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BACKGROUND: Allergic asthma affects nearly 300 million people worldwide and causes ahigh burden of disability and death. Effective treatments rely heavily on corticosteroids, which are associated with various complications. So, the alternative treatment is of significance. Hispidulin is a bioflavonoid found in herbs that were used in traditional medicine to treat inflammatory diseases, including asthma. This study aims to investigate the efficacy of hispidulin compound in the treatment of allergic lung inflammation using the mouse model of allergic asthma. METHODS: BALB/c mice were sensitized and challenged with chicken egg ovalbumin. Cells and cytokines from bronchoalveolar lavage (BAL) fluid were examined. Lung tissues were collected for histologic study. Mouse splenic CD4+ cells were cultured to observe the effect of hispidulin on T-helper 2 (Th2) cell differentiation in vitro. RESULTS: Hispidulin treatment could alleviate allergic airway inflammation as evidenced by a significant reduction in the inflammatory cell count and Th2 cytokines interleukin (IL)-4, IL-5, IL-13 in BAL fluid. Histologic examination of lung tissues revealed lower inflammatory cell infiltration to the bronchi and less airway goblet cell hyperplasia in the treatment group compared to the control group. At the cellular level, hispidulin (25, 50, and 100 µM) was found to directly suppress the differentiation and proliferation of Th2 cells and to suppress the production of Th2 cytokines, such as IL-4, IL-5, and IL-13, in vitro. CONCLUSIONS: Hispidulin treatment was shown to effectively decrease type 2 lung inflammation in an ovalbumin-induced allergic asthma mouse model by directly suppressing Th2 cell differentiation and functions.
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Asma , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Ovalbumina , Células Th2 , Animais , Asma/tratamento farmacológico , Asma/imunologia , Ovalbumina/imunologia , Células Th2/imunologia , Camundongos , Feminino , Pneumonia/imunologia , Pneumonia/tratamento farmacológico , Citocinas/metabolismo , Flavonas/farmacologia , Flavonas/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Pulmão/patologia , Pulmão/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ding-Chuan-Tang (Abbreviated as DCT) is frequently prescribed for treatment of respiratory diseases, including chronic obstructive pulmonary disease (COPD), which is characterized by coughing, wheezing, and chest tightness in traditional Chinese medicine (TCM). However, the potential mechanism of DCT has not been investigated. AIM OF STUDY: The aim of the study is to explore the efficiency of DCT in the treatment of COPD in vivo and in vitro, and to illustrate the possible mechanism against COPD. METHODS: COPD model was induced by exposure of mice to cigarette smoke (CS) for 16 weeks. Enzyme-linked immunosorbent assay (ELISA), immunofluorescence assay, Western blot, etc., were used to explore the efficiency and mechanisms of DCT. Network pharmacology analysis, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, etc., was performed to explore the potential targets in the treatment of DCT on COPD. RESULTS: DCT significantly alleviated pulmonary pathological changes in mouse COPD model, and inhibited inflammatory response induced by CS and LPS in vivo and in vitro. Network pharmacology analysis suggested that DCT alleviated COPD via inhibiting inflammation by regulating PI3K-AKT pathway. In cell-based models, DCT suppressed the phosphorylation of PI3K and AKT, which further regulated its downstream targets Nrf2 and NF-κB, and inhibited inflammatory response. CONCLUSIONS: DCT effectively attenuated COPD in the mouse model induced by CS. The therapeutic mechanism of DCT against COPD was closely associated with the regulation of PI3K-AKT pathway and its downstream transcription factors, Nrf2 and NF-κB.
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NF-kappa B , Doença Pulmonar Obstrutiva Crônica , Camundongos , Animais , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Farmacologia em Rede , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismoRESUMO
Lung inflammation and alveolar enlargement are the major pathological conditions of chronic obstructive pulmonary disease (COPD) patients. Rice bran oil (RBO), a natural anti-inflammatory and antioxidative agent, has been used for therapeutic purposes in several inflammatory diseases. This study aimed to investigate the anti-inflammatory and antioxidative effect of RBO on a cigarette smoke extract (CSE)-induced emphysema model in mice. The results indicated that CSE significantly induced airspace enlargement in mouse lung. Increased inflammatory cells, macrophage, and TNF-alpha levels in bronchoalveolar lavage fluid (BALF) were noticed in CSE-treated mice. RBO (low and high dose)-supplemented mice showed decreased total BALF inflammatory cell, macrophage, and neutrophil numbers and TNF-alpha levels (p < 0.05). Additionally, the administration of RBO decreased the mean linear alveolar intercept (MLI) in the CSE-treated group. Additionally, RBO treatment significantly increased the total antioxidant capacity in both mouse BALF and serum. However, RBO did not have an effect on the malondialdehyde (MDA) level. These findings suggested that RBO treatment ameliorates lung inflammation in a CSE-induced emphysema mice model through anti-inflammatory and antioxidant pathways. Therefore, the supplementation of RBO could be a new potential therapeutic to relieve the severity of COPD.
