arsenic up-regulates pro-inflammatory cytokines independents of TLR4 pathway. FA surprisingly mitigates the up-regulation of IL-1ß and TNF-α but not TLR4 and NF-kB. Moreover, FA increases the viability of MDDCs even at a high dose of arsenic. Totally, FA reduced inflammatory factors induced by arsenic. This finding confirmed that nettle and other medicinal plants containing similar structures with FA could be further analyzed as valuable candidates for the reduction of drastic effects of arsenic in human immune systems.


Assuntos
Arsênico/farmacologia , Células Dendríticas/efeitos dos fármacos , Fumaratos/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Monócitos/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Imunidade Adaptativa/efeitos dos fármacos , Adulto , Apresentação do Antígeno/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação/metabolismo , Masculino , Monócitos/metabolismo , Fagocitose/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
13.
Mol Med Rep ; 20(3): 2101-2110, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257518

RESUMO

Ischemia­reperfusion injury (IRI) is a notable cause of tissue damage during surgical procedures and a major risk factor in graft dysfunction in liver transplantation. Livers obtained from donors after circulatory death (DCD) are prone to IRI and toll­like receptor 4 (TLR4) serves a prominent role in the inflammatory response associated with DCD liver IRI. The present study was designed to investigate whether TAK242, a specific TLR4 inhibitor, improves hepatic IRI following a DCD graft and to investigate its underlying protective mechanisms. Male Sprague­Dawley rats were randomized into 4 groups: Control, TAK242, DCD and DCD+TAK242 groups. Rats were pretreated with TAK242 or its vehicle for 30 min, then the livers were harvested without warm ischemia (control group and TAK242 group) or with warm ischemia in situ for 30 min. The livers were stored in cold University of Wisconsin solution for 24 h and subsequently perfused for 60 min with an isolated perfused rat liver system. Rat liver injury was evaluated thereafter. When compared with the DCD group, DCD livers with TAK242 pretreatment displayed significantly improved hepatic tissue injury and less tissue necrosis (P<0.05). Compared with DCD livers, mechanistic experiments revealed that TAK242 pretreatment alleviated mitochondrial dysfunction, reduced reactive oxygen species and malondialdehyde levels and inhibited apoptosis. Additionally, TAK242 significantly inhibited the IRI­associated inflammatory response, indicated by the decreased expression of TLR4, interleukin (IL)­1ß, IL­6 and cyclooxygenase 2 at the mRNA and protein levels (P<0.05). TAK242 ameliorates DCD liver IRI via suppressing the TLR4 signaling pathway in rats. The results of the present study have revealed that TAK242 pretreatment harbors a potential benefit for liver transplantation.


Assuntos
Anti-Inflamatórios/farmacologia , Fígado/efeitos dos fármacos , Preservação de Órgãos/métodos , Traumatismo por Reperfusão/imunologia , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Adenosina/farmacologia , Alopurinol/farmacologia , Animais , Glutationa/farmacologia , Insulina/farmacologia , Fígado/imunologia , Fígado/patologia , Fígado/ultraestrutura , Transplante de Fígado , Masculino , Soluções para Preservação de Órgãos/farmacologia , Rafinose/farmacologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/imunologia , Isquemia Quente
14.
J Surg Res ; 243: 316-324, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31255931

