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Chronic inflammation can promote cancer development as observed in inflammation-induced colorectal cancer (CRC). However, the poor treatment outcomes emphasize the need for effective treatment. Astragalus polysaccharide (APS), a vital component of the natural drug Astragalus, has anti-tumor effects by inhibiting cancer cell proliferation and enhancing immune function. In this study, we found that APS effectively suppressed CRC development through activating CD8+ T cells and reversing its inhibitory state in the tumor microenvironment (TME) of AOM/DSS inflammation-induced CRC mice. Network pharmacology and clinical databases suggested that the STAT3/ Galectin-3(Gal-3)/LAG3 pathway might be APS's potential target for treating CRC and associated with CD8+ T cell dysfunction. In vivo experiments showed that APS significantly reduced phosphorylated STAT3 and Gal-3 levels in tumor cells, as well as LAG3 in CD8+ T cells. Co-culture experiments with MC38 and CD8+ T cells demonstrated that APS decreased the expression of co-inhibitory receptor LAG3 in CD8+ T cells by targeting STAT3/Gal-3 in MC38 cells. Mechanism investigations revealed that APS specifically improved CD8+ T cell function through modulation of the STAT3/Gal-3/LAG3 pathway to inhibit CRC development, providing insights for future clinical development of natural anti-tumor drugs and immunotherapies as a novel strategy combined with immune checkpoint inhibitors (ICIs).
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Antineoplásicos , Neoplasias Colorretais , Animais , Camundongos , Linfócitos T CD8-Positivos , Antineoplásicos/farmacologia , Inflamação/metabolismo , Neoplasias Colorretais/patologia , Polissacarídeos/metabolismo , Microambiente TumoralRESUMO
Idiopathic pulmonary fibrosis (IPF), as the most common idiopathic interstitial pneumonia, is caused by a complex interaction of pathological mechanisms. Interestingly, IPF frequently occurs in the middle-aged and elderly populations but rarely affects young people. Salvianolic acid B (SAB) exerts antioxidant, antiinflammatory, and antifibrotic bioactivities and is considered a promising drug for pulmonary disease treatment. However, the pharmacological effects and mechanisms of SAB on cellular senescence of lung cells and IPF development remain unclear. We used bleomycin (BLM)-induced pulmonary fibrosis mice and different lung cells to investigate the antisenescence impact of SAB and explain its underlying mechanism by network pharmacology and the Human Protein Atlas database. Here, we found that SAB significantly prevented pulmonary fibrosis and cellular senescence in mice, and reversed the senescence trend and typical senescence-associated secretory phenotype (SASP) factors released from lung macrophages and alveolar type II (AT2) epithelial cells, which further reduced lung fibroblasts activation. Additionally, SAB alleviated the epithelial-mesenchymal transition process of AT2 cells induced by transforming growth factor beta. By predicting potential targets of SAB that were then confirmed by chromatin immunoprecipitation-qPCR technology, we determined that SAB directly hampered the binding of transcription factor stimulating protein 1 to the promoters of SASPs (P21 and P16), thus halting lung cell senescence. We demonstrated that SAB reduced BLM-induced AT2 and macrophage senescence, and the subsequent release of SASP factors that activated lung fibroblasts, thereby dual-relieving IPF. This study provides a new scientific foundation and perspective for pulmonary fibrosis therapy.
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Benzofuranos , Depsídeos , Fibrose Pulmonar Idiopática , Pulmão , Pessoa de Meia-Idade , Idoso , Humanos , Camundongos , Animais , Adolescente , Pulmão/patologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/genética , Senescência Celular/fisiologia , Macrófagos Alveolares , Bleomicina/efeitos adversosRESUMO
Intestinal microbiota dysbiosis and metabolic disruption are well-known as the primary triggers of ulcerative colitis (UC). However, their role in regulating the group 3 innate lymphoid cells (ILC3s), which are essential for intestinal health, remains unexplored during the development of disease severity. Here, our results showed that the microbiota structure of patients with severe UC (SUCs) differed from those with mild UC (MiUCs), moderate UC (MoUCs), and healthy controls (HCs). Microbes producing secondary bile acids (SBAs) and SBAs decreased with the aggravation of UC, and a strong positive correlation existed between them. Next, fecal microbiota transfer was used to reproduce the human-derived microbiota in mice and decipher the microbiota-mediated inflammatory modulation during an increase in disease severity. Mice receiving SUC-derived microbiota exhibited enhancive inflammation, a lowered percentage of ILC3s, and the down-regulated expressions of bile acid receptors, including vitamin D receptor (VDR) and pregnane X receptor (PXR), in the colon. Similar to clinical results, SBA-producing microbes, deoxycholic acids (DCA), and 12-ketolithocholic acids (12-KLCA) were diminished in the intestine of these recipients. Finally, we compared the therapeutic potential of DCA and 12-KLCA in preventing colitis and the regulatory mechanisms mediated by ILC3s. 12-KLCA but not DCA represented a strong anti-inflammatory effect associated with the higher expression of VDR and the lower secretion of IL-17A from colonic ILC3s. Collectively, these findings provide new signatures for monitoring the acute deterioration of UC by targeting gut microbiota and bile acid metabolism and demonstrate the therapeutic and preventive potential of a novel microbiota-derived metabolite, 12-KLCA.
