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1.
Chemosphere ; 282: 131133, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34470170

RESUMO

The rapid development of carbon nanotubes (CNTs) in the field of fish disease control and prevention raises concerns about the toxicity and safe use in fish. This study was performed to assess the effect on histological changes, oxidative stress related markers in response to various concentrations of amine-functionalized single carbon nanotubes (NH2 f-SWCNT) (1, 10 and 100 mg kg-1 fish) in Channel Catfish (Ietalurus Punetaus) for up to 10 days. Moreover, pro-inflammatory cytokine genes and apoptotic genes were analyzed to obtain a better understanding of molecular mechanism of NH2 f-SWCNT induced toxicity. As a result, intraperitoneal (i.p.) administration of NH2 f-SWCNT caused dose-dependent and time-dependent injuries in the sampled tissues. In comparison with the control groups, decrease of catalase (CAT) activity and superoxide dismutase (SOD), and increase of malondialdehyde (MDA) and lactin dehydrogenase (LDH) were observed in all treatments. Real-time PCR assay showed inflammatory response with dose-dependent increase of tumor necrosis factor alpha (TNFα) and transient increase of interleukin 1ß (IL-1ß) in the liver. NH2 f-SWCNT administration induced increase of p38 as well as caspase-3 in all treatments compared to the control groups, indicating the involvement of p38-MAPK cascade and caspase-3 cascade in liver cell apoptosis. Overall, we conclude that NH2 f-SWCNT exert effects by direct injury and indirectly oxidative stress, resulting in inflammation and apoptosis, which provides data for understanding of the biological mechanisms underlying the toxicity of CNTs in fish.


Assuntos
Ictaluridae , Nanotubos de Carbono , Aminas , Animais , Apoptose , Inflamação/induzido quimicamente , Nanotubos de Carbono/toxicidade , Estresse Oxidativo
2.
J Photochem Photobiol B ; 222: 112281, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34388640

RESUMO

Photobiomodulation (PBM) has been applied as a non-invasive technique for treating temporomandibular joint symptoms, especially on painful condition's relief, however the anti-inflammatory mechanism underlying the effect of PBM remains uncertain. This study aims to evaluate the mechanisms of action of PBM (808 nm) in a carrageenan-induced inflammation on temporomandibular joint (TMJ) of rats. In this study male Wistar rats were pre-treated with irradiation of a low-power diode laser for 15 s on TMJ (infra-red 808 nm, 100 mW, 50 J/cm2 and 1.5 J) 15 min prior an injection in the temporomandibular joint of carrageenan (100 µg/TMJ). 1 h after the TMJ treatments, the rats were terminally anesthetized for joint cavity wash and periarticular tissues collect. Samples analysis demonstrated that PBM inhibit leukocytes chemotaxis in the TMJ and significantly reduces amounts of TNF-α, IL-1ß and CINC-1. In addition, Western blotting analysis demonstrated that PBM significantly decreased the protein levels of P2X3 and P2X7 receptors in the periarticular tissues. On the other hand, PBM was able to increase protein level of IL-10 (anti-inflammatory cytokine). In summary, it is possible to suggest that PBM inhibit inflammatory chemotaxis, modulation the balance of the pro- and anti-inflammatory characteristics of inflammatory cells.


Assuntos
Inflamação/terapia , Lasers Semicondutores/uso terapêutico , Terapia com Luz de Baixa Intensidade , Articulação Temporomandibular/efeitos da radiação , Animais , Carragenina/toxicidade , Movimento Celular/efeitos da radiação , Regulação para Baixo/efeitos da radiação , ELISPOT , Inflamação/induzido quimicamente , Interleucina-10/análise , Leucócitos/citologia , Leucócitos/metabolismo , Masculino , Ratos , Ratos Wistar , Receptores Purinérgicos P2X3/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Articulação Temporomandibular/metabolismo , Articulação Temporomandibular/patologia , Fator de Necrose Tumoral alfa/análise
3.
Braz J Med Biol Res ; 54(11): e11215, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34431873

RESUMO

This study investigated the acute blockade of endogenous melatonin (MLT) using Luzindole with or without systemic lipopolysaccharide (LPS) challenge and evaluated changes in inflammatory and oxidative stress markers in the mouse jejunum. Luzindole is an MT1/MT2 MLT receptor antagonist. Both receptors occur in the small intestine. Swiss mice were treated with either saline (0.35 mg/kg, ip), Luzindole (0.35 mg/kg, ip), LPS (1.25 mg/kg, ip), or Luzindole+LPS (0.35 and 1.25 mg/kg, ip, respectively). Jejunum samples were evaluated regarding intestinal morphometry, histopathological crypt scoring, and PAS-positive villus goblet cell counting. Inflammatory Iba-1, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, nuclear factor (NF)-kB, myeloperoxidase (MPO), and oxidative stress (NP-SHs, catalase, MDA, nitrate/nitrite) markers were assessed. Mice treated with Luzindole, LPS, and Luzindole+LPS showed villus height shortening. Crypt damage was worse in the LPS group. Luzindole, LPS, and Luzindole+LPS reduced the PAS-goblet cell labeling and increased Iba-1-immunolabelled cells compared to the saline group. Immunoblotting for IL-1ß, TNF-α, and NF-kB was greater in the Luzindole group. The LPS-challenged group showed higher MPO activity than the saline and Luzindole groups. Catalase was reduced in the Luzindole and Luzindole+LPS groups compared to saline. The Luzindole group showed an increase in NP-SHs, an effect related to compensatory GSH activity. The acute blockade of endogenous MLT with Luzindole induced early changes in inflammatory markers with altered intestinal morphology. The other non-detectable deleterious effects of Luzindole may be balanced by the unopposed direct action of MLT in immune cells bypassing the MT1/MT2 receptors.