RESUMO

BACKGROUND: 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine (LYRM03) has been shown to be beneficial in a rat model of acute lung injury (ALI). Nonetheless, the pharmacologic action of LYRM03 interference has not been demonstrated to occur through oxidative stress and apoptosis in a rat lipopolysaccharide (LPS)-induced ALI model, and the potential pathogenic mechanism needs to be clarified. Our research intended to explore the mechanism of action using an in vivo rat LPS-induced ALI model and highlight the associated pathogenesis. METHODS: Sprague-Dawley rats were randomly assigned to the following five groups: Sham; LPS (5 mg/kg); LPS + LYRM03 (5 mg/kg); LPS + LYRM03 (10 mg/kg); and LPS + LYRM03 (20 mg/kg). Pulmonary injury indicators were documented at 24 h after LPS-induced ALI. Morphologic alterations, such as the extent of the injury, were determined using hematoxylin-eosin staining. Furthermore, expression levels of oxidative stress indicators (malondialdehyde, superoxide dismutase, and glutathione peroxidase) and inflammatory molecules (tumor necrosis factor-α, interleukin-8, and interleukin-6) in circulation were observed. The production of apoptosis-associated proteins (poly ADP-ribose polymerase, c-caspase 3, B-cell lymphoma-2, and Bcl2 associated X), inflammatory mediators (high mobility group box-1, toll-like receptor 4, nuclear factor-kappa B p65, and myeloid differentiation primary response 88), and inhibitor of kappa B-α were determined through Western blotting. Real-time polymerase chain reaction was applied to assess the messenger RNA expression of the inflammatory mediators. RESULTS: The LPS-treated group exhibited a remarkable increase in the extent of the pulmonary injury, oxidative stress indicator secretion, inflammatory molecule release, and inflammatory mediator production and an increase in the inhibitor of kappa B-α levels relative to the Sham group. The LYRM03 (5 and 10 mg/kg)-treated groups exhibited a remarkable decrease relative to the LPS group. In addition, treatment with LYRM03 (20 mg/kg) powerfully limited the extent of the injury and demonstrated anti-inflammatory actions. CONCLUSIONS: The results of this investigation indicated that treatment with LYRM03 plays a role in lung defense by inhibiting the NF-κB/MyD88/TLR4 pathway.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Oligopeptídeos/uso terapêutico , Receptor 4 Toll-Like/antagonistas & inibidores , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Lipopolissacarídeos , Pulmão/enzimologia , Pulmão/patologia , Masculino , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Oligopeptídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo
15.
Eur J Pharmacol ; 857: 172422, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31152701

RESUMO

Cisplatin-induced acute renal injury is the most common and serious side effect, sometimes requiring discontinuation of the treatment. Thus, the development of new protective strategies is essential. The present study aimed to investigate the potential nephroprotective effect of tetramethylpyrazine (TMP) against acute renal damage induced by cisplatin in rats. Rats were administered 50 and 100 mg/kg TMP intraperitoneally before cisplatin (7 mg/kg). Acute nephrotoxicity was evident in cisplatin-treated rats where relative kidney weight, BUN and serum creatinine were markedly elevated. Cisplatin administration resulted in enhanced oxidative stress, evidenced by depleted GSH level as well as catalase and superoxide dismutase activities. Also, lipid peroxidation was boosted in comparison to the control. This was associated with inhibition of Nrf2 defense pathway. Moreover, cisplatin increased the expression of pro-inflammatory mediators in the kidney tissues. Cisplatin-induced apoptosis was depicted by elevated Bax mRNA expression and caspase-3 activity, as well as decreased Bcl2 mRNA expression. In addition, high mobility group box 1/toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-κB) signaling pathway was significantly upregulated, while peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression was significantly diminished in cisplatin-treated rats. Cisplatin-induced nephrotoxicity, oxidative stress, inflammation, apoptosis and the effect on Nrf2 defense pathway and HMGB1/TLR4/NF-κB as well as PPAR-γ expression were markedly ameliorated by TMP administration. Given the major nephrotoxicity of cisplatin cancer chemotherapy, TMP might be a potential candidate for neoadjuvant chemotherapy due to its antioxidant, anti-inflammatory and anti-apoptotic effects, in addition to its effect on Nrf2, HMGB1/TLR4/NF-κB signaling pathway and PPAR-γ expression.


Assuntos
Proteína HMGB1/antagonistas & inibidores , Rim/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/antagonistas & inibidores , PPAR gama/metabolismo , Pirazinas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Moléculas de Adesão Celular/genética , Cisplatino/efeitos adversos , Citoproteção/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/citologia , Rim/metabolismo , PPAR gama/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
16.
Int Immunopharmacol ; 73: 254-260, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31121415