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Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Animais , Humanos , Camundongos , Ácidos e Sais Biliares/metabolismo , Colite/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colo/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Imunidade Inata/efeitos dos fármacos , Interleucina-17/metabolismo , Interleucina-17/farmacologia , Linfócitos/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
Background and aim: Dachengqi Decoction (DCQD) as a classic traditional Chinese medicine has been reported to be effective in treating asthma, but its mechanism remains unknown. This study aimed to reveal the mechanisms of DCQD on the intestinal complications of asthma mediated by group 2 innate lymphoid cells (ILC2) and intestinal microbiota. Experimental procedure: Ovalbumin (OVA) was used to construct asthmatic murine models. IgE, cytokines (e.g., IL-4, IL-5), fecal water content, colonic length, histopathologic appearance, and gut microbiota were evaluated in asthmatic mice treated with DCQD. Finally, we administered DCQD to antibiotic-treated asthmatic mice to measure the ILC2 in the small intestine and colon. Results and conclusion: DCQD decreased pulmonary IgE, IL-4, and IL-5 levels in asthmatic mice. The fecal water content, the colonic length weight loss, and the epithelial damage of jejunum, ileum, and colon of asthmatic mice were ameliorated by DCQD. Meanwhile, DCQD greatly improved intestinal dysbiosis by enriching Allobaculum, Romboutsia and Turicibacter in the whole intestine, and Lactobacillus gasseri only in the colon. However, DCQD caused less abundant Faecalibaculum and Lactobacillus vaginalis in the small intestine of asthmatic mice. A higher ILC2 proportion in different gut segments of asthmatic mice was reversed by DCQD. Finally, significant correlations appeared between DCQD-mediated specific bacteria and cytokines (e.g., IL-4, IL-5) or ILC2. These findings indicate that DCQD alleviated the concurrent intestinal inflammation in OVA-induced asthma by decreasing the excessive accumulation of intestinal ILC2 in a microbiota-dependent manner across different gut locations.
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Pulmonary inflammation as one of the extraintestinal manifestations of ulcerative colitis (UC) has attracted extensive attention, and its pathogenesis is closely related to gut dysbiosis. Bifidobacterium animalis subsp. lactis BL-99 (BL-99) can alleviate osteoporosis caused by UC, but less research has been done on other extraintestinal manifestations (EIM) caused by UC. This study aimed to explore the role and potential mechanisms of BL-99 on DSS-induced pulmonary complications in colitis mice. The results showed that BL-99 decreased weight loss, disease activity index score, colonic pathology score, and the production of pro-inflammatory cytokines (e.g., TNF-α, IL-1ß, and IL-6) in colitis mice. BL-99 also alleviated DSS-induced lung pathological damage by suppressing the infiltration of pro-inflammatory cytokines, inflammatory monocytes, and macrophages. Furthermore, 16S rRNA gene sequencing showed lower abundances of several potentially pathogenic bacteria (e.g., Burkholderia, Shigella, and Clostridium perfringens) and enrichment in specific beneficial bacteria (e.g., Adlercreutzia and Bifidobacterium animalis) in colitis mice with BL-99 treatment. Targeted metabolomics suggested that BL-99 intervention promoted the production of intestinal acetate and butyrate. Finally, we observed that the pulmonary expression of primary acetate and butyrate receptors, including FFAR2, FFAR3, and, GPR109a, was up-regulated in BL-99-treated mice, which negatively correlated with inflammatory monocytes and macrophages. Altogether, these results suggest that BL-99 might be utilized as a probiotic intervention to prevent the incidence of colitis-related lung injury owing to its ability to shape the intestinal microbiota and suppress inflammation.
