ONCOLOGY REPORTS
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2025
·Vol. 53
·期 3
·1-14
·
IF 3.9
Dongsheng Lv,Xu Han,Liang Hao,Zhimin Sun,Aobo Zhang,Jing Liu,Liang Liu,Liqiang Liu
Cysteine‑ and glycine‑rich protein 2 (CSRP2) are closely associated with tumor invasion and metastasis. CSRP2 is significantly upregulated in glioma tissues and is associated with the clinical stage of the tumor. Overexpression of CSRP2 in glioma cells promotes the proliferation and metastasis of cancer cells, whereas CSRP2 knockdown inhibits the biological functions of tumor cells. Transcriptome sequencing of CSRP2‑knockdown U251M cells revealed that silencing of CSRP2 inhibited the JAK‑STAT1 signaling pathway, and differentially expressed genes were significantly enriched in cell processes related to necroptosis. Experiments on necroptosis in glioma cells using flow cytometry, Hoechst 33342/PI dual staining and transmission electron microscopy indicated that CSRP2 overexpression inhibited necroptosis in glioma cells. Western blotting results showed that overexpression of CSRP2 activated the JAK‑STAT1 signaling pathway, while the addition of the pathway inhibitor ruxolitinib promoted the phosphorylation of necroptosis proteins RIPK1, RIPK3 and MLKL. Therefore, it was hypothesized that CSRP2 maintains JAK‑STAT1 activation by inhibiting the protein inhibitor of activated STAT1, which then inhibits the necrotizing apoptosis of glioma cells.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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神经肿瘤学
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DOI
PubMed
高影响因子
Arabian Journal of Chemistry
·
2024
·
IF 5.3
Yi Chen,Shasha Song,Yongfang Wang,Xiaoli Zhang,Jiafen Zhang,Lili Wu,Jianbing Wu,Xinyu Li
Psoriasis is a common chronic inflammatory skin disease, which has seriously affected human health. Berberine is a plant alkaloid with significant anti-inflammatory effect. In this study, we aimed to determine whether topical application of berberine could ameliorate skin inflammation in psoriasis and explore the potential molecular mechanism. Imiquimod (IMQ)-induced psoriasis-like dermatitis in mice was firstly used to reveal the potential pathogenic mechanism. The transcriptome analysis showed that Janus kinase (JAK)-Signal transducer and activator of transcription (STAT) signaling pathway was significantly enriched in IMQ-induced dermatitis, which included the key genes such as Janus kinase 1 (JAK1), Interleukin-2 (IL2), Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA), Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (PIK3CB) and Signal transducer and activator of transcription 1 (STAT1). Network pharmacology and molecular docking then predicted that topical berberine may treat psoriasis by JAK-STAT signaling pathway, especially act on JAK1, IL2, PIK3CA and PIK3CB. Experimental studies in vivo further demonstrated that topical application of berberine could ameliorate IMQ-induced psoriasis-like skin inflammation by suppressing JAK-STAT signaling pathway. In addition, experimental studies in vitro showed that berberine could directly act on and enter into human immortalized keratinocytes (HaCaT cells). Meanwhile, berberine may inhibit the hyperproliferation and proinflammatory functions of HaCaT cells induced by Interferon-gamma (IFN-γ) via suppressing JAK1/STAT1 signaling pathway. In conclusion, this study suggested that berberine may be a promising topical agent to ameliorate skin inflammation in psoriasis.
研究领域:
皮肤病学
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药理学
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分子生物学
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免疫学
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DOI
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Huijuan Ma,Tingqian Wang,Junfeng Wang,Peiyao Wang,Qi Shu,Ruilin Qin,Sijia Li,Huan Xu
The correlation between formaldehyde (FA) exposure and prevalence of asthma has been widely reported. However, the underlying mechanism is still not fully understood. FA exposure at 2.0 mg/m 3 was found to exacerbate asthma in OVA-induced murine models. IFN-γ, the cytokine produced by T helper 1 (Th1) cells, was significantly induced by FA in serum and bronchoalveolar lavage fluid (BALF) of asthmatic mice, which was different from cytokines secreted by other Th cells. The observation was also confirmed by mRNA levels of Th marker genes in CD4+ T cells isolated from BALF. In addition, increased production of IFN-γ and expression of T-bet in Jurkat T cells primed with phorbol ester and phytohaemagglutinin were also observed with 100 μM FA treatment in vitro . Upregulated STAT1 phosphorylation, T-bet expression and IFN-γ production induced by FA was found to be restrained by STAT1 inhibitor fludarabine, indicating that FA promoted Th1 commitment through the autocrine IFN-γ/STAT1/T-bet pathway in asthma. This work not only revealed that FA could bias Th lineage commitment to exacerbate allergic asthma, but also identified the signaling mechanism of FA-induced Th1 differentiation, which may be utilized as the target for development of interfering strategies against FA-induced immune disorders.
