Astragaloside IV Alleviates the Experimental DSS-Induced Colitis by Remodeling Macrophage Polarization Through STAT Signaling.
Ontology highlight
ABSTRACT:
SUBMITTER: Tian L
PROVIDER: S-EPMC8473681 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Chemerin is present in various inflammatory sites and is closely involved in tissue inflammation. Recent studies have demonstrated that chemerin treatment can cause either anti-inflammatory or pro-inflammatory effects according to the disease model being investigated. Elevated circulating chemerin was recently found in patients with inflammatory bowel disease (IBD); however, the role of chemerin in intestinal inflammation remains unknown. In this study, we demonstrated that the administration of exogenous chemerin (aa17-156) aggravated the severity of dextran sulfate sodium (DSS)-induced colitis, which was characterized by higher clinical scores, extensive mucosal damage and significantly increased local and systemic production of pro-inflammatory cytokines, including IL-6, TNF-? and interferon (IFN-?). Interestingly, chemerin did not appear to influence the magnitudes of inflammatory infiltrates in the colons, but did result in significantly decreased colonic expression of M2 macrophage-associated genes, including Arginase 1 (Arg-1), Ym1, FIZZ1 and IL-10, following DSS exposure, suggesting an impaired M2 macrophage skewing in vivo. Furthermore, an in vitro experiment showed that the addition of chemerin directly suppressed M2 macrophage-associated gene expression and STAT6 phosphorylation in IL-4-stimulated macrophages. Significantly elevated chemerin levels were found in colons from DSS-exposed mice and from ulcerative colitis (UC) patients and appeared to positively correlate with disease severity. Moreover, the in vivo administration of neutralizing anti-chemerin antibody significantly improved intestinal inflammation following DSS exposure. Taken together, our findings reveal a pro-inflammatory role for chemerin in DSS-induced colitis and the ability of chemerin to suppress the anti-inflammatory M2 macrophage response. Our study also suggests that upregulated chemerin in inflamed colons may contribute to the pathogenesis of IBD.
| S-EPMC4085517 | biostudies-literature
Project description:BackgroundAccumulating evidence suggests that M2-polarized tumor-associated macrophages (TAMs) play an important role in cancer progression and metastasis, making M2 polarization of TAMs an ever more appealing target for therapeutic intervention. Astragaloside IV (AS-IV), a saponin component isolated from Astragali radix, has been reported to inhibit the invasion and metastasis of lung cancer, but its effects on TAMs during lung cancer progression have not been investigated.MethodsHuman THP-1 monocytes were induced to differentiate into M2 macrophages through treatments with IL-4, IL-13, and phorbol myristate acetate (PMA). We used the lung cancer cell lines A549 and H1299 cultured in conditioned medium from M2 macrophages (M2-CM) to investigate the effects of AS-IV on tumor growth, invasion, migration, and angiogenesis of lung cancer cells. Macrophage subset distribution, M1 and M2 macrophage-associated markers, and mRNA expression were analyzed by flow cytometry and quantitative PCR. The activation of adenosine monophosphate-activated protein kinase (AMPK) signaling pathways that mediate M2-CM-promoted tumor migration was detected using western blotting.ResultsHere we found that AS-IV significantly inhibited IL-13 and IL-4-induced M2 polarization of macrophages, as illustrated by reduced expression of CD206 and M2-associated genes, and that AS-IV suppressed the M2-CM-induced invasion, migration, and angiogenesis of A549 and H1299 cells. In vivo experiments demonstrated that AS-IV greatly inhibited tumor growth and reduced the number of metastases of Lewis lung cancer. The percentage of M2 macrophages was decreased in tumor tissue after AS-IV treatment. Furthermore, AS-IV inhibited AMPK? activation in M2 macrophages, and silencing of AMPK? partially abrogated the inhibitory effect of AS-IV.ConclusionsAS-IV reduced the growth, invasion, migration, and angiogenesis of lung cancer by blocking the M2 polarization of macrophages partially through the AMPK signaling pathway, which appears to play an important role in AS-IV's ability to inhibit the metastasis of lung cancer.
