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1.
Toxicol Lett ; 319: 49-57, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31693926

RESUMO

Blast lung injury is associated with high morbidity and mortality. Vaporized perfluorocarbon (PFC) inhalation has been reported to attenuate acute respiratory distress syndrome in humans and animal models. However, the effect of vaporized PFC on blast lung injury is still unknown. In this study, we investigated the protective effects and potential underlying mechanisms of action of vaporized PFC on blast lung injury in a canine model. This was a prospective, controlled, animal study in adult male hybrid dogs randomized to sham, blast (B), blast plus mechanical ventilation (B + M), and blast plus PFC (B + P) groups. All groups except for the sham were exposed to blast wave. The B + P group was treated with vaporized PFC for 1.5 h followed by 5.5 h mechanical ventilation. B + M group received 7.5 h mechanical ventilation and B group was observed for 7.5 h. Blast lung injury was induced using a shock tube. Blood gas, inflammatory cytokines, and oxidative stress were measured. Expression of nuclear factor (NF)-κB activation, mitogen-activated protein kinase (MAPK) and nuclear factor, erythroid 2 like 2 (Nrf2) were measured using western blot. Lung injury observed after blast exposure was marked by increased histopathological scores, ratio of lung wet to dry weight. PFC treatment attenuated blast lung injury as indicated by histopathological scores and ratio of lung wet to dry weight. PFC treatment downregulated interleukin (IL)-6, tumor necrosis factor (TNF)-α, and malondialdehyde (MDA), and upregulated superoxide dismutase (SOD) activity. PFC also suppressed expression of MAPK/NF-κB and Nrf2 protein levels. Our results suggest that PFC attenuated blast-induced acute lung injury by inhibiting MAPK/NF-κB activation and inducing Nrf2 expression in dogs.


Assuntos
Traumatismos por Explosões/tratamento farmacológico , Fluorcarbonetos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Administração por Inalação , Animais , Traumatismos por Explosões/patologia , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Cães , Fluorcarbonetos/administração & dosagem , Pulmão/patologia , Lesão Pulmonar/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos
2.
Acta Cir Bras ; 34(11): e201901104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31859817

RESUMO

PURPOSE: Myocardial ischemia/reperfusion (Ml/R) injury is a leading cause of damage in cardiac tissues, with high rates of mortality and disability. Biochanin A (BCA) is a main constituent of Trifolium pratense L. This study was intended to explore the effect of BCA on Ml/R injury and explore the potential mechanism. METHODS: In vivo MI/R injury was established by transient coronary ligation in Sprague-Dawley rats. Triphenyltetrazolium chloride staining (TTC) was used to measure myocardial infarct size. ELISA assay was employed to evaluate the levels of myocardial enzyme and inflammatory cytokines. Western blot assay was conducted to detect related protein levels in myocardial tissues. RESULTS: BCA significantly ameliorated myocardial infarction area, reduced the release of myocardial enzyme levels including aspartate transaminase (AST), creatine kinase (CK-MB) and lactic dehydrogenase (LDH). It also decreased the production of inflammatory cytokines (IL-1ß, IL-18, IL-6 and TNF-α) in serum of Ml/R rats. Further mechanism studies demonstrated that BCA inhibited inflammatory reaction through blocking TLR4/NF-kB/NLRP3 signaling pathway. CONCLUSION: The present study is the first evidence demonstrating that BCA attenuated Ml/R injury through suppressing TLR4/NF-kB/NLRP3 signaling pathway-mediated anti-inflammation pathway.


Assuntos
Cardiotônicos/farmacologia , Genisteína/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , NF-kappa B/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Aspartato Aminotransferases/sangue , Western Blotting , Creatina Quinase/sangue , Citocinas/sangue , Lactato Desidrogenases/sangue , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
3.
Life Sci ; 239: 117017, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678284

RESUMO

Saxagliptin (Saxa), a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, is widely used for the treatment of type 2 diabetes mellitus. It has been documented to have immunomodulatory and anti-inflammatory actions. Our objective was to delineate the protective effect and the underlying mechanism of Saxa-in comparison with Dexamethasone (Dexa) - in airway inflammation induced by ovalbumin (OVA) in mice. METHODS: Mice were OVA-sensitized and challenged for the induction of acute asthma. Mice were orally administrated Saxa or Dexa. Total and differential cell counts, lactate dehydrogenase (LDH) and total protein concentrations were assessed in bronchoalveolar lavage fluid (BALF). The toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-kB), reduced glutathione (GSH), and total nitrate/nitrite products (NOx) levels as well as myeloperoxidase (MPO) activity in lung tissues were measured. Histopathological examination of the lung specimens was carried out using the hematoxylin and eosin (H & E) staining. RESULTS: Histopathological examination revealed that both Saxa and Dexa ameliorated OVA-induced inflammatory changes and significantly reduced total and differential leukocyte counts, LDH and total protein level in BALF upon comparison with OVA group. In addition, both treatments significantly mitigated OVA-induced oxidative stress as evidenced by diminished lung NOx level and MPO activity and elevated GSH level. The elevation of TLR4 and NF-kB levels in lung tissue were ameliorated by Saxa and Dexa administration. CONCLUSION: Saxa had marked antiasthmatic effect in OVA-induced allergic asthma through modulation of TLR4 and NF-κB signaling. Also, Saxa may represent a promising therapeutic agent for acute allergic asthma.


