INFLAMMATION
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2026
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IF 5.4
Wang Zhengwei,Lin Jiani,Tan Guisen,Zhang Weimin,Chen Tao,Gao Ming,Liu Jiacheng,Wang Jianwei,Pan Tingzheng,Li Qingzhong,Zhang Hongtian,Shen Hongwei,He Xiaosheng,Liu Jiangang,Liu Zhuohao
The post-ischemic immune microenvironment critically balances neuroinflammation and tissue repair, making macrophage polarization a pivotal therapeutic target in cerebral infarction. Umbilical cord mesenchymal stromal cells (UCMSCs) modulate macrophage polarization primarily through paracrine signaling, while the key mediators and underlying mechanisms remain incompletely elucidated. Using proteomic array-based screening of co-culture supernatants, we identified soluble factors secreted by UCMSCs that regulate macrophage polarization. Stable soluble tumor necrosis factor receptor 1 (sTNFR1)-overexpressing (oe-sTNFR1) UCMSCs were generated via lentiviral transduction. The mechanisms by which sTNFR1 regulates macrophage polarization were investigated in vitro using immunoblotting, RT-qPCR, immunofluorescence, and flow cytometry. The therapeutic efficacy was evaluated in a rat model of middle cerebral artery occlusion (MCAO) via intracranial delivery of oe-sTNFR1 UCMSCs, with outcomes assessed via histological (Nissl and 2,3,5-triphenyltetrazolium chloride) staining, behavioral tests, and magnetic resonance imaging. To circumvent risks of genetic modification, a TNF-α-targeting nanobody (TNF-α Nb) was developed and tested in combination with wild-type UCMSCs. Proteomic analysis identified sTNFR1 as a key mediator secreted by UCMSCs for reprogramming macrophage polarization. oe-sTNFR1 UCMSCs enhanced macrophage chemotaxis and promoted reparative polarization in a paracrine-dependent manner. Mechanistically, UCMSC-derived sTNFR1 suppressed the NF-κB axis, which not only attenuated pro-inflammatory polarization but also derepressed SOCS3 signaling, thereby promoting the reparative phenotype. In MCAO rats, intracranial delivery of oe-sTNFR1 UCMSCs reshaped the post-ischemic brain microenvironment toward an anti-inflammatory and pro-repair state, improving neurological recovery through reduced infarct volume and improved functional outcomes. Furthermore, co-administration of the TNF-α Nb with wild-type UCMSCs enhanced a reparative myeloid phenotype and improved neurological outcomes compared to UCMSCs alone. This study establishes UCMSC-derived sTNFR1 as a key paracrine mediator of macrophage polarization via the sTNFR1/NF-κB/SOCS3 axis, facilitating functional recovery after ischemic stroke. The strategy combining a TNF-α Nb with UCMSCs offers a novel and clinically promising immunotherapeutic approach.
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Frontiers in Pharmacology
·
2025
·
IF 4.8
Yancen Li,Chengyu Wan,Fan Li,Guang Xin,Tao Wang,Qilong Zhou,Tingyu Wen,Shiyi Li,Xiaoting Chen,Wen Huang
Background: Isatidis Folium, a botanical drug widely used in traditional medicine, is known for its anti-inflammatory properties, including heat-clearing, detoxifying, and blood-cooling effects. Although its potential in sepsis treatment has been suggested, the bioactive metabolites and underlying mechanisms remain poorly understood.Methods: Network pharmacology and molecular docking were employed to identify the therapeutic effects and mechanisms of Indirubin, the major bioactive metabolite of Isatidis Folium, in sepsis treatment. In vivo, a cecal ligation and puncture (CLP)-induced mouse sepsis model was used to evaluate the protective effects of Indirubin through histopathological analysis, ELISA, and biochemical assays. In vitro, RAW264.7 cells were stimulated with LPS and treated with varying concentrations of Indirubin. The anti-inflammatory effects of Indirubin were assessed using ELISA, apoptosis assays, and Western blotting.Results: Network pharmacology analysis identified Indirubin as the major bioactive metabolite of Isatidis Folium and EGFR and SRC as its key molecular targets. Experimental validation demonstrated that Indirubin significantly improved survival rates, alleviated tissue injury, and suppressed inflammatory responses in sepsis models. Mechanistically, Indirubin inhibited LPS-induced activation of the EGFR/SRC/PI3K and NF-κB/MAPK pathways in macrophages, significantly reducing cell death and inflammation in RAW264.7 cells.Conclusion: Indirubin, the primary bioactive metabolite of Isatidis Folium, exerts protective effects against sepsis by targeting the EGFR/SRC/PI3K and NF-κB/MAPK signaling pathways in macrophages. These findings provide a mechanistic basis for the development of Indirubin as a multi-target therapeutic agent for sepsis treatment.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
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IF 4.8
Cheng Lu,ShiJun Deng,YanJiao Liu,ShengJin Yang,DingMei Qin,LiJuan Zhang,Rui-rui Wang,Yi Zhang
Available online Atopic dermatitis (AD) is a chronic, persistent inflammatory skin disease characterized by eczema-like lesions and itching. Although topical steroids have been reported for treating AD, they are associated with adverse effects. Thus, safer medications are needed for those who cannot tolerate these agents for long periods. Mangiferin (MAN) is a flavonoid widely found in many herbs, with significant anti-inflammatory and immunomodulatory activities. However, the potential modulatory effects and mechanisms of MAN in treating Th2 inflammation in AD are unknown. In the present study, we reported that MAN could reduce inflammatory cell infiltration and scratching at the lesion site by decreasing MC903-induced levels of Th2-type cytokines, Histamine, thymic stromal lymphopoietin, Leukotriene B4, and immunoglobulin E. The mechanism may be related to reductions in MAPK and NF-κB-associated protein phosphorylation by macrophages. The results suggested that MAN may be a promising therapeutic agent for AD.
