PHYTOMEDICINE
·
2024
·
IF 6.7
Wang Yi,Jiang Yu,Li Mingxing,Xiao Yaqin,Zhao Qianyun,Zeng Jiuping,Wei Shulin,Chen Shuhan,Zhao Yueshui,Du Fukuan,Chen Yu,Deng Shuai,Shen Jing,Li Xiaobing,Li Wanping,Wang Fang,Sun Yuhong,Gu Li,Xiao Zhangang,Wang Shengpeng,Wu Xu
Background Rosavin (RSV) is a naturally occurring compound isolated from Rhodiola species. While RSV has been reported with pharmacological activities of anti-oxidation, anti-inflammation, anti-stress and immunomodulation, its effect on colitis and the underlying mechanisms remain unclear. Purpose This study aims to investigate whether and how RSV alleviated colitis in mice. Study design and methods The protective effect of RSV (50, 100, 200 mg/kg, p.o.) was investigated in dextran sulfate sodium (DSS) mediated mouse models of acute and chronic colitis. Alterations in fecal microbiota were evaluated by 16S rRNA sequencing. Pseudo germ-free mice achieved by antibiotics treatment were applied to assess the RSV-mediated functional role of gut microbiota in colitis. RNA sequencing was performed to determine RSV-induced colonic response. Primary T cell culture was conducted to examine the effect of RSV on Th17 and Treg differentiation. Whole blood assay, dual luciferase reporter assay, and molecular docking methods were applied to investigate the mechanisms and targets of RSV in Th17 regulation. Results Oral RSV significantly relieved DSS-mediated acute and chronic colitis in mice, which recovered body weight loss, reduced disease activity index, alleviated colon injury, inhibited inflammation, suppressed the apoptosis of intestinal epithelia, and maintained intestinal barrier function. Moreover, RSV specifically regulated intestinal microbiota by recovering DSS-mediated microbial changes and elevating beneficial microbes such as Lactobacillus and Akkermansia . Antibiotics treatment experiment showed that the protective role of RSV was at least partially dependent on gut microbiota; however, in vitro incubation showed that RSV did not directly promote the growth of Lactobacillus and Akkermansia strains. Further analysis showed that RSV-mediated genetic alterations in colon were enriched in pathways related to lymphocyte regulation. Additionally, RSV regulated the balance of Th17/Treg in colitis mice. Importantly, RSV inhibited the differentiation of Th17 cell in vitro , suppressed the production of IL-17 by Th17 cells, and downregulated Rorc encoding RORγt and its downstream Il17 . RSV significantly inhibited the RORγt transcription activity and bound to its ligand binding domain. Conclusion RSV alleviates murine colitis through regulating intestinal immunity. Notably, RSV is identified as a novel regulator of Th17 cells that inhibits RORγt-mediated Th17 differentiation. These findings potentiate the Rhodiola -derived natural chemicals as novel anti-colitis agents.
研究领域:
药理学
·
免疫学
·
微生物学
·
分子生物学
✓ 已验证
DOI
高影响因子
MOLECULAR IMMUNOLOGY
·
2023
·
IF 3.6
Wei Zhong,Leheng Feng,Wei Tian,Hongbo Qu,Haibo Xu,Ke Ning,Li Liu,Wei Liu,Xiaowei Gong,Hong Chen
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease . This study aimed to investigate the role of SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) in the Th17 and Th17.1 differentiation and Treg/Th17 imbalance, which are major factors contributing to the pathogenesis of SLE. SLE patients and healthy individuals were recruited to detect the SMURF1 levels in naïve CD4 + cells from peripheral blood. Purified and expanded naïve CD4 + T cells were employed to evaluate the effects of SMURF1 on Th17 and Th17.1 polarization in vitro. MRL/lpr lupus model was employed to explore the disease phenotype as well as Treg/Th17 balance in vivo. The results showed that SMURF1 was down-regulated in naïve CD4 + T cells in peripheral blood of patients with SLE and in spleen of MRL/lpr mice. SMURF1 overexpression suppressed the polarization of naïve CD4 + T cells toward Th17 and Th17.1 phenotype and down-regulated the expression of retinoid-related orphan receptor-gammat (RORγt). Subsequently, SMURF1 down-regulation aggravated the disease phenotype, inflammation, and the Treg/Th17 imbalance in MRL/lpr mice. Furthermore, we found that SMURF overexpression promoted the ubiquitination and decreases the stability of RORγt. In conclusion, SMURF1 inhibited the polarization of Th17 and Th17.1 cells and improved the Treg/Th17 imbalance in SLE, which was mediated as least partly by the ubiquitination of RORγt.