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Bifidobacterium animalis , Colite Ulcerativa , Colite , Lesão Pulmonar , Animais , Camundongos , Bifidobacterium animalis/metabolismo , Butiratos/metabolismo , Colite/induzido quimicamente , Colite Ulcerativa/metabolismo , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Ácidos Graxos Voláteis/metabolismo , Lesão Pulmonar/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , RNA Ribossômico 16S/metabolismoRESUMO
With the concept of the gut-lung axis reinforced in recent years, emerging evidence has shown that intestinal homeostasis is vital for lung health. Nevertheless, the impacts of lung homeostasis on intestinal tracts and their mechanism are rarely studied. Our results showed that papain-induced asthmatic mice exhibited apparent colonic injuries compared with controls, including increased intestinal permeability, neutrophil and Th17 infiltration in the colonic lamina propria. Moreover, the intranasal administration of papain aggravated such colonic injuries in mice with dextran sulfate sodium-induced colitis, as evidenced by increased occult blood scores, shortened colon length, and accumulated neutrophils. The level of IL-17A was also higher in the serum of asthmatic mice than wild-type mice. Interestingly, the pathologic scores, the proportion of Th17 cells, and neutrophil infiltration in the colon were markedly reduced after IL-17A blocking. Similarly, longer length, lower pathologic scores, and fewer neutrophils were also observed in the colon of IL-17-deficient asthmatic mice. More importantly, we demonstrated that severe gastrointestinal symptoms could accompany clinical asthmatics. The frequencies of Th17 cells and the mRNA expression of IL-17A in the peripheral blood of these patients were significantly enhanced. Besides, the gastrointestinal symptom rating scale scores positively correlated with the frequencies of Th17 in asthmatics. These findings enlighten that IL-17A aggravates asthma-induced intestinal immune injury by promoting neutrophil trafficking, which facilitates the exploration of new potential biomarkers to treat asthma.
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Asma , Colite , Interleucina-17 , Neutrófilos , Animais , Asma/complicações , Colite/etiologia , Colite/imunologia , Sulfato de Dextrana , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Papaína/metabolismo , Células Th17RESUMO
This study explored whether Sagittaria sagittifolia polysaccharides(SSP) activates the nuclear factor erythroid-2-related factor2(Nrf2)/heme oxygenase-1(HO-1) signaling pathway to protect against liver damage jointly induced by multiple heavy metals. First, based on the proportion of dietary intake of six heavy metals in rice available in Beijing market, a heavy metal mixture was prepared for inducing mouse liver injury and HepG2 cell injury. Forty male Kunming mice were divided into five groups: control group, model group, glutathione positive control group, and low-and high-dose SSP groups, with eight mice in each group. After 30 days of intragastric administration, the liver injury in mice was observed by HE staining. In the in vitro experiment, MTT assay was conducted to detect the effects of SSP at 0.25, 0.5, 1, and 2 mg·mL~(-1) on HepG2 cell survival at different time points. The content of alanine transaminase(ALT) and aspartate aminotransferase(AST) in the 48-h cell culture fluid was measured using micro-plate cultivation method, followed by the detection of the change in reactive oxygen species(ROS) content by flow cytometry. The mRNA expression levels of Nrf2 and HO-1 in cells were determined by RT-PCR, and their protein expression by Western blot. HE staining results showed that compared with the model group, the SSP administration groups exhibited significantly alleviated inflammatory cell infiltration and fatty infiltration in the liver, with better outcomes observed in the high-dose SSP group. In the in vitro MTT assay, compared with the model group, SSP at four concentrations all significantly increased the cell survival rate, decreased the ALT, AST, and ROS content(P<0.05), and down-regulated Nrf2 and HO-1 mRNA and protein expression(P<0.05). SSP significantly improves inflammatory infiltration in the liver tissue of mice exposed to a variety of heavy metals and corrects the liver fat degeneration, which may be related to its regulation of the Nrf2/HO-1 signaling pathway, reduction of ROS, and alleviation of oxidative damage.
