PHYTOMEDICINE
·
2021
·
IF 5.34
Zi-ling Zou,Ming-hui Sun,Wei-feng Yin,Lei Yang,Ling-yi Kong
Background Osteoarthritis (OA) is an intractable degenerative disease of the whole joint, which is characterized by synovitis inflammation, cartilage damage, and chronic pain. Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) performs an important role in OA. Purpose We aim to investigate avicularin to protect cartilage extracellular matrix degradation (ECM) and suppresses inflammation both in rat and human chondrocytes . Methods 5-Ethynyl-2′-deoxyuridine (EdU) staining, Quantitative real-time PCR, TRAF6 plasmid transfection, Western blot , Measurement of nitric oxide (NO), ROS detection and Immunofluorescence were utilized in vitro . micro-CT scanning, Safranin O-Fast Green, toluidine blue and immunohistochemistry staining were performed in vivo . Results In vitro , avicularin attenuates the degradation of ECM and inflammation, which could inhibit the activation of TRAF6/MAPK pathway via targeting TRAF6. Increased MMP3 and MMP13 expressions and decreased Aggrecan and Collagen Ⅱ levels were observed in anterior cruciate ligament transection (ACLT) induced osteoarthritic rats. Interestingly, intra-articular injection of avicularin attenuates this phenomenon. Conclusions Taken together, our results indicate that avicularin suppresses cartilage extracellular matrix degradation and inflammation via TRAF6/MAPK activation by targeting TRAF6. These observations identify TRAF6 as a relevant drug target, and avicularin may as a potential therapeutic agent in osteoarthritis.
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CTS-Clinical and Translational Science
·
2020
·Vol. 14
·期 5
·2075-2084
·
IF 3.373
Hongtao He,Kuangyuan Qiao,Chao Wang,Wuhan Yang,Zhuo Xu,Zhilei Zhang,Yuming Jia,Chong Zhang,Li Peng
Hydrazinocurcumin (HZC), a synthetic derivative of curcumin (CUR), has been documented to show anticancer potential in impeding tumor growth in several cancers, including hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms remain unclear. This study aimed to explore the function and underlying mechanisms of HZC on HCC cells, which may involve the p38 mitogen activated protein kinase (MAPK) pathway. HZC was first purified and identified. HepG2 cells were then subjected to treatment with HZC or CUR of different concentrations and p38 MAPK signaling inhibitor (SB203580) to verify their effects on HCC cell apoptosis and proliferation. Furthermore, the functional relevance between HZC and the p38 MAPK pathway in HCC was examined. It was observed that 40 μM HZC exhibited the best pro-apoptosis effect in HCC cells. HZC was found to inhibit HCC cell proliferation and promote apoptosis, the effect of which was stronger than 5-fluorouracil (5-FU). More importantly, the anti-oncogenic effect of HZC and 5-FU was implicated with activation of the p38 MAPK pathway. In vivo experimental results showed that HZC inhibited tumor growth more effectively than 5-FU through the p38 MAPK pathway. These results provide evidence that HZC exerted anti-oncogenic and pro-apoptosis effects in HCC cells through activation of the p38 MAPK pathway.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Peizhi Jia,Daxin Chen,Ying Zhu,Meiling Wang,Jianwei Zeng,Ling Zhang,Qiaoyan Cai,Dawei Lian,Chunyu Zhao,Yaoyao Xu,Jianfeng Chu,Shan Lin,Jun Peng,Wei Lin
Ethnopharmacological relevance Liensinine(Lien, C 37 H 42 N 2 O 6 ) is an alkaloid compound from plumula nelumbinis that demonstrates an antihypertensive effect. The protective effects of Lien on target organs during hypertension are still unclear. Aim of the study : This study aimed to understand the mechanism of Lien during the treatment of hypertension, with emphasis on vascular protection. Materials and methods Lien was extracted and isolated from plumula nelumbinis for further study. In vivo model of Ang II-induced hypertension, non-invasive sphygmomanometer was used to detect the blood pressure in and out of the context of Lien intervention. Ultrasound was used to detect the abdominal aorta pulse wave and media thickness of hypertensive mice, and RNA sequencing was used to detect the differential genes and pathways of blood vessels. The intersection of Lien and MAPK protein molecules was detected by molecular interconnecting technique. The pathological conditions of abdominal aorta vessels of mice were observed by HE staining. The expression of PCNA, α-SMA, Collagen Type Ⅰ and Collagen Type Ⅲ proteins were detected by IHC. The collagen expression in the abdominal aorta was detected by Sirius red staining. The MAPK/TGF-β1/Smad2/3 signaling and the protein expression of PCNA and α-SMA was detected by Western blot. In vitro , MAPK/TGF-β1/Smad2/3 signaling and the protein expression of PCNA and α-SMA were detected by Western