Evidence-based Complementary and Alternative Medicine
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2022
·
IF 2.65
Li Li,Ru Liu,Jing He,Jing Li,Juan Guo,Yun Chen,Ke Ji
Objective. Microglial BV-2 cells are activated in the brain following insomnia. Naringin (NAR) is a polymethoxylated flavonoid that is also commonly found in citrus fruits and is known for its antioxidant potential. However, the effect of NAR on microglial cells has rarely been studied in the brain of an organism after insomnia. This study aimed to investigate the effects and potential mechanisms of action of NAR on microglial cell activation and inflammation. Methods. BV-2 cells were obtained from the China Center for Type Culture Collection and randomly divided into five treatment groups: control, model, NAR (10 μM), WP1066 (5 μM), and NAR + WP1066. With the exception of the control group, all groups were stimulated with LPS (1 μg/mL) for 6 h. CCK8 was used to quantify cell viability and a scratch test was performed to detect cell migration. The expression levels of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), nterleukin 10 (IL-10), and insulin like growth factor (1IGF-1) were measured by ELISA. Western blotting was performed to determine the levels of p-STAT3 and p-JAK. The Focalcheck™ Thin-Ring Fluorescent Microspheres kit was used to detect cell phagocytosis. Immunofluorescence was used to observe the expression of iNOS and arginase1 in BV-2 cells. Results. Compared with the control group, cell migration, cell viability, and the expression of IL-1β, IL-6, TNF-α, and iNOS were significantly increased in the model group, whereas the expression levels of IL-10, IGF-1, and arginase 1, as well as cell phagocytosis were reduced. With the increase in NAR concentration, cell migration, cell viability, the expression levels of IL-1β, IL-6, TNF-α, and iNOS decreased, while the expression of IL-10, IGF-1, and arginase 1 increased. Compared with the control group, p-STAT3, and p-JAK expression in the model group were significantly increased (P<0.05). Compared with the model group, the expression of p-STAT3 and p-JAK in the NAR, NAR + WP1066, and WP1066 groups was significantly decreased (). Conclusion. NAR treatment inhibited the proliferation, migration, and inflammation of BV-2 cells as well as the activation of microglia to the M1 phenotype. Conversely, NAR treatment promoted the activation of microglia to the M2 phenotype and enhanced the phagocytic function of BV-2 cells by regulating the activity of the JAK/STAT3 pathway.
研究领域:
神经科学
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免疫学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR PROBES
·
2019
·
IF 2.511
Danning Lou,Jun Wang,Xiaohang Wang
Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders worldwide and a major public health concern that is associated with grave consequences. Systemic complexity and feedback processes among diverse drivers of the depression disorder contribute to the considerable variation in responses to the treatment of depression . Dysfunctional microRNA (miRNA) is involved in MDD. miR-124 is enriched in the brain and may be critical in neuronal differentiation . Previous studies have shown the value of miRNA-124 as a putative therapeutic target and a biomarker for major depression. However, the detailed mechanism of action of miR-124 in depression remains poorly understood. Here, we observed that miR-124 was downregulated in the hippocampus of mice with chronic unpredictable mild stress (CUMS). Restoration of miR-124 expression significantly attenuated depressive-like behavior and inhibited microglial activation induced by CUMS. Mechanistically, miR-124 directly targeted signal transducer and activator of transcription 3 (STAT3) in BV2 cells; in addition, upregulation of miR-124 inhibited the increase of inducible nitric oxide synthetase and proinflammatory cytokines , including IL-6, IL-1β, TNF-α, and MCP-1, in LPS-stimulated BV2 cells. The collective data suggest that dysfunction of miR-124 may be a foundation for the development of depression by promoting microglial activation.
