PHYTOMEDICINE
·
2025
·
IF 8.3
Zhirui Du,Xueqiao Yan,Lin Cheng,Haiyu Shen,Guoguo Zhi,Baojie Li,Qian Yu
Background Dry eye disease (DED) is a multifactorial ocular condition marked by tear film instability, inflammation, and oxidative stress. Current therapies, including artificial tears and immunosuppressants, offer limited long-term benefit and potential side effects. Natural flavonoids such as luteolin possess anti-inflammatory and antioxidant properties, yet their therapeutic potential in DED remains underexplored. Purpose This study aimed to evaluate the therapeutic efficacy and mechanisms of luteolin in experimental DED. Methods Flavonoids were initially screened using lipopolysaccharide-stimulated RAW264.7 macrophages. A benzalkonium chloride-induced DED mouse model was treated with topical luteolin or cyclosporine A. Ocular surface evaluations included tear secretion, corneal fluorescein staining, and goblet cell density. Inflammatory and oxidative markers were examined via histology, immunofluorescence, and qPCR. RNA sequencing and network pharmacology were used to identify target pathways. In vitro studies with RAW264.7 cells and hyperosmolarity-stressed human corneal epithelial cells further validated mechanism-specific effects. Target engagement was further validated using pathway-specific pharmacological inhibitors. Ocular safety and pharmacokinetics were also assessed. Results Luteolin showed superior anti-inflammatory activity among tested flavonoids. It improved tear production, reduced epithelial damage, and preserved goblet cells. Mechanistically, it modulated macrophage-driven inflammation through JAK-STAT signaling and mitigated oxidative epithelial damage by suppressing the MAPK pathway. Transcriptomic and pharmacological analyses confirmed its dual immunomodulatory and cytoprotective roles. Combined STAT1/3 and MAPK inhibition mimicked its therapeutic effects. Topical luteolin was well-tolerated and achieved corneal bioavailability. Conclusions Luteolin provides a dual protective effect in DED by targeting inflammation and oxidative stress, supporting its development as a safe and effective disease-modifying therapy.
研究领域:
眼科
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免疫学
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分子生物学
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药理学
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炎症性疾病
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氧化应激
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信号转导
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转化医学
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2018
·Vol. 17
·期 6
·8385-8390
·
IF 1.922
Ting Li,Qingwen Zeng,Xingming Chen,Guojiang Wang,Haiqing Zhang,Aihua Yu,Hairui Wang,Yang Hu
Acne rosacea is a type of chronic dermatosis with the characteristics of erubescence, angiotelectasis and pustule formation. However, current treatment methods are limited due to the side effects. Artesunate demonstrated a promising therapeutic efficacy with a high safety margin. HaCaT cells were treated with antibacterial peptide LL‑37 to simulate rosacea caused by Demodex folliculorum (D. folliculorum) infection. Cell Counting kit 8 and flow cytometry assays were performed to measure cellular proliferation, apoptosis, the stage of the cell cycle and reactive oxygen species generation in order to determine the level of cell damage. Then the damaged cells were treated with different concentrations of artesunate and doxycycline to determine the therapeutic effect of artesunate. Pro‑inflammatory cytokines tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑6, IL‑8 and C‑C motif chemokine 2 (MCP‑1) were measured using an ELISA, while western blotting was used to detect the expression of Janus kinase 2 (JAK2) and signal transducer and transcription activator (STAT3). As a result, LL‑37 treated HaCaT cells decreased in cell viability, had an increased apoptotic rate and cell cycle arrest, indicating that cell damage caused by rosacea was simulated. In addition, upregulated concentrations of the pro‑inflammatory cytokines TNF‑α, IL‑6, IL‑8 and MCP‑1 were attenuated in the artesunate group in a dose‑dependent fashion, indicating the therapeutic effect of artesunate. Furthermore, higher concentrations of artesunate exhibited an improved effect compared with the doxycycline group. In addition, increased expression levels of JAK2 and STAT3 following treatment with LL‑37 suggested that rosacea caused by D. folliculorum infection may lead to inflammation through the JAK/STAT signaling pathway. In conclusion, the potential mechanism by which damage occurs in rosacea was revealed and a promising therapeutic method against rosacea was demonstrated.