研究领域:
免疫学
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呼吸病学
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毒理学
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DOI
PubMed
高影响因子
Regenerative Therapy
·
2024
·
IF 3.4
Shule Zhang,Dong Li,Linghong Liu,Qing Shi,Xiuli Ju
Introduction It is essential to acknowledge that the cardiovascular toxicity associated with anthracycline drugs can be partially attributed to the damage inflicted on blood vessels and endothelial cells. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have the potential to repair cellular processes and promote tissue regeneration through the transfer of signaling molecules such as miRNAs. In the present study, we investigated the effects of MSC-EVs on daunorubicin (DNR)-damaged human cardiac microvascular endothelial cells (HCMEC) and developing blood vessels of Chicken Chorioallantoic Membrane (CAM) in vivo. Materials and methods We constructed in vitro and in vivo models of DNR-damaged endothelial cells and developing blood vessel. Scratch wound assays, EdU assays, tube formation assays, and SA-β-Gal staining were used to evaluate the effects of MSC-EVs on cell migration, proliferation, angiogenesis capacity and cell senescence. Blood vessel area was used to assess the effects of MSC-EVs on CAM vasculature. RT-qPCR was used to detect the mRNA expression levels of inflammatory molecules. RNA sequencing was employed to compare differential gene expression and downstream regulatory mechanisms. RNA interference experiments and miRNA mimic overexpression experiments were used to validate the regulatory effects of target genes and downstream signaling pathways. Results We found that MSC-EVs improved the migration, proliferation, and angiogenesis of HCMEC, while also alleviating cellular senescence. The angiogenic effect on the developing blood vessels was confirmed in vivo. We identified that MSC-EVs downregulated the expression of PARP9, thereby inhibiting the STAT1/pSTAT1 signaling pathway. This downregulation effect is likely mediated by the transfer of miR-186-5p from MSC-EVs to HCMEC. Overexpression of miR-186-5p in DNR-damaged HCMEC also exhibited the aforementioned downregulation effect. In vivo, the introduction of miR-186-5p mimics enhanced angiogenesis in the CAM model. Conclusions To summarize, our study reveals that MSC-EVs can restore the cellular function of DNR-damaged HCMEC and alleviate cellular senescence through the miR-185-5p-PARP9-STAT1/pSTAT1 pathway. This finding highlights the potential of MSC-EVs as a therapeutic strategy for mitigating the detrimental effects of anthracycline-induced endothelial damage.
研究领域:
心血管毒性
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干细胞治疗
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分子生物学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
FEBS Journal
·
2021
·Vol. 289
·期 7
·1968-1983
·
IF 5.542
Ting-Ting Wei,Meng-Yuan Zhang,Xin-Hua Zheng,Tian-Hua Xie,Wenjuan Wang,Jian Zou,Yan Li,Hong-Ying Li,Jiping Cai,Xiaolu Wang,Jianxin Tan,Xusheng Yang,Yong Yao,Lingpeng Zhu
Retinal pigment epithelium (RPE) cell damage is implicated in the pathogenesis of age-related macular degeneration (AMD). An increase of interferon-γ (IFN-γ) levels was observed in patients with AMD, but whether inflammatory factors are causally related to AMD progression is unclear. Here, we demonstrate a direct causal relationship between IFN-γ and RPE cell death. IFN-γ induced human retinal pigment epithelial cell (ARPE-19) death accompanied by increases in Fe 2+ , reactive oxygen species, lipid peroxidation, and glutathione (GSH) depletion, which are main characteristics of ferroptosis. Mechanistically, IFN-γ upregulates the level of intracellular Fe 2+ through inhibiting Fe 2+ efflux protein SLC40A1 and induces GSH depletion by blocking cystine/glutamate antiporter, System xc-. At the same time, treatment with IFN-γ decreases the level of glutathione peroxidase 4 (GPx4), rendering the cells more sensitive to ferroptosis. JAK1/2 and STAT1 inhibitors could reverse the reduction of SLC7A11, GPx4 and GSH expression induced by IFN-γ, indicating IFN-γ induces ARPE-19 cell ferroptosis via activation of the JAK1-2/STAT1/SLC7A11 signaling pathway. The above results were largely confirmed in IFN-γ-treated mice in vivo . Finally, we used sodium iodate (NaIO 3 )-induced retinal degeneration to further explore the role of ferroptosis in AMD in vivo . Consistent with the role of IFN-γ, treatment with NaIO 3 decreased SLC7A11, GPx4 and SLC40A1 expressions. NaIO 3 -induced RPE damage was accompanied by increased iron, lipid peroxidation products (4-hydroxynonenal, malondialdehyde), and GSH depletion, and ferroptosis inhibitors could reverse the above phenomenon. Taken together, our findings suggest that inhibiting ferroptosis or reducing IFN-γ may serve as a promising target for AMD.