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Metais Pesados , Sagittaria , Animais , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Fígado , Masculino , Metais Pesados/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Polissacarídeos/farmacologia , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sagittaria/genética , Sagittaria/metabolismoRESUMO
The hepatic protective role of Sagittaria sagittifolia polysaccharide (SSP) and its possible mechanism were discussed in mice and L02 hepatocytes injured by heavy metals mixture of Cd + Cr (VI) + Pb + Mn + Zn + Cu. After 30-day intervention, blood and liver samples were collected for the relevant assessments. Methyl thiazolyl tetrazolium (MTT) assay showed 24 h was the best protecting point and the SSP protection at 1 mg/mL was strongest in L02 hepatocytes. SSP can alleviated hepatic injury, as evidenced by significantly decreased the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and the malondialdehyde (MDA) content, also increased the superoxide dismutase (SOD) activity and glutathione (GSH), total sulphydryl (T-SH) contents. SSP effectively reduced pathological damage of mice and accumulation of heavy metals in liver, as well as decreased the level of reactive oxygen species (ROS) in L02 hepatocytes. After SSP treatment, the protein expressions or gene transcription of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H dehydrogenase, quinone 1 (NQO1) and heme oxygenase1 (HO-1) decreased in L02. The protein expression of Nrf2 and NQO1 were increased while HO-1 was decreased in liver. Besides, SSP can attenuates apoptosis through reducing the protein expression of Bcl-2-associated X protein (Bax) and caspase-3, and increasing B-cell lymphoma gene 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl). SSP protects against six-heavy-metal-induced hepatic injury in mice and L02 hepatocytes. Supported by Nrf2 gene silencing, the mechanisms may correlate with activating Nrf2 pathway to mitigate oxidative stress and apoptosis.
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Linfoma de Células B , Metais Pesados , Sagittaria , Apoptose , Glutationa/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/farmacologia , Fígado/metabolismo , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Metais Pesados/metabolismo , Metais Pesados/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Polissacarídeos/metabolismo , Polissacarídeos/farmacologia , Sagittaria/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: Ulcerative colitis (UC) as one of the intractable diseases in gastroenterology seriously threatens human health. Respiratory pathology is a representative extraintestinal manifestation of UC affecting the quality of life of patients. Gegen Qinlian Decoction (GQD) is a classical traditional Chinese medicine prescription for UC or acute lung injury. This study was aimed to reveal the therapeutic effect of GQD on UC and its pulmonary complications and uncover its molecular mechanism mediated by myeloid cells and microbiota. METHODS: Mice with DSS-induced colitis were orally administrated with GQD. Overall vital signs were assessed by body weight loss and disease activity index (DAI). Pulmonary general signs were evaluated by pulmonary pathology and lung function. The mechanism of GQD relieving UC was characterized by detecting myeloid cells (neutrophils, macrophages, inflammatory monocytes, and resident monocytes) in colonic and lung tissues, related inflammatory cytokines, as well as the microbiota in bronchoalveolar lavage fluid (BALF) and feces. RESULTS: GQD significantly reduced weight loss, DAI scores, and lung injury but improved the lung function of colitis mice. The DSS-induced colonic and concurrent pulmonary inflammation were also alleviated by GQD, as indicated by the down-regulated expressions of inflammatory cytokines (TNF-α, IL-1ß, IL-6, CCR2, and CCL2) and the suppressed recruitment of neutrophils and inflammatory monocytes. Meanwhile, GQD greatly improved intestinal microbiota imbalance by enriching Ruminococcaceae UCG-013 while decreasing Parabacteroides, [Eubacterium]_fissicatena_group, and Akkermansia in the feces of colitis mice. Expectantly, GQD also restored lung microbiota imbalance by clearing excessive Coprococcus 2 and Ochrobactrum in the BALF of colitis mice. Finally, significant correlations appeared between GQD-mediated specific bacteria and inflammatory cytokines or immune cells. CONCLUSION: GQD could alleviate UC by decreasing excessive inflammatory myeloid cells and cytokines, and reshaping the microbiota between the colon and lung, which contributes to clarifying the mechanism by which GQD ameliorates colitis-associated pulmonary inflammation.