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Fumar Cigarros , Enfisema , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Camundongos , Animais , Antioxidantes/metabolismo , Pulmão/patologia , Óleo de Farelo de Arroz/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Fumar Cigarros/efeitos adversos , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Anti-Inflamatórios/uso terapêutico , Pneumonia/tratamento farmacológico , Líquido da Lavagem Broncoalveolar , Enfisema/induzido quimicamente , Enfisema/tratamento farmacológico , Produtos do TabacoRESUMO
Recent research has underscored the significant role of gut microbiota in managing various diseases, including intestinal and lung inflammation. It is now well established that diet plays a crucial role in shaping the composition of the microbiota, leading to changes in metabolite production. Consequently, dietary interventions have emerged as promising preventive and therapeutic approaches for managing these diseases. Plant-based dietary fibers, particularly polysaccharides and oligosaccharides, have attracted attention as potential therapeutic agents for modulating gut microbiota and alleviating intestinal and lung inflammation. This comprehensive review aims to provide an in-depth overview of the current state of research in this field, emphasizing the challenges and limitations associated with the use of plant-based dietary fibers and polysaccharides in managing intestinal and lung inflammation. By shedding light on existing issues and limitations, this review seeks to stimulate further research and development in this promising area of therapeutic intervention.
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Introduction: Most critically ill COVID-19 patients have bronchitis, pneumonia, and acute respiratory distress syndrome (ARDS) due to excessive inflammatory conditions. Corticosteroids have largely been prescribed for the management of inflammation in these patients. However, long-term use of corticosteroids in patients with comorbidities such as metabolic, cardiovascular, and other inflammatory disorders is ideally not recommended due to safety issues. A potential and safer anti-inflammatory therapy is therefore the need of the hour. Withania somnifera (WS), a well-known herbal medicine used during the pandemic in India to prevent SARS-CoV2 infection, also possesses anti-inflammatory properties. Methods: In the present study, we, therefore, evaluated the effect of the aqueous extract of the roots of W. somnifera in the cell-based assays and in the experimental animal models of LPS-induced inflammation. Results: In the NCI-H460, A549 cells and human peripheral blood mononuclear cells (PBMCs) pre-treatment with W. somnifera reduced the LPS-induced expression of the pro-inflammatory cytokines. In addition, W. somnifera extract also showed potent anti-inflammatory activity in the lung tissues of BALB/c mice challenged intranasally with LPS. We observed a marked reduction in the neutrophil counts in the broncho-alveolar lavage (BAL) fluid, inflammatory cytokines, and fibrosis in the mice lungs pre-treated with W. somnifera. Results obtained thus suggest the potential utility of W. somnifera extract in reducing airway inflammation and recommend the clinical evaluation of W. somnifera extract in COVID-19 patients with a high propensity for lung inflammation.
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Vanadium is available as a dietary supplement and also is known to be toxic if inhaled, yet little information is available concerning the effects of vanadium on mammalian metabolism when concentrations found in food and water. Vanadium pentoxide (V+5) is representative of the most common dietary and environmental exposures, and prior research shows that low-dose V+5 exposure causes oxidative stress measured by glutathione oxidation and protein S-glutathionylation. We examined the metabolic impact of V+5 at relevant dietary and environmental doses (0.01, 0.1, and 1 ppm for 24 h) in human lung fibroblasts (HLFs) and male C57BL/6J mice (0.02, 0.2, and 2 ppm in drinking water for 7 mo). Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) showed that V+5 induced significant metabolic perturbations in both HLF cells and mouse lungs. We noted 30% of the significantly altered pathways in HLF cells, including pyrimidines and aminosugars, fatty acids, mitochondrial and redox pathways, showed similar dose-dependent patterns in mouse lung tissues. Alterations in lipid metabolism included leukotrienes and prostaglandins involved in inflammatory signaling, which have been associated with the pathogenesis of idiopathic pulmonary fibrosis (IPF) and other disease processes. Elevated hydroxyproline levels and excessive collagen deposition were also present in lungs from V+5-treated mice. Taken together, these results show that oxidative stress from environmental V+5, ingested at low levels, could alter metabolism to contribute to common human lung diseases.NEW & NOTEWORTHY We used relevant dietary and environmental doses of Vanadium pentoxide (V+5) to examine its metabolic impact in vitro and in vivo. Using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), we found significant metabolic perturbations, with similar dose-dependent patterns observed in human lung fibroblasts and male mouse lungs. Alterations in lipid metabolism included inflammatory signaling, elevated hydroxyproline levels, and excessive collagen deposition were present in V+5-treated lungs. Our findings suggest that low levels of V+5 could trigger pulmonary fibrotic signaling.