研究领域:
免疫学
·
自身免疫性疾病
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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
✓ 已验证
DOI
PubMed
高影响因子
Antioxidants
·
2025
·Vol. 14
·期 4
·468
·
IF 6.6
Xin Zhang,Shuang Han,Zhu Zeng,Jie Dai,Yi Jia
Selenium-binding protein 1 (SELENBP1) has been implicated in cancer development, neurological disorders, tissue injury, metabolic regulation, and cell differentiation. Sepsis is characterized prominently by immunological dysregulation and severe organ damage. However, whether SELENBP1 improves sepsis by regulating immune cell activity remains unknown. Here, we detected an elevation of SELENBP1 levels in the blood of sepsis patients and in the livers of septic mice. Significantly, SELENBP1 knockout (KO) prolonged survival in septic mice. This phenomenon was accompanied by decreased liver damage, reduced inflammation levels, and an increased regulatory T cell/T helper 17 cell (Treg/Th17) ratio in the spleen. Additionally, SELENBP1 deficiency induced a redox imbalance and inhibited dendritic cell (DC) maturation, resulting in a tolerogenic DC (tolDC) phenotype and an increase in the Treg/Th17 ratio. Furthermore, SELENBP1-KO mature DCs (mDCs) alleviated liver injury by increasing the Treg/Th17 ratio in the spleen, thus improving the survival of septic mice. These findings indicate that SELENBP1 is involved in sepsis by regulating DC immune activity, which might provide a potential way for sepsis treatment.
研究领域:
免疫学
·
医学
✓ 已验证
DOI
PubMed
高影响因子
INFLAMMOPHARMACOLOGY
·
2020
·Vol. 28
·期 6
·1705-1716
·
IF 3.238
Zheng Kai,Jia Jia,Yan Shihai,Shen Hong,Zhu Ping,Yu Jiangyi
Immunological tolerance is critical for maintaining gut homeostasis. An imbalance between interleukin-17 (IL-17)-producing T helper 17 (T H 17) cells and regulatory T cells (T reg cells) is involved in ulcerative colitis (UC) pathogenesis. Dendritic cells (DCs) are able to induce T cell differentiation. Paeoniflorin (PF) is a monoterpene glucoside that is commonly used for treatment of autoimmune disease. However, the immunological mechanism of PF involvement in UC treatment is unclear. The present study aimed to explore whether PF can restore the T H 17/T reg balance by modulating DCs. The effects of PF on DCs, T H 17 cells and T reg cells were measured. Furthermore, PF-treated DCs were injected into mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. PF inhibited MHC-II and CD86 expression on the DC surface ( P < 0.05), decreased interleukin (IL)-12 secretion in vitro and in vivo ( P < 0.05), and restored the T H 17/T reg ratio in the mouse model of colitis ( P < 0.05). PF-treated DCs diminished T H 17 differentiation (4.26% in vitro and 1.64% in vivo) and decreased IL-17 expression ( P < 0.05) while inducing CD4 + CD25 + Foxp3 + T reg differentiation (7.82% in vitro and 6.85% in vivo) and increasing Foxp3 and IL-10 production ( P < 0.05). Additionally, both PF and PF-treated DCs improved colonic histopathology in the mouse model of colitis ( P < 0.05). In conclusion this study suggested that PF can ameliorate TNBS-induced colitis by modulating the DC-mediated T H 17/T reg balance.
研究领域:
免疫学
·
医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2023
·
IF 29
Qianmin Ou,Xinhua Qiao,Zhengshi Li,Luhan Niu,Fangcao Lei,Ruifeng Cheng,Ting Xie,Ning Yang,Yao Liu,Ling Fu,Jing Yang,Xueli Mao,Xiaoxing Kou,Chang Chen,Songtao Shi
Summary Over 50 billion cells undergo apoptosis each day in an adult human to maintain immune homeostasis. Hydrogen sulfide (H 2 S) is also required to safeguard the function of immune response. However, it is unknown whether apoptosis regulates H 2 S production. Here, we show that apoptosis-deficient MRL/ lpr (B6.MRL-Faslpr/J) and Bim −/− (B6.129S1-Bcl2l11tm1.1Ast/J) mice exhibit significantly reduced H 2 S levels along with aberrant differentiation of Th17 cells, which can be rescued by the additional H 2 S. Moreover, apoptotic cells and vesicles (apoVs) express key H 2 S-generating enzymes and generate a significant amount of H 2 S, indicating that apoptotic metabolism is an important source of H 2 S. Mechanistically, H 2 S sulfhydrates selenoprotein F (Sep15) to promote signal transducer and activator of transcription 1 (STAT1) phosphorylation and suppress STAT3 phosphorylation, leading to the inhibition of Th17 cell differentiation. Taken together, this study reveals a previously unknown role of apoptosis in maintaining H 2 S homeostasis and the unique role of H 2 S in regulating Th17 cell differentiation via sulfhydration of Sep15 C38 .