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EXPERIMENTAL ANIMALS
·
2024
·
IF 2.2
Zhi-Hui GUAN,Di YANG,Yi WANG,Jia-Bin MA,Guo-Nian WANG
Ischemia/reperfusion (I/R) is a pathological process that occurs in numerous organs and is often associated with severe cellular damage and death. Ectodysplasin-A2 receptor (EDA2R) is a member of the TNF receptor family that has anti-inflammatory and antioxidant effects. However, to the best of our knowledge, its role in the progression of myocardial I/R injury remains unclear. The present study aimed to investigate the role of EDA2R during myocardial I/R injury and the molecular mechanisms involved. In vitro, dexmedetomidine (DEX) exhibited a protective effect on hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury and downregulated EDA2R expression. Subsequently, EDA2R silencing enhanced cell viability and reduced the apoptosis of cardiomyocytes. Furthermore, knockdown of EDA2R led to an elevated mitochondrial membrane potential (MMP), repressed the release of Cytochrome C and upregulated Bcl-2 expression. EDA2R knockdown also resulted in downregulated expression of Bax, and decreased activity of Caspase-3 and Caspase-9 in cardiomyocytes, reversing the effects of H/R on mitochondria-mediated apoptosis. In addition, knockdown of EDA2R suppressed H/R-induced oxidative stress. Mechanistically, EDA2R knockdown inactivated the NF-κB signaling pathway. Additionally, downregulation of EDA2R weakened myocardial I/R injury in mice, as reflected by improved left ventricular function and reduced infarct size, as well as suppressed apoptosis and oxidative stress. Additionally, EDA2R knockdown repressed the activation of NF-κB signal in vivo. Collectively, knockdown of EDA2R exerted anti-apoptotic and antioxidant effects against I/R injury in vivo and in vitro by suppressing the NF-κB signaling pathway.
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PHYTOMEDICINE
·
2025
·
IF 8.3
Jiao Liu,Danye Niu,Yu Tang,Ruoheng Zheng,Yinyin Qin,Xiuqin Cheng,Shubo Pan,Jinfei Yuan,Xiaohua Shi,Jiao Yang
Background β-Hydroxy β-Methylbutyrate (HMB), derived from leucine, is known for its role in anti-oxidation and anti-inflammation. But, the application of HMB in IBD treatment is not fully understood, highlighting the requirement for further research. Purpose We aimed to examine the effects of HMB treatment on DSS-induced chronic colitis in mice and explore its underlying mechanisms. Methods To simulate colonic inflammation, a murine colitis model was generated by using DSS induction. Critical indicators such as body weight, colon length, disease activity index (DAI), and gross pathology were thoroughly monitored. Immunohistochemistry assay was conducted to assess the expression of Occludin and F4/80. Flow cytometry was employed to evaluate the expression levels of CD80 and CD86. qPCR was performed to measure cytokine expression (IL-6, IL-1β, TNF-α, IL-22, CXCL2, iNOS). RNA sequencing was carried out using bone-marrow derived dendritic macrophage cells (BMDMs). Results Our study indicates that HMB treatment substantially mitigated colonic damage in murine models of DSS-induced colitis, highlighting its anti-inflammatory potential. Notably, HMB significantly enhanced the expression of Occludin in these mice. Furthermore, HMB downregulated proinflammatory markers such as IL-6, IL-1β, and TNF-α as well as CXCL2 in the colon tissue. In vitro experiments also revealed that HMB reduced production of proinflammatory cytokines induced by DSS and suppressed the expression levels of CD80 and CD86 in macrophage cells. On a mechanistic level, we demonstrated the anti-inflammatory effects of HMB by reducing the phosphorylation of p-ERK and p-p65, thereby limiting cytokine production in both in vivo and in vitro settings. Conclusion These findings indicate that HMB possesses anti-inflammation against intestinal inflammation and may hold promise as a potential therapeutic candidate for IBD treatment. There's growing interest in combining traditional anti-inflammatory agents with supplements like HMB to improve outcomes in complex IBD cases. HMB's role in established muscle preservation and reduction of systemic inflammation as described in this study could make it a valuable adjunct in IBD therapy.
