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Objective: Bronchial asthma is a prevalent respiratory disorder characterized by airway inflammation. This study aimed to investigate the protective effect of Pingchuanning decoction (PCN) on airway inflammation in bronchial asthma, focusing on the role of autophagy and its underlying molecular mechanism. Methods: Using an in vitro lipopolysaccharide (LPS)-induced inflammatory damage model of human airway epithelial cells (16HBE), we assessed the effect of PCN. Various experiments were performed to evaluate the expression of autophagy-related genes, autophagosome and vesicle counts, and reactive oxygen species (ROS) levels. Results: First, PCN reduced LPS-induced cellular inflammation. Second, PCN decreased the number of autophagosomes and autophagic vesicles. And third, PCN significantly reduced reactive oxygen species (ROS) levels. Most importantly, PCN also down-regulated LPS-induced expression of HMGB1, Beclin-1, and autophagy-related gene 5 (ATG5) while enhancing the expression of B-cell lymphoma 2 (Bcl-2), which further reduced the LC3II/I ratio. Conclusion: PCN reduces the 16HBE inflammatory response by inhibiting the overexpression of ROS/HMGB1/Beclin-1 mediated cell autophagy. Therefore, it may serve as a potential drug for treating bronchial asthma.
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Asma , Proteína HMGB1 , Humanos , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/farmacología , Especies Reactivas de Oxígeno/uso terapéutico , Beclina-1/genética , Proteína HMGB1/genética , Proteína HMGB1/farmacología , Proteína HMGB1/uso terapéutico , Lipopolisacáridos , Asma/tratamiento farmacológico , Asma/metabolismo , Asma/patología , Autofagia/genética , Inflamación/tratamiento farmacológicoRESUMEN
Metabolism is undoubtedly significantly correlated with the efficacy and safety of traditional Chinese medicine. In clinic, Qi-Yu-San-Long decoction (QYSLD) has achieved good results in the treatment of non-small-cell lung cancer (NSCLC). Nevertheless, a detailed understanding of the compounds (prototypes and metabolites) of QYSLD and its dynamic metabolic profile in plasma has not been revealed. METHODS: In this study, a rapid and sensitive method based on ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF/MSE ), combined with a four-step analysis strategy, was established to investigate QYSLD metabolic profile in rat plasma. RESULTS: In all, 101 xenobiotics (41 prototypes and 60 QYSLD-related metabolites) were identified in rat plasma. The research uncovered metabolic profiles of alkaloids, saponins, flavonoids, iridoids, anthraquinones, and phenylpropanoids of QYSLD in rat plasma. The dynamic changes in these xenobiotics were also observed at different time intervals. At 0.5 h after oral administration, only 15 prototypes and 11 metabolites were detected. Within 24 h, 4 prototypes and 20 metabolites can still be detected. Four prototypes and 10 metabolites had the phenomenon of emergence-disappearance-reappearance in vivo. CONCLUSION: In rat plasma, 101 xenobiotics of QYSLD were identified and their dynamic metabolic profiles were systematically delineated, which laid a material basis for further research of the pharmacodynamic substances of QYSLD inhibiting NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Medicamentos Herbarios Chinos , Neoplasias Pulmonares , Ratas , Animales , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/química , Ratas Sprague-Dawley , Cromatografía Liquida , Xenobióticos , Administración OralRESUMEN
Research into traditional Chinese medicine metabolism in feces is one of the key avenues to understanding the fate of traditional Chinese medicines in vivo. In this study, we used ultraperformance liquid chromatography-quadrupole time-of-flight MS in combination with a post-targeted screening strategy to identify the prototype components and metabolites in rat feces after oral administration. Based on our group's previous research, the component database of Qi-Yu-San-Long decoction (QYSLD) was established. Prototype components were screened from the fecal samples based on summarized chromatographic and MS behaviors. According to the chemical structure characteristics of related compounds, the possible metabolic pathways were inferred, and the metabolites related to QYSLD were predicted. We extracted ion chromatograms by predicting the m/z values of metabolite excimer ions and identified related metabolites based on their retention time and fragmentation behavior. A total of 93 QYSLD-related xenobiotics were confirmed or tentatively identified in rat fecal samples, and the results indicated that the main metabolic pathways of QYSLD were hydrolysis, deglycosylation, oxidation, reduction, decarboxylation, methylation and acetylation. This study presents a rapid method for identifying the prototype components and metabolites, and offers valuable insights into the biotransformation profiling of QYSLD in rat feces.