研究领域:
神经科学
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分子生物学
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精神病学
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DOI
PubMed
高影响因子
American Journal of Translational Research
·
2019
·
IF 3.266
Hua Liu,Xiao-De Feng,Beng Yang,Rong-Liang Tong,Yue-Jie Lu,Di-Yu Chen,Lin Zhou,Hai-Yang Xie,Shu-Sen Zheng,Jian Wu
Dimethyl fumarate (DMF) is generally used to treat psoriasis and multiple sclerosis. In the present study, we aimed to investigate the effects of DMF on hepatocellular carcinoma progression and its mechanism of action. In vitro , cell viability was examined using CCK-8 assay; cell cycle was analyzed by flow cytometry; angiogenesis was detected using tube formation assay; and autophagic flux assay results were examined using fluorescence microscopy. We also used western blotting to explore the potential mechanisms. In vivo , tumor xenograft experiment was performed with nude mice, and liver function, renal function, and routine blood counts were assessed using biochemical tests. Dimethyl fumarate inhibited tumor growth and angiogenesis in hepatocellular carcinoma, both in vitro and in vivo . Dimethyl fumarate decreased autophagy in hepatocellular carcinoma cells. Treatment with DMF activated SOCS3, which led to repression of JAK1 and STAT3 phosphorylation. DMF inhibited cell proliferation, angiogenesis, and autophagy via activation of the SOCS3/JAK1/STAT3 signaling pathway. This finding may provide a novel approach for the treatment of hepatocellular carcinoma.
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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DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Hui Wang,Mengyu Zhang,Weipeng Gong,Jiaxuan Wu,Junping Zhang,Wenxiu Zhang,Yue Liu,Kui Wang,Canhua Huang,Jun Zhou,Sijin Wu,Yan Li,Tianliang Li
Signal transducer and activator of transcription 3 (STAT3) activation is crucial in intestinal inflammation and tumorigenesis. However, its metabolic regulation is not well understood. Herein, we identified a macrophage-dependent methionine-S-adenosylmethionine (SAM)-protein arginine methyltransferase 1 (PRMT1)-lactate dehydrogenase A (LDHA)-lactate axis that controls intestinal inflammation through STAT3 regulation. Specifically, SAM promoted STAT3 Y705 phosphorylation and upregulated anti-inflammatory interleukin-10 expression in macrophages. Additionally, genetic ablation of PRMT1 in myeloid cells not only impairs STAT3 activation but also exacerbates colitis and promotes inflammation-associated tumorigenesis. Mechanistically, PRMT1 directly methylates LDHA at R268/R269, thereby enhancing its activity and lactate production. Subsequently, the resulting lactate induces STAT3 lactylation at K709, stabilizing an open conformation that facilitates Y705 phosphorylation. Importantly, disruption of this modification through K709-specific inhibition effectively blocks STAT3 activation and, consequently, exacerbates colitis progression. Overall, this study reveals STAT3 lactylation as a novel post-translational modification that integrates methionine metabolism with glycolytic flux to regulate intestinal inflammation, highlighting the critical role of immunometabolism in colonic inflammation.
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高影响因子
iScience
·
2026
·Vol. 29
·期 6
·
IF 4.5
Haochang Song,Meng Yang,Shengquan Wu,Qihui Dai,Weihong Qin,Weiheng Xie,Yuzhi Chen,Xiaoyun Jiang,Xiaojun Zhang,Xiuqin Deng,Chuang Ouyang,Yunman Zhang,Xinguang Liu,Yingjie Zhu,Gonghua Huang
Andrographolide (AP), a diterpenoid extracted from Andrographis paniculata , has emerged as a promising treatment for Alzheimer’s disease (AD) in preclinical studies, but the underlying mechanisms remain incompletely defined. Here, we demonstrated that AP treatment improved cognition performance and reduced amyloid-β (Aβ) plaque accumulation in 5×FAD transgenic mice of both sexes, by mitigating microglial senescence. Proteomic analysis revealed that AP markedly decreased cholesterol content in the cerebral cortex. Using an in vitro low-density lipoprotein-induced senescence model, we found that AP significantly alleviated senescence in BV2 microglia while enhancing their phagocytic capacity. Mechanistically, AP mitigated microglial senescence by inhibiting STAT3 signaling. Overall, these findings identify a previously unrecognized immunometabolic mechanism for AP in the treatment of AD.