| S-EPMC6116548 | biostudies-literature
Project description:Mucosal changes in Crohn's disease (CD) and ulcerative colitis (UC), two major forms of inflammatory bowel disease (IBD), are characterized by a prominent infiltration of inflammatory cells including lymphocytes, macrophages, T cells and neutrophils. The precise etiology of IBD is unknown but it involves a complex interplay of factors associated with the immune system, environment, host genotype and enteric commensal bacteria. As there is no known safe cure for IBD, natural alternative therapeutic options without side effects are urgently needed. To this end, Soy-based foods, which have been eaten for centuries in Asian countries, have potential benefits, including lowering the incidence of coronary heart disease, atherosclerosis, type-2 diabetes, allergic response, and autoimmune diseases. This study describes the effect of Soy isoflavons 4', 5, 7 Trihydroxyisoflavone (genistein) on dextran sodium sulphate (DSS) induced experimental colitis. The extent and severity of disease was analyzed through body weight, histopathological analysis, cellular immune response, systemic cytokine levels, and inflammation score using a disease activity index. Genistein treatment significantly attenuated DSS-induced colitis severity and resulted in increase in body weight, colon length and reduction in inflammation score. Genistein also skews M1 macrophages towards the M2 phenotype. Further, gen also reduced the systemic cytokine levels as compared to vehicle control. This serves as the first detailed study towards natural soya based product that shows the polarization of M1 towards M2 macrophages, and reduction of systemic cytokine in part to attenuate the colitis symptoms. Thus, our work demonstrates that genistein, a soya compound, may be useful for the treatment of IBD.
| S-EPMC6053137 | biostudies-literature
Project description:The present study investigated whether the protective effect and mechanism of astragaloside IV (AS-IV) on heart failure (HF) involves small ubiquitin-like modifier (SUMO)-specific protease 1 (Senp1). Mouse HF was established by aortic constriction, inducing pressure overload. The model was confirmed by echocardiography 6 weeks after surgery. Mice were randomly divided into control, HF, HF+AS-IV, and AS-IV groups. Ventricular function was examined by echocardiography. Morphological changes of myocardial tissues were examined by H&E staining. The protein levels of the apoptosis-related proteins, cleaved caspase-3, caspase-3, Bcl2, Bax, and SUMO-Senp1 were determined by Western blotting. H2O2 in isolated mitochondria and cells was determined by Amplex Red. A reactive oxygen species (ROS) detection kit determined ROS levels in isolated mitochondria and HL-1 cells. JC-1 reagent measured mitochondrial membrane potential (ΔΨm). Apoptosis of HL-1 cells was examined by terminal deoxynucleotidyl transferase dUTP nick end labeling. Compared with the control group, the heart weight and heart mass/body weight ratio increased in the HF group (P<0.05). Furthermore, the ejection fraction and left ventricular shortening fraction decreased (P<0.05), while the left ventricular end-diastolic diameter (LVID;d) and end-systolic diameter (LVID;s) increased (P<0.05). Finally, mitochondrial ROS and H2O2 increased (P<0.05), while the ΔΨm decreased (P<0.05). However, AS-IV improved the cardiac function of HF mice, decreased the level of ROS and H2O2 in the myocardium, suppressed the decrease in ΔΨm, and decreased the apoptosis of myocardial cells (P<0.05). AS-IV also decreased the Senp1-overexpression. Furthermore, in HL-1 cells, Senp1-overexpression significantly inhibited the protective effects of AS-IV. AS-IV decreased oxidative stress in cardiomyocytes, decreased mitochondrial damage, inhibited ventricular remodeling, and ultimately improved cardiac function by inhibiting HF-induced Senp1-overexpression. This mechanism provides a novel theoretical basis and clinical treatment for HF.