RESUMO

The present study aims to investigate the effects of toll-like receptor 4 (TLR4) antagonist in an ovalbumin (OVA)-induced mouse model of combined allergic rhinitis and asthma syndrome (CARAS). An OVA-induced mouse model of CARAS was established and TLR4 antagonist, TAK-242, was administrated intranasally or intraperitoneally. The number of sneezing and nasal rubbing was counted. The frequency of different cell types in the bronchoalveolar lavage fluid (BALF) and nasal lavage fluid (NLF) was analyzed using flow cytometry. Expressions of protein in nasal mucosa and lungs were determined using western blotting. Levels of interleukin (IL)-4, IL-5, and IL-13 were determined using Enzyme-linked Immunosorbent Assay (ELISA). Histological scores were applied for the assessment of lung injury. Treatment of TAK-242 downregulated CCL2 expression and reduced monocyte infiltration in nasal mucosa and lung tissues. Additionally, treatment of TAK-242 ameliorated upper airway symptoms including the sneezing and nasal rubbing by the regulation of cytokines including IL-4, IL-5, and IL-13. Furthermore, treatment of TAK-242 ameliorated lower airway symptoms including decreasing the frequency of CD45+SiglecF+CD11b+CD11c- eosinophils in BALF and IL13+ Th2 cells in the lungs. In conclusion, treatment of TAK-242 ameliorated CARAS-related lung injury by inhibiting lymphocyte infiltration, reducing monocytes infiltration, as well as regulating the frequency of eosinophils and Th2 cells.


Assuntos
Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Monócitos/efeitos dos fármacos , Rinite Alérgica/tratamento farmacológico , Sulfonamidas/uso terapêutico , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos Endogâmicos BALB C , Monócitos/imunologia , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Ovalbumina , Sulfonamidas/farmacologia , Síndrome , Receptor 4 Toll-Like/imunologia
17.
Int Immunopharmacol ; 73: 49-56, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31078925

RESUMO

Diabetic retinopathy is a diabetes complication. During diabetic retinopathy development, the TLR4/NF-κB pathway is up-regulated. Apocynin is a nicotinamide adenine dinucleotide phosphate oxidase blocker which can reduce the superoxide radicals. It is demonstrated that apocynin can inhibit TLR4/NF-κB pathway in rats. We aim to figure out whether apocynin treatment is benefit for the diabetic retinopathy in rat model. The diabetes in rats was induced by streptozotocin. The treatment of apocynin (16 mg/kg/day) or vehicle in diabetic rat model was maintained for 12 weeks. The expression levels of relative genes in this research were shown through Western blot and qRT-PCR. Morphology of the retinas was shown by Hematoxylin-Eosin staining. The treatment of apocynin ameliorated biochemical indexes in diabetic rats and rescued the morphology of the retinas. After a 12 weeks apocynin treatment, the cell apoptosis, oxidative stress, and inflammatory in retina was reduced in diabetic rats. TLR4/NF-κB signaling pathway activity in diabetic rat retina was inhibited by apocynin. Based on our study, the treatment of apocynin ameliorates diabetic retinopathy in rats. The TLR4/NF-κB signaling pathway inhibition by apocynin is involved in this process. This result indicated a great therapeutic potential of apocynin in diabetic retinopathy treatment.


Assuntos
Acetofenonas , Antioxidantes , Diabetes Mellitus Experimental , Retinopatia Diabética , NF-kappa B/antagonistas & inibidores , Receptor 4 Toll-Like/antagonistas & inibidores , Acetofenonas/farmacologia , Acetofenonas/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
18.
Cell Biochem Funct ; 37(5): 348-358, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31066476

RESUMO

Pneumonia is an inflammatory disease that occurs in the lungs associated with pathogens or other factors. It has been well established that long noncoding RNA X inactivate-specific transcript (XIST) is involved in several cancers. The present study focused on the effect and detailed mechanism of XIST in lipopolysaccharide (LPS)-induced injury in pneumonia. Here, XIST was silenced by transfection with XIST-targeted siRNA, and then, mRNA expression, cell viability, apoptosis, and protein expression were, respectively, assessed by qRT-PCR, CCK-8, flow cytometry, and Western blotting. Luciferase reporter, RIP, and RNA pull-down assays were used to detect the combination of miR-370-3p and XIST. Besides, the tested proinflammatory factors were analysed by qRT-PCR and Western blot, and their productions were quantified by ELISA. The results showed that XIST expression was robustly increased in serum of patients with acute-stage pneumonia and LPS-induced WI-38 human lung fibroblasts cells. Functional analyses demonstrated that knockdown of XIST remarkably alleviated LPS-induced cell injury through increasing cell viability and inhibiting apoptosis and inflammatory cytokine levels. Mechanistically, XIST functioned as a competitive endogenous RNA (ceRNA) by effectively binding to miR-370-3p and then restoring TLR4 expression. More importantly, miR-370-3p inhibitor abolished the function of XIST knockdown on cell injury and JAK/STAT and NF-κB pathways. Taken together, XIST may be involved in progression of cell inflammatory response, and XIST/miR-370-3p/TLR4 axis thus may shed light on the development of novel therapeutics to the treatment of acute stage of pneumonia. SIGNIFICANCE OF THE STUDY: Our study demonstrated that XIST was highly expressed in patients with acute stage of pneumonia. Knockdown of XIST remarkably alleviated LPS-induced cell injury through increasing cell viability and inhibiting apoptosis and inflammatory cytokine levels through regulating JAK/STAT and NF-κB pathways.