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BRAIN RESEARCH BULLETIN
·
2024
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IF 3.5
Yu Bi,Ziyi Xie,Xiang Cao,Huanyu Ni,Shengnan Xia,Xinyu Bao,Qinyue Huang,Yun Xu,Qingxiu Zhang
Microglia-associated neuroinflammation plays essential roles in pathology of acute stroke. Cedrol, a natural compound extracted from ginger, has been shown to confer inhibitory effects on inflammation in various diseases. However, whether Cedrol suppresses neuroinflammation and protects brains from acute ischemic injury still remains unclear. In this study, we found that Cedrol inhibited microglia activation and the production of inflammatory factors in LPS-challenged microglia and the penumbra region of middle cerebral artery occlusion (MCAO) mice. We also found that Cedrol reduced the infarct size and mNSS scores and improved acute cerebral ischemia-induced behavioral outcomes, suggesting remarked neuroprotection of Cedrol. Molecular docking analysis showed that Cedrol bound to estrogen receptor β (ERβ) with moderate-strong affinity. Intriguingly, treatment with fulvestrant, an ER blocker, abolished the anti-inflammatory effects of Cedrol. Cedrol significantly reversed the LPS- and MCAO-induced increases in phosphorylation levels of IκB and NF-κB P65 in primary microglia and MCAO mice, respectively. Additionally, Cedrol was observed to rescue LPS-induced shuttling of NF-κB P65 from cytoplasm to nuclei in primary microglia, indicating inhibitory effects of Cedrol on NF-κB signaling. These results suggest microglia associated neuroinflammation may be mediated by ERβ-NF-κB signaling pathway. Together, our study reveals that Cedrol protected brain function from acute cerebral ischemia through inhibition of microglia-associated neuroinflammation via ERβ-NF-κB signaling pathways, and Cedrol may serve as an alternative option for treatment of acute stroke injury.
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PHYTOMEDICINE
·
2024
·
IF 6.7
Pingping Tuo,Risheng Zhao,Ning Li,Shuang Yan,Gege Yang,Chunmei Wang,Jinghui Sun,Haiming Sun,Mengyang Wang
Background Ang II induces hypertensive heart failure (HF) via hemodynamic and non-hemodynamic actions. Lycorine (LYC) is an alkaloid derived from Lycoris bulbs, and it possesses anti-cardiovascular disease-related activities. Herein, we explored the potential LYC-mediated regulation of Ang II-induced HF. Methods Over 4 weeks, we established a hypertensive HF mouse model by infusing Ang II into C57BL/6 mice using a micro-osmotic pump. For the final two weeks, mice were administered LYC via intraperitoneal injection. The LYC signaling network was then deduced using RNA sequencing. Results LYC administration strongly suppressed hypertrophy, myocardial fibrosis, and cardiac inflammation. As a result, it minimized heart dysfunction while causing no changes in blood pressure. The Nuclear Factor kappa B (NF-κB) network/phosphoinositol-3-kinase (PI3K)-protein kinase B (AKT) was found to be a major modulator of LYC-based cardioprotection using RNA sequencing study. We further confirmed that in cultured cardiomyocytes and mouse hearts, LYC reduced the inflammatory response and downregulated the Ang II-induced PI3K-AKT/NF-κB network. Moreover, PI3K-AKT or NF-κB axis depletion in cardiomyocytes completely abrogated the anti-inflammatory activities of LYC. Conclusion Herein, we demonstrated that LYC safeguarded hearts in Ang II -stimulated mice by suppressing the PI3K-AKT/NF-κB-induced inflammatory responses. Given the evidence mentioned above, LYC is a robust therapeutic agent for hypertensive HF.