Assuntos
Adamantano/análogos & derivados , Asma/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , NF-kappa B/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Doença Aguda , Adamantano/uso terapêutico , Animais , Asma/induzido quimicamente , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Dexametasona/uso terapêutico , L-Lactato Desidrogenase/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Óxido Nítrico/metabolismo , Ovalbumina , Peroxidase/metabolismo
4.
Medicine (Baltimore) ; 98(40): e17126, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577702

RESUMO

BACKGROUND: The aim of this study was to investigate the role of n-acetyl cysteine (NAC) in the lipopolysaccharide (LPS)-mediated induction of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) synthesis by human periodontal ligament fibroblast cells (hPDLFs). In addition, we aimed to determine the involvement of the nuclear factor-kappa B (NF-κB) pathway in any changes in IL-1ß and TNF-α expression observed in response to LPS and NAC. METHODS: HPDLFs were obtained by primary culture. The culture medium used in this experiment was Dulbecco's Modified Eagle Medium (DMEM low-glucose). Cells were stimulated with various concentrations of NAC or LPS. Cell proliferation was measured at various time-points with the cell Counting Kit 8 (CCK-8) assay. mRNA levels of IL-1ß and TNF-α were determined by real-time quantitative polymerase chain reaction (RT-qPCR) analysis. Protein levels of IL-1ß and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). Protein and mRNA expression levels of NF-κB were measured by western blot and RT-qPCR. RESULTS: The results showed that LPS treatment in hPDLFs induced mRNA and protein expression of IL-1ß, TNF-α, and NF-κB. However, these effects were eliminated by pretreatment with NAC. Pretreatment with both NAC (1 mmol/L) and BAY11-7082 (10 µmol/L) significantly inhibited the NF-κB activity induced by LPS. CONCLUSION: NAC inhibits the LPS-mediated synthesis of tumor TNF-α and IL-1ß in hPDLFs, through the NF-κB pathway.


Assuntos
Acetilcisteína/farmacologia , Fibroblastos/efeitos dos fármacos , Interleucina-1beta/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Fibroblastos/metabolismo , Humanos , Interleucina-1beta/biossíntese , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Ligamento Periodontal , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
5.
Cell Prolif ; 52(6): e12673, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31418947

RESUMO

OBJECTIVE: Inflammatory bowel disease (IBD) is a disorder intestinal inflammation and impaired barrier function, associated with increased epithelial expression of monocarboxylate transporter 4 (MCT4). However, the specific non-metabolic function and clinical relevance of MCT4 in IBD remain to be fully elucidated. METHODS: Lentivirus-mediated overexpression of MCT4 was used to assess the role of MCT4 in transcriptionally regulating ZO-1 and IL-6 expression by luciferase assays, WB and ChIP. IP was used to analyse the effect of MCT4 on the interaction NF-κB-CBP or CREB-CBP, and these MCT4-mediated effects were confirmed in vivo assay. RESULTS: We showed that ectopic expression of MCT4 inhibited ZO-1 expression, while increased pro-inflammatory factors expression, leading to destroy intestinal epithelial barrier function in vitro and in vivo. Mechanistically, MCT4 contributed NF-κB p65 nuclear translocation and increased the binding of NF-κB p65 to the promoter of IL-6, which is attributed to MCT4 enhanced NF-κB-CBP interaction and dissolved CREB-CBP complex, resulting in reduction of CREB activity and CREB-mediated ZO-1 expression. In addition, treatment of experimental colitis with MCT4 inhibitor α-cyano-4-hydroxycinnamate (CHC) ameliorated mucosal intestinal barrier function, which was due to attenuation of pro-inflammation factors expression and enhancement of ZO-1 expression. CONCLUSION: These findings suggested a novel role of MCT4 in controlling development of IBD and provided evidence for potential targets of IBD.