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Medicamentos Herbarios Chinos , Ratas , Animales , Ratas Sprague-Dawley , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/química , Cromatografía Liquida/métodos , Espectrometría de Masas/métodos , Heces/química , Administración OralRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD), a prevalent, progressive respiratory disease, has become the third leading cause of death globally. Increasing evidence suggests that intestinal and pulmonary microbiota dysbiosis is associated with COPD. Researchers have shown that T helper (Th) 17/regulatory T (Treg) imbalance is involved in COPD. Qibai Pingfei Capsule (QBPF) is a traditional Chinese medicine used to treat COPD clinically in China. However, the effects of QBPF intervention on the Th17/Treg balance and microbiota in the gut and lung are still poorly understood. METHODS: This study divided the rats into three groups (n = 8): control, model, and QBPF group. After establishing the model of COPD for four weeks and administering of QBPF for two weeks, Th17 cells, Treg cells, their associated cytokines, transcription factors, and intestinal and pulmonary microbiota of rats were analyzed. Furthermore, the correlations between intestinal and pulmonary microbiota and between bacterial genera and pulmonary function and immune function were measured. RESULTS: The results revealed that QBPF could improve pulmonary function and contribute to the new balance of Th17/Treg in COPD rats. Meanwhile, QBPF treatment could regulate the composition of intestinal and pulmonary microbiota and improve community structure in COPD rats, suppressing the relative abundance of Coprococcus_2, Prevotella_9, and Blautia in the gut and Mycoplasma in the lung, but accumulating the relative abundance of Prevotellaceae_UCG_003 in the gut and Rikenellaceae_RC9_gut_group in the lung. Additionally, gut-lung axis was confirmed by the significant correlations between the intestinal and pulmonary microbiota. Functional analysis of microbiota showed amino acid metabolism was altered in COPD rats in the gut and lung. Spearman correlation analysis further enriched the relationship between the microbiota in the gut and lung and pulmonary function and immune function in COPD model rats. CONCLUSIONS: Our study indicated that the therapeutic effects of QBPF may be achieved by maintaining the immune cell balance and regulating the gut-lung axis microbiota, providing references to explore the potential biomarkers of COPD and the possible mechanism of QBPF to treat COPD.
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Microbioma Gastrointestinal , Enfermedad Pulmonar Obstructiva Crónica , Animales , Pulmón , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Ratas , Linfocitos T Reguladores , Células Th17RESUMEN
Chronic obstructive pulmonary disease (COPD), a progressive respiratory disease, is characterized by the alveolar epithelium injury and persistent airway inflammation. It is documented that oscillation and dysregulated expression of circadian clock genes, like Bmal1, Per1, and Per2, involved in COPD pathogenies, including chronic inflammation and imbalanced autophagy level, and targeting the associations of circadian rhythm and autophagy is promising strategies in the management and treatment of COPD. Herein, we reviewed the mechanisms of the circadian clock and the unbalance of the autophagic level in COPD, as well as the link between the two, so as to provide further theoretical bases for the study on the pathogenesis of COPD.
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Autofagia/fisiología , Relojes Circadianos/fisiología , Enfermedad Pulmonar Obstructiva Crónica/etiología , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/fisiología , Proteína beta Potenciadora de Unión a CCAAT/fisiología , Relojes Circadianos/genética , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/fisiología , Melatonina/fisiologíaRESUMEN
Multidrug resistance associated protein-1 (MRP1) and Notch signaling are closely related and both play a critical role in chronic obstructive pulmonary disease (COPD) establishment and progression. The aim of our work was to test whether Notch1 is involved in allyl isothiocyanate (AITC) induced MRP1 expression. We used cigarette smoke extract (CSE) to simulate the smoking microenvironment in vitro. The results demonstrated that CSE led to apoptosis as well as reduced the expression of Notch1, Hes1, and MRP1, while AITC significantly reversed this downregulation. Transfected with Notch1 siRNA downregulated MRP1 expression and activity, aggravated the suppression effect by CSE, and abolished the AITC-induced Notch1, Hes1, and MRP1 expression. Validation of the correlation between Notch1 and MRP1 was implemented by gel-shift assays (electrophoretic mobility shift assay). The result revealed an interaction between a specific promoter region of MRP1 and the intracellular domain of Notch1. In conclusion, Notch1 signaling positively regulated MRP1 in 16HBE cells and AITC induced MRP1 expression and function may be attributed to Notch1 signaling. These findings show that Notch1 and MRP1 might have a potential protective effect in the COPD process and become a new therapeutic target for COPD or other lung diseases. It also provides a theoretical basis for the therapeutic effects of AITC.
