Cell Death Discovery
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2026
·
IF 10.4
Yuan Naonao,Ma Zhibo,Xue Zihan,Li Qingwen,Zhou Xi,Liu Jing,Lin Yanping,Gu Shiqi,Yi Sichuan,Lu Yao,Lan Peixiang
Distinct macrophage activation states play key roles in the formation and progression of heart allograft fibrosis. However, the exact molecular mechanisms that regulate the balance between inflammatory and pro-fibrotic macrophage responses during fibrosis remain poorly understood. Identifying and targeting the key molecule that regulates the differentiation of inflammatory and pro-fibrotic macrophages might be a pivotal strategy for mitigating fibrosis and prolonging allograft survival. Here, using single-cell sequencing analysis of human heart allografts fibrosis patient samples, we identified a population of macrophages that undergo epigenetic reprogramming through DNA methylation regulated by DNA methyltransferase DNMT1. DNMT1 small-molecule inhibitor 5-AzaC significantly attenuated graft fibrosis and prolonged allograft survival by inhibiting both inflammation and excessive tissue repair. Mechanistically, DNMT1-targeted macrophages suppress the DNA methylation level of the CpG island in the first intron of PTPRD, promoting PTPRD expression, which in turn inhibits the activity of STAT3 and STAT6 pathways, thereby suppressing the differentiation of inflammation and pro-fibrotic macrophages. Based on this, we developed a macrophage-targeted nanocarrier, MV/PEG-LPs, to load 5-AzaC, thereby enhancing its therapeutic precision for allograft fibrosis. Our results reveal a novel target, DNA methylation in macrophages, for the treatment of fibrosis-related diseases.
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
·
IF 5
Limin Chai,Qingting Wang,Yan Wang,Danyang Li,Qianqian Zhang,Yuqian Chen,Jin Liu,Huan Chen,Yuanjie Qiu,Nirui Shen,Jian Wang,Xinming Xie,Manxiang Li
To address the molecular mechanisms underlying macrophage migration inhibitory factor (MIF) induced pulmonary artery smooth muscle cells (PASMCs) proliferation, migration and vascular remodeling in pulmonary hypertension (PH), primary cultured rat PASMCs and monocrotaline (MCT)-induced rats with PH were applied in the present study. The results showed that MIF increased signal transducer and activator of transcription 3 (STAT3) phosphorylation, and then stimulated activating transcription factor 6 (ATF6) activation, subsequently triggered autophagy activation, which further led to programmed cell death factor 4 (PDCD4) lysosomal degradation, and eventually promoted PASMCs proliferation/migration. In lung tissues of MCT rats, MIF protein expression was elevated, phosphorylation of STAT3 and activation of ATF6 were increased, activation of autophagy was evident, and reduction of PDCD4 was observed. Intervention with MIF inhibitor 4-Iodo-6-phenylpyrimidine (4-IPP), ATF6 blocker melatonin or autophagy inhibitor chloroquine, confirmed the in vitro interaction among MIF, STAT3, ATF6, autophagy and PDCD4 in MCT induced rats with PH. Targeting MIF/STAT3/ATF6/autophagy/PDCD4 axis effectively prevented the development of PH by suppressing PASMCs proliferation and vascular remodeling. In conclusions, we demonstrate that MIF activates the STAT3/ATF6/autophagy cascade and then degrades PDCD4 leading to PASMCs proliferation/migration and pulmonary vascular remodeling, suggesting that intervention this axis might have potential value in management of PH.