Assuntos
Epitélio/efeitos dos fármacos , Interleucina-6/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo , Células CACO-2 , Colo/metabolismo , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Fator de Transcrição RelA/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Proteína da Zônula de Oclusão-1/efeitos dos fármacos
6.
J Neuroinflammation ; 16(1): 148, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319868

RESUMO

BACKGROUND: Neuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation of microglia, the principal immune effector cells of the brain, contributes to neuronal injury by release of neurotoxic products. Toll-like receptor 4 (TLR4), expressed on the surface of microglia, plays an important role in mediating lipopolysaccharide (LPS)-induced microglia activation and inflammatory responses. We have previously shown that curcumin and some of its analogues harboring an α,ß-unsaturated 1,3-diketone moiety, able to coordinate the magnesium ion, can interfere with LPS-mediated TLR4-myeloid differentiation protein-2 (MD-2) signaling. Fluoroquinolone (FQ) antibiotics are compounds that contain a keto-carbonyl group that binds divalent ions, including magnesium. In addition to their antimicrobial activity, FQs are endowed with immunomodulatory properties, but the mechanism underlying their anti-inflammatory activity remains to be defined. The aim of the current study was to elucidate the molecular mechanism of these compounds in the TLR4/NF-κB inflammatory signaling pathway. METHODS: The putative binding mode of five FQs [ciprofloxacin (CPFX), levofloxacin (LVFX), moxifloxacin, ofloxacin, and delafloxacin] to TLR4-MD-2 was determined using molecular docking simulations. The effect of CPFX and LVFX on LPS-induced release of IL-1ß and TNF-α and NF-κB activation was investigated in primary microglia by ELISA and fluorescence staining. The interaction of CPFX and LVFX with TLR4-MD-2 complex was assessed by immunoprecipitation followed by Western blotting using Ba/F3 cells. RESULTS: CPFX and LVFX bound to the hydrophobic region of the MD-2 pocket and inhibited LPS-induced secretion of pro-inflammatory cytokines and activation of NF-κB in primary microglia. Furthermore, these FQs diminished the binding of LPS to TLR4-MD-2 complex and decreased the resulting TLR4-MD-2 dimerization in Ba/F3 cells. CONCLUSIONS: These results provide new insight into the mechanism of the anti-inflammatory activity of CPFX and LVFX, which involves, at least in part, the activation of TLR4/NF-κB signaling pathway. Our findings might facilitate the development of new molecules directed at the TLR4-MD-2 complex, a potential key target for controlling neuroinflammation.


Assuntos
Ciprofloxacino/farmacologia , Inflamação/imunologia , Levofloxacino/farmacologia , Microglia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Humanos , Inflamação/metabolismo , Camundongos , Microglia/imunologia , NF-kappa B/efeitos dos fármacos , NF-kappa B/imunologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/imunologia
7.
Chem Biol Interact ; 310: 108743, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299241

RESUMO

Paraquat (PQ) is a widely characterized neurotoxicant able to induce a series of nervous system disorders, including neurobehavioral defects and neurodegenerative diseases. Despite the direct evidence that PQ could induce inflammatory responses in central nervous system and largely contribute to neurotoxicity, the putative adverse effects of PQ on the neuroimmune interactions have rarely been investigated. Therefore, the present study investigated underlying mechanisms of PQ-induced inflammatory response in BV-2 microglia cells. Proliferation, migration and phagocytosis of BV-2 cells upon PQ exposure were first investigated to demonstrate that PQ did stimulate BV-2 microglia into an active phenotype. Increased microglia M1 markers expression and decreased microglia M2 markers expression confirmed that PQ induces BV-2 cells towards M1 activation. The levels of pro-inflammatory cytokines were determined using ELISA and western blotting assays, showing that paraquat significantly promote the secretion of pro-inflammatory mediators such as tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6). The up-regulation of TLR4/MyD88 protein expressions and enhanced translocation of NF-κB p65 protein upon PQ exposure were further demonstrated. Taken together, our results suggested that PQ induces M1 microglia polarization by increased production of pro-inflammatory molecules, which could be explained by the activation of the TLR4-mediated NF-κB signaling pathway.


Assuntos
Inflamação/induzido quimicamente , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Paraquat/farmacologia , Animais , Citocinas/metabolismo , Camundongos , Microglia/patologia , NF-kappa B/efeitos dos fármacos , Paraquat/efeitos adversos , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo
8.
Life Sci ; 232: 116501, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31163175