研究领域:
皮肤科
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药理学
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细胞生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF HISTOCHEMISTRY
·
2022
·
IF 1.966
Haixia Li,Ning Su,Yaqiao Zhu,Wei Wang,Meihong Cai,Xiaohuan Luo,Wei Xia,Song Quan
Recurrent implantation failure (RIF) is defined as failure to achieve clinical pregnancy after at least 3 transfers of good-quality embryos by natural or artificial means. RIF is often a complex problem with a wide variety of etiologies and mechanisms as well as treatment options. In this study, using immunohistochemistry and Western blot, we demonstrated that the expression of leukemia inhibitory factor (LIF), Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3) was increased, while that of suppressor of cytokine signaling 1 (SOCS1) was decreased in RIF patients. Growth hormone (GH) administration proved to have positive effects on embryo implantation in RIF patients, but the action mechanism of GH has not been elucidated yet. To this aim, we studied the effects of GH on the proliferation in vitro of endometrial adenocarcinoma Ishikawa cells. GH stimulated the expression of LIF and SOCS1, and through SOCS1 inhibits the expression of phosphorylated STAT3, and finally inhibits the occurrence of RIF. Excessive phosphorylation of STAT can lead to decreased endometrial receptivity and abnormal embryo implantation. We also examined the effects of LIF overexpression and an LIF inhibitor (EC330) on the JAK/STAT pathway. LIF promoted cell proliferation, and the up-regulation of LIF increased the expression of SOCS1 and JAK1/STAT3 pathway-related genes in Ishikawa cells. As GH can inhibit the JAK1/STAT3 pathway through LIF, we hypothesize that upregulating SOCS1 may be a potential approach to treat RIF at the molecular level. GH can inhibit the JAK1/STAT3 pathway through LIF, up-regulating SOCS1 to treat RIF at the molecular level.
研究领域:
生殖生物学
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Li Jin,Xinyu Zheng,Chenxi Yu,Ping Li,Guiran Xiao
Metastasis is one of the most important factors related to malignant tumor development and therapeutic failure. Phytic acid (PA), a poly-phosphorylated inositol derivative in plant seeds and grains, has been shown to have antitumoral activity. However, the effect of PA on tumor metastasis and the underlying mechanisms remain uncharacterized. In the current study, we aimed to identify the effect of PA on tumor metastasis by employing a Drosophila model of malignant tumor Raf GOF Scrib −/− . We observed that PA supplementation in food inhibited the invasion and migration of tumors. Further studies indicated that PA drives Yki phosphorylation and inactivation through Lats kinase, which subsequently results in decreased expression of the JAK/STAT pathway ligands unpaired cytokines (Upds). Moreover, the reduced JAK/STAT pathway inhibits the recruitment and proliferation of hemocytes. To summarize, these findings provide valuable pathological and mechanistic insights into the potential application of PA for functional food or natural medicine development.
研究领域:
肿瘤学
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分子生物学
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遗传学
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产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2019
·
IF 3.17
Pian Gong,Zhan Zhang,Yichun Zou,Qi Tian,Shoumeng Han,Zhou Xu,Jianming Liao,Ling Gao,Qianxue Chen,Mingchang Li
Tetramethylpyrazine (TMP) has been studied in depth and is widely used in the treatment of many kinds of diseases in China. However, whether it has neuroprotective effects on cerebral ischemia remains unclear. An ischemia/reperfusion (I/R) injury animal model was established via middle cerebral artery occlusion in this study. We set several different groups in which the rats were performed in different ways to explore the effects of TMP on blood-brainbarrier (BBB) disruption and determine whether TMP relieved BBB disruption through blocking the JAK/STAT signaling pathway. Our results showed that TMP could reduce the neurological functional loss, decrease the brain edema and BBB permeability, as well as increase the expression of tight junction proteins via inhibiting the activation of JAK/STAT signaling pathway. Overall, we demonstrated that TMP promoted neurological recovery after I/R injury via restoring the integrity and function of BBB.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Toxicology Research
·
2024
·Vol. 13
·期 3
·
IF 2.2
Jin Huiyun,Liu Yanping,Lei Yuandi,Li Guilan,Huang Lian,Zhang Zhaohui
