Frontiers in Pharmacology
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2025
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IF 4.8
Jihong Bi,Yan Li,Lin Lu,Tingting Yin,Shaohua Mao,Run Zhang,Juan He,Xing Ni,Kai Wang,Jirui Bi
Objective: To investigate the protective effects of luteolin on ALI induced by lipopolysaccharide (LPS) in male mice and to explore the underlying mechanisms.Methods: A two-sample Mendelian randomization (MR) analysis was conducted to assess the causal relationship between hepatocyte growth factor (HGF) and acute respiratory distress syndrome (ARDS). Network pharmacology analysis was employed to identify herbs that mitigate inflammation and apoptosis by upregulating HGF expression and to determine the hub active ingredients. These findings were subsequently validated through in vivo experiments using an LPS-induced ALI mouse model. Lung histopathological examination, enzyme-linked immunosorbent assay, and Western blot analysis were performed to evaluate relevant biomarkers of inflammation and apoptosis.Results: The MR analysis demonstrated a causal effect of HGF on ARDS (IVW: β = −1.120, OR = 0.326, 95% CI = 0.116–0.916, P = 0.033). Among herbs associated with upregulating HGF expression, Salvia miltiorrhiza Bunge is involved in the negative regulation of apoptotic process and positive regulation of cell population proliferation. Luteolin was identified as the hub active ingredient extracted from S. miltiorrhiza Bunge. In LPS-induced ALI mice, luteolin significantly alleviated histopatholocial damage, inflammation, and apoptosis in the lungs. However, these protective effects were abrogated by c-Met inhibition.Conclusion: Luteolin attenuates inflammation and apoptosis in the lungs of LPS-induced ALI mice via activation of the HGF/c-Met pathway.
研究领域:
免疫学
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分子生物学
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药理学
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呼吸病学
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转化医学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Hui Tao,Hanhan Liu,Hanchen Zhang,Hong Ren,Binyu Wen,Jing Zhang,Jiaqi Du,Ziyi Cai,Zhihong Deng
Uveal melanoma (UM), a malignant tumor originating within the ocular, characterizes high metastasis and lethality among patients. Cancer stem cells (CSCs) distinguished by the c-Met protein are believed to mediate tumor metastasis in UM. However, the low bioavailability of c-Met inhibitors like Crizotilib (Criz) limits their clinical application. Herein, a GSH-responsive nanoparticle named NP @Oxa/Criz to precisely deliver Criz and Oxaliplatin (Oxa) is synthesized in this study. The dual-action mechanism of NP @Oxa/Criz inhibits the HGF/c-Met axis to prevent the nuclear translocation of β-Catenin, thereby reducing the transcription of metastasis-associated genes and undermining the stemness and metastasis of UM cells. Simultaneously, NP @Oxa/Criz induces immunogenic cell death to boost anti-tumor immunity. In vivo studies demonstrate that NP @Oxa/Criz can accumulate in tumor sites, significantly eradicating the primary UM in the ocular and suppressing the metastasis UM in the liver and peritoneal. The outcomes from this work illuminate the therapeutic mechanisms of NP @Oxa/Criz and provide a precise and potent nanotherapeutic strategy for clinical treatment and research in highly metastatic UM.