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Bronquios/citología , Células Epiteliales/efectos de los fármacos , Isotiocianatos/farmacología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Receptor Notch1/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/citología , Células Epiteliales/metabolismo , Humo/efectos adversos , Productos de Tabaco/análisisRESUMEN
The differences of transitional components and metabolic processes of Huatan Jiangqi Capsules(HTJQ) in rats under normal physiological and pathological conditions of COPD were analyzed by UPLC-Q-TOF-MS. The rat COPD model was established by passive smoking and intratracheal instillation of lipopolysaccharide. After the normal and COPD model rats were douched with HTJQ, the blood was collected from hepatic portal vein and the drug-containing serum samples were prepared by methanol precipitation of protein. Then, 10 batches of drug-containing serum samples of HTJQ were prepared and analyzed by UPLC serum fingerprint to evaluate the quality and stability of drug-containing serum samples. UPLC-Q-TOF-MS was used to collect the mass spectrometric information of the transitional components. Twenty-eight transitional components of HTJQ in normal rats and 25 transitional components of HTJQ in COPD model rats were identified by UPLC-Q-TOF-MS. Under pathological and physiological conditions, there were not only the same transitional components in rat serum, but also corresponding differences. Further studies showed that there were also differences in the metabolic process of transitional components between the two conditions. In normal rats, most of the metabolic types of transitional components were phase I reactions. In COPD model rats, phase â reactions decreased and phase â ¡ reactions increased correspondingly. With UPLC-Q-TOF-MS technology, the differences of transitional components and the metabolism process of HTJQ in rats under normal physiological and pathological conditions were analyzed. The results showed that types of transitional components and the activity of some metabolic enzymes would be changed in COPD pathological state, which would affect the metabolic process of bioactive components in vivo. It laid a foundation for further elucidating the metabolic process and pharmacodynamic substance basis of HTJQ.
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Medicamentos Herbarios Chinos/farmacocinética , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Suero/química , Animales , Cápsulas , Cromatografía Líquida de Alta Presión , Espectrometría de Masas , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , RatasRESUMEN
BACKGROUND: Pingchuanning decoction is a well-known traditional Chinese medicine for the treatment of airway inflammatory diseases, including asthma. However, the potential mechanism by which Pingchuanning decoction contributes to the amelioration of airway inflammation remains unknown. METHODS: A rat model of asthma was well established by inducing ovalbumin. Lipopolysaccharide-stimulated rat tracheal epithelial (RTE) cells were used as cellular model. Lung histopathology and goblet cell hyperplasia were assessed by hematoxylin-eosin (HE) and periodic acid Schiff staining, respectively. Total inflammatory cells count and RTE cell apoptosis were analyzed by flow cytometry. The autophagic activities were evaluated by immunohistochemical and immunofluorescence analysis and Western blot analysis of autophagy-related proteins. We also detected the effects of Pingchuanning decoction on phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and high-mobility group box 1 (HMGB1)-mediated toll-like receptor 4 (TLR4)/NF-κB pathways-related proteins and inflammatory cytokines using the Western blot analysis and enzyme-linked immunosorbent assay. RESULTS: Pingchuanning decoction effectively attenuated pulmonary pathology and autophagy. Treatment with Pingchuanning decoction activated PI3K/Akt/mTOR pathway and inhibited HMGB1/TLR4/NF-κB pathway, which could be overturned by LY294002, a PI3K antagonist, or rapamycin (Rapa), an autophagy inducer. CONCLUSION: Pingchuanning decoction exerted a therapeutic effect on asthma by inhibiting autophagy via PI3K/Akt /mTOR signaling pathway.