BackgroundChronic beryllium disease is characterized by granulomas and pulmonary fibrosis. Recent studies have shown that microRNAs (miRNAs) and circular RNAs (circRNAs) play critical roles in the pathogenesis and development of many diseases. However, the role of miRNAs and circRNAs in pulmonary fibrosis induced by beryllium sulfate (BeSO4) has not been elucidated.MethodsPrevious studies demonstrated hsa-miR-663b was down-regulated in the 150 μmol/L BeSO4-treated 16HBE cells, while hsa_circ_ 0004214 was up-regulated. Here we found epithelial-mesenchymal transition (EMT) involved in pulmonary fibrosis induced by BeSO4 (4, 8, and 12 mg/kg·BW) in SD rats.ResultsElevated expression of hsa-miR-663b blocked the EMT progression of 16HBE cells induced by 150 μmol/L BeSO4. Notably, the overexpression of hsa-miR-663b decreased the expression of leukemia inhibitory factor (LIF), which was predicted as a target gene of hsa-miR-663b by bioinformatics tools. Furthermore, elevated miR-663b inhibited the activation of the downstream Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway induced by BeSO4 in 16HBE cells. Previous study suggested that hsa_circ_0004214 had binding sites for hsa-miR-663b. The results indicated hsa_circ_0004214 alleviated the BeSO4-induced EMT via JAK-STAT pathway in 16HBE cells.ConclusionsCollectively, the overexpression of hsa-miR-663b and knockdown of hsa_circ_0004214 attenuated the EMT induced by BeSO4 through the inhibition of JAK-STAT signaling pathway. The aberrant expressed hsa-miR-663b and hsa_circ_0004214 stimulated by BeSO4 may exert an important function in the toxic mechanism of beryllium exposure to 16HBE cells, providing the potential therapeutic targets in chronic beryllium disease.
研究领域:
分子生物学
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毒理学
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肺科学
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基因组学
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产品关联
DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2021
·Vol. 22
·期 4
·1-10
·
IF 2.447
Jing Yang,Xiaoli Xie
The present study aimed to investigate the role and potential mechanism of action of tofacitinib (Tofa) in intestinal ischemia/reperfusion (I/R) injury. The normal rat small intestine epithelial cell line, IEC‑6, was used to establish an I/R injury model by inducing oxygen‑glucose deprivation/reoxygenation (OGD/R). Cells were divided into the following five groups: Control, OGD/R, OGD/R with 50, 100 and 200 nM Tofa. Following Tofa administration, cell viability was measured using Cell Counting Kit‑8 assay and a lactate dehydrogenase detection kit. The expression levels of cell apoptosis‑related proteins, Bcl‑2, cleaved‑caspase‑3 and cleaved‑caspase‑9 were detected using western blot analysis. Additionally, the levels of oxidative stress‑related markers, such as reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD), and inflammatory cytokines, TNF‑α, IL‑6 and IL‑1β were assessed using the colorimetric method. Western blot analysis was also used to measure the expression levels of the Janus kinase (JAK)/STAT3 signaling pathway‑related proteins, including phosphorylated (p)‑JAK1, p‑JAK3 and p‑STAT3. Subsequently, colivelin, an agonist of the JAK/STAT3 pathway, was used to investigate whether the effects of Tofa on intestinal I/R injury were mediated by this signaling pathway. The results showed that Tofa dose‑dependently elevated cell viability compared with that in the OGD/R group. By contrast, Tofa attenuated cell apoptosis, which was coupled with upregulated Bcl‑2 expression, downregulated cleaved‑caspase‑3 and downregulated cleaved‑caspase‑9 levels, in OGD/R‑induced IEC‑6 cells. Furthermore, the contents of ROS and MDA were significantly increased following exposure to OGD/R, which were accompanied by the decreased activity of SOD. These effects were reversed following cell treatment with Tofa. Consistently, Tofa intervention reduced the secretion levels of TNF‑α, IL‑6 and IL‑1β in a dose‑dependent manner. Additionally, Tofa markedly downregulated the phosphorylation levels of JAK1, JAK3 and STAT3 in OGD/R‑induced IEC‑6 cells. However, treatment with colivelin markedly reversed the inhibitory effects of Tofa on cell viability, cell apoptosis, oxidative stress and inflammation. Overall, the findings of the present study suggested that Tofa could protect against intestinal I/R injury by inhibiting the JAK/STAT3 signaling pathway, which may hold promise as a therapeutic agent for intestinal I/R injury.