Assuntos
Lipopolissacarídeos , Melatonina , Animais , Inflamação/induzido quimicamente , Jejuno , Camundongos , Triptaminas
4.
Int J Mol Sci ; 22(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34360675

RESUMO

In recent decades, interest in natural compounds has increased exponentially due to their numerous beneficial properties in the treatment of various acute and chronic diseases. A group of plant derivatives with great scientific interest is terpenic compounds. Among the plants richest in terpenes, the genus Ferula L. is one of the most representative, and ferutinin, the most common sesquiterpene, is extracted from the leaves, rhizome, and roots of this plant. As reported in the scientific literature, ferutinin possesses antioxidant and anti-inflammatory properties, as well as valuable estrogenic properties. Neurodegenerative and demyelinating diseases are devastating conditions for which a definite cure has not yet been established. The mechanisms involved in these diseases are still poorly understood, and oxidative stress is considered to be both a key modulator and a common denominator. In the proposed experimental system, co-cultured human neurons (SH-SY5Y) and human oligodendrocytes (MO3.13) were treated with the pro-inflammatory agent lipopolysaccharide at a concentration of 1 µg/mL for 24 h or pretreated with ferutinin (33 nM) for 24 h and subsequently exposed to lipopolysaccharide 1 µg/mL for 24 h. Further studies would, however, be needed to establish whether this natural compound can be used as a support strategy in pathologies characterized by progressive inflammation and oxidative stress phenomena.


Assuntos
Benzoatos/farmacologia , Cicloeptanos/farmacologia , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Neurônios/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Estresse Oxidativo , Sesquiterpenos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Técnicas de Cocultura , Escherichia coli , Humanos , Inflamação/induzido quimicamente , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Substâncias Protetoras/farmacologia
5.
Ecotoxicol Environ Saf ; 223: 112617, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34385058

RESUMO

PM2.5 is recently identified as a kind of material possessing severe biohazard. It can enter human body and exerts pathological effects on lung, eyes, and the central nervous system (CNS). Maternal exposure to PM2.5 can affect neural development and cause cognitive decline in offspring, with the underlying mechanisms unclear, however. The inflammasome monitors and responds to biological stressors, with HMGB1-NLRP3 inflammatory axis as an essential pathophysiological player outside the brain. The present work is to investigate its role in cognitive impairment induced by gestational exposure to PM2.5 in mice offspring. We found that HMGB1-NLRP3 pathway was activated in the hippocampus of mice offspring by gestational exposure to PM2.5 in a dose-dependent manner, with protein levels of HMGB1, NLRP3, and cleaved caspase-1 as approximately three times as high as those of control. And down-regulating HMGB1 during pregnancy could alleviate the resultant impairment on learning and working memory as well as hippocampal neurons, up-regulate the synapse related proteins of SYP and PSD-95 and correct the increased expression of 5-HT2A to comparable levels to control, as well as inhibiting the activation of microglia and decreasing the expression of HMGB1 and Iba1/HMGB1 double positive cells in the hippocampus of mice offspring. Meanwhile, protein levels of NLRP3, cleaved caspase-1, IL-1ß and IL-18, as well as TLR4, phosphorylated NF-κB, and MAPKs, were almost down-regulated to those of control. Therefore, HMGB1 intervention inhibits the NLRP3 inflammasome mediated hippocampal inflammatory response through TLR4/MAPKs/NF-κB signaling pathway, alleviating PM2.5-induced cognitive dysfunction. Further in vitro results suggest that PM2.5 can activate microglia and HMGB1-NLRP3 inflammatory axis. Pretreatment with HMGB1 inhibitor significantly reduced the phosphorylation of MAPKs and NF-κB, and inhibited the inflammatory response mediated by NLRP3 inflammasome similarly to those in vivo. These results suggest that PM2.5 exposure promotes the inflammatory response in hippocampus mediated by HMGB1-NLRP3 inflammatory axis in microglia, resulting in cognitive dysfunction in offspring, which could be alleviated by simultaneous HMGB1 suppression. These findings provide a theoretical basis for preventing cognitive impairment in offspring caused by environmental pollution during pregnancy.