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Antiasmáticos/farmacología , Asma/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Fosfatidilinositol 3-Quinasa/genética , Proteínas Proto-Oncogénicas c-akt/genética , Serina-Treonina Quinasas TOR/genética , Animales , Asma/inducido químicamente , Asma/genética , Asma/metabolismo , Autofagia/efectos de los fármacos , Autofagia/genética , Dexametasona/farmacología , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Regulación de la Expresión Génica , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ovalbúmina/administración & dosificación , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Resultado del TratamientoRESUMEN
This research explores the effects of Qibaipingfei (QBPF) capsules on pulmonary vascular relaxation in vitro and the relationship of the ATP-sensitive K+ (KATP) channel and nitric oxide (NO) pathway. Vasodilator effects of QBPF (0.125-2 g/kg) on rat pulmonary artery rings were observed using a multi-wire myograph system. The maximum relaxation (Emax) of QBPF was detected following treatment involving endothelial denudation, Nω-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4] oxadiazolo[4,3-α]quinoxalin-1-one (ODQ), or glyburide (GLYB). Furthermore, rat models of phlegm and blood stasis syndrome combined with chronic obstructive pulmonary disease (COPD) were established using compound factors. KIR6.1 and SUR2B protein expression was analyzed by western blotting. After 9,11-dideoxy-11-α],9-α]-epoxy-methanoprostaglandinF2α (U46619) was used to pre-constrict endothelium-intact pulmonary artery rings, QBPF induced the effects of concentration-dependent relaxation at a concentration for 50% of maximal effect (EC50) of 0.56 g/L and Emax of 84.30% ± 6.27%. After the endothelium was denuded, the vasodilator effects reduced significantly (P<0.01). QBPF-induced relaxation was inhibited by L-NAME, ODQ, and GLYB (P<0.01). The vasodilator effect was also attenuated in the model group (Emax=62.63%±10.02, EC50 = 0.72 g/L, P<0.01). In comparison with expression in the control group, SUR2B protein expression was down-regulated in the model group (P<0.01) but no significant difference was detected in KIR6.1 protein expression between the groups (P>0.05). QBPF and nicorandil (Nic) treatment up-regulated SUR2B KATP channel expression (P<0.05). QBPF induces endothelial-dependent relaxation in pulmonary artery rings in vitro, through a mechanism that potentially activates the KATP channel in pulmonary vascular smooth muscles via the NO-cyclic GMP (cGMP)-dependent pathway.
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GMP Cíclico/metabolismo , Medicamentos Herbarios Chinos/farmacología , Canales KATP/metabolismo , Óxido Nítrico/metabolismo , Vasodilatadores/farmacología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Animales , Cápsulas , Modelos Animales de Enfermedad , Técnicas de Cultivo de Órganos , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Ratas Sprague-Dawley , Pruebas de Función Respiratoria , Receptores de Sulfonilureas/metabolismo , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: To evaluate the effect of Liuweibuqi capsules on chronic obstructive pulmonary disease (COPD) through the JAK/STAT pathway. METHODS: Lung function was measured with a spirometer. Changes in lung histology were observed using H&E staining. Cigarette smoke extract combined with lipopolysaccharide (CSE+LPS) was used to establish the cellular COPD model. Cytokine levels were determined using ELISA, and changes in the JAK/STAT pathway were evaluated using western blotting. The CCK8 method and flow cytometry were used to measure cell viability and apoptosis, respectively. RESULTS: Liuweibuqi capsules reduced the damage in the lung tissues and the loss of lung function in the COPD rats. Additionally, the levels of interleukin (IL)-1ß, interferon γ (IFNγ), IL-6, tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-ß1 were higher, whereas IL-10 was lower in the model control (MC) and CSE+LPS groups than in the normal group. The phosphorylation levels of JAK1, JAK2, STAT1, STAT3 and STAT5 were higher and the levels of SOCS1 and SOCS3 were lower in the MC group and CSE+LPS group compared with the normal group. After Liuweibuqi capsule treatment, the expression of inflammatory cytokines and elements of the JAK/STAT pathway were lower. In addition, over-expression of STAT3 blocked the effects of the Liuweibuqi capsules on the release of inflammatory cytokines, cell viability and apoptosis. CONCLUSION: Our findings suggested that Liuweibuqi capsule might effectively ameliorate the progression of COPD via the JAK/STAT pathway.