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Fibrose Pulmonar Idiopática , Vanádio , Masculino , Humanos , Camundongos , Animais , Hidroxiprolina/metabolismo , Hidroxiprolina/farmacologia , Vanádio/toxicidade , Vanádio/metabolismo , Camundongos Endogâmicos C57BL , Pulmão/metabolismo , Fibrose Pulmonar Idiopática/patologia , Inflamação/patologia , MamíferosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Oleo-gum resin of Commiphora wightii (Arnott) Bhandari of family Burseraceae, commonly known as 'guggul', is a well known Ayurvedic drug used traditionally to treat various disorders including respiratory ailments. However, role of C. wightii in chronic obstructive pulmonary disease (COPD) is not known. AIM: The present work was designed to investigate the protective potential of standardized C. wightii extract/and its fractions against elastase-induced COPD-linked lung inflammation and to identify key bioactive constituent(s). MATERIAL AND METHODS: C. wightii oleo-gum resin extract was prepared using Soxhlet extraction technique and the resultant extract was standardized on basis of guggulsterone content using HPLC. The extract was partitioned by different solvents in increasing order of polarity. Standardized extract/its partitioned fractions were orally administered to male BALB/c mice 1 h prior to intra-tracheal instillation of elastase (1U/mouse). Anti-inflammatory effect was evaluated by analyzing inflammatory cells and myeloperoxidase activity in lungs. The various fraction(s) were subjected to column chromatography to isolate bioactive compound. Isolated compound was identified using 1H and 13C-NMR and analyzed for assessment of several inflammatory mediators using techniques like ELISA, PCR, and gelatin zymography. RESULTS: C. wightii extract attenuated elastase-induced lung inflammation in dose-dependent manner and Ethyl acetate fraction (EAF) provided maximum protection. EAF was subjected to column chromatography followed by assessment of bioactivity of each sub-fraction, ultimately leading towards isolation of two compounds i.e. C1 and C2. C1 seems to be the key active principle of C. wightii, as it displayed significant anti-inflammatory activity against elastase induced lung inflammation while C2 largely remains ineffective. C1 was identified as mixture of E- and Z-guggulsterone (GS). Reduction in the elastase induced lung inflammation by GS was associated with downregulation of expression of several COPD linked pro-inflammatory factors such as IL-6/TNF-α/IL-1ß/KC/MIP-2/MCP-1/G-CSF as well as normalization of redox imbalance as indicated by levels of ROS/MDA/protein carbonyl/nitrite/GSH etc. Further, 21 days prolonged administration of GS (10 mg/kg b.wt; once daily) protected against elastase-induced emphysema by mitigating expression/activity of MMP-2/-9 and increasing TIMP-1 expression. CONCLUSION: Overall, guggulsterone seems to be the key bioactive constituent responsible for exerting beneficial effects of C. wightii against COPD.
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Enfisema , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Masculino , Camundongos , Animais , Elastase Pancreática , Commiphora/química , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Enfisema Pulmonar/metabolismo , Enfisema/tratamento farmacológico , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/prevenção & controle , Anti-Inflamatórios/efeitos adversosRESUMO
As a life-threatening disorder, sepsis-associated lung injury is a dysregulated inflammatory response to microbial infection, characterized by the infiltration of inflammatory cells into lung tissues and excessive production of pro-inflammatory mediators. Therefore, immunomodulatory/anti-inflammatory agents are a potential treatment for sepsis-associated lung injury. Berberine, one of the well-studied medicinal plant-derived compounds, has shown promising anti-inflammatory potential in inflammatory conditions, through modulating excessive immune responses induced by various immune cells. A systematic literature search in electronic databases indicated several publications that studied the effect of berberine on lipopolysaccharide (LPS)-induced sepsis in preclinical investigations. The current review article aims to provide evidence on the effects of berberine against LPS-induced acute lung injury (ALI), together with underlying molecular mechanisms. The findings reveal that berberine through inhibiting the excessive production of multiple pro-inflammatory cytokines, suppressing the infiltration of immune cells into lung tissues, as well as preventing pulmonary edema and coagulation, can relieve pulmonary histopathological changes from LPS-mediated inflammation, thereby attenuating sepsis-associated lung injury and lethality in the experimental models. In conclusion, berberine shows great potential as a preventing and therapeutic agent for sepsis-associated lung injury, however, further proof-of-concept studies and clinical investigations are warranted for translating these preclinical findings into clinical practices.