研究领域:
心血管疾病
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分子生物学
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药理学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2021
·
IF 4.36
Le Shi,Ziqiao Yuan,Jing Liu,Rui Cai,Muhammad Hasnat,Hui Yu,Jing Feng,Zhanglian Wang,Qianqian Zhao,Min Wu,Xinxin Huang,Fei Shen,Lian Yin,Yun Yu,Tao Liang
Ethnopharmacological relevance Modified Simiaowan (MSW) is a traditional Chinese medicine formula that is composed of six herbs. It has been widely used in the treatment of gouty arthritis. Aim of the study This study was designed to investigate the effect of MSW on gouty arthritis and explore the possible mechanisms. Material and methods The rat gouty arthritis model was established by intra-articular injection of Monosodium Urate (MSU) crystal, and then treated with MSW for 5 days. The perimeter of the knee joints was measured in a time-dependent manner and serum samples were collected for the detection of TNF-α, IL-1β, and IL-6 protein levels by ELISA . The protein expressions of MMP-3, TIMP-3, STAT3, and p-STAT3 in cartilage tissues and C28/I2 cells were detected by Western blot , and the levels of proteoglycan in primary chondrocytes and cartilage tissues were determined by toluidine blue staining. In addition, AG490 and IL-6 were used in vitro to explore the function of IL-6/STAT3 pathway in the protective effect of MSU. Results MSW reduced the joint swelling rate in gouty arthritis model and inhibited MSU induced up-regulation of IL-1β, TNF-α, and IL-6 protein levels in serum and synovial fluid. IL-1β induced an increase in p-STAT3 and MMP-3 protein expression in C28/I2 cells, as well as a decrease in TIMP-3. MSW serum inhibited the protein expression changes induced by IL-1β in vitro . Furthermore, inhibition of STAT3 signaling negated the effect of MSW serum on p-STAT3, MMP-3, and TIMP-3 protein levels in C28/I2 cells. MSW also increased the content of proteoglycan significantly both in vivo and in vitro . Conclusion Our data indicated that MSW protected rats from MSU-induced experimental gouty arthritis and IL-1β/IL-6/STAT3 pathway played an essential role in the protective effect of MSU against GA.
研究领域:
药理学
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免疫学
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风湿病学
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中医
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Renwei Lu,Ruyi Zhao,Panpan Lian,Gang Chen,Ranran Wang,Junaid Wazir,Bojie Ma,Chaode Gu,Wenyuan Pu,Li Li,Zhiqiang Huang,Zhonglan Su,Da Huo,Hongwei Wang
Background Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and immune dysregulation. Although the natural flavonoid Phloretin (Phl) shows anti-inflammatory potential, its poor bioavailability limits its therapeutic use. Purpose This study aimed to elucidate the antipsoriatic mechanism of Phl and develop a targeted, thermoresponsive nanodelivery system to enhance its efficacy for topical treatment. Methods The therapeutic effects of Phl were assessed in an imiquimod (IMQ)-induced psoriasis mouse model. Network pharmacology, molecular docking, and molecular dynamics simulations were used to predict and verify the binding stability of Phl with its potential targets. Quantitative proteomics was conducted to provide a global view of the proteomic shifts and affected pathways. These results were validated in vivo and in cytokine-stimulated HaCaT keratinocytes using western blotting, RT-qPCR, and immunofluorescence. Phl-loaded thermoresponsive phase-change material nanoparticles (PCM-Phl) were synthesized, characterized, and evaluated both in vitro and in vivo . Results Phl administration significantly ameliorated erythema, scaling, and epidermal hyperplasia in psoriatic mice. This effect was mediated through the concurrent inhibition of the STAT3 and NF-κB signaling pathways, which suppressed keratinocyte hyperproliferation, aberrant differentiation, and proinflammatory cytokine expression. The PCM-Phl formulation prolonged drug retention at the lesion site, triggered by the inherent hyperthermia of psoriatic lesions and near-infrared irradiation, and demonstrated superior therapeutic outcomes compared to free Phl, achieving a more profound and sustained inhibition of the target pathways. Conclusion This study identified dual inhibition of STAT3 and NF-κB as key mechanisms for the antipsoriatic activity of Phl. Furthermore, it presents a promising thermoresponsive nanodelivery strategy that overcomes the biopharmaceutical barriers of Phl, offering a novel approach for topical treatment of psoriasis.