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PURPOSE: Chronic obstructive pulmonary disease (COPD), a prevalent obstructive airway disease, has become the third most common cause of death globally. Xuanbai Chengqi decoction (XBCQ) is a traditional Chinese medicine prescription for the acute exacerbation of COPD. Here, we aimed to reveal the therapeutic effects of XBCQ administration and its molecular mechanisms mediated by Th17/Treg balance and gut microbiota. METHODS: We determined the counts of Th17 and Treg cells in the serum of 15 COPD and 10 healthy subjects. Then, cigarette smoke extract-induced COPD mice were gavaged with low, middle, and high doses of XBCQ, respectively. Weight loss, pulmonary function and inflammation, Th17/Treg ratio, and gut microbiota were measured to evaluate the efficacy of XBCQ on COPD. RESULTS: COPD patients had a higher Th17/Treg ratio in the serum than healthy controls, which was consistent with the results in the lung and colon of COPD mice. The middle dose of XBCQ (M-XBCQ) significantly decreased the weight loss and improved the pulmonary function (FEV0.2/FVC) in COPD mice. Moreover, M-XBCQ alleviated lung inflammation by rectifying the Th17/Treg imbalance, reducing the expressions of TNF-α, IL-1ß, and MMP-9, and suppressing inflammatory cells infiltration. Meanwhile, M-XBCQ greatly improved the microbial homeostasis in COPD mice by accumulating probiotic Gordonibacter and Akkermansia but inhibiting the growth of pathogenic Streptococcus, which showed significant correlations with pulmonary injury. CONCLUSION: Oral M-XBCQ could alleviate COPD exacerbations by reshaping the gut microbiota and improving the Th17/Treg balance, which aids in elucidating the mechanism through which XBCQ as a therapy for COPD.
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Microbioma Gastrointestinal , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Humanos , Camundongos , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Pneumonia/prevenção & controle , Doença Pulmonar Obstrutiva Crônica/metabolismo , Linfócitos T Reguladores , Células Th17/metabolismoRESUMO
BACKGROUND: Hudi enteric-coated capsule (HDC) is a Chinese medicine prescribed to treat ulcerative colitis (UC). However, its anti-inflammatory active ingredients and mechanisms remain unknown. This study aimed to investigate the active components of HDC and explore its potential mechanisms against UC by integrating network pharmacology and experimental verification. METHODS: A DSS-induced colitis murine model was established to validate the efficacy of HDC by detecting disease activity index (DAI) and histopathological changes. Network pharmacological analysis was performed to identify the active compounds and core targets of HDC for the treatment of UC. The main compounds in HDC were identified by high-performance liquid chromatography. The relative expressions of HDC's core targets were also determined in vivo. Finally, molecular docking was applied to model the interaction between HDC and target proteins. RESULTS: In an in vivo experiment, HDC, especially the middle-dose HDC, effectively reduced clinical symptoms of UC, including weight loss, bloody stool, and colon shortening. Besides, the severity of colitis was considerably suppressed by HDC as evidenced by reduced DAI scores. A total of 118 active compounds and 69 candidate targets from HDC closely related to UC progression were identified via network pharmacology. Enrichment analysis revealed that the key targets of HDC correlated with the expressions of PTGS2, TNF-α, IL-6, and IL-1ß. Meanwhile, these cytokines were enriched in various biological processes through the IL-17/JAK2/STAT3 signaling pathway. The middle-dose HDC contributed more to ameliorating DSS-induced colitis through this signaling pathway than other dosages. Nine components binding to JAK2, STAT3, IL-17 and IL-6 were identified by molecular docking, confirming again the inhibition effects of HDC on the IL-17/JAK2/STAT3 signaling pathway. CONCLUSION: The HDC treatment, particularly the middle-dose, exerted an anti-UC effect in a multi-component, multi-target, and multi-mechanism manner, especially inhibiting the IL-17/JAK2/STAT3 signaling pathway to downregulate the secretion of proinflammatory cytokines.
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Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Cápsulas , Colite Ulcerativa/fisiopatologia , Citocinas/metabolismo , Preparações de Ação Retardada , Sulfato de Dextrana , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Interleucina-17/metabolismo , Janus Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Patients with long-duration ulcerative colitis (UC) had a higher risk of developing ulcerative colitis-associated carcinogenesis (UCAC) when compared to those with short-duration UC. This study aimed to discover the biomarker for cancer surveillance related to disease duration. METHODS: The microarrays were divided into short-duration (<10 years) UC, long-duration (≥10 years) UC, UCAC, and normal groups in the Gene Expression Omnibus (GEO) datasets. Differentially expressed genes (DEGs) of GEO and the hub genes of the selected weighted gene co-expression network analysis (WGCNA) were intersected to obtain the overlapping genes. Among these genes, the key gene was identified by using the protein-protein interaction (PPI) network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the cytoHubba of Cytoscape, and the expression levels. Also, immunofluorescence of human colonic mucosa and animal experiment were used to validate the expression trend of the key gene in the progress of UC developing into UCAC. RESULTS: Lipocalin-2 (LCN2) was more relevant with disease duration of UC and significantly negatively correlated with the risk of UCAC. The expression level of LCN2 in short-duration UC was higher than that of long-duration UC (P < 0.01), long-duration UC was higher than that of UCAC (P = 0.001), and UC and UCAC were all higher than that of the normal (P < 0.001). We then discovered that the expression trend of LCN2 in blood and stool samples was consistent with that in colorectal mucosa. CONCLUSION: The research indicates that LCN2 could be a novel biomarker to evaluate cancer surveillance related to disease duration of developing UC into UCAC. Compared with that of blood samples, stool detection of LCN2 may have more advantages for diagnosis value of early stage of UCAC as a complement to colonoscopy surveillance.