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Lesão Pulmonar Aguda , Berberina , Pneumonia , Sepse , Humanos , Lipopolissacarídeos/toxicidade , Berberina/farmacologia , Berberina/uso terapêutico , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Pulmão , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Anti-Inflamatórios/efeitos adversos , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/patologiaRESUMO
High dietary intake of ß-cryptoxanthin (BCX, an oxygenated provitamin A carotenoid) is associated with a lower risk of lung disease in smokers. BCX can be cleaved by ß-carotene-15,15'-oxygenase (BCO1) and ß-carotene-9',10'-oxygenase (BCO2) to produce retinol and apo-10'-carotenoids. We investigated whether BCX has protective effects against cigarette smoke (CS)-induced lung injury, dependent or independent of BCO1/BCO2 and their metabolites. Both BCO1-/-/BCO2-/- double knockout mice (DKO) and wild type (WT) littermates were supplemented with BCX 14 days and then exposed to CS for an additional 14 days. CS exposure significantly induced macrophage and neutrophil infiltration in the lung tissues of mice, regardless of genotypes, compared to the non-exposed littermates. BCX treatment significantly inhibited CS-induced inflammatory cell infiltration, hyperplasia in the bronchial epithelium, and enlarged alveolar airspaces in both WT and DKO mice, regardless of sex. The protective effects of BCX were associated with lower expression of IL-6, TNF-α, and matrix metalloproteinases-2 and -9. BCX treatment led to a significant increase in hepatic BCX levels in DKO mice, but not in WT mice, which had significant increase in hepatic retinol concentration. No apo-10'-carotenoids were detected in any of the groups. In vitro BCX, at comparable doses of 3-OH-ß-apo-10'-carotenal, was effective at inhibiting the lipopolysaccharide-induced inflammatory response in a human bronchial epithelial cell line. These data indicate that BCX can serve as an effective protective agent against CS-induced lung lesions in the absence of carotenoid cleavage enzymes.
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Dioxigenases , Produtos do Tabaco , Camundongos , Animais , Humanos , beta Caroteno/metabolismo , beta-Criptoxantina/farmacologia , Vitamina A , Dioxigenases/metabolismo , beta-Caroteno 15,15'-Mono-Oxigenase/genética , beta-Caroteno 15,15'-Mono-Oxigenase/metabolismo , Carotenoides/farmacologia , Carotenoides/metabolismo , Oxigenases , Pulmão/metabolismo , Camundongos KnockoutRESUMO
Interstitial macrophages (IMs) reside in the lung tissue surrounding key structures including airways, vessels, and alveoli. Recent work has described IM heterogeneity during homeostasis, however, there are limited data on IMs during inflammation. We sought to characterize IM origin, subsets, and transcriptomic profiles during homeostasis and lipopolysaccharide (LPS) induced acute lung inflammation. During homeostasis, we used three complementary methods, spectral flow cytometry, single-cell RNA-sequencing, and gene regulatory network enrichment, to demonstrate that IMs can be divided into two core subsets distinguished by surface and transcriptional expression of folate receptor ß (Folr2/FRß). These subsets inhabited distinct niches within the lung interstitium. Within FRß+ IMs we identified a subpopulation marked by coexpression of LYVE1. During acute LPS-induced inflammation, lung IM numbers expand. Lineage tracing revealed IM expansion was due to recruitment of monocyte-derived IMs. At the peak of inflammation, recruited IMs were comprised two unique subsets defined by expression of genes associated with interferon signaling and glycolytic pathways. As recruited IMs matured, they adopted the overall transcriptional state of FRß- resident IMs but retained expression in several origin-specific genes, such as IL-1ß. FRß+ IMs were of near-pure resident origin. Taken together our data show that during LPS-induced inflammation, there are distinct populations of IMs that likely have unique functions. FRΒ+ IMs comprise a stable, resident population, whereas FRß- ΙΜs represent a mixed population of resident and recruited IMs.
