PHYTOMEDICINE
·
2025
·
IF 8.3
Penghong Xu,Yuping Qian,Guo Xu,Jianlin Chu,Bingfang He
Background Inflammatory bowel disease (IBD), a chronic inflammatory condition categorized into ulcerative colitis (UC) and Crohn's disease (CD), affects a growing global patient population. Despite the prevalence, clinically there is a scarcity of effective therapeutic agents. Purpose This study investigated the therapeutic effects of fructosyl mangiferin (FM) on UC and elucidated its underlying mechanisms through in vivo and in vitro experiments. Methods In vivo , a UC model of C57BL/6J mice was established via dextran sulfate sodium (DSS) induction, and the therapeutic effects were assessed through intragastric administration. In vitro , the murine macrophage cell line RAW264.7 was stimulated with lipopolysaccharide (LPS) to establish an M1 polarization model and introduced to explore the role of FM in immune cells. Molecular docking was further employed to investigate the specific molecular mechanisms of FM. Results In vivo experimental findings indicate that FM, like mangiferin (M), preserves mucin secretion and the expression of occludin protein, and both significantly impede the progression of fibrosis associated with colitis. Additionally, FM effectively suppresses M1 macrophage polarization and exerts a pronounced inhibitory effect on the adaptive immune response, outperforming M in mitigating UC. In vitro results corroborate FM's inhibitory action on M1 polarization. Molecular docking studies identified FM as a potential signal transducer and activator of transcription 3 (STAT3) inhibitor, aligning with western blot analyses from both in vivo and i n vitro experiments. Conclusion In conclusion, following fructosylation, FM exhibits remarkable anti-inflammatory and colonic protective effects. FM's ability to control the progression of UC offers a novel strategy for its potential treatment, warranting further investigation into its clinical application.
研究领域:
免疫学
·
药理学
·
消化病学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Xin Li,Qilong Li,Ning Jiang,Kexin Zheng,Yiwei Zhang,Xiaoyu Sang,Ying Feng,Ran Chen,Qijun Chen
Background The property of dihydroartemisinin (DHA) in promoting host immunohomeostasis, apart from its potent antimalarial activity, has been well-recognized. However, the mechanism of DHA in activating macrophages to enhance host resistance to malaria remains unexplored. Purpose This study investigated the molecular mechanism by which DHA promotes the polarization of macrophages toward the M1 phenotype during the treatment of malaria. Methods The mouse macrophage cell line RAW 264.7 or the macrophages isolated from mice were stimulated with Plasmodium berghei ANKA infected red blood cells (iRBC) in the presence of DHA. The macrophage phenotypes in both in vivo and in vitro were determined using cytometric bead array and flow cytometry. To dissect the molecular mechanisms underlying macrophage responses to DHA, we initially profiled the expression of 90 genes associated with innate immunity, including the entire NLR family, in macrophages stimulated with DHA. This targeted screen strikingly revealed that only Nlrp12 was significantly upregulated among all tested NLR genes. The function of Nlrp12 was further dissected by Nlrp12 knockdown in macrophages with recombinant lentiviruses encoding Nlrp12 -specific shRNA, within the context of DHA treatment. To comprehensively define the molecular consequences of Nlrp12 deficiency, we performed an integrated analysis by combining single-cell RNA sequencing with label-free quantitative proteomic profiling. This allowed us to systematically characterize the complex transcriptomic and proteomic dynamics in DHA-treated macrophages upon Nlrp12 deletion. Results DHA induced macrophage polarization to M1 phenotype and enhanced phagocytosis by up-regulating the expression of NLRP12. Nlrp12 -knockdown in macrophages reduced the expression of M1 type-associated genes, resulting in a significantly increased expression of the translocator protein (TSPO), which suppressed the secretion of inflammation-associated cytokines and blunting macrophage M1 polarization. The results of single cell RNA sequencing further revealed that DHA promoted the conversion of classical M1 macrophages into lipocalin-2 (Lcn2) high M1 macrophages. Conclusion The activation of NLRP12 induced by DHA is crucial for M1 macrophage polarization, which plays a significant role in the clearance of Plasmodium parasites.