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OBJECTIVE: This study tests whether long-term intake of Allium tuberosum (AT) can alleviate pulmonary inflammation in ovalbumin (OVA)-induced asthmatic mice and evaluates its effect on the intestinal microbiota and innate lymphoid cells (ILCs). METHODS: BALB/c mice were divided into three groups: phosphate buffer saline, OVA and OVA + AT. The asthmatic murine model was established by sensitization and challenge of OVA in the OVA and OVA + AT groups. AT was given to the OVA + AT group by oral gavage from day 0 to day 27. On day 28, mice were sacrificed. Histopathological evaluation of lung tissue was performed using hematoxylin and eosin, and periodic acid-Schiff staining. The levels of IgE in serum, interleukin-5 (IL-5) and IL-13 from bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay. The ILCs from the lung and gut were detected by flow cytometry. 16S ribosomal DNA sequencing was used to analyze the differences in colon microbiota among treatment groups. RESULTS: We found that long-term intake of AT decreased the number of inflammatory cells from BALF, reduced the levels of IL-5 and IL-13 in BALF, and IgE level in serum, and rescued pulmonary histopathology with less mucus secretion in asthmatic mice. 16S ribosomal DNA sequencing results showed that AT strongly affected the colonic bacteria community structure in asthmatic mice, although it had no significant effect on the abundance and diversity of the microbiota. Ruminococcaceae and Desulfovibrionaceae were identified as two biomarkers of the treatment effect of AT. Moreover, AT decreased the numbers of ILCs in both the lung and gut of asthmatic mice. CONCLUSION: The results indicate that AT inhibits pulmonary inflammation, possibly by impeding the activation of ILCs and adjusting the homeostasis of gut microbiota in asthmatic mice.
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Cebolinha-Francesa , Microbioma Gastrointestinal , Pneumonia , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Imunidade Inata , Inflamação/tratamento farmacológico , Pulmão , Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/tratamento farmacológicoRESUMO
OBJECTIVE: In China, lamb and fish are well-known triggers for an asthma attack. Our investigation aims at assessing whether the long-term intake of lamb meat or Basa fish would aggravate pulmonary inflammation as well as exploring changes in the intestinal microbiota and immune cells in asthmatic mice. MATERIALS AND METHODS: The murine asthmatic model was established by intraperitoneal injection of ovalbumin (OVA) plus aluminum on day 0 and 14 and nebulization of OVA from day 21 to 27. Lamb meat or fish was administered to asthmatic mice by oral gavage from day 0 to 27. RESULTS: Our results showed that long-term consumption of lamb meat or Basa fish in asthmatic mice increased the number of inflammatory cells in bronchoalveolar lavage fluid (BALF), enhanced levels of IL-5, IL-13 in BALF and total IgE in serum, aggravated pulmonary inflammatory cell infiltration and mucus secretion. Long-term oral lamb enhanced the proportion of type 2 innate lymphoid cells (ILC2) from small intestine while it inhibited that of Treg from lung in asthmatic mice. Oral fish showed no remarkable effect on that of ILC2 from lung and small intestine but inhibited that of intestinal Treg in asthmatic mice. What's more, the chao-1 and observed species richness as well as PD whole tree diversity increased in asthmatic mice while these increments were inhibited after lamb treatment. PCA analysis indicated that there were significant differences in the bacterial community composition after lamb or fish treatment in asthmatic mice. Both lamb and fish treatment enhanced the abundance of colonic Alistipes in asthmatic mice. CONCLUSION: Collectively, long-term intake of lamb or fish shapes colonic bacterial communities and aggravates pulmonary inflammation in asthmatic mice, which provides reasonable food guidance for asthmatic patients.