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Receptor 2 de Folato , Pneumonia , Humanos , Monócitos/metabolismo , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/genética , Pneumonia/metabolismo , Inflamação/genética , Inflamação/metabolismo , Análise de Sequência de RNA/métodos , Receptor 2 de Folato/metabolismoRESUMO
Astragaloside IV is a biologically active substance derived from the traditional Chinese medicine Astragalus mambranaceus Bunge, and has antioxidant, anti-inflammatory, and anti-apoptotic properties. In this study, we aimed to investigate the effects of astragaloside IV on Klebsiella pneumonia rats and the underlying mechanisms. Klebsiella pneumoniae (K. pneumoniae) rats were treated with different dosages of astragaloside IV (5, 10, and 20 mg/kg) by intragastric administration. The levels of pro-inflammatory cytokines interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α in bronchoalveolar lavage fluid (BALF) were determined. Pathological changes of lung tissue were inspected by HE staining. The expression of transforming growth factor (TGF)-β1 in lung tissue was determined with immunohistochemistry, and the expression levels of TGF-β1, p-Smad2/Smad2, p-Smad3/Smad3, IκBα/p-IκBα, and p65/p-p65 in lung tissue were determined by western blot. The mechanism was further investigated with TGF-β1 inhibitor SB-431542. Astragaloside IV reduced the elevated levels of pro-inflammatory cytokines caused by K. pneumoniae and improved lung tissue damage in a dose-dependent manner. Astragaloside IV also decreased the expression of TGF-β1/Smad signaling pathway-related proteins and decreased the protein levels of inflammation-related p-IκBα and p65 in lung tissues induced by K. pneumoniae. Additionally, it was found that the effects of 20 mg/kg astragaloside IV were similar to SB-431542, which could improve pulmonary fibrosis induced by K. pneumoniae, decrease the levels of TGF-β1/Smad signaling pathway-related proteins in lung, and reduce inflammation at the same time. Astragaloside IV could alleviate the inflammation of rat pneumonia induced by K. pneumoniae through suppressing the TGF-β1/Smad pathway.
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In the wake of the COVID-19 pandemic, lung disorders have become a major health concern for humans. Allergic asthma is the most prevalent form of asthma, and its treatments target the inflammation process. Despite significant developments in the diagnosis and management of allergic asthma, side effects are a major concern. Additionally, its extreme heterogeneity impedes the efficacy of the majority of treatments. Thus, newer, safer therapeutic substances, such as natural products, are desired. Citrus junos Tanaka has traditionally been utilized as an anti-inflammatory, sedative, antipyretic, and antitoxic substance. In this study, the protective effects of Citrus junos Tanaka peel extract (B215) against lung inflammation were examined, and efforts were made to understand the underlying protective mechanism using an HDM-induced lung inflammation murine model. The administration of B215 reduced immune cell infiltration in the lungs, plasma IgE levels, airway resistance, mucus hypersecretions, and cytokine production. These favorable effects alleviated HDM-induced lung inflammation by modulating the NF-κB signaling pathway. Hence, B215 might be a promising functional food to treat lung inflammation without adverse effects.
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Asma , COVID-19 , Citrus , Pneumonia , Camundongos , Humanos , Animais , Pandemias , Modelos Animais de Doenças , COVID-19/metabolismo , Pulmão , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/metabolismo , ImunidadeRESUMO
BACKGROUND: Gut microbiome dysbiosis is associated with lung disease through the gut-lung axis. Abundant proteobacteria increase MMP-9 and contribute to tissue proteolysis followed by neutrophil recruitment, lung tissue injury, and perpetuation of chronic lung disease. We sought to determine if a scientifically formulated probiotic and herbal supplement could attenuate neutrophilic inflammation and improve lung structure and function in models of lung inflammation. METHODS: For in vitro experiments, epithelial cells exposed to proteobacteria were treated with resB-a blend of three probiotic Lactobacillus strains and turmeric, holy basil, and vasaka herbal extracts. For in vivo experimentation, mice exposed to pulmonary proteobacteria-derived lipopolysaccharide were treated by gavage with resB. RESULTS: In vitro, the bacterial and herbal components of resB decreased activity of the MMP-9 pathway. Mice exposed to LPS and pre- and post-treated with resB had decreased neutrophil recruitment and inflammatory biomarkers in bronchoalveolar lavage fluid, serum, and lung tissue compared to untreated mice. CONCLUSIONS: This study describes the mechanisms and efficacy of probiotic and herbal blend in pre-clinical models of lung injury and inflammation.