RESUMO

AIMS: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The disease mechanisms driving progressive MS remain unresolved. Without this information, current therapeutic strategies are unsatisfactory in preventing disease progression. Our previous work revealed that DL-3-n-butylphthalide (NBP) treatment reduced demyelination in an ethidium bromide mouse model of demyelination. Here, we examine the effect of NBP in the cuprizone model of demyelination by evaluating the pathologic, functional, and behavioral consequences of treatment with NBP. MATERIALS AND METHODS: Forty mice were divided randomly into 4 groups: a normal diet group, a cuprizone diet group, and two NBP groups (10 and 20 mg/kg). CNS infiltration by microglia, axon health and myelination were assessed using immunohistochemistry and electron microscopy, and the levels of cytoplasmic complexes were assessed by Western blotting. KEY FINDINGS: The results showed the neuroprotective effects of the NBP included suppressing the microglia activation through inhibition of nuclear factor-κB (NF-κB) expression, thus decreasing activation of the NF-κB signaling pathway. In particular, myelin density was increased due to an increased mean number of mature oligodendrocytes (OLs) in the high-dose NBP (20 mg/kg) subgroup through reduced oligodendrocyte apoptosis. Meanwhile, increased expression of myelin sheath proteins, including proteolipid protein (PLP) and myelin basic protein (MBP), was observed in the same subgroup. SIGNIFICANCE: These data suggest that NBP may not only have anti-inflammatory properties but also promote the survival of OLs in a mouse cuprizone model of demyelination. NBP may have a potential role in the treatment of MS.


Assuntos
Benzofuranos/farmacologia , Doenças Desmielinizantes/tratamento farmacológico , Esclerose Múltipla/metabolismo , Animais , Astrócitos/metabolismo , Axônios/patologia , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/fisiologia , Cuprizona/farmacologia , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/metabolismo , NF-kappa B/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oligodendroglia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
9.
Biomed Res Int ; 2019: 1847130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240205

RESUMO

Over years, various biological constituents are isolated from Traditional Chinese Medicine and confirmed to show multifunctional activities. Magnolol, a hydroxylated biphenyl natural compound isolated from Magnolia officinalis, has been extensively documented and shows a range of biological activities. Many signaling pathways include, but are not limited to, NF-κB/MAPK, Nrf2/HO-1, and PI3K/Akt pathways, which are implicated in the biological functions mediated by magnolol. Thus, magnolol is considered as a promising therapeutic agent for clinic research. However, the low water solubility, the low bioavailability, and the rapid metabolism of magnolol dramatically limit its clinical application. In this review, we will comprehensively discuss the last five-year progress of the biological activities of magnolol, including anti-inflammatory, antimicroorganism, antioxidative, anticancer, neuroprotective, cardiovascular protection, metabolism regulation, and ion-mediating activity.


Assuntos
Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Lignanas/metabolismo , Lignanas/farmacologia , Medicina Tradicional Chinesa , Anti-Inflamatórios/análise , Antineoplásicos/análise , Antioxidantes/análise , Compostos de Bifenilo/química , Compostos de Bifenilo/uso terapêutico , Fármacos Cardiovasculares/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Lignanas/química , Lignanas/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Magnolia/química , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/análise , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Braz J Med Biol Res ; 52(7): e8092, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31241712

RESUMO

Acute lung injury (ALI) is a serious clinical syndrome with a high rate of mortality. The activation of inflammation is well-recognized as a vital factor in the pathogenesis of lipopolysaccharide (LPS)-induced ALI. Therefore, suppression of the inflammatory response could be an ideal strategy to prevent ALI. Epigallocatechin-3-gallate (EGCG), mainly from green tea, has been shown to have an anti-inflammatory effect. The aim of the study was to explore whether EGCG alleviates inflammation in sepsis-related ALI. Male BALB/C mice were treated with EGCG (10 mg/kg) intraperitoneally (ip) 1 h before LPS injection (10 mg/kg, ip). The results showed that EGCG attenuated LPS-induced ALI as it decreased the changes in blood gases and reduced the histological lesions, wet-to-dry weight ratios, and myeloperoxidase (MPO) activity. In addition, EGCG significantly decreased the expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in the lung, serum, and bronchoalveolar lavage fluid, and alleviated the expression of TLR-4, MyD88, TRIF, and p-p65 in the lung tissue. In addition, it increased the expression of IκB-α and had no influence on the expression of p65. Collectively, these results demonstrated the protective effects of EGCG against LPS-induced ALI in mice through its anti-inflammatory effect that may be attributed to the suppression of the activation of TLR 4-dependent NF-κB signaling pathways.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Catequina/análogos & derivados , NF-kappa B/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Catequina/administração & dosagem , Modelos Animais de Doenças , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos
11.
Mol Med Rep ; 19(6): 4863-4871, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059064