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BIOMEDICINE & PHARMACOTHERAPY
·
2024
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IF 6.9
Tingting Chen,Gaoxiang Ai,Guihong Liang,Lingfeng Zeng,Di Zhao,Jun Liu,Yaoxing Dou
Inflammatory bowel disease is linked to a higher occurrence of bone loss. Oxyberberine can effectively improve experimental inflammatory bowel disease. However, no study has shown the effect of oxyberberine on inflammatory bowel disease induced bone loss. The present study was performed to investigate the role of oxyberberine in inflammatory bowel disease induced osteoporosis in chronic inflammatory bowel disease mice model. The inflammatory bowel disease mice were orally given two doses of oxyberberine daily. Blood, colon, and bone specimens were collected for biomarker assessments and histological examinations. Bone biomechanical properties and key proteins and genes involved in the receptor activator of nuclear factor kappa-B ligand/nuclear factor kappa-B signaling pathway were evaluated. Additionally, the binding characteristics of oxyberberine and receptor activator of nuclear factor kappa-B ligand were evaluated by in silico simulation. Results indicated that oxyberberine treatment significantly attenuated the macroscopic damage, colonic shortening, and histological injury from the colon. Furthermore, oxyberberine decreased serum inflammatory cytokine levels. The intervention with oxyberberine significantly mitigated the deterioration of bone mass, biomechanical properties, and microstructural parameters. Moreover, the upregulated osteoclast formation factors in model mice were significantly abolished by oxyberberine. In silico simulation results also showed that oxyberberine was firmly bound with target protein. Hence, our findings indicated that oxyberberine had the potential to mitigate inflammatory bowel disease induced inflammation in bone, inhibit osteoclast formation through regulating the receptor activator of nuclear factor kappa-B ligand/nuclear factor kappa-B signaling pathway, and might be a valuable approach in preventing bone loss associated with inflammatory bowel disease.
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Hepatology International
·
2025
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IF 6.1
Yang Yanfang,Wang Tao,Fu Yuyin,Li Xukui,Yu Fuxun
Background Hepatitis B virus (HBV) is a pathogen that poses a serious threat to human health. The interaction between HBV and host has made great progress in recent years. SUMOylation is involved in virus-related cancer progression, but there are fewer studies on the mechanism of SUMOylation on HBV replication and antiviral defense. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a critical adaptor of the NF-κB pathways. Here, we focus on the roles of TRIM28 in regulating TRAF6 SUMOylation in HBV-replicating cells. Methods The SUMO1-modified TRAF6 proteins were enriched from total cellular proteins by immunoprecipitation with anti-SUMO1 antibody, then the SUMOylated TRAF6 was detected by western blot using an anti-TRAF6 antibody. The interaction between TRAF6 and TRIM28 was identified by immunoprecipitation and LC–MS/MS. The modification sites of TRAF6 SUMOylation were identified by amino acid site mutation. Expression and localization of TRAF6 and TRIM28 were assessed by immunohistochemistry and immunofluorescence. The hydrodynamic injection HBV mouse model was used to determine the function of TRIM28-mediated TRAF6 SUMOylation in vivo. Results The results show that the levels of SUMO1-modified TRAF6 are elevated in HBV-replicating cells. Lys453 is a major SUMO1 modification site of TRAF6. There is an antagonistic interaction between SUMOylation and ubiquitination of TRAF6 protein. The SUMO ligase TRIM28 is responsible for catalyzing TRAF6 SUMOylation. Compared to the wild-type TRAF6, its SUMO site mutant TRAF6 K453R promotes NF-κB activation. Moreover, TRIM28 overexpression attenuates TRAF6-mediated NF-κB activation, thereby inhibiting HBV replication in vivo. Conclusions Our findings demonstrate that SUMO ligase TRIM28 affects the ability of TRAF6 on NF-κB activation, nucleocytoplasmic shuttling and HBV replication-related indicators. Our data reveal that TRIM28-mediated SUMOylation of TRAF6 is a novel mechanism to regulate the inflammatory response, which may pave the way for new strategies to control anti-HBV.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 15
·e70778
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IF 4.2
Hong Tang,Qi Dai,Ziyan Zhao,Weiye Ge,Danlei Li,Zelin Chang,Penglai Pi,Jia Li,Zheng Sun
Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumour, accounting for a significant proportion of adult brain tumours. It is associated with a poor prognosis and high recurrence rates. Although temozolomide (TMZ) remains the standard first-line chemotherapy for GBM, its clinical efficacy is often limited by the development of drug resistance and toxic effects on normal tissues. Melatonin (Mel), a natural indoleamine synthesised by the pineal gland, has demonstrated synergistic anti-tumour effects when combined with various chemotherapy agents in multiple studies. This study investigates the synergistic potential of Mel to enhance TMZ's therapeutic efficacy against GBM. The results demonstrate that the combination of Mel and TMZ significantly inhibits glioblastoma cell proliferation, migration, and invasion. Mechanistically, this synergistic effect is mediated through the NF-κB/COX-2 signalling pathway. Mel enhances TMZ's anti-tumour activity by inhibiting IκBα phosphorylation, suppressing NF-κB activation, and downregulating COX-2 expression. Additionally, the combination treatment induced apoptosis via activation of the Caspase-3 pathway. These results suggest that Mel can potentiate the therapeutic efficacy of TMZ in glioblastoma treatment, offering a promising strategy to overcome TMZ resistance while reducing its associated toxicity.
