Frontiers in Immunology
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2022
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IF 8.786
Huanhuan Xu,Titi Liu,Jin Li,Fei Chen,Jing Xu,Lihong Hu,Li Jiang,Zemin Xiang,Xuanjun Wang,Jun Sheng
Tumor necrosis factor (TNF)-stimulated nuclear factor-kappa B (NF-κB) signaling plays very crucial roles in cancer development and progression, and represents a potential target for drug discovery. Roburic acid is a newly discovered tetracyclic triterpene acid isolated from oak galls and exhibits anti-inflammatory activity. However, whether roburic acid exerts antitumor effects through inhibition of TNF-induced NF-κB signaling remains unknown. Here, we demonstrated that roburic acid bound directly to TNF with high affinity ( K D = 7.066 μM), blocked the interaction between TNF and its receptor (TNF-R1), and significantly inhibited TNF-induced NF-κB activation. Roburic acid exhibited antitumor activity in numerous cancer cells and could effectively induce G0/G1 cell cycle arrest and apoptosis in colorectal cancer cells. Importantly, roburic acid inhibited the TNF-induced phosphorylation of IKKα/β, IκBα, and p65, degradation of IκBα, nuclear translocation of p65, and NF-κB-target gene expression, including that of XIAP, Mcl-1, and Survivin, in colorectal cancer cells. Moreover, roburic acid suppressed tumor growth by blocking NF-κB signaling in a xenograft nude mouse model of colorectal cancer. Taken together, our findings showed that roburic acid directly binds to TNF with high affinity, thereby disrupting its interaction with TNF-R1 and leading to the inhibition of the NF-κB signaling pathway, both in vitro and in vivo . The results indicated that roburic acid is a novel TNF-targeting therapeutics agent in colorectal cancer as well as other cancer types.
研究领域:
肿瘤学
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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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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2018
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IF 3.977
Jian Fang,Qiuyan Chen,Baozhu He,Jiaxuan Cai,Yawen Yao,Yi Cai,Suowen Xu,Kannan R.R. Rengasamy,Shanmugaraj Gowrishankar,Shunmugiah Karutha Pandian,Tiansheng Cao
Tanshinone IIA is one of the most predominant bioactive constituents of Danshen , a traditional Chinese medicinal plant with multiple cardiovascular protective actions. Although Tanshinone IIA has been well documented for its endothelial protective efficacy, studies unveiling the mechanism and/or molecular targets for its pharmacological activity are still inadequate. In recent studies, it has been envisaged that the expression of pentraxin 3 (PTX3) was associated with atherosclerotic cardiovascular diseases (ACVD). Therefore, the current study was designed to evaluate the possible role of Tanshinone IIA in influencing the expression of PTX3 in endothelial cells and thereby prevents endothelial dysfunction . Molecular analyses through real-time PCR, western blot , and ELISA revealed that Tanshinone IIA down-regulates PTX3 gene expression as well as protein secretion in human endothelial cells in the presence or absence of TNF-α. Besides, Tanshinone IIA inhibits the adhesion of THP1 cells (a monocytic cell line) to activated-endothelial cells stimulated with TNF-α. Furthermore, mechanistic studies uncovered the role of p38 MAPK/NF-κB pathway in Tanshinone II-A mediated pharmacological effects. Thus, the present study exemplifies the manifestation of Tanshinone IIA as a plausible alternative natural remedy for ACVD by targeting PTX3.
研究领域:
药理学
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心血管疾病
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分子生物学
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传统中药
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6
Xufeng Qin,Weifeng Xu,Jiangnan Hu,Yong Dong,Renbo Ding,Shuheng Huang,Zhendong Zhao,Hong Chang,Xiaokun Wang,Shuai Dong
Glioma, a common primary brain tumor, is highly infiltrative and invasive, often leading to drug resistance and recurrence. Therefore, the development of novel therapeutic agents is urgently needed. Pseudellone C is a novel marine triindole alkaloid. Screening of its antiproliferative activity against 55 cell lines revealed its anti-CNS cancer potential. A total of 42 derivatives of Pseudellone C were designed and synthesized, and their inhibitory activities against two human glioma cell lines (U-87MG and LN-229) were evaluated using the CCK-8 assay. Ten derivatives exhibited potent antiproliferative activity with IC 50 values below 10 μmol, which are 18- to 39- fold more potent than Pseudellone C. Among these, derivative 4o demonstrated favorable blood-brain barrier permeability. Mechanistic studies revealed that 4o induces apoptosis primarily by activating the downstream caspase 3 cascade via the TNF/TNFR pathway. Structure-activity relationship correlations were systematically analyzed, and a pharmacophore model for further rational design was constructed.
