RESUMO
Acute lung injury (ALI) is a difficult condition to manage, especially when it is complicated by bacterial sepsis. Hibifolin, a flavonoid glycoside, has anti-inflammatory properties that make it a potential treatment for ALI. However, more research is needed to determine its effectiveness in LPS-induced ALI. In this study, male ICR mice were treated with hibifolin before LPS-induced ALI. Protein content and neutrophil count in bronchoalveolar lavage (BAL) fluid were measured by BCA assay and Giemsa staining method, respectively. The levels of proinflammatory cytokines and adhesive molecules were detected by ELISA assay. The expression of NFκB p65 phosphorylation, IκB degradation, and Akt phosphorylation was assessed by western blot assay. Hibifolin pre-treatment significantly reduced pulmonary vascular barrier dysfunction and neutrophil infiltration into the BAL fluid in LPS-induced ALI mice. In addition, LPS-induced expression of proinflammatory cytokines (IL-1ß, IL-6, TNF-α) and adhesive molecules (ICAM-1, VCAM-1) within the BAL fluid were markedly reduced by hibifolin in LPS-induced ALI mice. More, hibifolin inhibited LPS-induced phosphorylation of NFκB p65, degradation of IκB, and phosphorylation of Akt in lungs with ALI mice. In conclusion, hibifolin shows promise in improving the pathophysiological features and proinflammatory responses of LPS-induced ALI in mice through the NFκB pathway and its upstream factor, Akt phosphorylation.
RESUMO
Chlorpyrifos, widely used for pest control, is known to have various harmful effects, although its toxic effects in macrophages and the mechanisms underlying its toxicity remain unclear. The present study investigated the toxic effects of chlorypyrifos in a macrophage cell line. Here, we found that chlorpyrifos induced cytotoxicity and genotoxicity in RAW264.7 macrophages. Moreover, chlorpyrifos induced intracellular ROS production, subsequently leading to lipid peroxidation. Chlorpyrifos reduced the activation of antioxidative enzymes including superoxide dismutase, catalase, and glutathione peroxidase. Chlorpyrifos upregulated HO-1 expression and activated the Keap1-Nrf2 pathway, as indicated by enhanced Nrf2 phosphorylation and Keap1 degradation. Chlorpyrifos exerted effects on the following in a dose-dependent manner: cytotoxicity, genotoxicity, lipid peroxidation, intracellular ROS production, antioxidative enzyme activity reduction, HO-1 expression, Nrf2 phosphorylation, and Keap1 degradation. Notably, N-acetyl-L-cysteine successfully inhibited chlorpyrifos-induced intracellular ROS generation, cytotoxicity, and genotoxicity. Thus, chlorpyrifos may induce cytotoxicity and genotoxicity by promoting intracellular ROS production and suppressing the antioxidative defense system activation in macrophages.
Assuntos
Clorpirifos , Inseticidas , Proteína 1 Associada a ECH Semelhante a Kelch , Macrófagos , Fator 2 Relacionado a NF-E2 , Espécies Reativas de Oxigênio , Clorpirifos/toxicidade , Animais , Camundongos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Inseticidas/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Antioxidantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Superóxido Dismutase/metabolismo , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas de MembranaRESUMO
3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.
Assuntos
Endotélio Vascular , Fluorenos , NF-kappa B , Espécies Reativas de Oxigênio , Peixe-Zebra , Animais , Espécies Reativas de Oxigênio/metabolismo , Fluorenos/toxicidade , NF-kappa B/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Permeabilidade Capilar/efeitos dos fármacosRESUMO
ALI is a grave medical ailment that manifests as abrupt inflammation of the lungs and diminished oxygen levels. It poses a considerable challenge to the medical fraternity, with elevated rates of morbidity and mortality. Our research endeavors to investigate the potential of hibifolin, a flavonoid glucuronide, imbued with potent antioxidant properties, and its molecular mechanism to combat LPS-induced ALI in mice. The study utilized ICR mice to create an ALI model induced by LPS. Prior to LPS administration, hibifolin was given at 10, 30, or 50 mg/kg, or dexamethasone was given at 1 mg/kg to assess its preventative impact. Changes in lung tissue, pulmonary edema, and lipid peroxidation were analyzed using H&E stain assay, lung wet/dry ratio assay, and MDA formation assay, respectively. Activity assay kits were used to measure MPO activity and antioxidative enzymes (SOD, CAT, GPx) activity in the lungs. Western blot assay was used to determine the phosphorylation of Nrf-2 and AMPK2 in the lungs. Hibifolin demonstrated a concentration-dependent improvement in LPS-induced histopathologic pulmonary changes. This treatment notably mitigated pulmonary edema, lipid peroxidation, and MPO activity in ALI mice. Additionally, hibifolin successfully restored antioxidative enzyme activity in the lungs of ALI mice. Moreover, hibifolin effectively promoted Nrf-2 phosphorylation and reinstated AMPK2 phosphorylation in the lungs of ALI mice. The results indicate that hibifolin could effectively alleviate the pathophysiological impact of LPS-induced ALI. This is likely due to its antioxidative properties, which help to restore antioxidative enzyme activity and activate the AMPK2/Nrf2 pathway. These findings are valuable in terms of enhancing our knowledge of ALI treatment and pave the way for further investigation into hibifolin as a potential therapeutic option for lung injuries.