| S-EPMC8355636 | biostudies-literature
Project description:Intraperitoneal adhesion is a common complication after abdominal surgery, which seriously affects the quality of life of patients. HuoXueTongFu Formula (HXTF) plays an important role in the prevention and treatment of intraperitoneal adhesions. However, the molecular-related mechanisms are still not fully known. In this study, the model of Intrapetitoneal adhesion was established by cecum abrasion and treated with HXTF for one week. RAW264.7 cells were given LPS, IFN-γ, IL-4, HXTF-medicated serum, and PPAR-γ agonist/antagonist, respectively. Histopathology, flow cytometry, ELISA, real-time PCR, and Western blotting were used to further detect the related protein, M1/M2 polarization tendency, and PPAR-γ nuclear translocation. The deposition of collagen fibres reduced in the local area of rats after the operation with HXTF treatment. Similar to IL-4, HXTF induced a tendency for macrophages to polarize toward M2 and promoted peroxisome proliferator-activated receptor-gamma (PPAR-γ) nuclear translocation. Furthermore, the use of HXTF and PPAR-γ agonists downregulated macrophage M1 polarization-related factors IL-1, IL-6, and TNF-alpha and upregulated M2 polarization-related factors IL-4, IL-10, and TGF-beta 1. Meanwhile, the use of HXTF and PPAR-γ agonists downregulated the SOCS3/JAK2/STAT1 pathway and activated the SOCS1/STAT6/PPAR-γ pathway. These results show that HXTF may reduce intraperitoneal adhesion by inducing macrophage M2 polarization and regulating the SOCS/JAK2/STAT/PPAR-γ pathway.
| S-EPMC6854253 | biostudies-literature
Project description:Fenretinide (4-HPR), a synthetic retinoid, has attracted attention for its anti-inflammation activity. However, few studies have evaluated the effects of 4-HPR on ulcerative colitis (UC). The present study was performed to investigate the therapeutic effects of 4-HPR on UC, and to explore the mechanisms mainly focused on macrophage polarization involved in this progress. Intraperitoneally administered 4-HPR particularly at dose of 100 mg/kg obviously alleviated UC symptoms and restrained the mRNA expression of colonic IL-1β, IL-6, and TNF-α in dextran sulfate sodium (DSS)-induced mice. Further analysis showed that 4-HPR decreased the mRNA expression of M1 macrophage markers IL-12 and iNOS, while increased M2 macrophage markers Ym1, Arg1 and MRC1 in colonic tissue of mice received DSS. Consistently, an in vitro study revealed that 4-HPR decreased inflammatory response and M1 polarization, while enhanced M2 polarization in LPS-induced RAW264.7 cells. Interestingly, 4-HPR remarkably activated PPAR-γ which was an important regulator of macrophage polarization both in colonic tissue of UC mice and in LPS-induced RAW264.7 cells. Furthermore, these effects of 4-HPR in vivo and in vitro including anti-inflammation and modulation of macrophage polarization were partially abolished by treatment with PPAR-γ antagonist GW9662, indicating that 4-HPR activated PPAR-γ to exert its activities. Taken together, this study demonstrated that 4-HPR might be a potent anti-UC agent that works by regulating macrophage polarization via PPARγ.