研究领域:
药理学
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肿瘤学
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药物化学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Jiale Mao,Houxing Lei,Pingcui Xu,Shuang Liu,Jiwang Zhou,Mingrong Mei,Nani Wang,Xiaoqin Zhang
Ethnopharmacological relevance Melastoma dodecandrum (MD), a traditional ethnomedicine, has been widely used for the treatment of fractures, osteoarthritis, and osteoporosis due to its remarkable anti-inflammatory activity. However, the specific active components responsible for its therapeutic effects on orthopedic conditions remain unidentified. Aim of the study This study aimed to screen and identify key active components in MD using a combination of cell membrane chromatography and mass spectrometry, followed by cellular validation. Materials and methods A TNF-α-induced osteoblast injury model and an osteoblast membrane chromatography screening system were established to select and identify chemical components of MD that directly act on osteoblasts. The protective effects of MD on osteoblasts were assessed by evaluating cell viability, alkaline phosphatase (ALP) activity, cell mineralization and the expression of osteogenesis-related proteins OCN, RUNX2, and the TNF-α receptor protein TNFR1. Validation of the activity of individual components was also conducted. Results MD significantly improved the viability of osteoblasts under TNF-α-induced injury, enhanced ALP activity, stimulated the expression of OCN and RUNX2 proteins, and decreased the expression of TNFR1. Cell membrane chromatography screening identified 32 chemical components, including 21 flavonoids, 6 organic acids, 2 phenylpropanoids, 2 terpenes, and 1 nucleotide. Molecular docking revealed that isovitexin could bind to the specific receptor TNFR1 on the cell membrane. Furthermore, cellular validation demonstrated that isovitexin significantly protected osteoblasts. Conclusions MD and its pharmacologically active component, isovitexin, exhibit protective effects against TNF-α-induced inflammatory injury in osteoblasts, laying a solid foundation for future drug development.
研究领域:
药理学
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民族药理学
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细胞生物学
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质谱学
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色谱学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Zhiwan Chen,Mengfei Yuan,Haojing Li,Lihua Li,Binghong Luo,Lu Lu,Qi Xiang,Shan Ding
The inflammation of chronic wounds plays a key hindering role in the wound healing process. Slowing down the inflammatory response is significant for the repair of chronic wounds. Studies have revealed that succinate can inactivate gastrin D (GSDMD) and prevent cell pyroptosis. Chitosan has anti-inflammatory properties and is commonly used as wound healing material. Therefore, we used succinic anhydride to modify chitosan and found that N-succinylated chitosan (NSC) was more effective in inhibiting inflammation. The results showed that the stimulation of TNF-α and high glucose induces overexpression of capase-1 and TNF-α in human umbilical vein endothelial cells (HUVEC), and down-expression of CD31. However, the expression of capase-1 and TNF-α decreased, while the expression of CD31, VEGF and IL-10 was up-regulated significantly in dysfunctional HUVEC cells after treated by NSC. Moreover, NSC can speed wound healing, histological examination results showed that wounds treated with NSC exhibited faster epithelial tissue regeneration and thicker collagen deposition. Overall, this study results suggested that NSC has the function of restoring the physiological functions of dysfunctional HUVEC cells induced by high glucose and TNF-α, and can accelerate wound healing, indicating that NSC has good potential to be applied in inflammatory chronic wounds such as diabetic foot.