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PubMed
高影响因子
Advanced Healthcare Materials
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2026
·
IF 11
Jiahui Wang,Wanxin Hou,Xiuxiu Qiu,Yu Zhang,Li Tao,Yukun Chen,Beibei Hong,Lei Zhou,Hegen Li,Zhanxia Zhang
Lung cancer metastasis is the primary cause of patient mortality, underscoring an urgent need for highly effective and low-toxicity therapies. Ursolic acid (UA), a natural triterpenoid, possesses potent antitumor activity, yet its clinical translation has been hindered by poor water solubility, low bioavailability, and nonspecific distribution. To overcome these limitations, we developed a UA-loaded iron-based metal–organic framework (MOF) nanomedicine, termed Ursolic Acid-loaded Iron-MOF (UA@MOF). Harnessing the high surface area and tunable porosity of MOFs, this system enables efficient UA encapsulation and promotes tumor-targeted delivery through the enhanced permeability and retention (EPR) effect. Once internalized, UA suppresses the Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway, while iron ions released from the MOF induce ferroptosis in tumor cells via Fenton reactions. Together, these dual mechanisms act synergistically to inhibit tumor growth and metastasis. This work presents a novel strategy to improve the delivery and efficacy of natural antitumor agents, offering promising potential for the treatment of metastatic lung cancer.
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PubMed
高影响因子
Oncology Letters
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2018
·Vol. 17
·期 1
·652-659
·
IF 1.664
Hongchao Han,Jie Xu,Weiwei Ji,Lisheng Wang,Aikun Wang
Transmembrane protein with epidermal growth factor (EGF)‑like and two follistatin motifs 2 (TMEFF2) is downregulated in human gastric cancer, and its levels are associated with tumor aggressiveness. Herein, a positive correlation was identified between serum vitamin C levels (µg/ml) and mRNA levels of TMEFF2 in gastric cancer tissue. TMEFF2 silencing promotes cell proliferation in GES‑1 normal human gastric epithelial cells and AGS human gastric adenocarcinoma cells. Notably, vitamin C and AG490 exerted antiproliferative effects on the two cell lines. The present study demonstrated that small interfering (si)‑RNA‑TMEFF2 exerts pro‑proliferative effects on GES‑1 and AGS cells. The results revealed that vitamin C significantly inhibited the growth of GES‑1 and AGS cells by reducing cell viability, decreasing the expression of proliferating cell nuclear antigen (PCNA), and blocking the STAT3 pathway. Moreover, siRNA‑TMEFF2‑induced enhanced cell viability and PCNA expression were significantly reversed by additional vitamin C treatment; notably, markedly enhanced TMEFF2 expression was observed. Upregulated TMEFF2 expression was observed in association with the antiproliferative effect of AG490. In conclusion, serum vitamin C content (µg/ml) was positively correlated with the mRNA levels of TMEFF2 in gastric cancer tissue. Exploring novel drugs that target TMEFF2 is a potential therapeutic strategy for blocking human GC.
研究领域:
肿瘤学
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分子生物学
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药理学
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PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2019
·Vol. 44
·期 12
·2821-2831
·
IF 2.782
Zhai Ailing,Zhang Zeng,Kong Xiangjuan
Paeoniflorin (PF) has been reported to possess neuroprotective influences on cognitive dysfunction illness. In current research, we attempted to probe into the protective influences of PF against H 2 O 2 -induced damage and the underlying regulating mechanisms on hippocampal HT-22 cells. HT-22 cells were pretreated with PF, and then induced by H 2 O 2 . Afterwards, the influences of PF pretreatment were examined using CCK-8 assay, apoptosis assay, western blot and ROS assay, respectively. In addition, the expression of microRNA-135a (miR-135a) was analyzed and altered by qRT-PCR and cell transfection, respectively. After overexpression of miR-135a, the effects of miR-135a mimic on cell functions were detected again. Moreover, influences of H 2 O 2 , PF and miR-135a overexpression on JAK2/STAT3 and ERK1/2 signal pathways were further investigated. Further experiments verified that PF pretreatment alleviated H 2 O 2 -induced oxidative stress through increasing cell viability, inhibiting cell apoptosis, reducing ROS generation and activating JAK2/STAT3 and ERK1/2 pathways. Besides, expression of miR-135a was declined by PF pretreatment. Whereas, miR-135a mimic abrogated the protective effects triggered by PF pretreatment. These results indicated that PF can alleviate H 2 O 2 -induced oxidative stress by down-regulation of miR-135a via activation of JAK2/STAT3 and ERK1/2 pathways.