研究领域:
肿瘤学
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药剂学
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分子生物学
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DOI
PubMed
高影响因子
International Journal of Hepatology
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2016
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IF 0
Yunxia Tang,Qiongshu Li,Fanwei Meng,Xingyu Huang,Chan Li,Xin Zhou,Xiaoping Zeng,Yixin He,Jia Liu,Xiang Hu,Ji-Fan Hu,Tao Li
Human umbilical cord-derived mesenchymal stem cells (UCMSCs) are particularly attractive cells for cellular and gene therapy in acute liver failure (ALF). However, the efficacy of this cell therapy in animal studies needs to be significantly improved before it can be translated into clinics. In this study, we investigated the therapeutic potential of UCMSCs that overexpress hepatocyte growth factor (HGF) in an acetaminophen-induced acute liver failure mouse model. We found that the HGF-UCMSC cell therapy protected animals from acute liver failure by reducing liver damage and prolonging animal survival. The therapeutic effect of HGF-UCMSCs was associated with the increment in serum glutathione (GSH) and hepatic enzymes that maintain redox homeostasis, including γ-glutamylcysteine synthetase (γ-GCS), superoxide dismutase (SOD), and catalase (CAT). Immunohistochemical staining confirmed that HGF-UCMSCs were mobilized to the injured areas of the liver. Additionally, HGF-UCMSCs modulated apoptosis by upregulating the antiapoptotic Bcl2 and downregulating proapoptotic genes, including Bax and TNFα. Taken together, these data suggest that ectopic expression of HGF in UCMSCs protects animals from acetaminophen-induced acute liver failure through antiapoptosis and antioxidation mechanisms.
研究领域:
肝病学
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干细胞研究
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分子生物学
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基因治疗
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产品关联
DOI
PubMed
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2026
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IF 6
Jianhong Luo,Yuhao Jiang,Xudong Yin,Wenliang Xue,Jinyu Liu,Muyaxin Wang,Shasha Shi,Yuepu Pu,Xinsong Li
Acute liver injury (ALI), characterized by rapid hepatocyte damage induced by drugs, toxins, or viral infections, lacks clinically effective targeted therapies. Usually, the impaired hepatocytes significantly inhibit the uptake of medicines, leading to poor bioavailability and therapeutic outcome. Herein, a combination of hepatocyte growth factor (HGF) and interleukin-22 (IL-22) mRNAs delivered by N-acetylgalactosamine modified lipid nanoparticles (GalNAc-LNP) was developed to treat ALI. Tetra-antennary GalNAc cholesterol conjugate was first synthesized and incorporated into conventional LNP to encapsulate HGF/IL-22 mRNAs. After that, ALI mice model was applied to test the delivery effect of GalNAc-LNP. It was found that the GalNAc-LNP overcame delivery barriers caused by necrosis and inflammation, increasing protein expression of the encapsulated mRNA in the liver by 121.0%, owing to GalNAc- ASGPR targeting. Importantly, HGF/IL-22 mRNAs combination encapsulated within GalNAc-LNP markedly reduced necrotic foci, promoted hepatocyte regeneration, alleviated inflammatory response and accelerated recovery of liver function. The results demonstrated the synergistic effects of HGF-driven hepatocyte proliferation and IL-22-mediated inhibition of hepatic inflammation. Taken together, HGF/IL-22 mRNAs delivered by GalNAc-LNP possesses dual-target synergistic therapeutic output, holding potential for the treatment of ALI.
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DOI
PubMed
高影响因子
MEDICINAL CHEMISTRY RESEARCH
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2015
·Vol. 24
·期 8
·3327-3333
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IF 1.402
Ye Lianbao,Wu Jie,Yang Jiebo,Chen Weiqiang,Luo Yan,Zhang Yanmei
Abstract HGF/c-Met signaling pathway has come into the spotlight as a promising therapeutic target for inhibiting tumor growth and has become one of the leading molecular targets in cancer. Various strategies are currently in development to disrupt the HGF–Met signal transduction pathway, in which small molecular inhibitors have been a particularly active field. On the basis of the structures of two c-Met inhibitors, PF-04217903 and JNJ-38877605, some novel 7-[(quinolin-6-yl)methyl] purines ( 4a – 4e ) were rationally designed on the principle of bioisosterism strategy. These compounds were synthesized and evaluated as novel c-Met inhibitors. Molecular docking experiments analyzed the results and explained the molecular mechanism of eminent activities to c-Met. The results showed that all the title compounds were active against c-Met enzyme to some extent. Though these compounds did not demonstrate inhibition as we expected, this study provided important information for building diversification of chemical library and molecular docking experiment supplied the basis for further research works. Graphical Abstract Some novel
7-[(quinolin-6-yl)methyl] purines as potential c-Met inhibitors have been designed and prepared. Their synthesis and spectral characterization are reported here.