Assuntos
Disfunção Cognitiva , Proteína HMGB1 , Animais , Disfunção Cognitiva/induzido quimicamente , Feminino , Proteína HMGB1/metabolismo , Hipocampo/metabolismo , Humanos , Inflamação/induzido quimicamente , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Material Particulado/toxicidade , Gravidez
6.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445223

RESUMO

Increasing evidence suggests that systemic inflammation triggers a neuroinflammatory response that involves sustained microglia activation. This response has deleterious consequences on memory and learning capability in experimental animal models and in patients. However, the mechanisms connecting systemic inflammation and microglia activation remain poorly understood. Here, we identify the autotaxin (ATX)/lysophosphatidic acid (LPA)/LPA-receptor axis as a potential pharmacological target to modulate the LPS-mediated neuroinflammatory response in vitro (the murine BV-2 microglia cell line) and in vivo (C57BL/6J mice receiving a single i.p. LPS injection). In LPS-stimulated (20 ng/mL) BV-2 cells, we observed increased phosphorylation of transcription factors (STAT1, p65, and c-Jun) that are known to induce a proinflammatory microglia phenotype. LPS upregulated ATX, TLR4, and COX2 expression, amplified NO production, increased neurotoxicity of microglia conditioned medium, and augmented cyto-/chemokine concentrations in the cellular supernatants. PF8380 (a type I ATX inhibitor, used at 10 and 1 µM) and AS2717638 (an LPA5 antagonist, used at 1 and 0.1 µM) attenuated these proinflammatory responses, at non-toxic concentrations, in BV-2 cells. In vivo, we demonstrate accumulation of PF8380 in the mouse brain and an accompanying decrease in LPA concentrations. In vivo, co-injection of LPS (5 mg/kg body weight) and PF8380 (30 mg/kg body weight), or LPS/AS2717638 (10 mg/kg body weight), significantly attenuated LPS-induced iNOS, TNFα, IL-1ß, IL-6, and CXCL2 mRNA expression in the mouse brain. On the protein level, PF8380 and AS2717638 significantly reduced TLR4, Iba1, GFAP and COX2 expression, as compared to LPS-only injected animals. In terms of the communication between systemic inflammation and neuroinflammation, both inhibitors significantly attenuated LPS-mediated systemic TNFα and IL-6 synthesis, while IL-1ß was only reduced by PF8380. Inhibition of ATX and LPA5 may thus provide an opportunity to protect the brain from the toxic effects that are provoked by systemic endotoxemia.


Assuntos
Benzoxazóis/farmacologia , Encéfalo/metabolismo , Endotoxemia , Isoquinolinas/farmacologia , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Piperazinas/farmacologia , Piperidinas/farmacologia , Receptores de Ácidos Lisofosfatídicos , Animais , Encéfalo/patologia , Linhagem Celular , Modelos Animais de Doenças , Endotoxemia/induzido quimicamente , Endotoxemia/metabolismo , Endotoxemia/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Microglia/patologia , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/metabolismo
7.
FASEB J ; 35(9): e21870, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34436790

RESUMO

COVID-19 is often characterized by dysregulated inflammatory and immune responses. It has been shown that the Traditional Chinese Medicine formulation Qing-Fei-Pai-Du decoction (QFPDD) is effective in the treatment of the disease, especially for patients in the early stage. Our network pharmacology analyses indicated that many inflammation and immune-related molecules were the targets of the active components of QFPDD, which propelled us to examine the effects of the decoction on inflammation. We found in the present study that QFPDD effectively alleviated dextran sulfate sodium-induced intestinal inflammation in mice. It inhibited the production of pro-inflammatory cytokines IL-6 and TNFα, and promoted the expression of anti-inflammatory cytokine IL-10 by macrophagic cells. Further investigations found that QFPDD and one of its active components wogonoside markedly reduced LPS-stimulated phosphorylation of transcription factor ATF2, an important regulator of multiple cytokines expression. Our data revealed that both QFPDD and wogonoside decreased the half-life of ATF2 and promoted its proteasomal degradation. Of note, QFPDD and wogonoside down-regulated deubiquitinating enzyme USP14 along with inducing ATF2 degradation. Inhibition of USP14 with the small molecular inhibitor IU1 also led to the decrease of ATF2 in the cells, indicating that QFPDD and wogonoside may act through regulating USP14 to promote ATF2 degradation. To further assess the importance of ubiquitination in regulating ATF2, we generated mice that were intestinal-specific KLHL5 deficiency, a CUL3-interacting protein participating in substrate recognition of E3s. In these mice, QFPDD mitigated inflammatory reaction in the spleen, but not intestinal inflammation, suggesting CUL3-KLHL5 may function as an E3 for ATF2 degradation.