| S-EPMC8806340 | biostudies-literature
Project description:Ammonia is one of the major toxic components of metabolites in blood and tissues of high-producing dairy cows and could affect the health of bovine mammary glands. Bovine mammary epithelial cells are sensitive to oxidative stress induced by intensive cell metabolism. In our previous study, we found that ammonia could induce oxidative stress, apoptosis and inflammatory responses in bovine mammary epithelial cells. In the present study, the cytoprotective effects of astragaloside IV against ammonia in vitro were explored. The results demonstrated that pretreatment of MAC-T cells with astragaloside IV could potently suppress the increase in the level of intracellular reactive oxygen species (ROS) and the rate of cell apoptosis, inhibit the ammonia-induced inflammatory responses, and rescue the decrease of cell viability. Astragaloside IV prevented ammonia-induced endoplasmic reticulum stress. Astragaloside IV also significantly suppressed the levels of BAX, caspase 3 and p53 phosphorylation in ammonia-induced MAC-T cells. Nuclear factor erythroid 2-related factor 2(Nrf2) was essential for cytoprotective effects of astragaloside IV in MAC-T cells, as knockdown of Nrf2 dramatically abolished the prosurvival effects of astragaloside IV on treated cells. Furthermore, the PI3K/AKT and ERK/MAPK pathways were responsible for the induction of Nrf2 by astragaloside IV. In conclusion, astragaloside IV played a beneficial role against ammonia-induced damage of MAC-T cells. This provides a cue for future study to use astragaloside IV as a protective and curative agent against ammonia exposure of mammary glands in dairy cows.
| S-EPMC6386910 | biostudies-literature
Project description:The Notch signaling pathway participates in pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis. Astragaloside IV (AS‑IV) is an effective antiproliferative treatment for vascular diseases. The present study aimed to investigate the protective effects and mechanisms underlying AS‑IV on hypoxia‑induced PASMC proliferation and pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) model rats. Rats were divided into the following four groups: i) normoxia; ii) hypoxia (10% O2); iii) treatment, hypoxia + intragastrical administration of AS‑IV (2 mg/kg) daily for 28 days; and iv) DAPT, hypoxia + AS‑IV treatment + subcutaneous administration of DAPT (10 mg/kg) three times daily. The effects of AS‑IV treatment on the development of hypoxia‑induced PAH, right ventricle (RV) hypertrophy and pulmonary vascular remodeling were examined. Furthermore, PASMCs were treated with 20 µmol/l AS‑IV under hypoxic conditions for 48 h. To determine the effect of Notch signaling in vascular remodeling and the potential mechanisms underlying AS‑IV treatment, 5 mmol/l γ‑secretase inhibitor [N‑[N‑(3,5‑difluorophenacetyl)‑L‑alanyl]‑S‑phenylglycine t‑butyl ester (DAPT)] was used. Cell viability and apoptosis were determined by performing the MTT assay and flow cytometry, respectively. Immunohistochemistry was conducted to detect the expression of proliferating cell nuclear antigen (PCNA). Moreover, the mRNA and protein expression levels of Notch‑3, Jagged‑1, hes family bHLH transcription factor 5 (Hes‑5) and PCNA were measured via reverse transcription‑quantitative PCR and western blotting, respectively. Compared with the normoxic group, hypoxia‑induced PAH model rats displayed characteristics of PAH and RV hypertrophy, whereas AS‑IV treatment alleviated PAH and prevented RV hypertrophy. AS‑IV also inhibited hypoxia‑induced pulmonary vascular remodeling, as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia‑induced PAH model rats. Compared with normoxia, hypoxia promoted PASMC proliferation in vitro, whereas AS‑IV treatment inhibited hypoxia‑induced PASMC proliferation by downregulating PCNA expression in vitro and in vivo. In hypoxia‑treated PAH model rats and cultured PASMCs, AS‑IV treatment reduced the expression levels of Jagged‑1, Notch‑3 and Hes‑5. Furthermore, Notch signaling inhibition via DAPT significantly inhibited the pulmonary vascular remodeling effect of AS‑IV in vitro and in vivo. Collectively, the results indicated that AS‑IV effectively reversed hypoxia‑induced pulmonary vascular remodeling and PASMC proliferation via the Notch signaling pathway. Therefore, the present study provided novel insights into the mechanism underlying the use of AS‑IV for treatment of vascular diseases, such as PAH.