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Células Epiteliales Alveolares/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Quinasas Janus/metabolismo , Pulmón/efectos de los fármacos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Factores de Transcripción STAT/metabolismo , Transducción de Señal/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Animales , Células Cultivadas , Pulmón/metabolismo , Pulmón/patología , Masculino , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Ratas Sprague-DawleyRESUMEN
To investigate the ATP-sensitive potassium channel (KATP channel) protein expressions during different periods under hypoxia condition and explore the effect of Qibai Pingfei capsule medicated serum (hereinafter referred to as QBPF) on the correlation between the protein expressions of KATP channel and nitric oxide in rat pulmonary arterial smooth muscle cells(PASMCs). Qibai Pingfei capsules were given to SD rats via continuous gavage for 10 days to obtain QBPF. Primary rats PASMCs were cultured by the direct adherent culture method. Western blot was applied to detect the protein expression levels of KATP channel (Kir6.1 and SUR2B) in PASMCs. Then the noncompetitive inhibitor of NO synthase--Nω-nitro-L-arginine methyl ester(L-NAME) and KATP channel inhibitor--glyburide(GLYB) were applied respectively to evaluate the effect of QBPF on the protein expressions of KATP channel. The protein expressions of Kir6.1 and SUR2B were increased after 6-hour hypoxia treament, peaked at the 24-hour hypoxia treament, and decreased in both 48-hour and 72-hour hypoxia groups. Especially, QBPF could further up-regulate the Kir6.1 and SUR2B protein expressions under 24-hour hypoxia condition; however, such up-regulation effect could be blocked by KATP channel inhibitor GLYB and NO specific inhibitor L-NAME, indicating that QBPF played the role of opening KATP channel. The regulatory mechanism was probably associated with up-regulating KATP channel protein expression via NO relative pathway, involving pulmonary vasodilation, and thus relieving the occurence and development of COPD.
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Medicamentos Herbarios Chinos/farmacología , Canales KATP/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Óxido Nítrico/metabolismo , Animales , Arteria Pulmonar/citología , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To observe the changes in proportion of CD4 + CD25 + Foxp3 + regulatory T cells (Treg) in peripheral blood of different stages of CPOD and intervention of Qibai Pingfei Capsules. METHODS: The rats were randomly divided into three groups,including normal group, COPD group and Qibai Pingfei Capsules(2. 88 g/kg)group. At the end of 7,14,21 and 28 days,eight rats were sacrificed in each group. CD4 + CD25 + Foxp3 + Treg cells in peripheral blood were measured by flow cytometry method. RESULTS: Compared with normal group, the percentages of CD4 + % in peripheral blood were not significantly different at the end of 7, 14, 21 and 28 days. However, CD4 + CD25 + % and CD4 + CD25 + Foxp3 +/CD4 + were significantly increased and CD4 + CD25 + Foxp3 + Treg% were significantly decreased at the end of 14,21 and 28 days. Compared with model group, CD4 + CD25 + %, CD4 + CD25 + Foxp3 +/CD4 + were significantly decreased, CD4 + CD25 + Foxp3 + Treg % were significantly increased at different stages of CODP. CONCLUSION: Immune disorders may exist in COPD, and Treg cells may be involved in the process of COPD. Meanwhile,the protective effect in COPD rats of Qibai Pingfei Capsules may be associated with improving the percentage of suppressive CD4 + CD25 + Foxp3 + Tregs.
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Medicamentos Herbarios Chinos/farmacología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Linfocitos T Reguladores/efectos de los fármacos , Animales , Cápsulas , Modelos Animales de Enfermedad , Citometría de Flujo , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Ratas , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/efectos de los fármacos , Linfocitos T Reguladores/citologíaRESUMEN
Chronic obstructive pulmonary disease (COPD) exacerbations accelerate loss of lung function and increased mortality. The complex nature of COPD presents challenges in accurately predicting and understanding frequent exacerbations. The present study aimed to assess the metabolic characteristics of the frequent exacerbation of COPD (COPDFE) phenotype, identify potential metabolic biomarkers associated with COPDFE risk and evaluate the underlying pathogenic mechanisms. An internal cohort of 30 stable patients with COPD was recruited. A widely targeted metabolomics approach was used to detect and compare serum metabolite expression profiles between patients with COPDFE and patients with nonfrequent exacerbation of COPD (COPDNE). Bioinformatics analysis was used for pathway enrichment analysis of the identified metabolites. Spearman's correlation analysis assessed the associations between metabolites and clinical indicators, while receiver operating characteristic (ROC) analysis evaluated the ability of metabolites to distinguish between two groups. An external cohort of 20 patients with COPD validated findings from the internal cohort. Out of the 484 detected metabolites, 25 exhibited significant differences between COPDFE and COPDNE. Metabolomic analysis revealed differences in lipid, energy, amino acid and immunity pathways. Spearman's correlation analysis demonstrated associations between metabolites and clinical indicators of acute exacerbation risk. ROC analysis demonstrated that the area under the curve (AUC) values for Dfructose 1,6bisphosphate (AUC=0.871), arginine (AUC=0.836), L2hydroxyglutarate (L2HG; AUC=0.849), diacylglycerol (DG) (16:0/20:5) (AUC=0.827), DG (16:0/20:4) (AUC=0.818) and carnitineC18:2 (AUC=0.804) were >0.8, highlighting their discriminative capacity between the two groups. External validation results demonstrated that DG (16:0/20:5), DG (16:0/20:4), carnitineC18:2 and L2HG were significantly different between patients with COPDFE and those with COPDNE. In conclusion, the present study offers insights into early identification, mechanistic understanding and personalized management of the COPDFE phenotype.