RESUMO

Glaucoma is characterized by the death of retinal ganglion cells (RGCs) and visual field defects, and is a leading cause of blindness worldwide. Caffeic acid phenethyl ester (CAPE), a natural polyphenolic found in propolis from honeybee hives, can inhibit the activation of nuclear factor κ light­chain­enhancer of activated B cells (NF­κB) and has therapeutic potential in inflammatory disease. The present study used a rat model of optic nerve crush (ONC) injury to investigate the effect of CAPE on glaucoma. The death of RGCs at day 14 was significantly reduced in CAPE­treated animals compared with the non­treated group according to Brn3a and TUNEL staining. In addition, CAPE decreased the severity of inflammation in the retina, reflected by the decreased expression of inflammatory cytokines, including interleukin (IL)­8, IL­6, inducible nitric oxide synthase, cycloooxygenase­2, tumor necrosis factor­α and chemokine C­C ligand­2, in CAPE­treated rats. The hypertrophy of astrocytes and Müller cells (gliosis) caused by ONC was also found to be attenuated by CAPE, accompanied by the inhibition of NF­κB signaling. Similarly, in vitro, CAPE suppressed the proliferation and migration of primary astrocytes induced by lipopolysaccharide, as well as the activation of NF­κB. These results suggest that CAPE protected against RGC and attenuated inflammatory responses in a rat model of ONC by suppressing NF­κB activation.


Assuntos
Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/uso terapêutico , Células Ependimogliais/metabolismo , NF-kappa B/metabolismo , Álcool Feniletílico/análogos & derivados , Células Ganglionares da Retina/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/patologia , Glaucoma/tratamento farmacológico , Glaucoma/patologia , Gliose/tratamento farmacológico , Marcação In Situ das Extremidades Cortadas/métodos , Inflamação/tratamento farmacológico , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/efeitos adversos , Masculino , NF-kappa B/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Traumatismos do Nervo Óptico/metabolismo , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , Ratos , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/patologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Brn-3A/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
Microb Pathog ; 132: 369-373, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075430

RESUMO

Present study evaluates the protective effect of mollugin against Klebsiella pneumonia (KP) and also postulates the possible mechanism of its action. Klebsiella pneumoniae (2.4 × 108 CFU/ml) was used for the induction of KP. PMNs and WBC count was determined in the blood and bronchoalveolar lavage fluid (BALF) of Klebsiella pneumonia rat. Level of inflammatory cytokines in the blood of Klebsiella pneumonia rat was determined by ELISA methods. Moreover effect of mollugin was estimated by Western blot assay and RT-PCR method. Result of the study suggests that water content in lung was reduced in the mollugin treated group compared to pneumonia control group of rats. Count of PMNs and WBC were found to be reduced in mollugin treated group compared to pneumonia control group of rats. Level of inflammatory cytokines was also found to be reduced in the blood of mollugin treated group than pneumonia control group. Moreover treatment with mollugin attenuates the altered expression of p-MAPK, p-JNK and p-ERK protein and mRNA expression of NF-κB in the lung tissues of Klebsiella pneumonia rat. In conclusion, data of the study reveals that treatment with mollugin ameliorates Klebsiella pneumonia rat by reducing the lung inflammation. Inflammation of lung tissue was reduced by regulating the NF-κB/MAPK signaling pathway in mollugin treated group.


Assuntos
Klebsiella pneumoniae/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Piranos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/microbiologia , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Infecções por Klebsiella/sangue , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/patogenicidade , Pulmão/metabolismo , Pulmão/patologia , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Pneumonia/microbiologia , Piranos/uso terapêutico , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
13.
Balkan Med J ; 36(4): 245-250, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31140237

RESUMO

Background: Nuclear factor-kB is highly activated in cardiovascular disorders. However, few articles have targeted at the role of nuclear factor-kB inhibitor in heart failure. Aims: To evaluate the effects of nuclear factor-kB inhibitor pyrrolidine dithiocarbamate on cardiocyte apoptosis and cardiac function in a rat heart failure model. Study Design: Animal experiment. Methods: A stable and reproducible rat heart failure model (n=64) was prepared by injecting homologous microthrombotic particles into the left ventricle of Sprague­Dawley rats while obstructing the ascending aorta to produce coronary microembolization. Rats with heart failure were randomized into untreated (HFu) and pyrrolidine dithiocarbamate-treated (HFp) groups; the latter received an intraperitoneal injection of pyrrolidine dithiocarbamate (100 mg/kg/day) 1 h prior to surgery as well as on postoperative days 1-7. The sham group comprised 32 Sprague­Dawley rats. Eight rats from each group were sacrificed on days 1, 3, 7, and 14 postoperatively. Masson's trichrome staining was used to determine the micro-fibrotic area to indicate the severity of myocardial loss. Terminal transferase uridine triphosphate nick end labeling staining was used to detect apoptotic cardiomyocytes. Echocardiography and hemodynamics were performed to evaluate left ventricular function. Results: Rats with heart failure exhibited pathological changes evidenced by patchy myocardial fibrosis, remarkably elevated severity of myocardial loss, and persistently reduced left ventricular function. At the end of the study, compared with the HFu group, myocardial infarct size was reduced by 28% (p=0.001), cardiocyte apoptosis was suppressed (7.17%±1.47% vs 2.83%±0.75%, p<0.001), cardiac function parameters such as left ventricular ejection fraction (80%±4% vs 61%±6%), left ventricular + dP/dt max (4828±289 vs 2918±76 mmHg.s−1), left ventricular - dP/dt max (4398±269 vs 2481±365 mmHg.s−1), and left ventricular systolic pressure (126±13 vs 100±10 mmHg) were significantly increased, and left ventricular end-diastolic pressure was reduced (18±2 vs 13±1 mmHg) (p<0.001, for all) in the HFu group. Conclusion: Our rat model can adequately mimic heart failure via coronary vessel embolization. Moreover, pyrrolidine dithiocarbamate treatment can reduce cardiocyte apoptosis and improve cardiac function, which may be beneficial for patients with heart failure secondary to myocardial infarction.