研究领域:
免疫学
·
细胞生物学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Yilei Guo,Dandan Sun,Yajing Zhang,Xiaoxiao Yu,Yulai Fang,Changjun Lv,Qin Zhang,Yanrong Zhu,Simiao Qiao,Yufeng Xia,Zhifeng Wei,Yue Dai
The neuropeptide cortistatin (CST) has been reported to attenuate Th17 cell response in multiple disease models, but the mechanism of action remains obscure. Here, we show that either overexpression or exogenous addition of CST obviously restricts Th17 cell differentiation. As metabolic reprogramming plays an important role in Th17 cell development, we explore whether CST inhibits Th17 cell differentiation by regulating glycolysis. The results show that CST substantially attenuates the glycolysis during Th17 differentiation and down-regulates the mRNA expression of myelocytomatosis oncogene (Myc) and hexokinase 2 (HK2), the glycolysis rate-limiting enzyme. Following the overexpression of Myc and HK2, the inhibitory effect of CST on Th17 differentiation nearly disappears, suggesting that Myc-HK2 pathway is deeply involved. Furthermore, growth hormone secretagogue receptor 1 (GHSR1) is identified as the key receptor subtype for CST attenuating glycolysis and Th17 cell differentiation by the combined uses of CST with various receptor subtype blockers. The knockdown of GHSR1 abrogates the inhibition of CST on Th17 differentiation and glycolysis. Finally, in the colitis mice induced by dextran sulfate sodium, an intraperitoneal injection of CST markedly inhibits Th17 cell response and down-regulates the expression of HK2 in the Th17 cells, which is reversed by the combined use of GHSR1 antagonist. These findings suggest that inhibition of glycolysis is the key pathway for CST attenuating Th17 cell response, and GHSR1, Myc and HK2 are potential therapeutic targets of Th17 cell-related diseases.
研究领域:
免疫学
·
细胞生物学
·
神经内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY MECHANISMS AND METHODS
·
2025
·
IF 2.7
Dan Wang,Hui Sun,Kerong Hai,Ningkang Li,Yang Gu,Zengrui Ma
Traumatic brain injury (TBI), a prevalent neurological disorder in clinical practice, is primarily induced by external trauma. Propofol has been reported to alleviate the symptoms associated with TBI. In this study, a TBI model was established in mice using the controlled cortical impact (CCI) method. After treatment with propofol and BML-275, neuronal damage in the TBI model was assessed through the modified Neurological Severity Score (mNSS), Hematoxylin and Eosin (HE) staining, and Nissl staining. To investigate the role of the AMPK/SIRT1 pathway in propofol-regulated TBI, AMPKα-silenced vectors and overexpressed SIRT1 vectors were transfected. Western blot was performed to evaluate the expression of proteins involved in the AMPK/SIRT1 pathway and pyroptosis markers. The regulatory impact of Th17/Treg balance was examined by detecting the key transcription factors RORγt and FOXP3 through immunofluorescent staining and RT-qPCR. Enzyme-linked immunosorbent assay (ELISA) was used to measure IL-17 and IL-10 concentrations. Results showed that propofol significantly reduced neuronal injury in the TBI model, an effect that was reversed by BML-275. Moreover, propofol mitigated pyroptosis by downregulating Caspase-1 and GSDMD-N expression post-TBI. Propofol inhibited Th17 differentiation while promoting Treg differentiation by modulating RORγt/FOXP3 and IL-17/IL-10 levels. Silencing AMPKα markedly diminished propofol’s effects on Th17 and Treg differentiation, with these effects being reversed upon SIRT1 overexpression. Propofol suppressed neuronal pyroptosis through the regulation of Th17/Treg balance via activation of the AMPK/SIRT1 pathway. These findings suggest propofol exerts a protective effect against neuronal damage following TBI, potentially through the modulation of the Th17/Treg balance and AMPK/SIRT1 signaling pathway.