Assuntos
Lesão Pulmonar Aguda , Antioxidantes , Lipopolissacarídeos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Animais , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Masculino , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Transdução de Sinais/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Flavonoides/farmacologiaRESUMO
Macrophages play an important role in defending the body against invading pathogens. In the face of pathogens, macrophages become activated and release toxic materials that disrupt the pathogens. Macrophage overactivation can lead to severe illness and inflammation. Wogonin has several therapeutic effects, including anti-inflammatory, anticancer, antioxidant, and neuroprotective effects. No studies have investigated the cytotoxic effects of wogonin at concentrations of more than 0.1 mM in RAW264.7 cells. In this study, RAW 264.7 cells were treated with wogonin, which, at concentrations of more than 0.1 mM, had cytotoxic and genotoxic effects in the RAW264.7 cells, leading to apoptosis and necrosis. Further, wogonin at concentrations of more than 0.1 mM induced caspase-3, caspase-8, and caspase-9 activation and mitochondrial dysfunction and death receptor expression. These results suggest that wogonin induces apoptosis through upstream intrinsic and extrinsic pathways by exhibiting cytotoxic and genotoxic effects.
Assuntos
Apoptose , Flavanonas , Flavanonas/farmacologia , Macrófagos , Dano ao DNARESUMO
Cyclizine, an over-the-counter and prescription antihistamine, finds widespread application in the prevention and treatment of motion sickness, encompassing symptoms such as nausea, vomiting, dizziness, along with its effectiveness in managing vertigo. However, the overuse or misuse of cyclizine may lead to hallucinations, confusion, tachycardia, and hypertension. The molecular mechanisms underlying cyclizine-induced cytotoxicity and apoptosis remain unclear. During the 24 h incubation duration, RAW264.7 macrophages were exposed to different concentrations of cyclizine. Cytotoxicity was assessed through the lactate dehydrogenase assay. Flow cytometry employing annexin V-fluorescein isothiocyanate and propidium iodide was utilized to evaluate apoptosis and necrosis. Caspase activity and mitochondrial dysfunction were evaluated through a fluorogenic substrate assay and JC-1 dye, respectively. Flow cytometry employing fluorogenic antibodies was utilized to evaluate the release of cytochrome c and expression of death receptor, including tumor necrosis factor-α receptor and Fas receptor. Western blotting was utilized to evaluate the expression of the Bcl2 and Bad apoptotic regulatory proteins. The findings unveiled from the present study demonstrated that cyclizine exerted a concentration-dependent effect on RAW264.7 macrophages, leading to the induction of cytotoxicity, apoptosis, and necrosis. This compound further activated the intrinsic apoptotic pathway by inducing mitochondrial dysfunction, Bcl2/Bad exchange expression, cytochrome c liberation, and activation of caspases contained caspase 3, 8, and 9. Moreover, the activation of the extrinsic apoptotic pathway was observed as cyclizine induced the upregulation of death receptors and increased caspase activities. Based on our investigations, it can be inferred that cyclizine prompts cytotoxicity and apoptosis in RAW264.7 macrophages in a concentration-dependent manner by triggering both the intrinsic and extrinsic apoptotic pathways.