Assuntos
Fator 2 Ativador da Transcrição/metabolismo , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/farmacologia , Glucosídeos/farmacologia , Inflamação/tratamento farmacológico , Proteólise/efeitos dos fármacos , Ubiquitina Tiolesterase/deficiência , Animais , Linhagem Celular , Colite/induzido quimicamente , Colite/tratamento farmacológico , Proteínas Culina/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Sulfato de Dextrana/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Flavanonas/uso terapêutico , Glucosídeos/uso terapêutico , Inflamação/induzido quimicamente , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirróis/farmacologia , Pirrolidinas/farmacologia , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitinação
8.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360708

RESUMO

BACKGROUND: exposure to environmental contaminants has been linked to an increased risk of neurological diseases and poor outcomes. Chemical name of Atrazine (ATR) is 6-chloro-N-ethyl-N'-(1-methylethyl)-1,3,5-triazine-2,4-diamine, and it is the most commonly used broad-spectrum herbicide in agricultural crops. Several studies have demonstrated that ATR has the potential to be harmful to the brain's neuronal circuits. Until today nobody has explored the effect of ATR inhalation on young and aged mice. METHODS: young and aged mice were subject to 25 mg of ATR in a vehicle made with saline and 10% of Dimethyl sulfoxide (DMSO) every day for 28 days. At the end of experiment different behavioral test were made and brain was collected. RESULTS: exposure to ATR induced the same response in terms of behavioral alterations and motor and memory impairment in mice but in aged group was more marked. Additionally, in both young and aged mice ATR inhalations induced oxidative stress with impairment in physiological antioxidant response, lipid peroxidation, nuclear factor kappa-light-chain-enhancer of activated B cells (nf-κb) pathways activation with consequences of pro-inflammatory cytokines release and apoptosis. However, the older group was shown to be more sensitive to ATR inhalation. CONCLUSIONS: our results showed that aged mice were more susceptible compared to young mice to air pollutants exposure, put in place a minor physiologically response was seen when exposed to it.


Assuntos
Envelhecimento/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Atrazina/efeitos adversos , Encéfalo/metabolismo , Administração por Inalação , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Atrazina/farmacologia , Encéfalo/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos
9.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445540

RESUMO

Exposure to hydrochloric acid (HCl) represents a threat to public health. Children may inhale higher doses and develop greater injury because of their smaller airways and faster respiratory rate. We have developed a mouse model of pediatric exposure to HCl by intratracheally instilling p24 mice (mice 24 days old; 8-10 g) with 2 µL/g 0.1 N HCl, and compared the profile of lung injury to that in HCl-instilled adults (10 weeks old; 25-30 g) and their age-matched saline controls. After 30 days, alveolar inflammation was observed with increased proteinosis and mononuclear cells in the bronchoalveolar lavage fluid (BALF) in both HCl-instilled groups. Young p24 animals-but not adults-exhibited higher NLR family pyrin domain containing 3 (NLRP3) inflammasome levels. Increased amounts of Transforming Growth Factor-ß (TGF-ß) mRNA and its intracellular canonical and non-canonical pathways (p-Smad2 and p-ERK) were found in the lungs of both young and adult HCl-instilled mice. Constitutive age-related differences were observed in the levels of heat shock protein family (HSP70 and HSP90). HCl equally provoked the deposition of collagen and fibronectin; however, significant age-dependent differences were observed in the increase in elastin and tenascin C mRNA. HCl induced pulmonary fibrosis with an increased Ashcroft score, which was higher in adults, and a reduction in alveolar Mean Alveolar Linear Intercept (MALI). Young mice developed increased Newtonian resistance (Rn) and lower PV loops, while adults showed a higher respiratory system resistance and elastance. This data indicate that young p24 mice can suffer long-term complications from a single exposure to HCl, and can develop chronic lung injury characterized by a stronger persistent inflammation and lesser fibrotic pattern, mostly in the airways, differently from adults. Further data are required to characterize HCl time- and dose-dependent injury in young animals and to identify new key-molecular targets.


Assuntos
Lesão Pulmonar Aguda/patologia , Envelhecimento , Líquido da Lavagem Broncoalveolar/química , Ácido Clorídrico/toxicidade , Inflamação/patologia , Fibrose Pulmonar/patologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente
10.
Oxid Med Cell Longev ; 2021: 5520644, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457115

RESUMO

Age-related macular degeneration (AMD) is a common and severe blinding disease among people worldwide. Retinal inflammation and neovascularization are two fundamental pathological processes in AMD. Recent studies showed that P2X7 receptor was closely involved in the inflammatory response. Here, we aim to investigate whether A740003, a P2X7 receptor antagonist, could prevent retinal inflammation and neovascularization induced by oxidized low-density lipoprotein (ox-LDL) and explore the underlying mechanisms. ARPE-19 cells and C57BL/6 mice were treated with ox-LDL and A740003 successively for in vitro and in vivo studies. In this research, we found that A740003 suppressed reactive oxygen species (ROS) generation and inhibited the activation of Nod-like receptor pyrin-domain protein 3 (NLRP3) inflammasome and nuclear factor-κB (NF-κB) pathway. A740003 also inhibited the generation of angiogenic factors in ARPE-19 cells and angiogenesis in mice. The inflammatory cytokines and phosphorylation of inhibitor of nuclear factor-κB alpha (IKBα) were repressed by A740003. Besides, ERG assessment showed that retinal functions were remarkably preserved in A740003-treated mice. In summary, our results revealed that the P2X7 receptor antagonist reduced retinal inflammation and neovascularization and protected retinal function. The protective effects were associated with regulation of NLRP3 inflammasome and the NF-κB pathway, as well as inhibition of angiogenic factors.