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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胃肠病学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Kumar Ganesan,Cong Xu,Chunguang Xie,Yue Sui,Chuan Zheng,Fei Gao,Jianping Chen
Breast cancer (BC) is the most common cancer in women and is known for its tendency to spread to the bones, causing significant health issues and mortality. In this study, we aimed to investigate whether cryoprotective isoliquiritigenin-zein phosphatidylcholine nanoparticles (ISL@ZLH NPs) could inhibit BC-induced bone destruction and tumor metastasis in both in vitro and animal models. To evaluate the potential of ISL@ZLH NPs, we conducted various experiments. First, we assessed cell viability, colony formation, transwell migration, and wound healing assays to determine the impact of ISL@ZLH NPs on BC cell behavior. Western blotting, TRAP staining and ALP activity were performed to examine the effects of ISL@ZLH NPs on osteoclast formation induced by MDA-MB-231 cell-conditioned medium and RANKL treated RAW 264.7 cells. Furthermore, we assessed the therapeutic impact of ISL@ZLH NPs on tumor-induced bone destruction using a mouse model of BC bone metastasis. Treatment with ISL@ZLH NPs effectively suppressed BC cell proliferation, colony formation, and motility, reducing their ability to metastasize. ISL@ZLH NPs significantly inhibited osteoclast formation and the expression of factors associated with bone destruction in BC cells. Additionally, ISL@ZLH NPs suppressed JAK-STAT signaling in RAW264.7 cells. In the BCBM mouse model, ISL@ZLH NPs led to a significant reduction in osteolytic bone lesions compared to the control group. Histological analysis and TRAP staining confirmed that ISL@ZLH NPs preserved the integrity of bone structure, preventing invasive metastasis by confining tumor growth to the bone marrow cavity. Furthermore, ISL@ZLH NPs effectively suppressed tumor-induced osteoclastogenesis, a key process in BC-related bone destruction. Our findings demonstrate that ISL@ZLH NPs have the potential to inhibit BC-induced bone destruction and tumor metastasis by targeting JAK-STAT signaling pathways and suppressing tumor-induced osteoclastogenesis. These results underscore the therapeutic promise of ISL@ZLH NPs in managing BC metastasis to the bones.
研究领域:
肿瘤学
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药理学
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纳米技术
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Xianbin Wang,Wenjun Cao,Chuanfen Sun,Yutie Wang,Mingyu Wang,Jiarong Wu
Rheumatoid arthritis (RA) is a chronic and symmetrical autoimmune disease that primarily characterized with articular synovial hyperplasia, joint swelling, cartilage and bone destruction. The in-depth understanding of the role of immune signaling pathway inhibitors provides inspiration for the construction of new and more effective strategy for RA therapy. In this study, by loading methotrexate (MTX) into an acetalated dextran biopolymer, AcDEX, we developed a pH-sensitive, MTX-loaded and molecularly targeted nanodrug [email protected] NPs) to decrease the toxicity of MTX and simultaneously enhance its therapeutic effect. The resultant [email protected] NPs showed the spherical morphology and notable pH-responsiveness with high drug loading of 88.32%. As demonstrated in vitro and in vivo , the reduced cytotoxicity of both RAW264.7 cells and LPS-activated RAW264.7 cells treated with [email protected] NPs was found compared to free MTX. Upon intravenous administration into adjuvant-induced arthritis (AIA) rat model, the nanodrug had potent pharmacokinetic and pharmacodynamic profiles, which can accumulate in RA lesions and release MTX inhibitors for regulating the JAK-STAT pathways. As a result, the [email protected] NPs achieved the cartilage and bone protective and a better anti-inflammatory effect with negligible systemic toxicity, suggesting the strong potential of safe and effective nanodrug for RA therapy as well as other autoimmune diseases.