Assuntos
Ciclizina , Doenças Mitocondriais , Humanos , Ciclizina/metabolismo , Ciclizina/farmacologia , Citocromos c/metabolismo , Mitocôndrias/metabolismo , Apoptose , Caspases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Macrófagos , Necrose/metabolismo , Doenças Mitocondriais/metabolismoRESUMO
Obesity is associated with accumulation of inflammatory immune cells in white adipose tissue, whereas thermogenic browning adipose tissue is inhibited. Dietary fatty acids are important nutritional components and several clinical and experimental studies have reported beneficial effects of docosahexaenoic acid (DHA) on obesity-related metabolic changes. In this study, we investigated effects of DHA on hepatic and adipose inflammation and adipocyte browning in high-fat diet-induced obese C57BL/6J mice, and in vitro 3T3-L1 preadipocyte differentiation. Since visceral white adipose tissue has a close link with metabolic abnormality, epididymal adipose tissue represents current target for evaluation. A course of 8-week DHA supplementation improved common phenotypes of obesity, including improvement of insulin resistance, inhibition of macrophage M1 polarization, and preservation of macrophage M2 polarization in hepatic and adipose tissues. Moreover, dysregulated adipokines and impaired thermogenic and browning molecules, considered obesogenic mechanisms, were improved by DHA, along with parallel alleviation of endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and mitochondrial DNA stress-directed innate immunity. During 3T3-L1 preadipocytes differentiation, DHA treatment decreased lipid droplet accumulation and increased the levels of thermogenic, browning, and mitochondrial biogenesis molecules. Our study provides experimental evidence that DHA mitigates obesity-associated inflammation and induces browning of adipose tissue in visceral epididymal adipose tissue. Since obesity is associated with metabolic abnormalities across tissues, our findings indicate that DHA may have potential as part of a dietary intervention to combat obesity.
Assuntos
Dieta Hiperlipídica , Ácidos Docosa-Hexaenoicos , Camundongos , Animais , Ácidos Docosa-Hexaenoicos/metabolismo , Camundongos Obesos , Dieta Hiperlipídica/efeitos adversos , Tecido Adiposo Marrom/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Adipócitos , Tecido Adiposo Branco/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , TermogêneseRESUMO
OBJECTIVES: This cohort study investigated the correlation between Parkinson's disease (PD) risk and chronic obstructive pulmonary disease (COPD) risk under particulate matter with an aerodynamic diameter ≤2.5 µm (PM2.5) exposure. METHODS: Data from the National Health Research Institutes of Taiwan were used in this study. The Environmental Protection Administration of Taiwan established an air quality monitoring network for monitoring Taiwan's general air quality. COPD was indicated by at least 3 outpatient records and 1 hospitalization for COPD. After the implementation of age, sex, and endpoint matching at a 1:4 ratio, 137 patients and 548 patients were included in the case group and control group, respectively. Based on the 2005 World Health Organization (WHO) standards, monthly air particle concentration data were classified into the following 4 groups in analyses of exposure-response relationships: normal level, and 1.0, 1.5, and 2.0 times the WHO level ([concentration ≥2]×25 µg/m3×number of exposure months). RESULTS: A multivariate logistic regression revealed that the 1.0 and 1.5 WHO level groups did not significantly differ from the normal level group, but the 2.0 WHO level did (odds ratio, 4.091; 95% confidence interval, 1.180 to 14.188; p=0.038). CONCLUSIONS: Elevated PM2.5 concentrations were significantly correlated with an increased risk of PD among patients with COPD. Furthermore, exposure to high PM2.5 levels can further increase the risk of PD.
Assuntos
Doença de Parkinson , Doença Pulmonar Obstrutiva Crônica , Humanos , Estudos de Coortes , Doença de Parkinson/epidemiologia , Taiwan/epidemiologia , Estudos de Casos e Controles , Exposição Ambiental/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Material Particulado/efeitos adversosRESUMO
Cyclizine exhibits sedation and treatment of nausea, vomiting, and motion sickness due to antihistaminic and antimuscarinic effects. Cyclizine has the potential for abuse due to the hallucinogenic and euphoric effect. The response of overdose and illegal abuse of cyclizine includes confusion, tremors, chest pain, ataxia, seizures, and lead to suicide. Macrophage plays the important role in the innate immunity. However, over activation of macrophages results in pro-inflammatory responses in peripheral tissues. In the present study, cyclizine was found to enhanced the generation of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6. We further found that secretion of nitrogen oxide (NO) induced by cyclizine via expression of inducible nitric oxide synthases (iNOS). Cyclizine exhibited parallel stimulation of phosphorylation of nuclear factor-κB (NFκB) p65, and its up-stream factor Akt. These results indicated that the expression of pro-inflammatory cytokines, pro-inflammatory mediators, and adhesion molecules would be induced by cyclizine via activation of Akt-NFκB pathway in macrophages.