Assuntos
Inflamação/tratamento farmacológico , Lipoproteínas LDL/toxicidade , Neovascularização Patológica/tratamento farmacológico , Estresse Oxidativo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/química , Retinite/tratamento farmacológico , Animais , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Espécies Reativas de Oxigênio/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Retinite/induzido quimicamente , Retinite/metabolismo , Retinite/patologia , Transdução de Sinais
11.
Oxid Med Cell Longev ; 2021: 9932099, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457120

RESUMO

Oxidative stress, inflammation, and apoptosis are crucial in the pathogenesis of acute liver failure (ALF). 4-Octyl itaconate (OI) showed antioxidative and anti-inflammatory properties in many disease models. However, its role in lipopolysaccharide- (LPS-)/D-galactosamine- (D-GalN-) induced ALF is still not investigated. Here, we established an ALF murine model induced by LPS/D-GalN administration. And we found that OI improved survival rate in the murine ALF model. Our results also showed that OI alleviated LPS/D-GalN-induced hepatic histopathological injury and reduced the serum activities of alanine transaminase and aspartate transaminase. Moreover, OI reduced serum levels of proinflammatory cytokines such as monocyte chemotactic protein-1, tumor necrosis factors-α, and interlukin-6. Additionally, OI mitigated oxidative stress and alleviated lipid peroxidation in a murine model of ALF. This was evaluated by a reduction of thiobarbituric acid reactive substances (TBARS) in liver tissues. In addition, OI increased the ratio of reduced glutathione/oxidized glutathione and the activities of antioxidant enzymes including catalase and superoxide dismutase. Moreover, the apoptosis of hepatocytes in the liver was inhibited by OI. Furthermore, we found that OI inhibited LPS-induced nuclear translocation and activation of factor-kappa B (NF-κB) p65 in macrophages which could be inhibited by OI-induced activation of nuclear factor erythroid-2-related factor (Nrf2) signaling. Additionally, D-GalN-induced reactive oxygen species (ROS) generation and apoptosis in hepatocytes were inhibited by OI-induced activation of Nrf2 signaling. Therefore, the underlying mechanism for OI's protective effect in LPS/D-GalN-induced ALF may be associated with deactivation of NF-κB signaling in macrophages to reduce inflammation and inhibition of ROS-related hepatocyte apoptosis by activating Nrf2. In conclusion, OI showed a protective role in LPS/D-GalN-induced ALF by reducing inflammation, enhancing antioxidant capacity, and inhibiting cell apoptosis.


Assuntos
Apoptose , Galactosamina/toxicidade , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda/tratamento farmacológico , Estresse Oxidativo , Succinatos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais
12.
Life Sci ; 283: 119852, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34332979

RESUMO

Nonalcoholic fatty liver disease (NAFLD) occurs due to lipid metabolic disorders, which is associated with hepatic oxidative stress and inflammation. There is no definitive drug treatment for this disease. Accordingly, the present study aimed to evaluate the effects of dimethyl fumarate (DMF) as one of the superior effective drugs that induces a transcription factor of nuclear factor erythroid 2-related factor 2 (Nrf2) on development of NAFLD in mice. The metabolic disturbance in High-fat diet (HFD)-treated animals was associated with hyperlipidemia, increased activity levels of hepatic enzymes in serum, hyperglycemia, hyperinsulinemia, oxidative stress and inflammation. DMF supplementation had anti-inflammatory, antioxidant, anti-lipogenic and molecular compatibility effects induced by HFD in mice. In comparison to the HFD group, the DMF therapy could significantly suppress the sterol regulatory element binding protein-1 c (SREBP-1c) gene and protein levels, as well as upregulate the Nrf2 gene and protein levels. Additionally, the anti-inflammatory activity was observed for the DMF by inhibiting the nuclear factor kappa B (NF-κB) level. DMF reduces the development of NAFLD induced by HFD in mice through the modulation of transcription factors Nrf2, SREBP-1c and NF-κB. Thus, DMF can be considered as an effective candidate in the treatment of human NAFLD.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fumarato de Dimetilo/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
13.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445767

RESUMO

The c-Jun N-terminal kinases (JNKs) are implicated in many neuropathological conditions, including neurodegenerative diseases. To explore potential JNK3 inhibitors from the U.S. Food and Drug Administration-approved drug library, we performed structure-based virtual screening and identified azelastine (Aze) as one of the candidates. NMR spectroscopy indicated its direct binding to the ATP-binding site of JNK3, validating our observations. Although the antihistamine effect of Aze is well documented, the involvement of the JNK pathway in its action remains to be elucidated. This study investigated the effects of Aze on lipopolysaccharide (LPS)-induced JNK phosphorylation, pro-inflammatory mediators, and cell migration in BV2 microglial cells. Aze was found to inhibit the LPS-induced phosphorylation of JNK and c-Jun. It also inhibited the LPS-induced production of pro-inflammatory mediators, including interleukin-6, tumor necrosis factor-α, and nitric oxide. Wound healing and transwell migration assays indicated that Aze attenuated LPS-induced BV2 cell migration. Furthermore, Aze inhibited LPS-induced IκB phosphorylation, thereby suppressing nuclear translocation of NF-κB. Collectively, our data demonstrate that Aze exerts anti-inflammatory and anti-migratory effects through inhibition of the JNK/NF-κB pathway in BV2 cells. Based on our findings, Aze may be a potential candidate for drug repurposing to mitigate neuroinflammation in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Movimento Celular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Ftalazinas/farmacologia , Animais , Linhagem Celular , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
14.
Part Fibre Toxicol ; 18(1): 29, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34353337