研究领域:
神经科学
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2021
·
IF 11.556
Yumeng Miao,Yun Zheng,Yanzhi Geng,Ling Yang,Na Cao,Yue Dai,Zhifeng Wei
Background: Peroxisome proliferator-activated receptor gamma (PPARγ) has the ability to counter Th17 responses, but the full mechanisms remain elusive. Herein, we aimed to elucidate this process in view of cellular metabolism, especially glutaminolysis. Methods: MTT, CCK-8, Annexin V-FITC/PI staining or trypan blue exclusion assays were used to analyze cytotoxicity. Flow cytometry and Q-PCR assays were applied to determine Th17 responses. The detection of metabolite levels using commercial kits and rate-limiting enzyme expression using western blotting assays was performed to illustrate the metabolic activity. ChIP assays were used to examine H3K4me3 modifications. Mouse models of dextran sulfate sodium (DSS)-induced colitis and house dust mite (HDM)/lipopolysaccharide (LPS)-induced asthma were established to confirm the mechanisms studied in vitro . Results: The PPARγ agonists rosiglitazone and pioglitazone blocked glutaminolysis but not glycolysis under Th17-skewing conditions, as indicated by the detection of intracellular lactate and α-KG and the fluorescence ratios of BCECF-AM. The PPARγ agonists prevented the utilization of glutamine and thus directly limited Th17 responses even when Foxp3 was deficient. The mechanisms were ascribed to restricted conversion of glutamine to glutamate by reducing the expression of the rate-limiting enzyme GLS1, which was confirmed by GLS1 overexpression. Replenishment of α-KG and 2-HG but not succinate weakened the effects of PPARγ agonists, and α-KG-promoted Th17 responses were dampened by siIDH1/2. Inhibition of KDM5 but not KDM4/6 restrained the inhibitory effect of PPARγ agonists on IL-17A expression, and the H3K4me3 level in the promoter and CNS2 region of the il-17 gene locus down-regulated by PPARγ agonists was rescued by 2-HG and GLS1 overexpression. However, the limitation of PPARγ agonists on the mRNA expression of RORγt was unable to be stopped by 2-HG but was attributed to GSH/ROS signals subsequent to GLS1. The exact role of PPARγ was proved by GW9662 or PPARγ knockout, and the mechanisms for PPARγ-inhibited Th17 responses were further confirmed by GLS1 overexpression in vivo . Conclusion: PPARγ agonists repressed Th17 responses by counteracting GLS1-mediated glutaminolysis/2-HG/H3K4me3 and GSH/ROS signals, which is beneficial for Th17 cell-related immune dysregulation.
研究领域:
免疫学
·
细胞代谢
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2024
·Vol. 21
·期 1
·1-17
·
IF 9.3
Gao Dandan,Zou Bin,Zhu Kunyuan,Bi Shijun,Zhang Wenxu,Yang Xinyu,Lai Jieyu,Liang Guobiao,Pan Pengyu
Background Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disorder primarily caused by the rupture of aneurysm, which results in a high mortality rate and consequently imposes a significant burden on society. The occurrence of SAH initiates an immune response that further exacerbates brain damage. The acute inflammatory reaction subsequent to SAH plays a crucial role in determining the prognosis. Th17 cells, a subset of T cells, are related to the brain injury following SAH, and it is unclear how Th17 cells are cleared in the brain. Meningeal lymphatic vessels are a newly discovered intracranial fluid transport system that has been shown to drain large molecules and immune cells to deep cervical lymph nodes. There is limited understanding of the role of the meningeal lymphatic system in SAH. The objective of this research is to explore the impact and underlying mechanism of drainage Th17 cells by meningeal lymphatics on SAH.Methods Treatments to manipulate meningeal lymphatic function and the CCR7-CCL21 pathway were administered, including laser ablation, injection of VEGF-C geneknockout, and protein injection. Mouse behavior was assessed using the balance beam experiment and the modified Garcia scoring system. Flow cytometry, enzyme-linked immunosorbent assays (ELISA), and immunofluorescence staining were used to study the impact of meningeal lymphatic on SAH drainage. Select patients with unruptured and ruptured aneurysms in our hospital as the control group and the SAH group, with 7 cases in each group. Peripheral blood and cerebrospinal fluid (CSF) samples were assessed by ELISA and flow cytometry.Results Mice with SAH showed substantial behavioral abnormalities and brain damage in which immune cells accumulated in the brain. Laser ablation of the meningeal lymphatic system or knockout of the CCR7 gene leads to Th17 cell aggregation in the meninges, resulting in a decreased neurological function score and increased levels of inflammatory factors. Injection of VEGF-C or CCL21 protein promotes Th17 cell drainage to lymph nodes, an increased neurological function score, and decreased levels of inflammatory factors. Clinical blood and CSF results showed that inflammatory factors in SAH group were significantly increased. The number of Th17 cells in the SAH group was significantly higher than the control group. Clinical results confirmed Th17 cells aggravated the level of neuroinflammation after SAH.Conclusion This study shows that improving the drainage of Th17 cells by meningeal lymphatics via the CCR7-CCL21 pathway can reduce brain damage and improve behavior in the SAH mouse model. This could lead to new treatment options for SAH.