Assuntos
NF-kappa B , Proteínas Proto-Oncogênicas c-akt , Humanos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ciclizina/metabolismo , Ciclizina/farmacologia , Anti-Inflamatórios/farmacologia , Macrófagos , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Lipopolissacarídeos/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
Microglia have both protective and pathogenic properties, while polarization plays a decisive role in their functional diversity. Apart from being an energetic organelle, mitochondria possess biological capabilities of signaling and immunity involving mitochondrial dynamics. The N-methyl-D-aspartate (NMDA)-type glutamate receptor displays excitatory neurotransmission, excitatory neurotoxicity and pro-inflammatory properties in a membrane location- and cell context-dependent manner. In this study, we have provided experimental evidence showing that by acting on mitochondrial dynamics, NMDA receptors displayed pro-inflammatory properties, while its non-competitive inhibitor MK801 exhibited anti-inflammatory potential in Lipopolysaccharide (LPS)-challenged BV-2 microglia cells. LPS stimulation increased the protein phosphorylation of cells regarding their NMDA receptor component subunits and Calcium/Calmodulin-dependent Protein Kinase II (CaMKII), along with mobilizing intracellular calcium. Additionally, parallel changes occurred in the activation of Transforming Growth Factor-ß (TGF-ß)-Activated Kinase 1 (TAK1), NF-κB p65 and NF-κB DNA binding activity, acquisition of pro-inflammatory M1 polarization and expression of pro-inflammatory cytokines. LPS-treated cells further displayed signs of mitochondrial dysfunction with higher expressions of the active form of Dynamin-Related Protein 1 (Drp1), NADPH Oxidase-2 (NOX2) expression and the generation of DCFDA-/MitoSOX-sensitive Reactive Oxygen Species (ROS). NMDA receptor blockade by MK801, along with CaMKII inhibitor KN93, Drp1 inhibitor Mdivi-1 and antioxidant apocynin alleviated LPS-induced pro-inflammatory changes. Other than the reported CaMKII/TAK1/NF-κB axis, our in vitro study revealed the CaMKII/Drp1/ROS/NF-κB axis being an alternative cascade for shaping pro-inflammatory phenotypes of microglia upon LPS stimulation, and MK801 having the potential for inhibiting microglia activation and any associated inflammatory damages.
RESUMO
Traditional herbal medicine Ligusticum wallichii Franchat (Chuan Xiong) is frequently prescribed and highly recommended to patients with stroke. Rodent studies have demonstrated the neuroprotective effects of its active component tetramethylpyrazine against post-stroke brain injury and highlighted its role in antioxidant, anti-inflammation, and anti-apoptosis activity. Using permanent cerebral ischemia in rats and oxygen/glucose deprivation and reoxygenation (OGDR) in rat primary neuron/glia cultures, this study sheds light on the role of mitochondria as crucial targets for tetramethylpyrazine neuroprotection. Tetramethylpyrazine protected against injury and alleviated oxidative stress, interleukin-1ß release, and caspase 3 activation both in vivo and in vitro. Reduction of mitochondrial biogenesis- and integrity-related proliferator-activated receptor-gamma coactivator-1 alpha, mitochondrial transcription factor A (TFAM), translocase of outer mitochondrial membrane 20, mitochondrial DNA, and citrate synthase activity, as well as activation of mitochondrial dynamics disruption-related Lon protease, dynamin-related protein 1 (Drp1) phosphorylation, stimulator of interferon genes, TANK-binding kinase 1 phosphorylation, protein kinase RNA-like endoplasmic reticulum kinase phosphorylation, eukaryotic initiation factor 2α phosphorylation, and activating transcription factor 4 were revealed in permanent cerebral ischemia in rats and OGDR in neuron/glia cultures. TMP alleviated those biochemical changes. Our findings suggest that preservation or restoration of mitochondrial dynamics and functional integrity and alleviation of mitochondria-oriented pro-oxidant, pro-inflammatory, and pro-apoptotic cascades are alternative neuroprotective mechanisms of tetramethylpyrazine. Additionally, mitochondrial TFAM and Drp1 as well as endoplasmic reticulum stress could be targeted by TMP to induce neuroprotection. Data of this study provide experimental base to support clinical utility and value of Chuan Xiong towards stroke treatment and highlight an alternative neuroprotective target of tetramethylpyrazine.