RESUMO

BACKGROUND: An important aspect of nanomaterial (NM) risk assessment is establishing relationships between physicochemical properties and key events governing the toxicological pathway leading to adverse outcomes. The difficulty of NM grouping can be simplified if the most toxicologically relevant dose metric is used to assess the toxicological dose-response. Here, we thoroughly investigated the relationship between acute and chronic inflammation (based on polymorphonuclear neutrophil influx (% PMN) in lung bronchoalveolar lavage) and the retained surface area in the lung. Inhalation studies were performed in rats with three classes of NMs: titanium dioxides (TiO2) and carbon blacks (CB) as poorly soluble particles of low toxicity (PSLT), and multiwall carbon nanotubes (MWCNTs). We compared our results to published data from nearly 30 rigorously selected articles. RESULTS: This analysis combined data specially generated for this work on three benchmark materials - TiO2 P25, the CB Printex-90 and the MWCNT MWNT-7 - following subacute (4-week) inhalation with published data relating to acute (1-week) to subchronic (13-week) inhalation exposure to the classes of NMs considered. Short and long post-exposure recovery times (immediately after exposure up to more than 6 months) allowed us to examine both acute and chronic inflammation. A dose-response relationship across short-term and long-term studies was revealed linking pulmonary retained surface area dose (measured or estimated) and % PMN. This relationship takes the form of sigmoid curves, and is independent of the post-exposure time. Curve fitting equations depended on the class of NM considered, and sometimes on the duration of exposure. Based on retained surface area, long and thick MWCNTs (few hundred nm long with an aspect ratio greater than 25) had a higher inflammatory potency with 5 cm2/g lung sufficient to trigger an inflammatory response (at 6% PMN), whereas retained surfaces greater than 150 cm2/g lung were required for PSLT. CONCLUSIONS: Retained surface area is a useful metric for hazard grouping purposes. This metric would apply to both micrometric and nanometric materials, and could obviate the need for direct measurement in the lung. Indeed, it could alternatively be estimated from dosimetry models using the aerosol parameters (rigorously determined following a well-defined aerosol characterization strategy).


Assuntos
Nanoestruturas , Nanotubos de Carbono , Administração por Inalação , Animais , Líquido da Lavagem Broncoalveolar , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Exposição por Inalação/efeitos adversos , Pulmão , Nanoestruturas/toxicidade , Nanotubos de Carbono/toxicidade , Tamanho da Partícula , Ratos
15.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361111

RESUMO

Maternal smoking is a risk factor of preterm prelabor rupture of the fetal membranes (pPROM), which is responsible for 30% of preterm births worldwide. Cigarettes induce oxidative stress and inflammation, mechanisms both implicated in fetal membranes (FM) weakening. We hypothesized that the receptor for advanced glycation end-products (RAGE) and its ligands can result in cigarette-dependent inflammation. FM explants and amniotic epithelial cells (AECs) were treated with cigarette smoke condensate (CSC), combined or not with RAGE antagonist peptide (RAP), an inhibitor of RAGE. Cell suffering was evaluated by measuring lactate dehydrogenase (LDH) medium-release. Extracellular HMGB1 (a RAGE ligand) release by amnion and choriodecidua explants were checked by western blot. NF-κB pathway induction was determined by a luciferase gene reporter assay, and inflammation was evaluated by cytokine RT-qPCR and protein quantification. Gelatinase activity was assessed using a specific assay. CSC induced cell suffering and HMGB1 secretion only in the amnion, which is directly associated with a RAGE-dependent response. CSC also affected AECs by inducing inflammation (cytokine release and NFκB activation) and gelatinase activity through RAGE engagement, which was linked to an increase in extracellular matrix degradation. This RAGE dependent CSC-induced inflammation associated with an increase of gelatinase activity could explain a pathological FM weakening directly linked to pPROM.