研究领域:
药理学
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伤口愈合
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炎症
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细胞生物学
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材料科学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2024
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IF 6.7
Tingwen Zhang,Yue Zhong,Yan Shi,Chengcheng Feng,Lu Xu,Zheng Chen,Xin Sun,Yan Zhao,Xialin Sun
Background The pathogenesis of acute liver injury (ALI) has been a pressing issue in the medical scientific community. We previously found that 5-O-methylvisammioside (MeV) from Saposhnikovia divaricata (Turcz.) Schischk has excellent anti-inflammatory properties. However, the mechanism by which MeV protects against ALI still needs to be deeply investigated. Purpose In the present study, we established an acetaminophen (APAP) -induced ALI mouse model and pre-protected the mice with MeV. Methods & Results Our findings indicate that MeV (5 and 10 mg/kg) lowered the blood levels of alanine aminotransferase and aspartate aminotransferase and reduced the infiltration of inflammatory cells in the liver. MeV initially showed an inhibitory effect on ALI. We then analyzed the molecular mechanisms underlying the effects of MeV by transcriptomic and metabolomic analyzes. Through transcriptomic analysis, we identified 4675 differentially expressed genes between the APAP+MeV group and the APAP-induced ALI group, which were mainly enriched in the MAPK pathway, the TNF pathway, and the NF-κB pathway. Through metabolomic analysis, we found that 249 metabolites in the liver were differentially regulated between the APAP+MeV group and the APAP- induced ALI group, which were mainly enriched in the arachidonic acid pathway. The mRNA expression levels of key genes (encoding TNF-α, p38, AP-1, RelB, IL-1β, and Ptges), as determined by RT-PCR analysis, were consistent with the RNA-seq data. The ELISA results indicate that MeV markedly decreased the serum levels of TNF-α and IL-1β in mice. Finally, the key proteins in the NF-κB and MAPK pathways were examined using immunoblotting. The results showed that MeV decreased IκB-α phosphorylation and inhibited the nuclear translocation of NF-κB. In addition, MeV reduced the hepatic inflammatory burst mainly by inhibiting the phosphorylation of p38 and JNK in the MAPK pathway. Conclusion The present study demonstrated (i) that MeV could ameliorate APAP-induced ALI by inhibiting arachidonic acid metabolism and the TNF, MAPK, and NF-κB pathways, and (ii) that MeV is a promising drug candidate for the prevention of ALI.
研究领域:
药理学
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分子生物学
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肝病学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
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2025
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IF 2.5
Yingpei Miao,Shuqing Yu,Qingcui Zhang,Xiaomei Li,Bowei Xia,Li Yang,Xiaobin Li,Junwei He
Leonurus japonicus Houtt. (LJ) is a pivotal traditional Chinese medicine remedy for thrombosis; however, its potential mechanisms and active constituents remain unclear. In this study, LJ exhibits a significant antithrombotic effect on an arteriovenous bypass thrombosis rat, characterized by reductions in thrombus wet and dry weights, decreased maximum aggregation rate, increased thrombus formation inhibition rate, aggregation inhibition rate, alterations in fibrinogen and antithrombin III levels, and shortened coagulation indicators. Moreover, LJ significantly enhanced the erythrocyte staining area and intensity in an arachidonic acid-induced zebrafish heart. Network pharmacology indicated that LJ alleviates thrombosis by regulating TNF and IL-17 pathways. Metabolomics revealed that LJ significantly modulated 29 endogenous differential metabolites, linking it to the regulation of primary bile acid biosynthesis, IL-17, and TNF pathways. Zebrafish experiments and molecular docking suggested that kaempferol and apigenin exhibit antithrombotic effects by modulating TNF and IL-17 proteins. Finally, molecular dynamics simulation validated that kaempferol and apigenin have strong binding capabilities with TLR4, STAT3, TNF-α, and IL-17A, and their binding free energies are −20 to −27 and −13 to −15 kcal/mol, respectively. In conclusion, LJ exerts its antithrombotic effect by regulating lipid metabolism and inhibiting TLR4/STAT3/TNF-α/IL-17A pathways, with kaempferol and apigenin identified as bio-constituents. This plant holds significant potential for development and utilization in antithrombotic therapies. Graphical This study is the first to integrate network pharmacology, rat model, metabolomics, zebrafish model, molecular docking, and MD simulation techniques to elucidate the anti-thrombotic effect and mechanism of Leonurus japonicus by modulating lipid metabolism and inhibiting TLR4/STAT3/TNF-α/IL-17A pathways, with kaempferol and apigenin identified as primary pharmacological constituents.