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Cytokine storm refers to the dysregulated production of inflammatory mediators leading to hyperinflammation. They are often detrimental, and worsen the severity of COVID-19 and other infectious or inflammatory diseases. Cannabinoids are known to have anti-inflammatory effects but their possible therapeutic value on cytokine storms has not been fully elucidated. In vivo and ex vivo studies were carried out to investigate the effects of high-THC and high-CBD extracts on cytokine production in immune cells. Significant differences between the extracts were observed. Subsequent experiments focusing on a specific high CBD extract (CBD-X) showed significant reductions in pro-inflammatory cytokines in human-derived PBMCs, neutrophils and T cells. In vivo mouse studies, using a systemically inflamed mouse model, showed reductions in pro-inflammatory cytokines TNFα and IL-1ß and a concurrent increase in the anti-inflammatory cytokine IL-10 in response to CBD-X extract treatment. Lung inflammation, as in severe COVID-19 disease, is characterized by increased T-cell homing to the lungs. Our investigation revealed that CBD-X extract impaired T-cell migration induced by the chemoattractant SDF1. In addition, the phosphorylation levels of T cell receptor (TCR) signaling proteins Lck and Zap70 were significantly reduced, demonstrating an inhibitory effect on the early events downstream to TCR activation. In a lung inflamed mouse model, we observed a reduction in leukocytes including neutrophil migration to the lungs and decreased levels of IL-1ß, MCP-1, IL-6 and TNFα, in response to the administration of the high-CBD extract. The results presented in this work offer that certain high-CBD extract has a high potential in the management of pathological conditions, in which the secretion of cytokines is dysregulated, as it is in severe COVID-19 disease or other infectious or inflammatory diseases.
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Tratamento Farmacológico da COVID-19 , Síndrome da Liberação de Citocina , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: Echinocystic acid (ECA), a pentacyclic triterpene enriched in various herbs, promotes anti-inflammatory and antioxidant activity; however, its therapeutic effects on atopic dermatitis (AD) or atopic march and the underlying mechanisms of action have not yet been fully elucidated. PURPOSE: This study aimed to elucidate the effects and molecular mechanisms of ECA on AD and allergic inflammation. METHODS: We evaluated the inhibitory effects of ECA using a house dust mite (HDM)-induced AD mouse model and human keratinocytes. RESULTS: The results revealed that ECA improved AD symptoms by decreasing epidermal/dermal thickness, immune cell infiltration, and restoring skin barrier function, as well as an imbalanced immune response. In addition, repeated epicutaneous HDM challenges aggravated allergic inflammation in mice lungs, which was caused by the infiltration of immune cells and collagen deposition, whereas ECA alleviated these symptoms. Moreover, ECA suppressed the expression of T helper cell-derived cytokines, phosphorylation of extracellular signal-regulated kinase, and signal transducer and activator of transcription 1 in the skin and lungs of mice with HDM-induced AD, as well as inhibited the translocation of nuclear factor-κB in HaCaT keratinocytes. CONCLUSION: This is the meaningful study to demonstrate that ECA improves allergic inflammation of the skin and lungs through recovery of the skin barrier, regulation of immune balance, and alleviation of lung inflammation, suggesting that ECA has therapeutic potential as an antiatopic and antiallergic agent that blocks the progression of AD to atopic march.