Assuntos
Âmnio/patologia , Células Epiteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Fumaça/efeitos adversos , Adulto , Âmnio/efeitos dos fármacos , Âmnio/imunologia , Âmnio/metabolismo , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptor para Produtos Finais de Glicação Avançada
16.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209324

RESUMO

Asthma oxidative stress disturbances seem to enable supplementary proinflammatory pathways, thus contributing to disease development and severity. The current study analyzed the impact of two types of oral vitamin D (VD) supplementation regimens on the redox balance using a murine model of acute ovalbumin-induced (OVA-induced) asthmatic inflammation. The experimental prevention group received a long-term daily dose of 50 µg/kg (total dose of 1300 µg/kg), whereas the rescue group underwent a short-term daily dose of 100 µg/kg (total dose of 400 µg/kg). The following oxidative stress parameters were analyzed in serum, bronchoalveolar lavage fluid (BALF) and lung tissue homogenate (LTH): total oxidative status, total antioxidant response, oxidative stress index, malondialdehyde and total thiols. Results showed that VD significantly reduced oxidative forces and increased the antioxidant capacity in the serum and LTH of treated mice. There was no statistically significant difference between the two types of VD supplementation. VD also exhibited an anti-inflammatory effect in all treated mice, reducing nitric oxide formation in serum and the expression of nuclear factor kappa B p65 in the lung. In conclusion, VD supplementation seems to exhibit a protective role in oxidative stress processes related to OVA-induced acute airway inflammation.


Assuntos
Asma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Vitamina D/farmacologia , Animais , Asma/induzido quimicamente , Asma/metabolismo , Asma/patologia , Modelos Animais de Doenças , Feminino , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade
17.
Pain Res Manag ; 2021: 4919391, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239653

RESUMO

Objective: Inflammation and pain are involved in the pathophysiology of various clinical conditions. This investigation aims to probe the analgesic and anti-inflammatory activity of Maltoamide F. Methods: The possible toxicity of Maltoamide F was evaluated by an acute toxicity test. To assess the anti-inflammatory and antinociceptive effects of Maltoamide F on rats, the models of carrageenan-caused paw edema, xylene-induced ear edema, arachidonic-acid- (AA-) induced ear edema, formalin-caused plantar edema, and cotton-pellet-induced granuloma were established. Levels of TNF-α, PGE-2, and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA). Results: Maltoamide F was safe at oral doses of 1-10 mg/kg for rats. Maltoamide F (1 mg/kg, 5 mg/kg, and 10 mg/kg) notably reduced carrageenan-induced edema percentage of paws in rats and decreased levels of PGE-2, IL-6, and TNF-α in homogenates of foot tissues. Maltoamide F (1 mg/kg, 5 mg/kg, and 10 mg/kg) reduced levels of PGE-2, IL-6, and TNF-α in foot tissues of formalin-induced rats. Maltoamide F (1 mg/kg, 5 mg/kg, and 10 mg/kg) repressed AA-induced increase of ear thickness in rats and reduced levels of PGE-2, IL-6, and TNF-α in homogenates of ear tissues. Maltoamide F (1 mg/kg, 5 mg/kg, and 10 mg/kg) reduced xylene-induced weight of ear edema in rats and reduced levels of PGE-2, IL-6, and TNF-α in homogenates of ear tissues. Maltoamide F (1 mg/kg, 5 mg/kg, and 10 mg/kg) reduced levels of PGE-2, IL-6, and TNF-α in homogenates of cotton ball granuloma of cotton-pellet-induced rats. Conclusions: Maltoamide F possessed anti-inflammatory and analgesic activity in inflammatory models of rats.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Cicloexanonas/farmacologia , Ácidos Graxos Monoinsaturados/farmacologia , Inflamação/tratamento farmacológico , Animais , Inflamação/induzido quimicamente , Masculino , Manejo da Dor/estatística & dados numéricos , Ratos , Ratos Sprague-Dawley
18.
Life Sci ; 282: 119827, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34273373

RESUMO

AIMS: We aimed to investigate the effect of PBDEs (47, 99, 209) on cellular events involved in epigenetic modification, inflammation, and epithelial mesenchymal transition (EMT). MATERIALS AND METHODS: We studied: 1) ERK1/2 phosphorylation; 2) Enhancer of Zester Homolog 2 (EZH2); 3) Histone H3 tri-methylated in lysine 27 (H3K27me3); 4) K-RAS; 5) silencing disabled homolog 2-interacting protein gene (DAB2IP), 6) let-7a; 7) Muc5AC/Muc5B, and 8) IL-8 in a 3D in vitro model of epithelium obtained with primary Normal Human Bronchial Epithelial cells (pNHBEs) or A549 cell line, chronically exposed to PBDEs (47, 99, 209). KEY FINDINGS: PBDEs (10 nM, 100 nM and 1 µM) increased ERK1/2 phosphorylation, and EZH2, H3K27me3, and K-RAS protein expression, while decreased DAB2IP and Let-7a transcripts in pNHBEs ALI culture. Furthermore PBDEs (47, 99) (100 nM) increased Muc5AC and Muc5B mRNA, and PBDE 47 (100 nM) IL-8 mRNA via EZH2 in pNHBEs. Finally, PBDEs (100 nM) affected EZH2, H3K27me3, K-RAS protein expression, and DAB2IP, Let-7a transcripts and cell invasion in A549 cells. Gsk343 (methyltransferase EZH2 inhibitor) (1 mM) and U0126 (inhibitor of MEK1/2) (10 µM) were used to show the specific effect of PBDEs. SIGNIFICANCE: PBDE inhalation might promote inflammation/cancer via EZH2 methyltransferase activity and H3K27me3, k-RAS and ERk1/2 involvement, generating adverse health outcomes of the human lung.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Células Epiteliais , Retardadores de Chama/administração & dosagem , Éteres Difenil Halogenados/efeitos adversos , Neoplasias Pulmonares , Proteínas de Neoplasias/metabolismo , Mucosa Respiratória , Células A549 , Idoso , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Feminino , Retardadores de Chama/farmacologia , Éteres Difenil Halogenados/farmacologia , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mucosa Respiratória/enzimologia , Mucosa Respiratória/patologia
19.
Am J Physiol Lung Cell Mol Physiol ; 321(3): L533-L544, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34231388