Assuntos
Isquemia Encefálica , Oxigênio , Ratos , Animais , Glucose , Isquemia Encefálica/tratamento farmacológico , Infarto Cerebral , Mitocôndrias/metabolismoRESUMO
Periodontal disease is often neglected and overlooking its initial symptoms can lead to tooth loss and systemic diseases. Patients with otitis media are at high risk of vestibular and balance dysfunction, consequently, and vertigo. Vertigo and dizziness are conditions with high reported incidences; they worsen with age and can burden health systems. The present study investigated whether periodontal disease causes dizziness. Research data covering 2008 through 2013 were retrieved from the National Health Insurance Research Database of Taiwan. Patients who were newly diagnosed as having periodontal disease or dizziness after at least 1 hospital admission or 3 outpatient visits were enrolled as participants. For our controls, we randomly selected individuals without periodontal disease who were sex- and age-matched with the investigated participants. In total, we enrolled 445 patients with periodontal disease and 1780 controls. The Kaplan-Meier curve indicated that the cumulative incidence of dizziness was significantly higher among the patients with periodontal disease relative to the controls. After adjustment for sex, age, income level, urbanization level, month of onset, and comorbidities, Cox proportional-hazards analysis revealed that patients with periodontal disease had an increased risk of dizziness (hazard ratio [HR]: 1.306, 95% confidence interval (CI): 1.155, 1.475). Compared with the controls, the risk of dizziness among patients with periodontal disease was higher for both female (HR: 1.439, 95%: 1.203, 1.720) and male patients (HR: 1.284, 95%: 1.123, 1.468); this risk was higher even when January (HR: 1.302, 95% CI: 1.145, 1.480), February (HR: 1.337, 95% CI: 1.178, 1.518), or March was excluded (HR: 1.308, 95% CI: 1.151, 1.487) and for patients without Ménière disease. Therefore, periodontal disease is not only a risk factor for dizziness but also an independent risk factor for dizziness. Future studies could clarify the mechanisms linking periodontal disease to dizziness.
Assuntos
Tontura , Doenças Periodontais , Adulto , Feminino , Humanos , Masculino , Estudos de Coortes , Comorbidade , Incidência , Doenças Periodontais/epidemiologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia , Vertigem , Estudos de Casos e ControlesRESUMO
Bisphenol A-glycidyl methacrylate (BisGMA) is a methacrylate monomer that is mainly used in three-dimensional structures to reconstruct dental and bony defects. BisGMA has toxic and proinflammatory effects on macrophages. Rutin is a natural flavonol glycoside that is present in various plants and has useful biological effects, such as anti-inflammatory, anticancer, and antioxidative effects. The aim of this study was to investigate the anti-inflammation of rutin in macrophages after exposure to BisGMA. Pretreatment of the RAW264.7 macrophage with rutin at 0, 10, 30, and 100 µM for 30 min before being incubated with BisGMA at 0 or 3 µM. Proinflammatory cytokines and prostaglandin (PG) E2 were detected by enzyme-linked immunosorbent assay (ELISA). Nitric oxide (NO) was detected by the Griess assay. Expression and phosphorylation of proteins were measured by Western blot assay. Pretreatment with rutin inhibited the BisGMA-induced generation of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and PGE2, in macrophages. Rutin also suppressed the BisGMA-induced secretion of NO and expression of inducible nitric oxide synthase (iNOS) in a concentration-dependent manner. Furthermore, rutin suppressed the mitogen-activated protein kinase (MAPK) phosphorylation in a concentration-dependent manner. Finally, rutin suppressed the BisGMA-induced phosphorylation of nuclear factor (NF)-κB p65 and degradation of inhibitor of κB (IκB). These results indicate that the concentration of rutin has an inhibitory effect on proinflammatory mediator generation, MAPK phosphorylation, NF-κB p65 phosphorylation, and IκB degradation. In conclusion, rutin is a potential anti-inflammatory agent for BisGMA-stimulated macrophages through NF-κB p65 phosphorylation and IκB degradation resulting from MAPK phosphorylation.