研究领域:
癌症研究
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药物化学
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分子生物学
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产品关联
DOI
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
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2026
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IF 4.1
Zihan Li,Boxuan Xie,Xilei Liu,Zihan He,Zhongwei Zhang,Jianming Zhou,Tong Zhou,Huai Wang
As the most frequently occurring cancer worldwide, lung cancer is notoriously diagnosed at advanced stages, resulting in high mortality rates. The primary factor underlying this persistent global health burden remains tobacco consumption. Nicotine, a key component of cigarette smoke, is one of the major contributing factors to the development of lung cancer, but the molecular mechanisms remain incompletely elucidated. α7-nAChR, β2-AR, and HGF/c-Met are known to contribute to lung cancer development, respectively. However, the specific signaling cascade through which they interact in nicotine-induced malignancy is unclear. In this study, using CCK-8 assays across a range of concentrations (0–5 μM), we determined that 1 μM nicotine treatment for 48 h optimally enhances A549 cell proliferation, establishing this condition for subsequent experiments. This study uncovers nicotine’s role in driving malignant behaviors including proliferation, migration, and invasion in nonsmall cell lung cancer A549 cells. Notably, nicotine potently stimulated migration and invasion, accompanied by upregulation of Cyclin D1 and MMP-2, and downregulation of BAX, BAD, and Caspase-3. Mechanistically, nicotine induced synergistic engagement of α7-nAChR and β2-AR, leading to activation of the HGF/c-Met/PI3K/AKT axis and enhancing the secretion of both HGF and MMP-2. Importantly, we reveal a previously unrecognized bidirectional regulatory loop between α7-nAChR and β2-AR that functionally converges on the HGF/c-Met axis, which acts as a critical signaling hub to drive the downstream PI3K/AKT pathway and facilitate tumor progression. Our findings provide the first evidence of a coordinated α7-nAChR/β2-AR interface regulating HGF/c-Met signaling that orchestrates both intracellular signaling and extracellular secretory programs in nicotine-promoted lung cancer progression. This offers innovative insights for identifying potential antitumor therapeutic targets and presents novel perspectives for the prevention and clinical management of lung cancer, particularly in smokers with nonsmall cell lung cancer.
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DOI
PubMed
高影响因子
Science Bulletin
·
2025
·
IF 21.1
Min Nie,Danqing Huang,Dandan Wang,Yuanjin Zhao,Lingyun Sun
Refractory wounds (RWs) are a common and severe complication of many diseases; however, the existing therapeutic methods are unsatisfactory in clinical practice. Here, we observed significant downregulation of the hepatocyte growth factor (HGF) in plasma samples from patients with autoimmune diseases. We used electroporation to deliver a plasmid containing HGF to induce its overexpression on mesenchymal stromal cells (MSC HGF ) and loaded them into an injectable hydrogel to treat RWs in patients with clinical autoimmunity. The MSC HGF exhibited stable HGF expression and secretion. In addition, they displayed a self-reinforcing loop, enhanced migration, and improved anti-apoptosis capacity via the autocrine activation of the c-Met-mediated phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Furthermore, the HGF (as well as other bioactive factors) secreted from the MSC HGF significantly augmented the migration and angiopoiesis of vascular endothelial cells, decreased the cellular inflammation of macrophages, and improved extracellular matrix remodeling in fibroblasts. According to these features, we demonstrated that the MSC HGF -loaded injectable hydrogel boosted cellular functions and afforded a long-acting healing efficacy in the treatment of clinical autoimmune patients with RWs. Therefore, the genetically engineered MSC HGF and their dispersed hydrogel system will have clinical significance for wound therapy.