研究领域:
药理学
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神经科学
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分子生物学
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PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
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2023
·
IF 3.5
Wenbin Wang,Shiyang Zhou,Wenming Jiang,Guangying Chen
A series of 1-(2-oxocyclohexyl)butane-1, 3-dione derivatives were designed and synthesized as TLR4 inhibitors by modifying the core structure of the lead compound ((6, 8-dioxo-1, 2, 3, 4, 6, 7, 8, 8a-octahydronaphthalen-2-yl) carbamate)). In vitro , compound 3p significantly inhibited the proliferation of rat synovial cells, inhibited the proliferation of LPS-induced RAW264.7 cells, and inhibited TLR4 activity, with IC 50 values of 1.21 ± 0.09 μM, 0.73 ± 0.05 μM and 0.43 ± 0.03 μM, respectively, which was superior to the positive control methotrexate. In vivo anti-rheumatoid arthritis evaluation, compound 3p can significantly inhibit the inflammatory factors TNF-α, IL-1β and IL-6, so as to achieve the therapeutic purpose. In the preliminary mechanism study, compound 3p has obvious regulatory effects on the abnormal increase of TLR4, JAK2 and STAT3 protein and gene expression related to inflammatory signaling pathway in RAW264.7 cells. In summary, this study aims to develop more effective candidates for rheumatoid arthritis.
研究领域:
免疫学
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药理学
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医学
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PubMed
高影响因子
FOLIA HISTOCHEMICA ET CYTOBIOLOGICA
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2025
·
IF 2.2
Jianuo Li,Yuhuai Guo,Xiangxin Zeng,Hongzhao Tian,Yapeng Han,Shuo Cai,Min Sun
Introduction. The aberrant activation of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signalling pathway is involved in spinal cord injury (SCI) progression. Electroacupuncture (EA) stimulation is effective in alleviating SCI, but the mechanism is poorly understood. Material and methods. An SCI model was constructed by cord contusion at T10, and AG490 (a JAK2 inhibitor) served as a positive control in this study. We evaluated the effects of EA on locomotor activity and spinal damage in SCI rats. The effects of EA on astrocytes and microglia and on the JAK2/STAT3 signalling pathway in the cells were investigated. Results. Behavioural tests showed that hind limb motor function of rats was improved after EA stimulation. The therapeutic effects of EA stimulation in restoring motor function, alleviating injured spinal cords, and inhibiting spinal cord neuronal apoptosis in SCI rats, were similar to those of AG490. Increased STAT3 activation was observed in astrocytes and microglia in the spinal cord of SCI rats, and this was reversed by EA stimulation. EA alleviated astrogliosis and inhibited microglia M1 polarisation in SCI rat spinal cords. In addition, RNA expression levels of pro-inflammatory factors IL-6, CXCL1, and TNF-α in rat spinal cords were suppressed by EA stimulation, while the expression level of the anti-inflammatory factor heme oxygenase 1 was increased. Meanwhile, the expression of p-JAK2, p-STAT3, and JAK2/STAT3 downstream targets SOCS3 and COX-2 in the spinal cord of SCI rats was inhibited by EA stimulation. Interestingly, the observed effects were comparable to those treated with EA. Conclusions. Our findings demonstrate that EA stimulation ameliorates SCI in rats and exerts an inhibitory effect on the JAK2/STAT3 signalling pathway.