研究领域:
药理学
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中医药学
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心血管疾病
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系统生物学
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计算生物学
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动物学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
ACS Omega
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2023
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IF 4.1
Yi Chen,Yongfang Wang,Shasha Song,Xiaoli Zhang,Lili Wu,Jianbing Wu,Xinyu Li
Baicalin (BAI), the main active component of Scutellaria baicalensis, has significant anti-inflammatory and antibacterial effects. Echinacoside (ECH), an active component from Echinacea purpurea, has significant antiangiogenesis and antioxidant effects. In previous studies, BAI or ECH has been used for some skin inflammation problems by topical treatment. Psoriasis (PSO) is a common inflammatory skin disease with typical features such as excessive inflammatory response and vascular proliferation in skin lesions. Because of the anti-inflammatory effect of BAI and the antiangiogenic activity of ECH, it is proposed that the combination of BAI and ECH can ameliorate psoriatic skin lesions better than a single component. This study aims to explore the effects and potential mechanisms of BAI combined with ECH on imiquimod (IMQ)-induced psoriatic skin lesions by topical treatment. Transcriptome analysis first showed that the TNF signaling pathway and the VEGF signaling pathway were significantly enriched in IMQ-induced psoriatic skin lesions. Topical application of BAI combined with ECH could ameliorate IMQ-induced skin lesions in mice, especially the better effects of B2-E1 (BAI/ECH = 2:1). Network pharmacology analysis and molecular docking indicated that BAI-treated PSO on the skin by regulating the TNF signaling pathway, and ECH treated PSO on the skin by regulating the VEGF signaling pathway. Meanwhile, the ELISA test and the qPCR assay showed that BAI combined with ECH could inhibit the expression of key cytokines and genes related to the TNF signaling pathway and the VEGF signaling pathway. Zebrafish experiments demonstrated the anti-inflammatory and antiangiogenic effects of BAI combined with ECH and revealed the potential mechanisms associated with regulating the inflammation-related TNF signaling pathway and the angiogenesis-related VEGF signaling pathway. This suggested that BAI combined with ECH may be a promising topical agent to ameliorate psoriatic skin lesions in the future.
研究领域:
药理学
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皮肤病学
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分子生物学
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炎症研究
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血管生成研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
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2018
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IF 3.466
Yuzhe Huang,Jian Guo,Shuangying Gui
The current treatments used in inflammatory bowel disease (IBD) therapy have significant side effects. Thus, it is very necessary to position and release TNF-α siRNA in inflamed tissues. Here, we demonstrate that poly(lactic- co -glycolic acid) can pack TNF-α siRNA efficiently into nanoparticles (NPs), and galactosylated chitosan (GC) can be grafted onto the NP surface, improving the RAW 264.7 macrophage-targeting kinetics of the NPs in vitro. Next, we orally administered GC-modified NPs loaded with TNF-α siRNA to C57BL/6 mice treated with 3% dextran sodium sulfate (DSS) to investigate their use in the treatment of colitis . When TNF-α siRNA loaded NPs were released into the colitis tissues of mice, GC-modified NPs (GPNs) alleviated the inflammation more efficiently than unmodified PGLA NPs (PNs). A series of colitis parameters (e.g., weight loss, myeloperoxidase (MPO) activity) demonstrated that GPNs have better anti-inflammatory effects than PNs. As indicated by flow cytometry, grafting GC onto NPs increased the macrophage uptake capacity and improved the kinetics of endocytosis. Collectively, our findings indicate that GC- modified TNF-α siRNA loaded NPs are powerful and efficient nanoscale materials for the delivery of therapeutic molecules to colitis tissues.
研究领域:
药学
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生物技术
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纳米医学
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炎症研究
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2023
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IF 5.6
Zhang Xiuying,Chen Qilei,Zhao Jia,Zhao Wei,Fan Ni,Wang Yu,Chen Hubiao,Rong Jianhui
Myocardial infarction (MI) is a highly prevalent and lethal disease worldwide. Prevention and timely recovery are critical for the control of the recurrence and heart failure in MI survivors. The present study was designed to investigate the cardioprotective activity of the herbal medicine formula Baoyuan Decoction (BYD) and identify the active compounds and molecular targets. The ethanolic BYD extract (BYDE) was prepared by water extraction and ethanol precipitation of four herbal medicines, Astragali Radix, Ginseng Radix et Rhizoma, Cinnamomi Cortex, and Glycyrrhizae Radix et Rhizoma. Initially, BYDE was validated for the cardioprotective effectiveness in a mouse model of ischemia injury and rat cardiomyocyte H9C2 cells. As results, BYDE effectively reduced infarct size from 56% to 37% and preserved cardiac functions in mouse MI model while protected H9C2 cells against oxygen glucose deprivation. Subsequent network pharmacology analysis revealed that 122 bioactive ingredients, including flavonoids and saponins from the UPLC-MS/MS profile of BYDE, might target 37 MI-related proteins, including inflammatory and apoptotic mediators (e.g., TNF, NFKB1, CASPs, TNFRSF1A, CXCL12, BCL2A1). Pathway enrichment analysis suggested that BYDE might control the cardiac inflammation via targeting the tumor necrosis factor-alpha (TNF-α)/nuclear factor-κB (NF-κB) pathway while the selected targets were also implicated in IL-17 signaling pathway, lipid and atherosclerosis. Consequently, adenosine, ginsenoside Rh2, isoliquiritigenin, and licochalcone A were selected to generate the four-compound mixture AGILe and validated for the inhibitory effects on the TNF-α/NF-κB pathway. The results of the present study suggested that the mixture AGILe might be a potential cardioprotective remedy against MI.