研究领域:
免疫学
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寄生虫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
DongXue Ma,YuXin Zhang,Jia Zhang,Jun Shi,ShanHu Gao,Fei Long,Xin Wang,XingYu Pu,Jiayao Sun,Shuang Liang,Richard D. Cannon,Silas Villas-Boas,Ting-Li Han
Introduction: Escherichia coli Nissle 1917 (EcN) is one of the most extensively studied nonpathogenic Gram-negative probiotic strains worldwide. Recent research has highlighted the ability of EcN outer membrane vesicles (OMVs) to enhance the phagocytosis and proliferation of RAW264.7 macrophages. However, the impact of EcN-OMVs on M1/M2 polarization and metabolic modulation remains unknown.Methods: In this study, we evaluated the metabolic effects of EcN-OMVs on RAW264.7 macrophage polarization using metabolomic, transcriptomic, and fluxomic approaches.Reuslts: We found that the RAW264.7 macrophages phagocytosed EcN-OMVs, triggering upregulation of the HIF-1, mTORC1, and NF-κB signaling pathways. This metabolic reprogramming enhanced glycolysis, suppressed the TCA cycle, elevated intracellular reactive oxygen species (ROS), TNF-α, IL-6, IL-1β, ATP, and nitric oxide (NO) production, and promoted macrophage proliferation, migration, invasion, and M1-type polarization.Discussion: In summary, this research establishes a theoretical foundation for utilizing probiotic OMVs in immunomodulatory therapeutic applications.
研究领域:
免疫学
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微生物学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
·
2025
·
IF 3.8
Jiajia Chen,Huanle Liu,Yanfang Fu,Xiaolan Chen,Shiqin Zhang,Yongqi Yang,Shengwen Li,Guixiang Wang,Tian Lan
Background Chronic liver inflammation is a major cause of death in patients with liver fibrosis and cirrhosis, which pose a serious health threat worldwide, and there is no effective anti-hepatic fibrosis drug. Kaempferol (KA), a flavonoid polyphenol extracted from many edible plants and traditional Chinese medicine, has been reported to possess anti-inflammatory, antioxidant, and antitumor activities and has an ameliorating effect on liver fibrosis or other fibroproliferative diseases. However, the specific regulatory mechanism of KA-reversed macrophage M1 polarization is still obscure. This study aimed to investigate the protective effects of KA on carbon tetrachloride (CCl 4 )-induced liver fibrosis in mice through M1 polarization. Methods C57BL/6 mice were intraperitoneally injected with CCl 4 twice weekly to induce liver fibrosis. Male mice were randomly divided into four groups (n = 5): the oil group, the CCl 4 group, the low-dose KA-treatment CCl 4 group (50 mg/kg/d KA), and the high-dose KA-treatment CCl 4 group (100 mg/kg/d KA). An equal amount of solvent was given to each group by intraperitoneal injection. Results The results indicated that KA decreased liver pathologic changes, hepatic macrophage recruitment, and serum alanine aminotransferase (ALT) levels. Notably, it reduced the activation of M1-type macrophages in the liver. The expression of proinflammatory cytokines and genes associated with M1 macrophages, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, and inducible nitric oxide synthase (iNOS), was also decreased. The core targets, signaling pathways, and possible mechanisms related to the M1 polarization of KA were analyzed by network pharmacology and molecular docking. Further analysis revealed that KA regulated MAPK/NF-κB signaling pathways. Finally, the results indicated that KA regulates M1 macrophage activation by modulating the MAPK/NF-κB signaling pathways. Conclusions This study revealed that KA ameliorated liver injury, inflammation, and fibrosis by inhibiting macrophage M1 polarization through the MAPK/NF-ҡB signaling pathway, highlighting KA as a potential novel agent for the prevention and treatment of liver fibrosis.