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高影响因子
ARCHIVES OF PHARMACAL RESEARCH
·
2023
·
IF 6.7
Song Xiaoping,Wang Lina,Tang Wei,Yuan Luyao,Liu Qingchao,Li Jing,Fan Daidi
Gefitinib, as the first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has achieved great advances in the treatment of non-small cell lung cancer (NSCLC), but drug resistance will inevitably occur. Therefore, exploring the resistance mechanism of gefitinib and developing new combination treatment strategies are of great importance. In our study, the results showed that selumetinib (AZD6244) synergistically inhibited the proliferation of NSCLC with gefitinib. Selumetinib also enhanced gefitinib-induced apoptosis and migration inhibition ability in gefitinib-resistant lung cancer cell lines. Subsequently, the negative regulation between MIG6 and STAT3 was observed and verified through the STRING database and western blotting assays. Sustained activation of STAT3 was significantly downregulated when co-treatment with selumetinib in gefitinib-resistant cells. However, the downregulation of p-STAT3, resulting from the combination of selumetinib and gefitinib was counteracted by the deletion of MIG6, suggesting that selumetinib enhanced gefitinib sensitivity by regulating MIG6/STAT3 in NSCLC. In contrast, p-STAT3 was further inhibited after treatment with gefitinib and selumetinib when MIG6 was overexpressed. Furthermore, the combined administration of selumetinib and gefitinib effectively promoted the sensitivity of lung cancer xenografts to gefitinib in vivo, and the tumor inhibition rate reached 81.49%, while the tumor inhibition rate of the gefitinib monotherapy group was only 31.95%. Overall, MIG6/STAT3 negative regulation plays an important role in the sustained activation of STAT3 and the resistance to EGFR-TKIs. Our study also suggests that EGFR-TKIs combined with MEK1/2 inhibitors, such as selumetinib, may be beneficial to those NSCLC patients who develop a primary or acquired resistance to EGFR-TKIs, providing theoretical support for combining TKIs and selumetinib in clinical cancer treatment.
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 19
·14532
·
IF 5.6
Ji-Rong Xie,Xiao-Jie Chen,Gang Zhou
Oral squamous cell carcinoma (OSCC) poses a significant obstacle to the worldwide healthcare system. Discovering efficient and non-toxic medications is crucial for managing OSCC. Nuciferine, an alkaloid with an aromatic ring, is present in the leaves ofNelumbo nucifera. It has been proven to play a role in multiple biological processes, including the inhibition of inflammation, regulation of the immune system, formation of osteoclasts, and suppression of tumors. Despite the demonstrated inhibitory effects of nuciferine on different types of cancer, there is still a need for further investigation into the therapeutic effects and potential mechanisms of nuciferine in OSCC. Through a series of in vitro experiments, it was confirmed that nuciferine hindered the growth, movement, and infiltration, while enhancing the programmed cell death of OSCC cells. Furthermore, the administration of nuciferine significantly suppressed the signal transducer and activator of transcription 3 (STAT3) signaling pathway in comparison to other signaling pathways. Moreover, the activation of the STAT3 signaling pathway by colivelin resulted in the reversal of nuciferine-suppressed OSCC behaviors. In vivo, we also showed the anti-OSCC impact of nuciferine using the cell-based xenograft (CDX) model in nude mice. Nonetheless, colivelin diminished the tumor-inhibiting impact of nuciferine, suggesting that nuciferine might partially impede the advancement of OSCC by suppressing the STAT3 signaling pathway. Overall, this research could offer a fresh alternative for the pharmaceutical management of OSCC.Keywords:cell-derived xenograft;nuciferine;oral squamous cell carcinoma;signal transducer and activator of transcription 3;tumor growth
研究领域:
肿瘤学
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药理学
·
分子生物学
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PubMed
高影响因子
LIFE SCIENCES
·
2021
·
IF 5.037
Rui Huang,Qixia Yang,Tiantian Wang
Aims Norcantharidin (NCTD) exhibits antitumor, anti-inflammatory, and anti-fibrosis properties, which makes NCTD an attractive candidate for the treatment of pathological scars. This study was designed to investigate the potential effects of NCTD on fibroblast proliferation and explore the underlying mechanisms. Materials and methods First, cell viability and cell apoptosis were evaluated to determine the effects of NCTD on human skin fibroblasts, at 10, 50, and 100 μM. To explore the mechanism, bioinformatics analyses, chromatin immunoprecipitation, RNA immunoprecipitation, and RNA pulldown assays, and luciferase reporter assays were performed to verify the relationships among NCTD, signal transducer and activator of transcription 3 (STAT3), annexin A2 pseudogene 2 (ANXA2P2), and ubiquitin-associated protein 2-like (UBAP2L) mRNA in fibroblasts. Loss-of-function experiments were performed to investigate the roles played by STAT3, ANXA2P2, and UBAP2L in the proliferation and apoptosis of fibroblasts. Key findings We found that NCTD administration induced fibroblast apoptosis and inhibited fibroblast proliferation in a dose-dependent manner. Mechanistically, NCTD inhibited ANXA2P2 transcription through the inhibition of STAT3 phosphorylation. Subsequently, ANXA2P2 was found to enhance the physical interaction between UBAP2L mRNA and lin-28 homolog B (LIN28B), which increased the stability and levels of UBAP2L mRNA. Loss-of-function assays demonstrated that ANXA2P2 and UBAP2L knockdown induced fibroblast apoptosis and suppressed fibroblast proliferation. Significance In conclusion, we confirmed that NCTD inhibits fibroblast proliferation by inhibiting the STAT3/ANXA2P2/UBAP2L axis, which suggested that NCTD could represent a new candidate for the treatment of pathological scars.