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International Journal of Medical Sciences
·
2025
·Vol. 22
·期 15
·3839-3853
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IF 3.2
Wen Weijia,Li Jiaying,Yuan Li,Liao Yan,Shao Caixia,Xu Dingze,Jiang Hongye,Liao Yuandong,Liu Pan,Zhang Chunyu,Yao Shuzhong,Wang Wei
Lymph node metastasis (LNM) confers significant treatment failure and adverse clinical outcomes in cervical cancer (CCa). However, large unknown lies in the mechanisms underlying LNM in CCa. In this study, we discovered that PRDX3 is elevated in CCa with LNM and associates with poor prognosis in CCa patients. Moreover, multivariate logistic analysis revealed that PRDX3 is an independent predictor of LNM in CCa. Functional investigations demonstrated that PRDX3 promotes invasion, lymphangiogenesis, and LNM of CCa. Mechanistically, PRDX3 activates NF-κB signaling pathway and upregulates the downstream pro-metastatic molecules VEGF-C and MMP-9 in CCa cells. Furthermore, PRDX3 could inhibit the anoikis of detached CCa cells by reducing the ROS level and hence promote LNM in CCa. Importantly, genetic inhibition of PRDX3 potently slows LNM of CCa. These findings highlight a novel PRDX3-mediated mechanism of LNM in CCa and recognize PRDX3 as a promising predictive marker and target of clinical intervention for LNM in CCa.
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Drug Design Development and Therapy
·
2025
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IF 5.1
Fangbin Liu,Jiyuan Chen,Chunai Gong,Minyan Chen,Gang Yang,Chun Chen,Ru Yao,Shengnan Li,Rong Wang,Yongfang Yuan
Introduction Xerostomia, commonly caused by Sjögren disease (SjD) or head and neck radiotherapy, significantly impairs patients’ quality of life, yet effective treatments remain limited. Traditional Chinese Medicine (TCM) offers promising alternatives due to its favourable efficacy and low toxicity. Shatai Heji (STHJ), a compound TCM formulation designed to nourish yin and invigorate qi, shows therapeutic potential for xerostomia. This study aimed to establish quality control standards for STHJ and evaluate its pharmacodynamics, safety, and mechanisms of action in models of xerostomia.Methods A qualitative identification method was developed for the twelve herbal components of STHJ, with quantification of active constituents, focusing on quality markers for Astragalus and Rehmannia. Xerostomia was induced in Sprague–Dawley (SD) rats using a muscarinic receptor antagonist, and in BALB/c mice with SjD. Histological examination of major organs and salivary glands was performed, and aquaporin-5 (AQP5) expression in submandibular glands was assessed via Western blotting and immunohistochemistry. Therapeutic effects were evaluated through salivary secretion, glandular weight, and biochemical markers. In SjD mice, submandibular gland immunofluorescence and ELISA were used to assess inflammatory cytokines (TNF-α, TNF-β, IFN-γ, IL-6) and autoantibodies (anti-SSA/Ro, anti-SSB/La). Western blotting was used to analyse NF-κB and MAPK p38 pathway activation. Acute toxicity was assessed in SD rats.Results STHJ significantly improved xerostomia symptoms, increased salivary output, upregulated AQP5, and preserved glandular morphology. It reduced fibrosis, suppressed inflammatory cytokine expression, and inhibited immune cell infiltration. Mechanistically, STHJ attenuated activation of NF-κB and MAPK p38 pathways. No acute toxicity was observed.Conclusion This is the first study to establish quality control standards for STHJ and to demonstrate its anti-inflammatory and immunomodulatory effects in xerostomia models. The findings suggest that STHJ may serve as a safe and effective therapeutic option for xerostomia associated with SjD and other conditions.
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