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Biomarcadores , Metabolómica , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/sangre , Masculino , Femenino , Metabolómica/métodos , Anciano , Biomarcadores/sangre , Persona de Mediana Edad , Curva ROC , Metaboloma , Progresión de la Enfermedad , Carnitina/sangre , Carnitina/análogos & derivadosRESUMEN
Shenqi-Tiaoshen formula (SQTSF) is a traditional Chinese medicine (TCM) prescription that has been employed in the treatment of chronic obstructive pulmonary disease (COPD). Clinical practice has demonstrated that SQTSF is an effective prescription for stable COPD. However, owing to the complexity of TCM prescription, there is a lack of in-depth understanding of the chemical components of SQTSF and its in vivo metabolism studies. In this study, a comprehensive analytical strategy based on ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was established to identify the chemical components, the absorbed components, and the metabolites of SQTSF given by gavage in rats, and analyze their dynamic changes. As a result, 86 chemical components of SQTSF were characterized, which were mainly categorized into flavonoids, saponins, organic acids, terpenoids, etc. Among them, 13 compounds were confirmed unambiguously by reference standards. Furthermore, 20 prototype components and 46 metabolites were detected in rat plasma at different time points. It was found that one prototype component and thirteen metabolites could be detected during the entire 24 h, indicating that these compounds were slowly eliminated and thus accumulated in vivo over a prolonged duration. Interestingly, the phenomenon that three prototype components and fourteen metabolites reappeared after a period of disappearance from the plasma was found. It was also observed that different prototype components may generate the same metabolite. The metabolic processes of SQTSF in rats mainly included oxidation, reduction, hydration, demethylation, deglycosylation, methylation, acetylation, glucuronidation, glutathionylation, and associated combination reactions. Overall, the present study identified the chemical components of SQTSF and their dynamic metabolic profile in rat plasma, which provided a systematic and applicable strategy for screening and characterization of the prototype components and metabolites of TCM compound preparations.
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Medicamentos Herbarios Chinos , Enfermedad Pulmonar Obstructiva Crónica , Ratas , Animales , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Metaboloma , Medicamentos Herbarios Chinos/químicaRESUMEN
Background: Solasonine, as a major biological component of Solanum nigrum L., has demonstrated anticancer effects against several malignancies. However, little is understood regarding its biological target and mechanism in non-small cell lung cancer (NSCLC). Methods: We conducted an analysis on transcriptomic data to identify differentially expressed genes (DEGs), and employed an artificial intelligence (AI) strategy to predict the target protein for solasonine. Subsequently, genetic dependency analysis and molecular docking were performed, with Acetylcholinesterase (ACHE) selected as a pivotal marker for solasonine. We then employed a range of bioinformatic approaches to explore the relationship between ACHE and solasonine. Furthermore, we investigated the impact of solasonine on A549 cells, a human lung cancer cell line. Cell inhibition of A549 cells following solasonine treatment was analyzed using the CCK8 assay. Additionally, we assessed the protein expression of ACHE, as well as markers associated with apoptosis and inflammation, using western blotting. To investigate their functions, we employed a plasmid-based ACHE overexpression system. Finally, we performed dynamics simulations to simulate the interaction mode between solasonine and ACHE. Results: The results of the genetic dependency analysis revealed that ACHE could be identified as the pivotal target with the highest docking affinity. The cell experiments yielded significant findings, as evidenced by the negative regulatory effect of solasonine treatment on tumor cells, as demonstrated by the CCK8 assay. Western blotting analysis revealed that solasonine treatment resulted in the downregulation of the Bcl-2/Bax ratio and upregulation of cleaved caspase-3 protein expression levels. Moreover, we observed that ACHE overexpression promoted the expression of the Bcl-2/Bax ratio and decreased cleaved caspase-3 expression in the OE-ACHE