Assuntos
Apoptose/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , NF-kappa B/efeitos dos fármacos , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Animais , Apoptose/fisiologia , Modelos Animais de Doenças , Embolia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , NF-kappa B/análise , Pirrolidinas/metabolismo , Pirrolidinas/uso terapêutico , Ratos/genética , Ratos/metabolismo , Ratos Sprague-Dawley , Tiocarbamatos/metabolismo , Tiocarbamatos/uso terapêutico
14.
Med Sci Monit ; 25: 2567-2576, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30957795

RESUMO

BACKGROUND The aim of this study was to assess the effects and mechanisms of allicin in a sepsis-induced lung injury in vivo study. MATERIAL AND METHODS The rats (n=54) were divided into 6 groups: Normal, DMSO, LPS, LPS+LD, LPS+MD, and LPS+HD groups. After being treated by different methods, we collected the lung tissues of different groups and evaluated the pathology by HE staining and positive apoptosis cells by TUNEL. We assessed the W/D ratio, inflammatory cytokines (TNF-alpha, IL-6 and IL-1ß), and relative protein expressions (TLR4, MyD88, NF-kappaB, caspase-3, and caspase-9) by IHC assay. RESULTS Compared with LPS group, the lung injury and positive cell number of allicin treated groups were significantly improved with dose-dependent (P<0.05, respectively) and the W/D ratio and TNF-alpha, IL-6 and IL-1ß concentration were significantly down-regulation compared with those of LPS group with dose-dependent (P<0.05, respectively). By IHC, the TLR4, MyD88, NF-kappaB, caspase-3 and caspase-9 protein activities of allicin treated groups were significantly suppressed compared with those of LPS group (P<0.05, respectively) in lung tissues. CONCLUSIONS This in vivo study shows that allicin improved sepsis-induced lung injury by regulation of TLR4/MyD88/NF-kappaB.


Assuntos
Lesão Pulmonar/tratamento farmacológico , Ácidos Sulfínicos/metabolismo , Ácidos Sulfínicos/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Diferenciação Celular , Citocinas/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Lesão Pulmonar/metabolismo , Masculino , Fator 88 de Diferenciação Mieloide/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sepse/complicações , Sepse/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
15.
Med Sci Monit ; 25: 2852-2858, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30997898

RESUMO

BACKGROUND We examined the anticancer potential of anthecotulide against SK-MEL-24 malignant melanoma cells. The apoptotic and autophagic effects of anthecotulide were also investigated. MATERIAL AND METHODS The cell viability of SK-MEL-24 human malignant melanoma cells was evaluated by WST-1 assay. Fluorescence microscopy using acridine orange and ethidium bromide staining, as well as Western blot analysis, were used to study apoptotic effects induced by anthecotulide. Autophagy was assessed by Western blot analysis and fluorescence microscopy. Effects of anthecotulide on cell cycle progression were analyzed by flow cytometry. RESULTS The results revealed that anthecotulide exerts significant growth-inhibitory effects on SK-MEL-24 cells. The IC50 of anthecotulide against the SK-MEL-24 cells was found to be 10 µM. However, the anticancer effects against the normal cells were minimal (IC50; 100 µM). Investigation of the underlying mechanism revealed that anthecotulide prompts apoptotic cell death of the SK-MEL-24 cells, which was linked with increased expression of Bax and decreased expression of Bcl-2. It also triggered concentration-dependent activation of caspase 3 and 9. Anthecotulide induced autophagy in the SK-MEL-24 cells, which was associated with upregulation of LC3 II and Beclin-1 expression. Anthecotulide also halted the SK-MEL-24 cells at S-phase of the cell cycle and downregulated the expression of Cyclin B1. However, the expression of p27 was upregulated. CONCLUSIONS These results indicate anthecotulide is a potent lead molecule for the treatment of melanoma. In vivo and other related experiments are warranted to further assess this promising drug candidate.