研究领域:
再生医学
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基因治疗
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伤口愈合
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干细胞治疗
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Stem Cells International
·
2018
·
IF 3.989
Yong-Heng Luo,Juan Chen,En-Hua Xiao,Qiu-Yun Li,Yong-Mei Luo
Demethylating agent zebularine is reported to be capable of inducing differentiation of stem cells by activation of methylated genes, though its function in hepatocyte differentiation is unclear. p38 signal pathway is involved in differentiation of hepatocytes and regulating of DNA methyltransferases 1 (DNMT1) expression. However, little is known about the impact of zebularine on bone marrow mesenchymal stem cells (BMMSCs) and p38 signaling during hepatic differentiation. The present study investigated the effects of zebularine on hepatic differentiation of rabbit BMMSCs, as well as the role of p38 on DNMT1 and hepatic differentiation, with the aim of developing a novel strategy for improving derivation of hepatocytes. BMMSCs were treated with zebularine at concentrations of 10, 20, 50, and 100 μM in the presence of hepatocyte growth factor; changes in the levels of hepatic-specific alpha-fetoprotein and albumin were detected and determined by RT-PCR, WB, and immunofluorescence staining. Expression of DNMT1 and phosphorylated p38 as well as urea production and ICG metabolism was also analyzed. Zebularine at concentrations of 10, 20, and 50 μM could not affect cell viability after 48 h. Zebularine treatment leads to an inhibition of DNMT activity and increase of hepatic-specific proteins alpha-fetoprotein and albumin in BMMSCs in vitro; zebularine addition also induced expression of urea production of and ICG metabolism. p38 signal was activated in BMMSCs simulated with HGF; inhibition of p38 facilitated the synthesis of DNMT1 and albumin in cells. Zebularine restrained DNMT1 and phosphorylated p38 which were induced by HGF. Therefore, this study demonstrated that treatment with zebularine exhibited terminal hepatic differentiation of BMMSCs in vitro in association with hepatocyte growth factor; p38 pathway at least partially participates in zebularine-induced hepatic differentiation of rabbit BMMSCs.
研究领域:
干细胞研究
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分子生物学
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细胞信号传导
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表观遗传学
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DOI
高影响因子
BIOMATERIALS
·
2016
·
IF 8.387
Zhentao Man,Xiaoqing Hu,Zhenlong Liu,Hongjie Huang,Qingyang Meng,Xin Zhang,Linghui Dai,Jiying Zhang,Xin Fu,Xiaoning Duan,Chunyan Zhou,Yingfang Ao
Cartilage tissue engineering is the hotspot of cartilage repair. The allogenic chondrocytes appear to be a promising source of seed cells in cartilage tissue engineering. In this study, we aimed to transplant allogenic chondrocytes with chitosan hydrogel (CS)-demineralized bone matrix (DBM) hybrid scaffold (CS/DBM) to repair rabbit cartilage injury with one-step operation. After the CS/DBM scaffold was successfully fabricated, it showed that the porous CS filled the large pores of DBM, which improved the distribution of seed cells in the CS/DBM scaffold. The allogenic chondrocytes at second passage were transplanted with different scaffolds to repair rabbit cartilage injury. Twenty-four weeks after surgery, the cartilage defect in the CS/DBM group was successfully filled as shown by MRI. Moreover, the histological score of CS/DBM group was significantly higher than that of the other groups. On the aspect of biomechanical property , the regenerated cartilage in the CS/DBM group were superior to those in the other groups as determined by nanoindentation . Meanwhile, no obvious inflammatory response was observed after the transplantation of allogenic chondrocytes at 24 weeks post-surgery. Furtherly, gene expression profile for cells within the repair tissue was compared with the allogenic chondrocytes before transplantation using Agilent microarray and RT-qPCR. The results showed that some genes beneficial to cartilage regeneration, such as BMP-7, HGF , and IGF-1, were upregulated one month after transplantation. Consequently, our study demonstrated that the transplantation of allogenic chondrocytes with CS/DBM scaffold successfully repaired rabbit cartilage injury with only one-step operation, thereby providing new insights into cartilage tissue engineering.
研究领域:
组织工程
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骨科
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
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