group. Notably, solasonine treatment rescued the Bcl-2/Bax ratio and cleaved caspase-3 expression in OE-ACHE cells compared to OE-ACHE cells without solasonine treatment, suggesting that solasonine induces apoptosis. Besides, solasonine exhibited its anti-inflammatory effects by inhibiting P38 MAPK. This was supported by the decline in protein levels of IL-1ß and TNF-α, as well as the phosphorylated forms of JNK and P38 MAPK. The results from the molecular docking and dynamics simulations further confirmed the potent binding affinity and effective inhibitory action between solasonine and ACHE. Conclusions: The findings of the current investigation show that solasonine exerts its pro-apoptosis and anti-inflammatory effects by suppressing the expression of ACHE.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Acetilcolinesterasa/genética , Caspasa 3/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Simulación del Acoplamiento Molecular , Inteligencia Artificial , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Antiinflamatorios/uso terapéuticoRESUMEN
Background: A potential link between asthma and frailty has been suggested in previous studies. However, the nature of the causal relationship between these two conditions warrants further investigation. Therefore, this study assessed the bidirectional causality between asthma and frailty risk using two-sample Mendelian randomization (MR). Methods: The study data were obtained from the genome-wide association study (GWAS) dataset, with 337,159 samples representing asthma data and 175,226 samples representing frailty. The causal relationship between the two disorders was assessed by selecting the single nucleotide polymorphisms (SNPs), significantly associated with both asthma and frailty. The inverse variance weighting (IVW) method was used as the main analytical method to estimate the possible influence of causality. Sensitivity analysis was also performed using Mr-Egger intercept, funnel plot, "leave-one-out," and Cochran Q test. In addition, potential mediators were investigated by risk factor analysis. Result: The IVW method showed an increased risk of frailty due to increased genetic susceptibility factors and the number of to asthma (OR = 2.325, 95%CI:1.958-2.761; p = 6.527498e-22), while no horizontal pleiotropy was observed for the Mr-Egger intercept (p = 0.609) and the funnel plot. The Cochran Q value was 72.858, p = 0.024, and there was heterogeneity in the Cochran Q-value. No single SNP was observed for "leave-one-out" that had a biasing effect on the instrumental variables. In addition, genetic susceptibility to frailty was associated with asthma (OR = 1.088, 95%CI:1.058-1.119; p = 4.815589e-09). In the causal relationship described above, several risk factors for frailty are complex, with asthma leading to a significant reduction in physical activity endurance. Conclusion: Our findings suggest a probable positive causal effect of asthma on the risk of developing frailty, potentially mediated by reduced physical activity endurance. At the same time, a causal relationship exists between frailty and asthma. Therefore, assessment strategies for frailty should include asthma and vice versa.
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In this study, we have employed metabolomics technology in combination with network pharmacology to ascertain the key metabolites and hub genes. The objective was to explore the pathway of Qibai Pingfei Capsule (QBPF) in treating COPD through metabolomics. We identified 96 differential metabolites in the lung tissues of rats belonging to control and model groups, out of which 47 were observed to be critical (VIP >2, p < 0.05). Furthermore, 16 important differential metabolites were reversed after QBPF treatment. Using network pharmacology, we identified 176 core targets of 81 drug-active ingredients. Our comprehensive analysis of network pharmacology and metabolomics enabled us to identify a core target, prostaglandin-endoperoxide synthase 2 (PTGS2), and a core metabolic pathway for glutathione metabolism. Finally, the result of molecular docking showed that PTGS2 had strong binding activity to 18 compounds including Fumarine and Kaempferol, etc.. PTGS2 is a marker of ferroptosis, so we wanted to explore whether QBPF could inhibit ferroptosis in COPD. The results showed that ferroptosis was involved in the pathogenesis of COPD, and QBPF could inhibit the occurrence of ferroptosis. In conclusion, the mechanism of QBPF for treating COPD may be related to PTGS2 expression, glutathione metabolism and ferroptosis.