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Dermatite Atópica , Animais , Citocinas/metabolismo , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Queratinócitos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ácido Oleanólico/análogos & derivados , Pyroglyphidae , PeleRESUMO
BACKGROUND: Evidence supports a critical role of vitamin D status on exacerbation in chronic obstructive pulmonary disease, indicating the need to avoid vitamin D deficiency in these patients. However, oral vitamin D supplementation is limited by the potential risk for hypercalcemia. In this study, we investigated if local delivery of vitamin D to the lungs improves vitamin D-mediated anti-inflammatory action in response to acute inflammation without inducing hypercalcemia. METHODS: We studied vitamin D sufficient (VDS) or deficient (VDD) mice in whom 1α,25(OH)2D3 (0.2 µg/kg) or a vehicle followed by lipopolysaccharide (LPS 25 µg) were delivered to the lung as a micro-spray. RESULTS: Local 1α,25(OH)2D3 reduced LPS-induced inflammatory cells in bronchoalveolar lavage (BAL) in VDS (absolute number of cells: - 57% and neutrophils - 51% p < 0.01) and tended to diminish LPS-increased CXCL5 BAL levels in VDS (- 40%, p = 0.05) while it had no effect on CXCL1 and CXCL2 in BAL and mRNA in lung of VDS and VDD. It also significantly attenuated the increased IL-13 in BAL and lung, especially in VDD mice (- 41 and - 75%, respectively). mRNA expression of Claudin-18 in lung was significantly lower in VDS mice with local 1α,25(OH)2D3 while Claudin-3, -5 and -8 mRNA levels remained unchanged. Finally, in VDD mice only, LPS reduced lung mRNA expression of adhesion junction Zona-occludens-1, in addition to increasing uric acid and total protein in BAL, which both were prevented by local 1α,25(OH)2D3. CONCLUSION: Under normal levels of vitamin D, local 1α,25(OH)2D3 nebulization into the lung efficiently reduced LPS induction of inflammatory cells in BAL and slightly attenuated LPS-increase in CXCL5. In case of severe vitamin D deficiency, although local 1α,25(OH)2D3 nebulization failed to significantly minimize cellular inflammation in BAL at this dose, it prevented epithelial barrier leakage and damage in lung. Additional research is needed to determine the potential long-term beneficial effects of local 1α,25(OH)2D3 nebulization on lung inflammation.
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Pneumonia , Deficiência de Vitamina D , Animais , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Camundongos , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/prevenção & controle , Vitamina DRESUMO
Acute lung injury (ALI) is characterized by severe inflammation. Vitamin D3 is discussed to reduce inflammation in ALI, but the mechanism is not well understood. This study assesses the effect of different calcitriol administration strategies on inflammation and the lung microbiota composition in ALI. In a mouse model, the alveolus and airway pathology are assessed by immunohistology. mRNA expression is determined by Real-Time Quantitative PCR and protein expressions is detected by Western-blotting. The composition of microbiota is performed by 16s DNA high-throughput sequencing. Short-term vitamin D3 supplementation prevents lipopolysaccharide-induced ALI by preventing pro-inflammatory cytokines including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). In contrast, long-term treatment over 3 days, 6 days, or 10 days had no such effect. Short-term vitamin D3, but not long-term pretreatment significantly reduces the phosphorylation of signal transducer and activator of transcription 3 and suppressor of cytokine signaling 3, but upregulates the phosphorylation of inhibitor of nuclear factor-κ-gene binding. Furthermore, an increased relative abundance of Rodentibacter genus in LPS-challenged mice bronchoalveolar lavage fluid is observed, which is sensitive to short-term vitamin D3 treatment, effectively alleviating the Rodentibacter abundance. Correlation analysis shows that the load of Rodentibacter positively correlated with the IL-1ß, IL-6, and TNF-α gene expression. The data support that a single administration of vitamin D3 may work as an adjuvant therapy for acute lung inflammation.
Assuntos
Lesão Pulmonar Aguda , Lipopolissacarídeos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/química , Colecalciferol/farmacologia , Citocinas/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/toxicidade , Pulmão , Camundongos , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The flower buds of Tussilago farfara L. (Abbreviated as FTF) were widely used in traditional Chinese medicine (TCM) to treat respiratory diseases, including asthma, dry throat, great thirst, turbid saliva, stinky pus, and coughs caused by various causes. AIM OF STUDY: The aim of study is to explore the efficiency of FTF in vitro and in vivo for the treatment of lung inflammation, and to illustrate the possible mechanisms of FTF in treating inflammation-related respiratory diseases targeting NOD-like receptor 3 (NLRP3) inflammasome, nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear transcription factor-κB (NF-κB). METHODS: Lung inflammation model in vivo was induced by exposure of mice to cigarette smoke (CS) for two weeks. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), inflammatory factors, and histology in lung tissues were investigated in presence or absence of ethanol extract of the flower buds of T. farfara L. (FTF-EtOH). In the cell-based models, nitric oxide (NO) assay, flow cytometry assay, enzyme-linked immunosorbent assay (Elisa), and glutathione (GSH) assay were used to explore the anti-inflammatory and anti-oxidant effects of FTF-EtOH. Possible anti-inflammatory mechanisms of FTF targeting NLRP3 inflammasome, Nrf2, and NF-κB have been determined using western blot, quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), immunofluorescence assay, nuclear and cytoplasmic extraction, and ubiqutination assay. RESULTS: FTF-EtOH suppressed CS-induced overproduction of inflammatory factors [e.g., tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß)], and upregulation of the content of intracellular MDA in the lung homogenate of mice. In cell-based models, FTF-EtOH reduced the lipopolysaccharide (LPS)-induced overproduction of inflammatory factors, and attenuated the CS extract-induced overgeneration of reactive oxygen species (ROS). Furthermore, FTF-EtOH up-regulated Nrf2 and its downstream genes through enhancing the stability of Nrf2 protein, and inhibited the activation of NF-κB and NLRP3 inflammasome, which have been confirmed by detecting the protein levels in the mouse model. CONCLUSIONS: FTF-EtOH effectively attenuated lung inflammation in vitro and in vivo. The protection of FTF-EtOH against inflammation was produced by activation of Nrf2 and inhibitions of NF-κB and NLRP3 inflammasome. These datas definitely support the ethnopharmacological use of FTF as an anti-inflammatory drug for treating respiratory diseases in TCM.