研究领域:
眼科学
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细胞生物学
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2026
·Vol. 40
·期 5
·e71641
·
IF 4.3
Xiaoxue Wang,Zexin Zhu
Rosacea is a chronic inflammatory dermatological disorder involving the activation of various signaling pathways. Imperatorin (IMP), a coumarin compound, has been documented to exhibit anti‐inflammatory properties. Nevertheless, its therapeutic efficacy in managing rosacea remains unexplored. Bioinformatics and network pharmacology approaches were utilized to elucidate potential signaling pathways and molecular targets of IMP in the context of rosacea. Subsequently, to assess the in vivo therapeutic efficacy of IMP, murine models exhibiting rosacea‐like inflammatory responses were developed. Additionally, in vitro experiments were conducted to elucidate the molecular mechanisms underlying the anti‐rosacea effects of IMP. Our findings demonstrated that both intraperitoneal and topical administration of IMP significantly attenuated skin inflammation in mice with LL37‐induced rosacea models. Mechanistic investigations, guided by bioinformatics and network pharmacology analyses, revealed an interaction between JNK1 and STAT1. IMP was found to directly bind to JNK1 and STAT1, disrupting their interaction, thereby inhibiting STAT1 phosphorylation and nuclear translocation. This inhibition resulted in decreased production of STAT1‐mediated inflammatory mediators in keratinocytes. These results suggest that IMP may serve as a promising therapeutic agent for inflammatory skin diseases by targeting the crosstalk between JNK1 and STAT1. IMP treatment disrupts the interaction between JNK1 and STAT1, thereby attenuating STAT1 activity. This interference subsequently diminishes the phosphorylation and nuclear translocation of STAT1, which ultimately results in a reduced production of inflammatory cytokines and chemokines. Consequently, this process alleviates the symptoms of rosacea.
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PubMed
高影响因子
Biochemistry and Cell Biology
·
2022
·Vol. 100
·期 3
·
IF 3.73
Fei Wang,Jian-jun Xia,Li-juan Shen,Ting-ting Jiang,Wu-lin Li,Da-li You,Qing Chang,Shan-you Hu,Li Wang,Xiao Wu
Intracerebral hemorrhage (ICH) is a kind of fatal stroke with the highest mortality and morbidity in the world. To date, there is no effective treatment strategy for ICH. Curcumin, a major active ingredient of Curcuma longa L., possesses a potential anti-inflammatory activity in many types of disease. In the current study, the mechanism underlying curcumin attenuated ICH-induced neuronal apoptosis and neuroinflammation was explored. Herein, we studied that curcumin decreased brain edema and improved neurological function by using brain edema measurement, assessment of neurological-deficient score, immunofluorescence, and Western blotting analyses after ICH. The results showed that curcumin improved ICH-induced neuronal apoptosis and neuroinflammation. Functionally, the polarization of microglia was assessed by immunofluorescence and Western blotting analyses after ICH in the absence or presence of curcumin. The results suggested that the M1-type microglia were activated after ICH, while the effect was blocked by curcumin treatment, suggesting that curcumin alleviates the neuroinflammation and apoptosis of neurons by suppressing the M1-type polarization of microglia. Mechanically, M1 polarization of microglia was regulated by JAK1/STAT1, and the activation of JAK1/STAT1 was blocked by curcumin. Meanwhile, the protective function of curcumin can be blocked by RO8191, an activator of JAK1. Taken together, our study suggested that curcumin improved the ICH-induced brain injury through alleviating M1 polarization of microglia/macrophage and neuroinflammation via suppressing the JAK1/STAT1 pathway.