Assuntos
Proteínas Quinases Ativadas por Mitógeno , NF-kappa B , NF-kappa B/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Bis-Fenol A-Glicidil Metacrilato/metabolismo , Bis-Fenol A-Glicidil Metacrilato/farmacologia , Rutina/farmacologia , Macrófagos , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Lipopolissacarídeos/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismoRESUMO
Background: Hidradenitis suppurativa were associated with comorbidities in various organ systems. Inflammatory dermatological diseases such as pyoderma gangrenosum were reported to be associated with hidradenitis suppurativa. Nevertheless, as for the association between hidradenitis suppurativa and psoriasis, evidences were insufficient. In many studies, the association between psoriasis and hidradenitis suppurativa has been reported. However, some evidence seems to be controversial. The purpose of the systematic review and meta-analysis was to assess whether there was significant association between HS and psoriasis. Methods: On June 01, 2022, we appraised 2,795 articles from databases including PubMed, Web of Science and Embase. Search syntaxes were based on 'hidradenitis suppurativa' or 'acne inversa' with "psoriasis", "comorbidities" or 'epidemiology'. Synonyms were determined based on MeSH terms and Emtree. Observational results that evaluated the odds ratio for people with hidradenitis suppurativa who had psoriasis were extracted for qualitative synthesis. Results: After the selection process of the initial 2,795 studies, ten observational studies, including 3 cohort studies, 1 case-control study, and 6 cross-sectional studies, were extracted for critical appraisal. Based on the integration of 7 studies (with more than 560,000 participants included), people with hidradenitis suppurativa had a higher risk of having psoriasis, with a 2.67-fold risk (95% CI, 1.84, 3.87). The association remained in the sensitivity analyses utilizing strict adjustment models. In the analysis that only included studies with a similar study design and adjustments in obesity-related factors, the risk of people with hidradenitis suppurativa having psoriasis was 3.24 (95% CI, 2.27, 4.62). In male patients with HS, the risk of having psoriasis was 4.30-fold higher than male patients without HS (95% CI, 2.37, 7.78). Likewise, in an analysis including 3 cross-sectional studies, the risk of female HS patients having psoriasis was 3.94-fold higher than female HS-free patients (95% CI, 2.34, 6.63). Conclusions: The co-occurrence of hidradenitis suppurativa and psoriasis can greatly increase the burden of the disease. Psoriasis could be one of the critical comorbidities of hidradenitis suppurativa and should be recommended for future screening and follow up. The association between the two diseases should be kept in mind in managing hidradenitis suppurativa patients. More prospective studies are needed to establish the true magnitude of the association between psoriasis and hidradenitis suppurativa.
Assuntos
Hidradenite Supurativa , Psoríase , Humanos , Masculino , Feminino , Estudos Transversais , Estudos de Casos e Controles , Hidradenite Supurativa/complicações , Hidradenite Supurativa/epidemiologia , Psoríase/epidemiologia , Psoríase/complicações , ComorbidadeRESUMO
Rutin, also called quercetin-3-rhamnosyl glucoside, is a natural flavonol glycoside present in many plants. Rutin is used to treat various diseases, such as inflammation, diabetes, and cancer. For polymeric biomaterials, triethylene glycol dimethacrylate (TEGDMA) is the most commonly used monomer and serves as a restorative resin, a dentin bonding agent and sealant, and a bone cement component. Overall, TEGDMA induces various toxic effects in macrophages, including cytotoxicity, apoptosis, and genotoxicity. The aim of this study was to investigate the protective mechanism of rutin in alleviating TEGDMA-induced toxicity in RAW264.7 macrophages. After treatment with rutin, we assessed the cell viability and apoptosis of TEGDMA-induced RAW264.7 macrophages using an methylthiazol tetrazolium (MTT) assay and Annexin V-FITC/propidium iodide assay, respectively. Subsequently, we assessed the level of genotoxicity using comet and micronucleus assays, assessed the cysteinyla aspartate specific proteinases (caspases) and antioxidant enzyme (AOE) activity using commercial kits, and evaluated the generation of reactive oxygen species (ROS) using a dichlorodihydrofluorescein diacetate (DCFH-DA) assay. We evaluated the expression of heme oxygenase (HO)-1, the expression of nuclear factor erythroid 2 related factor (Nrf-2), and phosphorylation of AMP activated protein kinase (AMPK) using the Western blot assay. The results indicated that rutin substantially reduced the level of cytotoxicity, apoptosis, and genotoxicity of TEGDMA-induced RAW264.7 macrophages. Rutin also blocked the activity of caspase-3, caspase-8, and caspase-9 in TEGDMA-stimulated RAW264.7 macrophages. In addition, it decreased TEGDMA-induced ROS generation and AOE deactivation in macrophages. Finally, we found that TEGDMA-inhibited slightly the HO-1 expression, Nrf-2 expression, and AMPK phosphorylation would be revered by rutin. In addition, the HO-1 expression, Nrf-2 expression, and AMPK phosphorylation was enhanced by rutin. These findings indicate that rutin suppresses TEGDMA-induced caspase-mediated toxic effects through ROS generation and antioxidative system deactivation through the Nrf-2/AMPK pathway. Therefore, rutin has the potential to serve as a novel antitoxicity agent for TEGDMA in RAW264.7 macrophages.