研究领域:
药理学
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肝脏病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2025
·
IF 5.5
Su-Yu Yang,Shu-Tong Li,Tian-Hua Li,De-Jin Ma,Jun-Jie Yu,Yang Liu,Yang Yu,Xue-Tao Li,Juan Zang,Zi-Min Yuan,Liang Kong
Hepatocellular carcinoma (HCC) represents a significant health challenge that requires urgent attention, primarily due to the limited application of chemotherapeutic drugs. This limitation arises from the high infiltration of immune cells within the tumor microenvironment, which diminishes the effectiveness of the therapeutic agents. Consequently, exploring the combination of drug therapy with the M1 polarization mechanism is considered a promising strategy to address this issue. In this study, we designed a hierarchically targeted micelle system responsive to reactive oxygen species (ROS), enabling the synergistic delivery of the hydrophobic drugs sorafenib (Sof) and dehydrodiisoeugenol (Deh) through the integration of a ROS-sensitive bond (thioacetal ketones, TK) and a specific targeting group (glycyrrhetinic acid, GA). The results demonstrated that TK-GA-Sof/Deh-Ms exhibited excellent encapsulation efficiency and stability. The cumulative release rates of Sof and Deh from TK-GA-Sof/Deh-Ms at 48 h were recorded as 49.67 ± 0.02% and 43.90 ± 0.01%, respectively. The online SynergyFinder2.0 software was used to calculate a ZIP synergy score of 6.339 for Sof and Deh, indicating synergy. The combination showed a more significant antitumor effect. The IC50 value of TK-GA-Sof/Deh-Ms was 13.21 ± 1.36 μM. Notably, Deh not only promotes the polarization of M1 macrophages but also effectively inhibits the activation of M2 macrophages. In summary, this study introduces a stepwise-targeting micelle system for liver cancer that possesses dual functions─tumor inhibition and macrophage regulation, thereby paving the way for innovative treatment strategies for hepatocellular carcinoma.
研究领域:
药剂学
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肿瘤学
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生物医学工程
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产品关联
DOI
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Yue Zhang,Hongmin Lu,Lulu Hou,Xin Zhang,Tiantian Guo,Ruoqi Wang,Qi Wang,Mingwei Xing
Acetochlor is a widely used and highly effective herbicide. Its overuse poses significant threats to biosecurity and ecological integrity, particularly affecting free-ranging birds. Data on its impact, especially mechanisms of liver toxicity in chickens, are lacking. Thus, we established an animal-cell-animal model to explore intrinsic mechanisms at multiple levels. We found that acetochlor exposure caused liver cell swelling, inflammatory cell accumulation, and lipid deposition. Transcriptomic analyses revealed that differential gene were mainly enriched in hepatic immune, inflammatory, and programmed cell death pathways. We next focused on the gene GPR120, conducting transfection and agonism experiments in LMH, HD11, and co-cultured cells. Acetochlor significantly increased ROS accumulation, activated the NLRP3 inflammasome, and which induced PANoptosis. HD11 cells exhibited M1 polarization with upregulated pro-inflammatory factors. Silencing GPR120 exacerbated cellular damage and immune responses, whereas its agonist, GSK7A, dramatically reduced macrophage M1 polarization and mitigated immune damage to LMH cells. Finally, we returned to animal studies, adding Omega-3-a known GPR120 agonist-to the diet. Omega-3 effectively reversed acetochlor-induced hepatitis and PANoptosis. Given that acetochlor residues pose potential threats to ecosystems and avian health, it is crucial to strengthen residue control, conduct risk assessments, and explore targeted pathways and nutritional supplementation to counteract these negative impacts.
研究领域:
毒理学
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免疫学
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分子生物学
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兽医学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
·
IF 4.8
Ran Sun,Yan-Fang Wang,Xue Yang
The key to the treatment of multiple sclerosis (MS) is to promote the transition from inflammation-induced demyelination to remyelination. Polarization of microglia towards M1 or M2 phenotype is critical in this transition. Interferon induced protein with tetratricopeptide repeats 3 (IFIT3) is involved in inflammatory reaction and up-regulated in M1-polarized macrophages. However, its effect on microglia during MS has not been reported. In this paper, we demonstrated the important role of IFIT3 in selectively regulating microglia polarization. The expression of IFIT3 was increased when microglia were polarized towards M1, but did not change under M2 polarization. The knockdown of IFIT3 selectively inhibited M1 polarization, while M2 polarization was not affected by IFIT3 silencing. Furthermore, the activation of signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa-B (NF-ĸB) signaling in M1 polarized microglia was suppressed by downregulating IFIT3. In experimental autoimmune encephalitis (EAE) mice, an animal model of MS, IFIT3 expression was upregulated. The disease progression, inflammatory infiltration and demyelination in the EAE mice were alleviated by silencing IFIT3. The inhibitory effects of IFIT3 knockdown on M1 polarization and STAT1 and NF-ĸB pathways were also confirmed in the spinal cord of EAE mice. In summary, our findings suggest that IFIT3 selectively intensified microglia polarization towards the pro-inflammatory M1 phenotype, and may contribute to the progression of MS.