研究领域:
药理学
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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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PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2018
·
IF 3.616
Xuanxuan Dai,Changtian Yin,Guilong Guo,Yi Zhang,Chenguang Zhao,Jianchang Qian,Ouchen Wang,Xiaohua Zhang,Guang Liang
Triple negative breast cancer (TNBC) is an aggressive subgroup of human breast cancer. In this study, we have examined the potential of Schisandrin B (Sch B), a bioactive chemical compound found in Schisandra chinensis , against TNBC. We used MDA-MB-231, BT-549, and MDA-MB-468 TNBC cells and immunodeficient mice to study the effect of Sch B. Our results show that Sch B inhibits TNBC growth by inducing cell cycle arrest and by triggering apoptotic death. Sch B also inhibited the migration and colony formation of tumor cells, and prevented the growth of TNBC cells in mice. We found that these inhibitory activities were mediated through suppression of signal transducer and activator of transcription-3 (STAT3) phosphorylation and nuclear translocation. Taken together, our studies show that Sch B has potent anti-tumor activity against TNBC via a novel mechanism involving STAT3 inactivation.
研究领域:
肿瘤学
·
分子生物学
·
药理学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2020
·
IF 4.225
Cao Hui-Hui,Liu Dong-Yi,Lai Ye-Cai,Chen Yu-Yao,Yu Lin-Zhong,Shao Meng,Liu Jun-Shan
Background: Malignant melanoma is an extremely aggressive and metastatic cancer, and highly resistant to conventional therapies. Signal transducer and activator of transcription 3 (STAT3) signaling promotes melanoma development and progression, which has been validated as an effective target in melanoma treatment. Natural naphthoquinone shikonin is reported to exert anti-melanoma effects. However, the underlying mechanisms have not been fully elucidated.Purpose: This study aims to evaluate the anti-melanoma activities of shikonin and explore the involvement of STAT3 signaling in these effects.Methods: Zebrafish tumor model was established to evaluate the anti-human melanoma effects of shikonin in vivo. MTT assay and colony formation assay were employed to investigate the anti-proliferative effects of shikonin on human melanoma A375 and A2058 cells. Flow cytometry was used to analyze cell cycle distribution and apoptosis induction. Wound healing assay and Transwell chamber assay were conducted to examine the cell migratory and invasive abilities. Immunofluorescence assay was used to observe F-actin, Tubulin, and STAT3 localization. Western blotting was used to determine the expression levels of proteins associated with apoptosis and key proteins in the STAT3 signaling pathway. Immunoblotting was performed in DSS cross-linked cells to determine the homo-dimerization of STAT3. Gelatin zymography was employed to evaluate the enzymatic activity of MMP-2 and MMP-9. Transient transfection was used to overexpress STAT3 in cell models.Results: Shikonin suppressed melanoma growth in cultured cells and in zebrafish xenograft models. Shikonin induced melanoma cells apoptosis, inhibited cell migration and invasion. Mechanistic study indicated that shikonin inhibited the phosphorylation and homo-dimerization of STAT3, thus reduced its nuclear localization. Further study showed that shikonin decreased the levels of STAT3-targeted genes Mcl-1, Bcl-2, MMP-2, vimentin, and Twist, which are involved in melanoma survival, migration, and invasion. More importantly, overexpression of constitutively active STAT3 partially abolished the anti-proliferative, anti-migratory, and anti-invasive effects of shikonin.Conclusion: The anti-melanoma activity of shikonin is at least partially attributed to the inhibition on STAT3 signaling. These findings provide new insights into the anti-melanoma molecular mechanisms of shikonin, suggesting its potential in melanoma treatment.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
·
动物模型
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2026
·
IF 6
Yawen Yao,Min Zhang,Sai Xu,Guoping Wu,Xinwang Meng,Juan Li,Hua Yu