研究领域:
神经科学
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药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Si-yu Liu,Chang-qing Wang,Tong-tong Luo,Gui-juan Cui,Yuan Zhang,Xing-ju Zou,Zi-jian Zhang,Wen-xiu Liu,Chen Sun,Cheng Peng
Ethnopharmacological relevance Scutellaria baicalensis , a traditional Chinese medicine herb, has been classically used to treat diarrhea and dysentery caused by damp heat in Traditional Chinese Medicine. And it has been demonstrated to alleviate colonic mucosal inflammation in ulcerative colitis. However, the mechanism through which its main active ingredient, baicalin, alleviates ulcerative colitis remains unclear. Aim of the study This study investigated whether baicalin regulates macrophages to ameliorate ulcerative colitis through the JAK1/STAT1/SOCS1 pathway. Materials and methods LPS-induced RAW264.7 cells were used to investigate the anti-inflammatory and regulatory effects of baicalin on macrophage polarization. The NO content was assessed by a Griess assay, and label-free optical diffraction tomography for live-cell imaging and confocal imaging were conducted to observe macrophage polarization and analyze the expression of CD86 and CD206. The protective effect of baicalin on DSS-induced colitis mice was evaluated through the Disease Activity Index (DAI) system, endoscopy, enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (HE) staining, Alcian Blue periodic acid Schiff (AB-PAS) staining, and immunofluorescence. Macrophages in the lamina propria of the colon were analyzed by tiling light sheet microscopy imaging and flow cytometry. Western blotting (WB) was used to evaluate the expression of JAK1/STAT1/SOCS1 pathway members, and the expression of the downstream transcription factors were quantified through qPCR. Key results Baicalin markedly inhibited NO levels induced by LPS and delayed the timing and quantity of macrophage polarization toward the M1 phenotype. Furthermore, baicalin ameliorated the symptoms of colitis in mice, such as diarrhea, hematochezia, weight loss, colon shortening, decreased spleen weight, pathological changes, intestinal mucosal barrier dysfunction, and decreased DAI and inflammatory factor levels. Moreover, baicalin promoted macrophage polarization toward the M2 phenotype and inhibited the polarization of M1 macrophages in the intestinal lamina propria. Mechanistically, baicalin inhibited the phosphorylation of JAK1 and STAT1 and restored the negative feedback inhibition of JAK1/STAT1 by upregulating SOCS1. In addition, baicalin reduced the mRNA levels of downstream genes. Conclusions and implications Baicalin can alleviate intestinal inflammation, ameliorate intestinal barrier damage, and regulate macrophage polarization by inhibiting M1 macrophage polarization in an ulcerative colitis model. This protective effect was achieved through the JAK1/STAT1/SOCS1 pathway.
研究领域:
药理学
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免疫学
·
民族药理学
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分子生物学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 6.8
Zhipeng Zhang,Hongyan Lai,Shaofang Tian,Yingjie Song,Cunwuliji Na,Xiang Shi,Changhong He,Liuye Shi,Shengyun Wang,Fawad Ali,Fu Shu,Baoshun Zhang
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease with a high global incidence rate, intricately linked to metabolic disorders. It is characterized by steatosis, inflammation, and hepatocyte ballooning. STAT1 is a transcription factor involved in metabolic regulation and progression of inflammatory responses. In this study, we have identified STAT1 as a novel therapeutic target for NASH. Using our established STAT1 inhibitor screening platform, we identified the compound ZDZ-553, which is characterized by a chromone skeleton, demonstrates potent inhibitory activity against STAT1, and exhibits a favorable safety profile. In the NASH mouse model experiment, ZDZ-553 significantly ameliorated liver steatosis and inflammatory responses. These findings collectively suggest that ZDZ-553 could be a promising candidate for treatment of NASH, highlighting the therapeutic potential of targeting STAT1.