研究领域:
药理学
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心脏病学
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中医药
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分子生物学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
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2023
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IF 3.7
Lei Huang,Shunyi Lu,Mengxuan Bian,Jiayi Wang,Jieqin Yu,Jun Ge,Jian Zhang,Qintong Xu
Oxidative stress is one of the most important factors in changing bone homeostasis. Redox homeostasis plays a key role in the osteogenic differentiation of bone mesenchymal stem cells (BMSCs) and the angiogenesis ability of human umbilical vein endothelial cells (HUVECs) for bone regeneration. Currently, this study assessed the effects of punicalagin (PUN) on BMSCs and HUVECs. Cell viability was determined by CCK-8 assay. A flow cytometry analysis was adopted to detect macrophage polarization. The production of reactive oxygen stress (ROS), glutathione (GSH), malonaldehyde (MDA) and superoxide dismutase (SOD) activities were evaluated by using commercially-available kits. Osteogenic capacity of BMSCs was evaluated by ALP activity, ALP staining and ARS staining. The expression of osteogenic-related proteins (OCN, Runx-2, OPN) and Nrf/HO-1 levles were evaluated by Western blotting. Osteogenic-related genes (Osterix, COL-1, BMP-4, ALP) were evaluated by RT-PCR. Migration ability and invasion ability of HUVECs were evaluated by wound healing assay and Transwell assay. Angiogenic ability was detected by tube formation assay and the expression of angiogenic-related genes (VEGF, vWF, CD31) were evaluated by RT-PCR. Results showed that PUN alleviated oxidative stress by TNF-α, enhanced osteogenic differentiation in BMSCs and angiogenesis in HUVECs. Moreover, PUN regulate immune microenvironment by promoting the polarization of M2 macrophages and reduce the oxidative stress related products by activating Nrf2/HO-1 pathway. Altogether, these results suggested that PUN can promote osteogenic capacity of BMSCs, angiogenesis of HUVECs, alleviate oxidative stress via Nrf2/HO-1 pathway, offering PUN as a novel antioxidant agent for treating bone loss diseases.
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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干细胞研究
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骨再生
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ORAL DISEASES
·
2024
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IF 2.9
Yifei Deng,Junhong Xiao,Xin Huang,Zhengguo Cao
Objective Inflammatory stimuli compromise the differentiation potency of human periodontal ligament cells (hPDLCs). Macrophage-derived exosomes (M-Exo) play a role in several aspects of cellular activity. This study investigated how M-Exo contributes to the osteo-/cementogenic differentiation of hPDLCs under inflammation and the mechanism involved. Methods M-Exo was identified by transmission electron microscopy, western blotting (WB), and dynamic light scattering. The internalization of M-Exo by hPDLCs was observed. After M-Exo treatment, the osteo-/cementogenic markers were detected by RT-qPCR and WB, and alkaline phosphatase (ALP) activity by ALP staining. Tumor necrosis factor alpha (TNF-ɑ) was applied to simulate inflammation. The rescue effect of M-Exo on TNF-ɑ-suppressed differentiation was validated. The p38 MAPK pathway activity was tested and a specific inhibitor was applied to explore the mechanism. Results M-Exo was successfully isolated, identified and internalized by hPDLCs. M-Exo enhanced the osteo-/cementogenic differentiation of hPDLCs, as indicated by upregulated osteo-/cementogenic markers and elevated ALP activity. Moreover, TNF-ɑ inhibited the differentiation capabilities of hPDLCs, on which M-Exo showed a rescue effect. M-Exo activated the p38 MAPK pathway and SB203580 attenuated its promotion effect. Conclusion This study showed that M-Exo ameliorated the TNF-ɑ-suppressed osteo-/cementogenic differentiation of hPDLCs partly through the p38 MAPK pathway.
研究领域:
牙科研究
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细胞生物学
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炎症
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组织工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）