A chondroitin sulfate-functionalized GSH-responsive lipid-nanoparticle (CSD@DNLP) was developed for co-delivering doxorubicin (DOX) and nifuroxazide (NIF) in metastatic melanoma treatment. • Chondroitin sulfate-functionalization improved cellular uptake through targeting CD44-receptors and enhanced drugs release in tumor-mimic environment. • Synergistic effects were observed in tumor growth inhibition and metastasis repression through NIF-mediated STAT3 phosphorylation blockade and DOX-induced DNA damage. • CSD@DNLP demonstrated a promising strategy in metastatic melanoma. Tumor metastasis results in high mortality rate in patients with advanced melanoma. The hyperphosphorylation of signal transducer and activator of transcription 3 (STAT3) is closely associated with the proliferation and metastasis of melanoma. Here, we proposed a lipid-nanoparticle (CSD@DNLP) derived from the chondroitin sulfate (CS)-conjugated deoxycholic acid (DOCA) polymer (CS-ss-DOCA, CSD) for the co-delivery of doxorubicin (DOX) and STAT3 inhibitor nifuroxazide (NIF) in metastatic melanoma treatment. The superior affinity between CS and overexpressed CD44 receptors in B16F10 cells resulted in 3.3-fold enhancement of cellular uptake compared to free DOX. CSD@DNLP maintained structural stability in physiological conditions, while achieving 75.15% cumulative release within 48 h under a tumor-mimic concentration of glutathione (GSH, 20 mM). Synergistic effects were observed through NIF-mediated STAT3 phosphorylation blockade and DOX-induced DNA damage, resulting in 3.2-fold enhancement in apoptotic cells versus free drugs. In lung metastasis mice, CSD@DNLP suppressed metastatic nodule formation (36% of free DOX + NIF) via dual downregulation of matrix metalloproteinases-2 (MMP-2) and metalloproteinases-2 (MMP-9). This CS-functionalized GSH-responsive lipid-nanoparticle demonstrates a promising strategy in metastatic melanoma. Download: Download high-res image (162KB) Download: Download full-size image
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PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Xuehui Li,Yunxiao Qiao,Xinyi Xu,Jinyu Zhu,Chuang Xie,Shan Lin,Lingfan Xu,Fuwen Yuan
Background Natural products from traditional medicinal plants represent an important source of anti-cancer agents and lead compounds for drug development. Saikosaponin D (SSD), a triterpenoid saponin isolated from Radix Bupleuri, exhibits anti-tumor activity but is limited by a narrow therapeutic window and cytotoxicity. Objective This study aimed to evaluate the anti-tumor activity of 6′'-O-acetylsaikosaponin D (6′'-O-acSSD), a naturally occurring acetylated derivative of Saikosaponin D that is identified in Radix Bupleuri , and to elucidate its underlying molecular mechanisms. Methods The anti-cancer effects of 6′'-O-acSSD were assessed using multiple cancer cell models, three-dimensional tumor spheroids, and patient-derived tumor organoids. Transcriptomic and bioinformatic analyses were performed to identify regulated cell death pathways. Molecular docking, molecular dynamics simulation, cellular thermal shift assays, western blotting, and CUT&Tag profiling were used to identify molecular targets and define transcriptional reprogramming. Results 6′'-O-acSSD markedly suppressed cancer cell proliferation, migration, and invasion and elicited a transcriptional program distinct from that induced by SSD. Transcriptomic and biochemical analyses revealed preferential activation of ferroptosis-associated signatures, including enhanced lipid peroxidation. Mechanistically, 6′'-O-acSSD engaged STAT3, inhibited its phosphorylation, and extensively remodeled STAT3 chromatin occupancy. Functional analyses showed that STAT3 inhibition was required for the full anti-tumor activity of 6′'-O-acSSD. Notably, blockade of ferroptosis only partially rescued cell viability, whereas STAT3 targeting additionally triggered apoptosis-associated transcriptional and biochemical changes. The anti-tumor effects of 6′'-O-acSSD were further validated in patient-derived tumor organoids. Conclusion 6′'-O-acSSD exerts potent anti-tumor effects by targeting STAT3-dependent transcriptional programs and inducing coordinated ferroptosis and apoptosis. These findings highlight the therapeutic potential of structurally optimized natural products for anti-cancer treatment.
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高影响因子
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