RESUMO

Store-operated calcium entry (SOCE) is involved in the pathogenesis of airway inflammation and remodeling in asthma. Store-operated calcium entry-associated regulatory factor (SARAF) can downregulate SOCE. We sought to investigate the role of SARAF in the regulation of airway inflammation and remodeling in asthma mice models, as well as in the functional regulation of human airway smooth muscle cells (hASMCs). Balb/c mice were sensitized and challenged with ovalbumin to establish the asthma mice models. Mice were transfected with lentivirus, which expressed the SARAF gene + GFP (green fluorescence protein) or the negative control gene + GFP. Airway resistance was measured with the animal pulmonary function system. Airway inflammation and remodeling were evaluated via histological staining. In vitro cultured hASMCs were transfected with scrambled small interfering RNA (siRNA) or SARAF-specific siRNA, respectively. The proliferation, migration rate, hypertrophy, and SOCE activity of hASMCs were examined with Cell Counting Kit-8, wound healing test, bright field imaging, and Ca2+ fluorescence imaging, respectively. SARAF expression was measured by quantitative real-time PCR. Asthma mice models showed decreased SARAF mRNA expression in the lungs. SARAF overexpression attenuated airway inflammation, resistance, and also remodeling. Downregulation of SARAF expression with siRNA promoted the proliferation, migration, hypertrophy, and SOCE activity in hASMCs. SARAF plays a protective role against airway inflammation and remodeling in asthma mice models by blunting SOCE; SARAF may also be a functional regulating factor of hASMCs.


Assuntos
Remodelação das Vias Aéreas/imunologia , Asma/imunologia , Proteínas de Ligação ao Cálcio/imunologia , Regulação da Expressão Gênica/imunologia , Pulmão/imunologia , Proteínas de Membrana/imunologia , Miócitos de Músculo Liso/imunologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Remodelação das Vias Aéreas/genética , Resistência das Vias Respiratórias/efeitos dos fármacos , Resistência das Vias Respiratórias/genética , Resistência das Vias Respiratórias/imunologia , Animais , Asma/induzido quimicamente , Asma/genética , Proteínas de Ligação ao Cálcio/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Pulmão/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Miócitos de Músculo Liso/patologia
20.
Medicina (Kaunas) ; 57(6)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201357

RESUMO

Background and Objectives: Bromelain is a mixture of protease obtained from pineapple fruits or stems. Even though the biological mechanism of action of bromelain has not been completely understood, it is well known that bromelain possesses anticancer, anti-inflammatory and immunomodulatory effects. This study investigated the anti-inflammatory effects of bromelain on lipopolysaccharide (LPS)-induced human dental pulp cells (hDPCs). Materials and Methods: Cell viability after bromelain treatment was measured using WST-1 assay. We exposed hDPCs to 5 µg/mL of LPS with 2.5 or 5 µg/mL of bromelain. We performed reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay to detect interleukin-1ß, interleukin-6, and interleukin-8 levels. Western blots were used to detect intercellular adhesion molecules-1 (ICAM-1) and vascular cell adhesion molecules-1 (VCAM-1) levels. Immunofluorescence staining and Western blots were used to determine bromelain's anti-inflammatory mechanism. We also performed alkaline phosphatase and Alizarin red staining to verify mineralization nodule formation. Results: Bromelain at 2.5, 5, 10, or 20 µg/mL did not affect the viability of hDPCs significantly. LPS increased interleukin-1ß, interleukin-6, interleukin-8, ICAM-1 and VCAM-1 expression in hDPCs. Bromelain significantly decreased interleukin-1ß, interleukin-6, interleukin-8, ICAM-1, and VCAM-1 levels in hDPCs, which were stimulated by LPS. Bromelain treatment significantly reduced p65 phosphorylation in the cytoplasm and the nucleus. It also significantly decreased phosphorylation levels of extracellular signal-related kinases (ERK) and p38 mitogen-activated protein kinases (p38). Bromelain also promoted ALP activity and mineralized nodule formation. Conclusions: Bromelain inhibits the expression of inflammatory cytokines in LPS-stimulated hDPCs. The inhibitory effect of bromelain on inflammatory mediators is related to decreased NF-κB and the MAPK pathway. Therefore, bromelain might have the potential to be used for regenerative endodontics, including vital pulp therapy.


Assuntos
Bromelaínas , Lipopolissacarídeos , Anti-Inflamatórios/farmacologia , Bromelaínas/farmacologia , Células Cultivadas , Polpa Dentária , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico
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