Assuntos
Proteínas Quinases Ativadas por AMP , Rutina , Proteínas Quinases Ativadas por AMP/metabolismo , Antioxidantes/farmacologia , Apoptose , Ácido Aspártico , Materiais Biocompatíveis/farmacologia , Cimentos Ósseos/farmacologia , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Caspases/metabolismo , Adesivos Dentinários , Glucosídeos/farmacologia , Glicosídeos/farmacologia , Macrófagos/metabolismo , Polietilenoglicóis , Ácidos Polimetacrílicos , Propídio , Quercetina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Rutina/farmacologiaRESUMO
Composites, resins, and sealants that are commonly used in orthopedics and dentistry are based on 2,2-bis[p-(2'-hydroxy-3'-methacryloxypropoxy)phenylene]propane (BisGMA), which induces proinflammatory responses in macrophages. The present study aimed to explore the anti-inflammatory responses of wogonin, which is a natural dihydroxyl flavonoid compound, in BisGMA-treated macrophages. According to the findings, wogonin exhibits anti-inflammatory, antiallergic, anticancer, and antioxidative properties. The generation of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS) were noted to be inhibited by wogonin in BisGMA-treated macrophages. Furthermore, the production of proinflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 was reduced. In addition, BisGMA-induced nuclear factor (NF)-κB p65 phosphorylation and inhibitor of κB (IκB) degradation were inhibited. Finally, the BisGMA-induced phosphorylation of mitogen-activated protein kinases (MAPKs), including p38 MAPK, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) was inhibited. All these effects were induced by wogonin in the macrophages in a concentration-dependent manner. Similar inhibitory effects of wogonin were observed on the production of NO and proinflammatory cytokines, expression of iNOS, phosphorylation of NF-κB p65 and MAPK, and degradation of IκB. These results indicated that rutin is a potential anti-inflammatory agent for BisGMA-treated macrophages that undergo NFκB p65 phosphorylation and IκB degradation through upstream MAPK phosphorylation. Therefore, wogonin inhibits BisGMA-induced proinflammatory responses in macrophages through the regulation of the NFκB pathway and its upstream factor, MAPK.
Assuntos
Lipopolissacarídeos , NF-kappa B , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Macrófagos , Anti-Inflamatórios/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Óxido Nítrico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fosforilação , Citocinas/metabolismo , Ciclo-Oxigenase 2/metabolismoRESUMO
Background: Migraine is deemed a neurovascular disorder and there is growing evidence on the increased risk of cardiovascular disease, especially ischemic stroke, in patients with migraine. However the risk of peripheral artery disease (PAD) and stroke in migraineurs and the association between migraineurs with or without aura is still under debate. Our study aimed to identify the risk of PAD and stroke in migraineurs with or without aura. Methods: This was a population-based cohort study utilizing Taiwan Longitudinal Health Insurance Database (LHID2010). Patients with coding of migraine from 2002 to 2011 were enrolled and those with established cardiovascular disease defined as myocardial infarction, stroke, PAD, venous thromboembolism, atrial fibrillation and heart failure diagnosis before the index date were excluded. Participants were categorized into migraine group, migraine without aura group, and migraine with aura group respectively. The subjects in the three groups were propensity score-matched randomly to their counterparts without migraine. The study outcome was PAD and stroke. The Cox proportional hazard model was used to estimate the hazard ratios with 95% confidence interval (CI) for the association between migraine and the incident events of disease, after controlling for related variables. Results: The migraine, migraine without aura, and migraine with aura group included 5,173 patients, 942 patients and 479 patients respectively after propensity score-matching. The migraine group had an increased risk of PAD [adjusted hazard ratio (aHR): 1.93; 95% confidence interval (CI): 1.45-2.57; p < 0.001] and stroke (aHR: 1.55; 95% CI: 1.35-1.77; p < 0.001) compared to their non-migraine controls. Both the groups of migraine without aura and with aura had an increased risk of stroke (aHR: 1.49, 95% CI: 1.11-2.00; p = 0.008; aHR: 1.63, 95% CI: 1.10-2.43; p = 0.016). With regards to the outcome of PAD, the group of migraine with aura had a trend of an increased risk but did not reach statistical significance (aHR: 1.95, 95% CI: 0.86-4.40; p = 0.108). Conclusion: Migraineurs without established cardiovascular disease had a significantly increased risk of PAD and stroke, and the risk of stroke persists in migraineurs with or without aura, with an increased trend of PAD in migraineurs with aura. Our study result should remind clinical physicians of the risk of PAD in the future among migraineurs even without established cardiovascular disease currently, and screening for PAD and stroke may be needed in caring patients with migraine.