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OBJECTIVE: To research the algae-inhibitory effect and mechanism of a plant source n-caprylic acid extracted from coconut oil on M. aeruginosa. METHODS: The M. aeruginosa were treated with 0, 12.5, 25, 50 and 100 µL/L densities of coconut oil n-caprylic acid respectively. And the change of algal density, cell permeability and antioxidant ability were measured. RESULTS: The greater the concentration of coconut oil n-caprylic acid, the stronger the inhibition on M. aeruginosa. When the concentration was 100 µL/L and processed time was 96 h, the inhibition ratio on M. aeruginosa reached 99%. Compared with the control group, the algal liquid conductivity, nucleic acid content and protein content of experimental groups increased significantly. The SOD activity enhanced with the increasing of coconut oil n-caprylic acid concentration (under 25 µL/L), but when beyond a certain concentration (exceed 25 µL/L), its activity weakened greatly. And the MDA content increased with the increasing of coconut oil n-caprylic acid concentration. CONCLUSION: Coconut oil n-caprylic acid has a significant inhibiting effect on M. aeruginosa. Its mechanism may be largely related to cell membrane permeability change and antioxidant capacity reducing.
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Caprilatos/farmacologia , Microcystis/efeitos dos fármacos , Óleos de Plantas/química , Antioxidantes , Óleo de CocoRESUMO
Follicular helper T cells (T(FH) cells) are responsible for effective B cell-mediated immunity, and Bcl-6 is a central factor for the differentiation of T(FH) cells. However, the molecular mechanisms that regulate the induction of T(FH) cells remain unclear. Here we found that the E3 ubiquitin ligase Itch was essential for the differentiation of T(FH) cells, germinal center responses and immunoglobulin G (IgG) responses to acute viral infection. Itch acted intrinsically in CD4(+) T cells at early stages of T(FH) cell development. Itch seemed to act upstream of Bcl-6 expression, as Bcl-6 expression was substantially impaired in Itch(-/-) cells, and the differentiation of Itch(-/-) T cells into T(FH) cells was restored by enforced expression of Bcl-6. Itch associated with the transcription factor Foxo1 and promoted its ubiquitination and degradation. The defective T(FH) differentiation of Itch(-/-) T cells was rectified by deletion of Foxo1. Thus, our results indicate that Itch acts as an essential positive regulator in the differentiation of T(FH) cells.
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Diferenciação Celular , Linfócitos T Auxiliares-Indutores/citologia , Ubiquitina-Proteína Ligases/fisiologia , Animais , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/fisiologia , Centro Germinativo/imunologia , Interleucina-2/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-6/fisiologia , Células Th2/imunologiaRESUMO
The constitution of traditional Chinese medicine was established in 1970s by Chinese scholars, in which the constitutions of Chinese people were classified into nine types for study. The phlegm-dampness constitution is one of the nine constitutions and is the most common type in constitution study. Genomics studies found four upregulated genes: COPS8, GNPDA1, CD52 and ARPC3; and six downregulated genes: GSPT2, CACNB2, FLJ20584, UXS1, IL21R and TNPO in the phlegm-dampness constitution. Gene functional analyses on genes affecting the differences between the phlegm-dampness constitution and the balanced constitution indicated that people with phlegm-dampness constitution were susceptible to hyperlipemia and diabetes. Results of epidemiological surveys also revealed that people with phlegm-dampness constitution have a much higher risk of obesity, metabolic syndrome, hypertension and diabetes than people with a balanced constitution. Therefore, differentiation of phlegm-dampness constitution could be performed in the normal population with the Constitution of Chinese Medicine Scale to estimate the risks of those diseases for prediction. For people with phlegm-dampness constitution, Chinese medicine could be used to reduce risk of related diseases. Constitution-based strategies in disease prevention and treatment are consistent with the current proposed 4P medical mode (personalized, predictive, preventive and participatory). With the rising burden of global disease and increasing medical expenditure, the objectives of medicine are transforming from treatment to prevention. Thus, studies on the phlegm-dampness constitution of traditional Chinese medicine are significantly important for the prediction and prevention of related diseases and maintenance of human health.
Assuntos
Suscetibilidade a Doenças , Tratamento Farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Genética Médica , Genômica , Humanos , Medicina Tradicional ChinesaRESUMO
OBJECTIVE: To investigate the effects and mechanisms of Gong-tone music on the immunological function in rats with the Chinese medicine syndrome of Liver (Gan)-qi stagnation and Spleen (Pi)-qi deficiency (LSSD). METHODS: Twenty five male Wistar rats of SPF grade were randomly divided into 5 groups: normal group, model group, Xiaoyao Powder () group, Gong-tone group and combined group (the combination of Gong-tone and Xiaoyao Powder), with 5 rats in each group. The rat model for the Chinese medicine syndrome of LSSD was induced by chronic bandage and irregular diet. The course of treatment was 21 days. After the treatment, the levels of serum gastrin and IgG were detected by enzyme-linked immunoabsorbent assay (ELISA). Phagocytosis of macrophages was detected by the neutral red uptake assay and T cell proliferation was investigated by 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The serum gastrin, macrophage phagocytosis, IgG level and proliferation ability of T cells in the model group were significantly decreased compared with those in the normal group (P <0.05). Compared with those in the model group, the serum levels of gastrin, macrophage phagocytosis, IgG level and proliferation ability of T cells in Gong-tone, Xiaoyao Powder, and combined groups were significantly increased (P <0.05). The combined group was superior to either Gong-tone group or Xiaoyao Powder group. CONCLUSION: Gong-tone music may upregulate the immunological function and play a role in adjuvant therapy in the Chinese syndrome of LSSD.