研究领域:
神经科学
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医学
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PubMed
高影响因子
FITOTERAPIA
·
2025
·
IF 2.6
Zongchao Li,Ruoxuan Xu,Can Li,Chenglin Chi,Xiaoli Yang,Shufang Yang,Rongxia Liu
The pericarp of Zanthoxylum bungeanum Maxim. (ZBM) is an edible spice with medicinal value, and it has anti-obesity, anti-inflammatory, and cardiovascular protective effects. This study investigated the therapeutic effect of ZBM on atherosclerosis (AS) and its potential mechanisms. An in vivo experimental model of AS was established on apolipoprotein-E deficient (ApoE −/− ) mice to evaluate the efficacy of ZBM. Serum metabolomics combined with the vascular smooth muscle cell (VSMC) proliferation model were subsequently conducted to analyze the mechanisms. Results showed that ZBM effectively alleviated blood lipid disorders, aortic lipid accumulation, and intimal thickness in mice. Metabolomics indicated that ZBM mainly regulated 5 major metabolic pathways, including TCA cycle, steroid hormone biosynthesis, sphingolipid metabolism, glyoxylate and dicarboxylate metabolism, glycerophospholipid metabolism, which affected lipid metabolism and cell proliferation. Further experiments showed that ZBM inhibited VSMC proliferation likely because it blocked the signal transducer activator of transcription 3 (STAT3) phosphorylation and activated nuclear factor E2-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, resulting in G0/G1 phase arrest and reactive oxygen species (ROS) clearance.
研究领域:
药理学
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代谢组学
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心血管疾病
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PubMed
高影响因子
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2025
·Vol. 137
·期 1
·e70058
·
IF 3.3
Mengtian Pan,Xiang Li,Xinjuan Tian,Lele Zixin Yang,Weirong Fang
Ischemic stroke (IS) is one of the most sinister diseases and the second leading cause of death in the world. Eugenol (EUG) is a natural and biologically active component that can be extracted from various plants. Studies have found that EUG can alleviate middle cerebral artery occlusion and reperfusion (MCAO/R) injury in mice, but the specific mechanism remains vague. Tripartite motif protein 59 (TRIM59) is a member of TRIM protein family, a group of E3 ubiquitin ligases. In this article, we conducted both in vivo and in vitro experiments to determine the effect of EUG on ischemia–reperfusion injury and to explore the underlying mechanisms by manipulating the expression of TRIM59. Results showed that EUG alleviates acute injury and promotes functional repair of mouse IS by enhancing the phagocytosis of microglia through up-regulating the TRIM59, activating the STAT3 pathway and promoting the expression of CD11b.
研究领域:
神经科学
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药理学
·
分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Jiong Wang,Chenchen Qian,Yue Chen,Tianyang Jin,Yongsheng Jiang,Lijiang Huang,Xinyan Fu,Dong Yang,Leiming Jin,Bo Jin,Yi Wang
ABSTRACT Background Hyperglycemic induced cardiac hypertrophy and cardiac inflammation are important pathological processes in diabetic cardiomyopathy. β-elemene (Ele) is a natural compound extracted from Curcuma Rhizoma and has anti-tumor effects. It also has therapeutic effects in some inflammatory diseases. However, the therapeutic effect of Ele on diabetic cardiomyopathy is not clear. The purpose of this study was to evaluate the effect of Ele on hyperglycemia-caused cardiac remodeling and heart failure. Methods C57BL/6 mice were intraperitoneally injected with streptozotocin to induce DCM, and Ele was administered intragastric after 8 weeks to investigate the effect of Ele. RNA sequencing of cardiac tissue was performed to investigate the mechanism. Results Ele markedly inhibited cardiac inflammation, fibrosis and hypertrophy in diabetic mice, as well as in high glucose-induced H9c2 cells. RNA sequencing showed that cardioprotective effect of Ele involved the JAK/STAT3-NF-κB signaling pathway. Ele alleviated heart and cardiomyocyte inflammation in mice by blocking diabetes-induced JAK2 and STAT3 phosphorylation and NF-κB activation. Conclusions The study found that Ele preserved the hearts of diabetic mice by inhibiting JAK/STAT3 and NF-κB mediated inflammatory responses, suggesting that Ele is an effective therapy for DCM.
研究领域:
药理学
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心脏病学
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糖尿病
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DOI
PubMed
高影响因子
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