| S-EPMC7716412 | biostudies-literature
Project description:Akkermansia muciniphila has been proved to play a crucial role in the progression of colitis, but its underlying mechanism remains inconclusive. In this study, we aim to investigate the effect of A. muciniphila on the development of acute colitis and explore the underlying mechanism. We found that the fecal level of A. muciniphila was decreased in ulcerative colitis (UC) patients compared to the healthy people in the GMrepo database. Oral administration of A. muciniphila strain BAA-835 significantly ameliorated the symptoms in dextran sulfate sodium (DSS)-induced acute colitis, evidenced by decreased body weight loss, colon length shortening, and colon histological inflammatory score. In addition, the number of goblet cells and the mucin family were enhanced after A. muciniphila treatment. Furthermore, proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein 1 (MCP-1) had a downward trend. Mechanistically, the expression of NLRP3, caspase-1 p20, and IL-1β p17 were upregulated in A. muciniphila-treated mice. Additionally, the colon tissues from high-A. muciniphila UC patients had a higher NLRP3 expression than that from low-A. muciniphila UC patients. Moreover, the upregulation of NLRP3 was observed in mouse macrophage Raw264.7 cells and bone marrow-derived macrophage (BMDM) cells after incubation with A. muciniphila. To clarify whether the protective effect of A. muciniphila in colitis depends on NLRP3, we performed the NLRP3-deficient assay in NLRP3-/- mice in vivo. The evidence showed that NLRP3 deficiency eliminated the protective effects of A. muciniphila in acute colitis. In conclusion, A. muciniphila alleviates DSS-induced acute colitis by NLRP3 activation, which enriches the mechanism and provides a new prospect for the probiotic-based treatment of colitis. IMPORTANCE The gut microbiota and host immune response interaction influences the progression of intestinal inflammatory disease. As a well-recognized next-generation probiotic, Akkermansia muciniphila has been proved to play a crucial role in the progression of colitis, but its underlying mechanism remains inconclusive. We found that oral administration of A. muciniphila strain BAA-835 significantly ameliorated the symptoms of acute colitis. Mechanistically, the expression of NLRP3 was upregulated in the A. muciniphila group, and the protective effect of A. muciniphila in colitis depends on NLRP3 activation. This enriches the mechanism and provides a new prospect for the probiotic-based treatment of colitis, which would promote a deeper understanding of the complex characteristics of A. muciniphila and provide guidance for the treatment of human colitis in the future.
| S-EPMC8510245 | biostudies-literature
Project description:Previous studies have revealed that mesenchymal stem cells (MSCs) alleviate inflammatory bowel disease (IBD) by modulating inflammatory cytokines in the inflamed intestine. However, the mechanisms underlying these effects are not completely understood. We sought to investigate the therapeutic effects of human adipose tissue-derived (hAT)-MSCs in an IBD mouse model and to explore the mechanisms of the regulation of inflammation. Dextran sulfate sodium-induced colitis mice were infused with hAT-MSCs intraperitoneally and colon tissues were collected on day 10. hAT-MSCs were shown to induce the expression of M2 macrophage markers and to regulate the expression of pro- and anti-inflammatory cytokines in the colon. Quantitative real time-PCR analyses demonstrated that less than 20 hAT-MSCs, 0.001% of all intraperitoneally injected hAT-MSCs, were detected in the inflamed colon. To investigate the effects of hAT-MSC-secreted factors in vitro, transwell co-culture system was used, demonstrating that tumour necrosis factor-?-induced gene/protein 6 (TSG-6) released by hAT-MSCs induces M2 macrophages. In vivo, hAT-MSCs transfected with TSG-6 small interfering RNA, administered intraperitoneally, were not able to induce M2 macrophage phenotype switch in the inflamed colon and had no significant effects on IBD severity. In conclusion, hAT-MSC-produced TSG-6 can ameliorate IBD by inducing M2 macrophage switch in mice.
| S-EPMC5507867 | biostudies-other