Assuntos
Inflamação/tratamento farmacológico , Pneumopatias/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Fumaça/efeitos adversos , Tussilago/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Flores/química , Humanos , Inflamação/induzido quimicamente , Pneumopatias/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/química , Mucosa Respiratória/citologia , NicotianaRESUMO
This study is an attempt to characterize the chemical composition and antioxidant activity of olive leaves variety (namely Bouricha variety) that is very widespread in the East of Algeria. The aqueous extract (AE) of leaves was initially analyzed for its phenolic profile. Using the liquid chromatography coupled to tandem mass spectrometry analysis, it was possible to identify the predominant components in the AE of the leaves. This extract was hydrolyzed with acid and gave hydroxytyrosol (HT). AE and HT were evaluated for their 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity, ferric reducing antioxidant power and total antioxidant activity by phosphomolybdenum method. The antioxidant and anti-asthmatic activities of these extracts were examined in a model of experimental asthma in Wistar rats. For measuring the intensity of the airway inflammation, oxidative stress parameters were analyzed in lungs and a histological study of this tissue was performed. The obtained results showed that the sensitization of the ovalbumin (OVA) group induced lung inflammation and severe lipid peroxidation (LPO) revealed by a significant increase in malondialdehyde (MDA) levels and a decrease in the non-enzymatic and enzymatic antioxidant systems. However, the administration of AE and HT extracts significantly improved the antioxidant state in asthma disease and provided evidence for the relation between phenolic compounds and the high antioxidant activity of olive leaves extracts, especially HT more than AE.
Assuntos
Asma , Olea , Argélia , Animais , Antioxidantes , Asma/induzido quimicamente , Asma/tratamento farmacológico , Extratos Vegetais/farmacologia , Folhas de Planta , Ratos , Ratos WistarRESUMO
Acute lung injury (ALI) is a kind of lung disease mainly caused by excessive inflammatory reaction. At present, there is a lack of effective therapeutic drugs in clinic. The aim of this study was to investigate the improvement effect of Panax notoginseng saponins (PNS) on ALI and its potential mechanism. The model of wild-type C57BL/6J mice was established by intratracheal instillation of 50 μL 25 mg·mL-1 lipopolysaccharide (LPS). 24 h later, 200 and 400 mg·kg-1 PNS was given intragastric, respectively. 24 h after administration, the improvement effect of PNS on ALI mice was evaluated by lung function, wet-to-dry weight ratio (W/D), total protein, interleukin 6 (IL6) and tumor necrosis factor α (TNFα) concentration of bronchoalveolar lavage fluid (BALF), expression levels of IL6 and TNFα in lung tissues, pathological changes of lung tissues and expression of inflammatory cells in BALF. The protein expression levels of NF-κB and its upstream kinases in Raw264.7 cells and ALI mice lung tissues were further detected to evaluate the potential mechanism of PNS improving ALI mice. The experimental scheme was approved by the Animal Experiment Ethics Committee of Shanghai University of Traditional Chinese Medicine. It was found that 400 mg·kg-1 PNS could significantly improve the lung function of ALI mice, reduce the contents of W/D, BALF total protein, IL6 and TNFα, neutrophils expression in BALF and the infiltration of inflammatory cells in lung tissue. In Raw264.7 cells and ALI mice lung tissue, PNS significantly reduced the expression of NF-κB, reduced the protein expression and phosphorylation of NF-κB, promoted the expression of IκBα, and inhibited the inflammatory response. This study showed that PNS can improve ALI by inhibiting the activity of NF-κB, inhibiting the release of inflammatory factors and inflammatory cells infiltration, alleviating lung inflammation.