Assuntos
Lactonas/farmacologia , Melanoma/tratamento farmacológico , Sesquiterpenos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Caspases/efeitos dos fármacos , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Melanoma/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Microb Pathog ; 132: 51-58, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31028862

RESUMO

Porcine Circovirus Type 2 (PCV2) is a pathogen that has the ability to cause devastating disease manifestations in pig populations with major economic implications. Our previous research found that Hsp90 is required for PCV2 production in PK-15 and 3D4/31 cells. The aim of this study was to evaluate the effect of Hsp90 inhibitor regulating PCV2 replication and to explore its underlying mechanism. In PK-15 and 3D4/31 cells treated with 17-AAG after viral adsorption, replication of PCV2 was attenuated as assessed by quantitating the expression of viral protein. Following NF-κB activation it was observed that 24hpi with PCV2 was significantly inhibited in the presence of 17-AAG. The expression of Hsp90 associated client proteins in PCV2-infected cells were also reduced in the presence of 17-AAG. However, treatment with MG-132 failed to rescue 17-AAG mediated reduction of PCV2 production in host cells. Thus, Hsp90 regulates PCV2 by modulating cellular signaling proteins. These results highlight the importance of cellular proteins during PCV2 infection and the possibility of targeting cellular chaperones for developing new anti-rotaviral strategies.


Assuntos
Benzoquinonas/antagonistas & inibidores , Circovirus/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/genética , Lactamas Macrocíclicas/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Benzoquinonas/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Infecções por Circoviridae/tratamento farmacológico , Infecções por Circoviridae/virologia , Proteínas de Choque Térmico HSP90/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Lactamas Macrocíclicas/química , Leupeptinas/antagonistas & inibidores , NF-kappa B/efeitos dos fármacos , Suínos , Doenças dos Suínos/virologia
17.
Phytother Res ; 33(5): 1562-1569, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30932261

RESUMO

In view of the recognized anti-tumor properties of eugenol against non-small cell lung cancer (NSCLC) in cell culture, here we further set out to investigate the potential therapeutic effect of eugenol in vivo and elucidate the underlying molecular mechanism. The relative expression levels of TRIM59 and p65 in NSCLC were quantified by real-time polymerase chain reaction. Xenograft tumor model was established with TRIM59-deficient H1975 cells, and tumor progression was monitored. Kaplan-Meier's analysis was performed to measure overall survival. Protein levels of TRIM59 and p65 in xenograft tumor were determined by western blot. Direct binding of p65 on the TRIM59 promoter was analyzed by chromatin immunoprecipitation assay, and the regulatory effect was interrogated with luciferase reporter assay. Both TRIM59 and p65 were up-regulated in NSCLC. Eugenol treatment significantly inhibited xenograft tumor progression and prolonged the overall survival of tumor-bearing mice. Mechanistically, eugenol suppressed p65 expression, which subsequently decreased TRIM59 expression. TRIM59 deficiency fully recapitulated the anti-tumoral phenotype elicited by eugenol. Ectopic expression of TRIM59 completely abolished the tumor suppressive effect of eugenol, which underlined the predominant role of TRIM59 in mediating the signaling downstream of eugenol treatment. Eugenol inhibited NSCLC via repression NF-κB-TRIM59 pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Eugenol/química , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Membrana/efeitos dos fármacos , Metaloproteínas/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Animais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , NF-kappa B/metabolismo , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Life Sci ; 226: 68-76, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928406

RESUMO

AIMS: Rheumatoid arthritis is usually accompanied by various comorbidities especially on the psychological side such as depression. This study aimed at revealing the potential curative effects of venlafaxine (VFX), a serotonin/norepinephrine reuptake inhibitor (SNRI), on experimentally-induced arthritis in rats. METHODS: Arthritis was induced by injecting complete Freund's adjuvant (CFA, 0.1 ml, s.c.). One day thereafter, VFX (50 mg/kg, p.o.) was given for 21 days. Methotrexate was used as a standard disease modifying anti-rheumatic drug. KEY FINDINGS: CFA injection caused prominent arthritis evident by the increase in the hind paw and ankle diameter accompanied by elevating tumor necrosis factor-alpha, interleukin-6, interleukin-17 and matrix metalloproteinase-3 levels, effects that were diminished by VFX. Moreover, VFX down regulated gene expressions of receptor activator of nuclear factor kappa-B (NF-кB) ligand and signal transducer and activator of transcription-3 beside hampering immunohistochemical expression of vascular endothelial growth factor and NF-кB. This SNRI also improved the oxidant status of the hind limb as compared to the arthritic group. Nonetheless, MTX was better in amendment of arthritis authenticated by its effect on some inflammatory and oxidative stress biomarkers. SIGNIFICANCE: This study provides a novel therapeutic use of VFX as a considerable anti-arthritic drug and offers an incentive to expand its use in RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Cloridrato de Venlafaxina/metabolismo , Cloridrato de Venlafaxina/farmacologia , Animais , Antirreumáticos , Artrite Experimental/metabolismo , Artrite Reumatoide , Biomarcadores , Modelos Animais de Doenças , Adjuvante de Freund/farmacologia , Interleucina-17/metabolismo , Interleucina-6 , Masculino , Metaloproteinase 3 da Matriz , Metotrexato/farmacologia , NF-kappa B/efeitos dos fármacos , Estresse Oxidativo , Ligante RANK/efeitos dos fármacos , Ligante RANK/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa
19.
Phytomedicine ; 58: 152864, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30878874