Assuntos
Epilepsia , Enxaqueca com Aura , Enxaqueca sem Aura , Infarto do Miocárdio , Doença Arterial Periférica , Acidente Vascular Cerebral , Estudos de Coortes , Epilepsia/complicações , Humanos , Enxaqueca com Aura/complicações , Enxaqueca com Aura/epidemiologia , Enxaqueca sem Aura/complicações , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Doença Arterial Periférica/complicações , Doença Arterial Periférica/epidemiologia , Fatores de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/etiologiaRESUMO
Macrophages are mainly active cells of the immune system and play a role in the defense of pathogens. However, the overactivation of macrophages by fatal pathogens can result in toxic responses. 2-hydroxyethyl methacrylate (HEMA), which is a hydrophilic monomer, is used in dental adhesive reagents and composite resins as well as biocompatible hydrogels. The mechanisms underlying the genotoxicity engendered by HEMA-induced apoptosis that leads to cytotoxicity remain unclear. Accordingly, this study was conducted to clarify such mechanisms. The results showed that HEMA induced cell toxicity in RAW264.7 macrophages depending on the concentration. A higher HEMA concentration was associated with a higher level of apoptosis and genotoxicity. Moreover, HEMA induced a concentration-dependent increase in mitochondrial dysfunction and the intrinsic caspase pathway, including the activation of caspase-3 and caspase-9. HEMA was also found to upregulate intracellular reactive oxygen species generation and to decrease the activity of antioxidant enzymes, including superoxide dismutase and catalase. Taken together, the mitochondrial-dependent intrinsic caspase pathway and intracellular reactive oxygen species accumulation were found to mediate HEMA-induced genotoxicity and apoptosis, leading to cytotoxicity in RAW264.7 macrophages.
RESUMO
Spinal microglia are crucial to neuronal hyper-excitability and pain hypersensitivity. The local anesthetic bupivacaine is commonly used for both peripheral and spinal anesthesia. The pain-relief effects resulting from the peripheral and systemic administration of bupivacaine have been previously reported. In this study, the preventive effects of intrathecal bupivacaine administration against neuropathic pain were revealed in a rat model of sciatic nerve chronic constriction injury (CCI). Using a CCI rat model, pain hypersensitivity, characterized by mechanical allodynia and thermal hyperalgesia, correlated well with microglia M1 polarization, activation and pro-inflammatory cytokine expression in both spinal cord dorsal horns and sciatic nerves. Bupivacaine attenuated pain behaviors and inflammatory alternations. We further identified that the Interferon Regulatory Factor 5 (IRF5)/P2X Purinoceptor 4 (P2X4R) and High Mobility Group Box 1 (HMGB1)/Toll-Like Receptor 4 (TLR4)/NF-κB inflammatory axes may each play pivotal roles in the acquisition of microglia M1 polarization and pro-inflammatory cytokine expression under CCI insult. The relief of pain paralleled with the suppression of microglia M1 polarization, elevation of microglia M2 polarization, and inhibition of IRF5/P2X4R and HMGB1/TLR4/NF-κB in both the spinal cord dorsal horns and sciatic nerve. Our findings provide molecular and biochemical evidence for the anti-neuropathic effect of preventive bupivacaine.