研究领域:
药学
·
纳米技术
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免疫学
·
风湿病学
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产品关联
DOI
PubMed
高影响因子
Journal for ImmunoTherapy of Cancer
·
2024
·Vol. 12
·期 10
·e009416
·
IF 10.3
Hua Huang,Yuwen Pan,Qiuwen Mai,Chunyu Zhang,Qiqiao Du,Yuandong Liao,Shuhang Qin,Yili Chen,Jiaming Huang,Jie Li,Tianyu Liu,Qiaojian Zou,Yijia Zhou,Li Yuan,Wei Wang,Yanchun Liang,Chao Yun Pan,Junxiu Liu,Shuzhong Yao
Background Cervical cancer remains a global health challenge. The identification of new immunotherapeutic targets may provide a promising platform for advancing cervical cancer treatment. Objective This study aims to investigate the role of CUB domain-containing protein 1 (CDCP1) in cervical cancer progression and evaluate its potential as a therapeutic target. Methods We performed comprehensive analyses using patient cohorts and preclinical models to examine the association between CDCP1 expression and cervical cancer prognosis. Then in immunodeficient and immunocompetent mouse models, we further investigated the impact of CDCP1 on the tumor immune microenvironment, focusing on its effects on tumor-infiltrating T cells, including cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs). Mechanistic studies were performed to elucidate the pathways involved in CDCP1-mediated immune modulation, in particular its interaction with the T cell receptor CD6 and the activation of the JAK-STAT signaling pathway. Results Our results show that CDCP1 overexpression is associated with poor prognosis and T cell infliction in cervical cancer. Specifically, it affects the activity of CTLs and Tregs. Mechanistically, CDCP1 binds to CD6 and inhibits the JAK-STAT pathway of T cells. The study further demonstrates that targeting CDCP1 with the inhibitor 8-prenylnaringenin (8PN) effectively suppresses tumor growth in vivo and enhances antitumor immunity. Conclusions CDCP1 plays a critical role in cervical cancer progression by modulating the tumor immune microenvironment. Targeting CDCP1 offers a promising therapeutic strategy to improve the outcome of patients with cervical cancer.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症治疗
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DOI
PubMed
高影响因子
Nanoscale
·
2020
·Vol. 12
·期 45
·23013-23027
·
IF 6.895
Ziqian Wang,Chenyue Zhan,Fang Zeng,Shuizhu Wu
Rheumatoid arthritis (RA) is a common chronic autoimmune disease associated with progressive disability, systemic complications, and poor prognosis. The improved understanding of the roles of immune signaling pathway inhibitors has shed light on designing new and more effective approaches for RA treatment. In this work, an inflammation-responsive and molecularly targeted drug system has been developed for RA therapy. The drug carrier was synthesized by covalently grafting hydrophobic cholesterol (Chol) molecules onto a hydrophilic chondroitin sulfate (CS) chain via the inflammation-responsive diselenide bonds (SeSe). The resultant amphiphilic polymer CSSeSeChol readily forms nanoparticles (NPs) and encapsulates two kinase inhibitors tofacitinib and SP600125 in aqueous media. Upon administration into the RA mouse model, the nanodrug accumulates in RA lesions and releases the inhibitors for regulating the JAK-STAT and JNK pathways. As a result, the nanodrug exhibits satisfactory efficacy in RA treatment by suppressing the expression of relevant pro-inflammatory cytokines, blocking the activation of osteoclasts and providing protection for cartilage and joints.
研究领域:
药理学
·
纳米技术
·
免疫学
·
风湿病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Lingdi Niu,Haoyuan Duan,Jiaqing Wang,Zheng Jia,Hai Li,Junjie Guo,Shuhe Zhang,Ning Liu,Yaxin Miao,Junwei Ge,Fang Wang
Trained immunity refers to the ability of trained innate immune cells to generate an immune memory that produces rapid, broad-spectrum, and long-lasting protection against heterologous stimuli. Based on the rapid and broad-spectrum protection that the peptidoglycan backbone from lactic acid bacteria, bacterium-like particles (BLPs), offers, we hypothesized that BLPs enhance protection through trained immunity. Here, we found that combining BLP with a vaccine significantly improves protective efficacy against methicillin-resistant Staphylococcus aureus (MRSA) infection, accompanied by changes in trained immunity markers. We demonstrate that BLP-induced trained immunity macrophages exhibit increased cytokine secretion and phagocytic activity in vitro. In an in vivo model, BLP confers protection against S. aureus 26003 even without specific antigens. In an ex vivo model, BLP induces increased markers of trained immunity. Transcriptome analysis suggests that BLP may induce trained immunity by activating the IL-6-JAK-STAT3 pathway through TLR2 receptor activation, thereby modulating macrophage metabolic reprogramming and function. In summary, our study establishes that BLP induction of trained immunity, along with regulated metabolic reprogramming and macrophage function, may contribute to enhancing vaccine efficacy. Our findings elucidate a novel mechanism for BLP-mediated immune enhancement, critical for the application of BLP as a vaccine vector to construct a vaccine that combines specific immune response with innate immune response.
研究领域:
免疫学
·
微生物学
·
疫苗学
·
分子生物学
·
传染病学
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产品关联
DOI
PubMed
高影响因子
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