研究领域:
神经科学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2023
·
IF 4.8
Yi-Jin Wu,Sa-Sa Zhang,Qin Yin,Ming Lei,Qi-Hai Wang,Wen-Gang Chen,Ting-Ting Luo,Peng Zhou,Cong-Lan Ji
Background α-Mangostin (MG) showed the potentials in alleviating experimental arthritis, inhibiting inflammatory polarization of macrophages/monocytes, and regulating peroxisome proliferators-activated receptor γ (PPAR-γ) and silent information regulator 1 (SIRT1) signals. The aim of this study was to analyze the correlations among the above-mentioned properties.Methods Antigen-induced arthritis (AIA) was established in mouse, which was treated with MG in combination with SIRT1/PPAR-γ inhibitors to clarify the role of the two signals in the anti-arthritic actions. Pathological changes were systematically investigated. Phenotypes of cells were investigated by flow cytometry. Expression and co-localization of SIRT1 and PPAR-γ proteins in joint tissues were observed by the immunofluorescence method. Finally, clinical implications from the synchronous up-regulation of SIRT1 and PPAR-γ were validated by experiments in vitro.Results SIRT1 and PPAR-γ inhibitors (nicotinamide and T0070097) reduced the therapeutic effects of MG on AIA mice, and abrogated MG-induced up-regulation of SIRT1/PPAR-γ and inhibition of M1 polarization in macrophages/monocytes. MG has a good binding affinity to PPAR-γ, and MG promoted the co-expression of SIRT1 and PPAR-γ in joints. Synchronously activating SIRT1 and PPAR-γ was revealed to be necessary by MG to repress inflammatory responses in THP-1 monocytes.Conclusion MG binds PPAR-γ and excites this signaling to initiate ligand-dependent anti-inflammatory activity. Due to certain unspecified signal transduction crosstalk mechanism, it then promoted SIRT1 expression and further limited inflammatory polarization of macrophages/monocytes in AIA mice.
研究领域:
免疫学
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药理学
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风湿病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2025
·
IF 11.3
Ru-Yang Zhao,Mu-Zi Li,Qi-Qian Wang,Fu-Wei Jiang,Yi Zhao,Jin-Long Li
Butachlor (BTR), a globally prevalent amide herbicide, poses significant environmental health risks due to its bioaccumulation potential and documented chronic toxicity in mammalian systems. Given the spleen's pivotal role in orchestrating systemic immune homeostasis, this study investigated BTR-induced immunopathological mechanisms in ICR mice following 28-day subacute exposure (10 mg/kg). Histopathological examination revealed significant disorganization of the splenic marginal zone architecture, concomitant with ultrastructural mitochondrial abnormalities and a reduction in mitochondrial membrane potential (ΔΨm). Mitochondrial permeability transition pore opening triggered cytoplasmic translocation of mitochondrial DNA (mtDNA), activating the stimulator of interferon genes (STING) pathway—a master regulator of innate immunity. STING activation initiated bifurcated downstream signaling, evidenced by TBK1 phosphorylation and subsequent IRF3 / NF-κB nuclear translocation. This dual signaling cascade simultaneously executed immunogenic cell death via Gasdermin D-dependent pyroptosis (cleaved GSDMD-NT) and drove macrophage polarization (IFN-α / β, IL-1β, TNF-α). Crucially, pharmacological STING inhibition with C-176 attenuated both pyroptosis (GSDMD cleavage reduced) and inflammatory cytokine surge. Our findings not only pioneer the identification of the mtDNA-STING axis as the central mechanism underlying BTR-induced splenic immunotoxicity but also validate STING inactivation as a targeted strategy to mitigate herbicide-associated immune dysfunction. This work provides critical insights for environmental toxicant risk assessment and immunomodulatory.