Assuntos
Apoptose/efeitos dos fármacos , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , MicroRNAs/antagonistas & inibidores , Pneumonia/tratamento farmacológico , RNA Longo não Codificante/genética , RNA Interferente Pequeno/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Doença Aguda , Adulto , Células Cultivadas , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Masculino , MicroRNAs/análise , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Pneumonia/diagnóstico , Pneumonia/metabolismo , RNA Longo não Codificante/biossíntese , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/análise , Receptor 4 Toll-Like/metabolismo
19.
Cell Mol Life Sci ; 76(18): 3667-3678, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31062071

RESUMO

Cardiolipins (CLs) are tetra-acylated diphosphatidylglycerols found in bacteria, yeast, plants, and animals. In healthy mammals, CLs are unsaturated, whereas saturated CLs are found in blood cells from Barth syndrome patients and in some Gram-positive bacteria. Here, we show that unsaturated but not saturated CLs block LPS-induced NF-κB activation, TNF-α and IP-10 secretion in human and murine macrophages, as well as LPS-induced TNF-α and IL-1ß release in human blood mononuclear cells. Using HEK293 cells transfected with Toll-like receptor 4 (TLR4) and its co-receptor Myeloid Differentiation 2 (MD2), we demonstrate that unsaturated CLs compete with LPS for binding TLR4/MD2 preventing its activation, whereas saturated CLs are TLR4/MD2 agonists. As a consequence, saturated CLs induce a pro-inflammatory response in macrophages characterized by TNF-α and IP-10 secretion, and activate the alternative NLRP3 inflammasome pathway in human blood-derived monocytes. Thus, we identify that double bonds discriminate between anti- and pro-inflammatory properties of tetra-acylated molecules, providing a rationale for the development of TLR4 activators and inhibitors for use as vaccine adjuvants or in the treatment of TLR4-related diseases.


Assuntos
Cardiolipinas/farmacologia , Macrófagos/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Ligação Competitiva , Cardiolipinas/química , Cardiolipinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CXCL10/metabolismo , Células HEK293 , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Antígeno 96 de Linfócito/genética , Antígeno 96 de Linfócito/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Monócitos/citologia , Monócitos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ligação Proteica , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/metabolismo
20.
Eur J Pharmacol ; 853: 256-263, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30930249

RESUMO

Numerous links exist between inflammation and tumor development. Toll-like receptor 4 (TLR4) expression by tumor cells can be a contributing factor that promotes tumor cell proliferation, survival, migration, and metastasis. In this study, we explored the impact of TLR4 inhibition using TAK-242, a specific inhibitor of TLR4, on the invasion properties of ovarian (A2780CP, 2008C13, SKOV3, and A2780S) and breast (MCF7, SKBR3, MDA-MB-231, and BT-474) cancer cell lines. Six out of eight cell lines expressed TLR4 and its downstream mediators (MyD88, NF-ĸB1, and RELB), indicating that these cell lines could be proper candidates for the TLR4 inhibition. TAK-242 induced a cytotoxic effect on all tested cell lines; however, a different cell sensitivity pattern was noticeable. Interestingly, in the TLR4-expressing cell lines, there was a significant correlation between the TLR4/MyD88 expressions and the cancer cell response to TAK-242: the higher the expression, the higher the IC50. To the best of our knowledge, no study has addressed the effects of TAK-242 on invasive abilities of cancer cells and our study suggests for the first time that TAK-242 could considerably decrease invasion properties of ovarian and breast cancer cell lines. We found that not only did TAK-242 reduce the enzymatic activity of MMP2 and MMP9, but also down-regulated gene expressions of epithelial-mesenchymal transition (EMT)-related genes. In sum, it seems that targeting TLR4 using TAK-242 possesses novel promising potential in cancer treatment strategies and may prevent invasion in patients suffering from ovarian and breast cancers, especially in those with over-expression of TLR4.


Assuntos
Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Receptor 4 Toll-Like/metabolismo
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