RESUMO

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory condition of the intestines and is difficult to cure once diagnosed. The efficacy of the current clinical treatment for UC is limited. Common anti-inflammatory drugs are prone to adverse effects, while novel biological agents are expensive, although tolerated by patients. Therefore, an urgency exists to find more safe and effective drugs to treat UC. Osthole is an active constituent isolated from the fruit of Cnidium monnieri (L.) Cuss. Osthole has anti-inflammatory activities and offers certain intestinal protection. These characteristics indicate that osthole has the potential to inhibit UC. PURPOSE: The study was conducted to investigate the anti-inflammatory potential of osthole in LPS-induced RAW 264.7 cells and dextran sulphate sodium (DSS)-induced ulcerative colitis in mice. METHODS: In in vitro experiments, mouse monocyte-macrophage RAW 264.7 cells were stimulated by 1 µg/ml LPS to produce inflammatory mediators. Griess reagent was used to determine Nitric Oxide (NO) production, and ELISA kits were used to determine the levels of PGE2, TNF-α, and IL-6. The anti-inflammatory mechanisms of osthole were detected using western blot. In in vivo experiments, UC was induced via the intragastric administration of 3.5% DSS to BALB/C mice for 7 days. During the experiment, clinical signs and body weight were monitored and recorded daily to calculate the DAI score. At the end of the experiment, the colon lengths were measured. The colonic histopathological lesions were evaluated. MPO activity and TNF-α levels were determined using the corresponding kits. The protein expression of TNF-α and NF-κB pathways were analysed using western blot. RESULTS: In an in vitro study, osthole inhibited the production of NO, PGE2, TNF-α, and IL-6 in LPS-induced RAW 264.7 cells. The results of western blot showed that osthole inhibited the expression of iNOS, COX-2, p38 MAPK and IκB α in RAW 264.7 cells. On this basis, in DSS-induced UC mice, it was found that osthole relieved the symptoms of UC by inhibiting weight loss, colon shortening and the DAI score, and simultaneously alleviating colon tissue lesions. It was also found that osthole reduced the levels of TNF-α in serum and colon tissues and effectively inhibited the activity of MPO. The western blot results showed that osthole reduced the expression of NF-κB p65 and p-IκB α and increased the content of IκB α in colon tissues. CONCLUSION: Osthole exerted anti-inflammatory effects by blocking the activation of the NF-κB and MAPK/p38 pathways. Additionally, osthole possesses therapeutic potential in the treatment of UC.


Assuntos
Anti-Inflamatórios/farmacologia , Cnidium/química , Colite Ulcerativa/tratamento farmacológico , Cumarínicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Colite Ulcerativa/patologia , Dinoprostona/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB C , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Fitoterapia ; 135: 15-21, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30923011

RESUMO

Rhododendron micranthum is used traditionally as a remedy for the treatment of chronic bronchitis in China. To clarify the chemical basis and provide a reference for the rational use of this medicinal plant, a phytochemical study was carried out on the twigs and leaves of R. micranthum, which afforded eight new compounds (1-8) and eight known compounds (9-16). Their structures were rigorously determined by comprehensive HRESIMS, NMR and electronic circular dichroism (ECD) analyses. The anti-inflammatory activities of these compounds were evaluated. Compounds 3, 13, and 14 suppressed the transcription of the NF-κB-dependent reporter gene in LPS-induced 293T/NF-κB-luc cells at 10 µM, while no effect on cell viability was observed.


Assuntos
Anti-Inflamatórios/química , Bronquite Crônica/tratamento farmacológico , Lignanas/química , Compostos Fitoquímicos/química , Rhododendron/química , Sesquiterpenos/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , China , Genes Reporter , Células HEK293 , Humanos , Lignanas/isolamento & purificação , Lignanas/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , NF-kappa B/efeitos dos fármacos , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Plantas Medicinais , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia
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