研究领域:
神经科学
·
免疫学
·
脑血管疾病
·
淋巴系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2024
·
IF 13.2
Xiaoqing Han,Panpan Song,Rui Cai,Heng Zhu,Jiao Yan,Xingbo Wang,Yanjing Wang,Yaqing Kang,Yuting Ma,Liming Wang,Haiyuan Zhang
Rheumatoid arthritis (RA) is a common chronic inflammatory disease capable of causing the disability. Although various antioxidant strategies have been attempted for prevention and treatment of RA through scavenging the free radicals, the therapeutic effect is limited. Recently, it is reported that the unremitting course of RA intensely correlates with the persistence of immunologic memory, in which the imbalance of T helper 17 (Th17) cells/regulatory T (Treg) cells plays an important role. Herein, we constructed Janus mesenchymal stem cell (MSC)-hitchhiked melanin nanoparticles (MSC FM ) for RA therapy, where one half of MSC kept intact for chemotactically migrating towards the RA inflammatory sites and efficiently restoring the Th17/Treg balance based on the property of MSCs, while the other half hitchhiked the iron-doped melanin (FM) nanoparticles (NPs) and release them to scavenge free radicals for maintaining the durability of Th17/Treg balance. In vitro studies indicated MSC FM could migrate towards CXCL12 inflammatory cytokine, scavenge reactive oxygen and nitrogen species, inhibit Th17 cell proliferation and induce Treg cell production. Further in vivo studies corroborated that intravenously injected MSC FM could target the RA site of collagen-induced arthritis mouse model and alleviate the pathological progression of RA. MSC FM holds great potential as an anti-inflammatory agent for RA management.
研究领域:
免疫学
·
纳米医学
·
风湿病学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Jiaxin Li,Meng Li,Chengdong Zhang,Yachen Fei,Yuxiao Wang,Zhiqi Zhong,Chengjun Peng,Mengjie Li,Shuangying Gui,Jian Guo
Periodontitis is a multifactorial inflammatory disease characterized by severe alveolar bone damage and attachment loss. The imbalance of T help 17 (Th17) / regulatory T cells (Treg) induces excessive interleukin (IL)-17, which leads to alveolar bone damage and aggravates the development of periodontitis. Therefore, we proposed a therapeutic strategy to restore Th17/Treg homeostasis by interfering reactive oxygen species (ROS)-macrophage polarization cascade using active targeting microemulsions-based thermosensitive hydrogel. Folic acid-modified quercetin-loaded microemulsions (FA-Qu-MEs) were dispersed in poloxamer 407 and poly(N-isopropylacrylamide) matrix of hydrogel (FA-Qu-MEs@Gel). FA-Qu-MEs@Gel could be locally injected into the periodontal pocket and sustainedly release drugs. FA-Qu-MEs exhibited excellent ROS scavenging potency by targeting macrophages, resulting M1 phenotype macrophage from to M2 phenotype macrophage. Subsequently, the phenotypic changes of macrophages lead to decreased expression of IL-6 and tumor necrosis factor-α, which inhibited activated Th17, while IL-10 secreted by M2 macrophages promoted Treg differentiation. Finally, the restored Th17/Treg homeostasis reduced the level of IL-17 to accelerate alveolar bone regeneration. This study deigns a novel system that promote alveolar bone regeneration by remodeling Th17/Treg homeostasis via regulating ROS-macrophages polarization cascade for periodontitis treatment.
研究领域:
口腔医学
·
免疫学
·
药剂学
✓ 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）