研究领域:
环境毒理学
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免疫学
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分子生物学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
3 Biotech
·
2021
·Vol. 11
·期 12
·1-13
·
IF 2.406
Tang Miaolong,Cai Jimin,Wang Yan,Huan Zhirong,Yao Hao,Xu Ce,Ge Xin,Song Sheng
Hemorrhage shock (HS) is a major threat to patients with trauma and spontaneous bleeding, resulting in multi-organ failure including the kidney. Tyrosine kinase nonreceptor 1 (TNK1) has been shown to be upregulated in the kidney of experimental HS and patients with severe trauma . The study aims to investigate the role of TNK1 and the underlying mechanism in HS-induced kidney injury. A model of HS was established with femoral artery bloodletting, followed by resuscitation in Sprague–Dawley rats. Renal expression of TNK1 was abnormally induced by HS in rats. Knockdown of TNK1 alleviated HS-induced cell apoptosis and the level of proinflammatory cytokines (TNF-α, IL-6 and IL-1β) in the kidney. The expression of M1 macrophage markers (CD86 and iNOS) and the activation of STAT1 were inhibited by TNK1 knockdown in HS rats. In vitro, human monocyte THP-1 cells were treated with 20 ng/mL interferon-gamma plus 100 ng/mL lipopolysaccharide to induce M1 polarization. TNK1 knockdown exerted inhibitory effect on macrophage M1 polarization, M1-type inflammatory cytokine production and STAT1 activation in THP-1 cells. In conclusion, downregulation of TNK1 alleviates HS-induced kidney injury by suppressing macrophage M1 polarization, inflammation and kidney cell apoptosis, in which the deactivation of STAT1 signaling may be involved.
研究领域:
医学
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免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
GENES AND IMMUNITY
·
2024
·
IF 5
Yue Wu,Huiling Zhou,Yuxin Liu,Ling Wang,Feng Gao,Qicai Liu
Repeated implantation failure (RIF) is one of the most prominent problems in the field of assisted reproduction. Neu5Gc on the surface of decidual macrophages (dMΦ) leads to different activation patterns of dMΦ, which affects embryo implantation and development. Cmah −/− (Neu5Gc-deficient) mice induced to produce anti-Neu5Gc antibodies in vivo were given a special diet rich in Neu5Gc and their fertility was monitored. The long-term diet rich in Neu5Gc induced the decrease of endometrial receptivity of female mice. The pregnancy rate of female mice fed the normal diet was 63.6% ( n = 11) and the average number of embryos was 9.571 ± 1.272, while the pregnancy rate of female mice fed the diet rich in Neu5Gc was 36.4% ( n = 11) and the average number of embryos in pregnant mice was 5.750 ± 3.304. The intake of Neu5Gc and the production of anti-Neu5Gc antibody led to M1 polarization of endometrial dMΦ and abnormal embryo implantation.
研究领域:
生殖生物学
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免疫学
·
胚胎学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Ruixi Li,Qiang Tao,Jiandong Zha,Shikai Wang,Xiaozhun Huang,Jicai Wang,Hang Zhai,Shengjie Hong,Guangquan Zhang
Currently, suppressing macrophage M1 polarization and HSC activation are recognized as potential therapeutic strategies for liver cirrhosis. Ubiquitin-like with PHD and RING Finger Domains 1 (UHRF1) is a crucial epigenetic modulator implicated in maintaining DNA methylation and chromatin structure. Knockdown of high mobility group A protein 2 (HMGA2) was reported to ameliorate hepatic inflammation and fibrosis in nonalcoholic fatty liver disease. Here, the elaborate effect of UHRF1-mediated HMGA2 promoter methylation was investigated during the progression of liver cirrhosis. Transcriptomic sequencing of liver tissues of cirrhotic patients was carried out and a mouse model with liver cirrhosis was established by intraperitoneal injection of carbon tetrachloride (CCl 4 ) twice weekly for four consecutive weeks. Lipopolysaccharide (LPS)-induced RAW264.7 were transduced with overexpressed UHRF1 adenovirus and cell supernatant was applied as the conditional medium to cultivate hepatic stellate cells (HSCs). Notably, in vivo experiments, enhanced UHRF1 expression alleviated fibrosis and inflammation of mouse livers. In vitro experiments, upregulated UHRF1 suppressed CCl 4 -stimulated macrophage M1 polarization and HSC activation. Moreover, MSP assay revealed that methylation was enhanced on HMGA2 promoter at −599/2−450 site after UHRF1 overexpression. More intriguingly, ChIP and Co-IP results clarified that UHRF1 interacted with DNA methyltransferase 1 (DNMT1), thereby bound to HMGA2 promoter and facilitated its methylation. Furthermore, increased HMGA2 level abolished the inhibitory effects of UHRF1 upregulation on the mRNA expression of pro-inflammatory genes of macrophages and genes encoding collagen of HSCs. Collectively, UHRF1 weakened HMGA2 expression by catalyzing its promoter methylation, thereby blocked macrophage M1 polarization and mitigated liver cirrhosis.
研究领域:
分子生物学
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表观遗传学
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肝脏病学
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免疫学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）