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Background: Chronic obstructive pulmonary disease (COPD) affects approximately 400 million people worldwide and is associated with high mortality and morbidity. The effect of EPHX1 and GSTP1 gene polymorphisms on COPD risk has not been fully characterized. Objective: To investigate the association of EPHX1 and GSTP1 gene polymorphisms with COPD risk. Methods: A systematic search was conducted on 9 databases to identify studies published in English and Chinese. The analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines (PRISMA). The pooled OR and 95% CI were calculated to evaluate the association of EPHX1 and GSTP1 gene polymorphisms with COPD risk. The I2 test, Q test, Egger's test, and Begg's test were conducted to determine the level of heterogeneity and publication bias of the included studies. Results: In total, 857 articles were retrieved, among which 59 met the inclusion criteria. The EPHX1 rs1051740 polymorphism (homozygote, heterozygote, dominant, recessives, and allele model) was significantly associated with high risk of COPD risk. Subgroup analysis revealed that the EPHX1 rs1051740 polymorphism was significantly associated with COPD risk among Asians (homozygote, heterozygote, dominant, and allele model) and Caucasians (homozygote, dominant, recessives, and allele model). The EPHX1 rs2234922 polymorphism (heterozygote, dominant, and allele model) was significantly associated with a low risk of COPD. Subgroup analysis showed that the EPHX1 rs2234922 polymorphism (heterozygote, dominant, and allele model) was significantly associated with COPD risk among Asians. The GSTP1 rs1695 polymorphism (homozygote and recessives model) was significantly associated with COPD risk. Subgroup analysis showed that the GSTP1 rs1695 polymorphism (homozygote and recessives model) was significantly associated with COPD risk among Caucasians. The GSTP1 rs1138272 polymorphism (heterozygote and dominant model) was significantly associated with COPD risk. Subgroup analysis suggested that the GSTP1 rs1138272 polymorphism (heterozygote, dominant, and allele model) was significantly associated with COPD risk among Caucasians. Conclusion: The C allele in EPHX1 rs1051740 among Asians and the CC genotype among Caucasians may be risk factors for COPD. However, the GA genotype in EPHX1 rs2234922 may be a protective factor against COPD in Asians. The GG genotype in GSTP1 rs1695 and the TC genotype in GSTP1 rs1138272 may be risk factors for COPD, especially among Caucasians.
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Background: This study aims to explore the factors influencing the coagulation function of patients with chronic obstructive pulmonary disease (COPD) and its effects on thrombosis. Methods: A total of 155 COPD patients, including 118 patients with acute exacerbation of COPD (AECOPD) and 37 patients with stable COPD (SCOPD), were enrolled in this study. Meanwhile, 50 patients with gastrointestinal polyps found during physical examination and treated with surgery in the same period were enrolled as the control group. The basic data, routine blood tests, C-reactive protein (CRP), procalcitonin (PCT), and coagulation indexes of the three groups were collected, as well as arterial blood gas indexes of AECOPD patients. Results: The differences in erythrocyte count and hemoglobin among groups were not statistically significant. Compared with the SCOPD group and control group, white blood cell (WBC), neutrophil percentage, PCT, CRP, prothrombin time (PT), and fibrinogen (FIB) in the AECOPD group increased significantly, while the international normalized ratio (INR) decreased (P < 0.05). The differences in activated partial thromboplastin time (APTT) and D-dimer among groups were not statistically significant (P > 0.05). Thrombin time (TT) in the AECOPD group was shorter than that of the control group, and PT was longer than that of the SCOPD group (P < 0.05). Five patients with AECOPD and one patient with SCOPD had venous thrombosis. Conclusion: The abnormal coagulation function in AECOPD patients is related to the degree of infection and hypercapnia, which may be a risk factor for thrombosis.
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OBJECTIVE: To study the functional mechanism of pingchuanning decoction in treatment of airway remodeling in asthmatic rats. METHODS: Eighty healthy Wistar male rats were randomized into eight groups (n=10 rats each): Normal group, asthma model group, dexamethasone group, guilong kechuanning group, xiaoqinglong decoction group, and pingchuanning decoction low-, middle-, and high-dose groups. The rats of all but the normal group were made into asthma models through intraperitoneal injection and aerosol inhalation of ovalbumin. All treatments were administered at the first stimulation of asthma onset (third week of modeling), and the rats were killed after stimulating asthma attacks for 4 weeks. The general conditions of rats and pathomorphological changes of the lung tissues were observed. The expression of nerve growth factor (NGF) of the lung tissues was measured with immunohistochemical methods, and the content of clara cell secretory protein (CCSP) mRNA was determined with RT-PCR. RESULTS: Compared with the normal group, the contents of NGF and CCSP mRNA in the lung tissues of the model group were significantly changed (P < 0.01). Compared with the model group, the indices of pingchuanning decoction and other treatment groups were improved to some extent (P < 0.05 or P < 0.01). CONCLUSIONS: Pathological changes of airway inflammation and remodeling were present in these rat asthma models. Pingchuanning decoction had an intervention effect on these experimental models. Its functional mechanism may be related to multiple factors, including alleviation of airway inflammation, relief of bronchial smooth muscle spasm, and inhibition of airway remodeling.