Assuntos
Percepção Auditiva , Depressão/imunologia , Fígado/imunologia , Música , Qi , Baço/imunologia , Animais , Comportamento Animal , Peso Corporal , Proliferação de Células , Depressão/sangue , Gastrinas/sangue , Imunoglobulina G/sangue , Macrófagos/citologia , Masculino , Fagocitose , Ratos , Ratos Wistar , Síndrome , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismoRESUMO
OBJECTIVE: To observe the effects of Dureping Injection on the contents of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in the lung tissue of mice with pneumonia of influenza virus infection. METHODS: Sixty-six ICR mice were randomly divided into the normal group, the model group, the low, middle, and high dose Dureping Injection groups (0.435, 0.870, and 1.740 mg/d, respectively), and the positive control group (Ribavirin, 2.500 mg/d), 11 in each. The pneumonia of mice with influenza virus infection model was established using influenza virus strain FM1. Mice were intraperitoneally injected with 0. 3 mL FM1 starting from the infection day, once daily. Five days later mice were killed to calculate the lung index. The pathomorphological changes of the lung tissue were observed using routine HE stained sections. The contents of MMP-9 and TIMP-1 in the homogenate of the lung tissue were detected by ELISA double antibody sandwich method. RESULTS: Compared with the normal group, obvious inflammation occurred in the lung tissue of mice in the model group. The lung index, the content of MMP-9, and the value of MMP-9/TIMP-1 increased significantly in the model group (P < 0.01) , while the content of TIMP-1 was not significantly different (P > 0.05). Compared with the model group, the content of MMP-9 in the low and middle dose Dureping Injection groups, and the positive control group was significantly lowered (P < 0.01). The content of TIMP-1 in the low, middle, and high dose Dureping Injection groups, as well as the positive control group significantly increased (P < 0.01) and the value of MMP-9/TIMP-1 decreased (P < 0.01). CONCLUSION: Dureping Injection could alleviate the inflammatory injury of the lung tissue through decreasing the content of MMP-9, elevating the content of TIMP-1 in the lung tissue, and regulating the value of MMP-9/TIMP-1 of mice with pneumonia of influenza virus infection, thus alleviating the inflammatory injury of the lung tissue.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Pulmão/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Pneumonia Viral/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Orthomyxoviridae , Infecções por Orthomyxoviridae/patologia , Pneumonia Viral/patologia , Scutellaria baicalensisRESUMO
A polyepitope chimeric antigen incorporating multiple protective and conservative epitopes from multiple antigens of Plasmodium falciparum has been considered to be more effective in inducing multiple layers of immunity against malaria than a single stage- or single antigen-based vaccine. By modifying the molecular breeding approach to epitope shuffling, we have constructed a polyepitope chimeric gene that encodes 11 B-cell and T-cell proliferative epitope peptides derived from eight key antigens mostly in the blood stage of Plasmodium falciparum. A 35-kDa antigen encoded by this gene, named Malaria RCAg-1, was purified from an E. coli expression system. Immunization of rabbits and mice with the purified protein in the presence of Freund's adjuvant strongly generated long-lasting antibody responses that recognized the corresponding individual epitope peptide in this vaccine as well as blood stage parasites. CD4(+) T-cell responses were also elicited as shown by the enhancement of T-cell proliferation, IFN-gamma and IL-4 level. In vitro assay of protection revealed that vaccine-elicited antibodies could efficiently inhibit the growth of blood-stage parasites. Additionally, the chimeric antigen was recognized by human serum specimens from malaria patients and individuals living in the endemic area. Our studies indicate the potential of M.RCAg-1 recombinant protein as malaria candidate vaccines as well as the rationale of the epitope shuffling technology applied in designing malaria vaccines.