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2018
·Vol. 42
·期 4
·1925-1934
·
IF 2.784
Yunfei Ma,Tuo Tang,Lili Sheng,Ziqian Wang,Hong Tao,Qing Zhang,Yao Zhang,Zhilin Qi
The anti‑inflammatory effects of aloin, a bioactive ingredient extracted from Aloe vera, have been described previously. The present study aimed to assess these effects and explore the underlying molecular mechanisms. RAW264.7 cells were incubated with different doses of aloin (100, 150 and 200 µg/ml) and lipopolysaccharide (LPS; 100 ng/ml) for the indicated times. Then, inducible nitric oxide synthase (iNOS) and cyclooxygenase‑2 expression levels were detected by western blot analysis and reverse transcription polymerase chain reaction (RT‑PCR).The concentrations of inflammatory cytokines in the cell culture supernatant were determined by ELISA. Total nitric oxide (NO) assay and reactive oxygen species (ROS) kits were used to detect NO and ROS levels, respectively. Mitogen‑activated protein kinase, nuclear factor κB and Janus kinase‑signal transducer and activator of transcription (JAK‑STAT) pathway activation were verified by western blot analysis. Confocal and nucleocytoplasmic separation experiments were used to detect STAT nuclear translocation. It was identified that aloin decreased the level of LPS‑induced iNOS expression, inhibiting the release of interleukin (IL)‑1β, IL‑6, tumour necrosis factor‑α and NO dose‑dependently. Mechanistically, aloin suppressed LPS‑induced JAK1‑STAT1/3 activation and STAT1/3 nuclear translocation. Additionally, LPS‑induced ROS production was inhibited by aloin. Collectively, these data suggest that aloin attenuated LPS‑induced inflammation by inhibiting ROS‑mediated activation of the JAK1‑STAT1/3 signalling pathway, thereby inhibiting the nuclear translocation of STAT1/3 in RAW264.7 cells. The present study provides an experimental basis for the clinical application of aloin in inflammatory‑associated diseases.
研究领域:
免疫学
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药理学
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细胞生物学
·
分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Siyu Liu,Guijuan Cui,Tongtong Luo,Yang Zhang,Yihan Yuan,Fu Peng,Chen Sun,Cheng Peng
Ulcerative colitis (UC) is a chronic idiopathic intestinal inflammatory disease, and its onset is closely related to immune disorders and intestinal barrier defects. Paeoniflorin (PF) is a natural component with anti-inflammatory and immunomodulatory activities. This study aims to explore whether PF can alleviate UC by regulating macrophage polarization and protecting intestinal barrier homeostasis. The results demonstrated that PF significantly improved colitis in mice induced by DSS, manifested as a reduction in disease activity index score, alleviation of colonic edema, restoration of colonic length, inhibition of spleen enlargement, maintenance of intestinal tissue structure integrity, and protection of intestinal barrier function. In vitro, PF not only inhibited apoptosis following DSS-induced injury, but also upregulated the expression of tight junction protein ZO-1, mucin MUC2, and epithelial adhesion molecule E-cadherin. Moreover, PF could inhibit the polarization of RAW264.7 macrophages to the M1 phenotype and promote their transformation to the M2. Mechanism studies further revealed that PF could inhibit JAK1/STAT1 phosphorylation and upregulate SOCS1 protein expression. In conclusion, this study suggests that PF may exert therapeutic effects on UC by regulating macrophage polarization and enhancing intestinal barrier function through modulation of the JAK1/STAT1/SOCS1 pathway.
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DOI
PubMed
高影响因子
JOURNAL OF NEUROIMMUNOLOGY
·
2026
·
IF 3.1
Jingkun Wu,Liang Hou,Qinghua Zhu,Hongbin Wang,Naizhu Wang
Interferon regulatory factor 8 (Irf8) is a transcription factor expressed only in the microglia in the brain and directs the expression of many genes that serve microglial functions. This report investigates the role of Irf8 in microglia during the progression of hypertensive intracerebral hemorrhage (ICH). L-NAME and angiotensin II initiated the ICH mouse model after stereotactic injection of knockdown and overexpression vectors. Inflammatory responses were induced in the mouse microglia cell line BV-2 using lipopolysaccharide (LPS), and lentiviral infection was conducted to manipulate gene expression. Irf8 was significantly overexpressed in the brain tissues of ICH mice and LPS-induced BV-2 cells. Downregulation of Irf8 hampered microglial M1 polarization and the inflammatory response and partially alleviated limb dysfunction caused by neurological impairment resulting from ICH. Irf8 interacted with the signal transducer and activator of transcription 1 (Stat1), thus mediating the transcriptional activation of Stat1 on tripartite motif-containing protein 5 (Trim5) in microglia. Overexpression of Trim5 reversed the inhibitory effect of sh-Irf8 on the inflammatory response in microglia and exacerbated cerebral hemorrhage in ICH mice. Thus, it was suggested that Irf8 overexpression activated the Stat1/Trim5 axis and mediated a microglial proinflammatory phenotype, thereby exacerbating hypertensive ICH.
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PubMed
高影响因子
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