blot, and the expression of α-SMA was detected by immunofluorescence; ELISA was used to detect the effect of ERK/MAPK inhibitor PD98059 on Ang Ⅱ-induced TGF-β1secrete; and the detection TGF-β1and α-SMA protein expression by Western blot; Western blot was used to detect the effect of ERK/MAPK stimulant12-O-tetradecanoyl phorbol-13-acetate (TPA) on the protein expression of TGF-β1 and α-SMA. Results Lien displayed an antihypertensive effect on Ang Ⅱ-induced hypertension, reducing the pulse wave conduction velocity of the abdominal aorta and the thickness of the abdominal aorta vessel wall, ultimately improving the pathological state of blood vessels. RNA sequencing further indicated that the differential pathways expressed in the abdominal aorta of hypertensive mice were enriched in proliferation-related markers compared with the Control group. The profile of differentially expressed pathways was ultimately reversed by Lien. Particularly, MAPK protein demonstrated good binding with the Lien molecule. In vivo, Lien inhibited Ang Ⅱ-induced abdominal aorta wall thickening, reduced collagen deposition in the ventral aortic vessel, and prevented the occurrence of vascular remodeling by inhibiting MAPK/TGF-β1/Smad2/3 signaling activation. In addition, Lien inhibited the activation of Ang II-induced MAPK and TGF-β1/Smad2/3 signaling, attenuating the expression of PCNA and inhibiting the reduction of α-SMA, collectively playing a role in the inhibition of Ang Ⅱ-induced hypertensive vascular remodeling. PD98059 alone could inhibit Ang Ⅱ-induced elevation of TGF-β1 and the decrease of α-SMA expression. Further, PD98059 combined with Lien had no discrepancy with the inhibitors alone. Simultaneously TPA alone could significantly increase the expression of TGF-β1 and decrease the expression of α-SMA. Further, Lien could inhibit the effect of TPA. Conclusion This study helped clarify the protective mechanism of Lien during hypertension, elucidating its role as an inhibitor of vascular remodeling and providing an experimental basis for the research and development of novel antihypertensive therapies.
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OncoTargets and Therapy
·
2022
·
IF 4.345
Rong Wang,Danni Deng,Naiyuan Shao,Yuan Xu,Lian Xue,Ya Peng,Yatian Liu,Feng Zhi
Background Glioblastoma multiforme (GBM) is the most malignant primary tumor of the central nervous system and is associated with a very poor prognosis. No further improvements in outcomes have been reported since radiotherapy-temozolomide therapy was introduced. Therefore, developing new agents to treat GBM is important.Aim This study aimed to evaluate the anti-tumor effect of evodiamine (Evo) on GBM cells, and to determine the underlying mechanisms involved.Results According to MTT assay results, Evo significantly inhibited the cell proliferation in a time- and dose-dependent manner. Fluorescence microscopy and flow cytometry analyses revealed that Evo induced cell apoptosis in a concentration-dependent manner. Moreover, Evo induced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) disruption. Finally, Evo induced apoptosis in cancer cells by suppressing PI3K/AKT signaling and inducing MAPK phosphorylation (p38 and JNK, but not ERK) to regulate apoptotic proteins (Bax, Bcl-2, Cytochrome c, Caspase-3, and PARP).Conclusion In summary, Evo inhibits cell proliferation by inducing cellular apoptosis via suppressing PI3K/AKT and activating MAPK in GBM; these results indicate that Evo may be regarded as a new approach for GBM treatment.
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PHYTOTHERAPY RESEARCH
·
2022
·Vol. 37
·期 2
·578-591
·
IF 6.388
Na Yang,Chunpeng Zou,Wu Luo,Diyun Xu,Mengyang Wang,Yi Wang,Gaojun Wu,Peiren Shan,Guang Liang
Chronic inflammation plays an important role in hypertensive heart failure. Suppressing angiotensin II (Ang II)-induced cardiac inflammation may contribute to the treatment of hypertension-associated heart failure. Sclareol, a natural product initially isolated from the leaves and flowers of Salvia sclarea , possesses antiinflammatory and immune-regulation activity in various systems. However, its effect on Ang II-induced cardiac remodeling remains unknown. In this study, we have explored the potential effects of sclareol on Ang II-induced heart failure. In vivo experiments were conducted in mice with Ang II-pump infusion for 28 days. Sclareol administration at 5 mg·kg −1 ·d −1 significantly reduced the expression of myocardial injury markers. Sclareol also exerts protective effects against Ang II-induced cardiac dysfunction in mice which is associated with alleviated cardiac inflammation and fibrosis. Transcriptome analysis revealed that inhibition of the Ang II-activated mitogen-activated protein kinase (MAPK) pathway contributed to the protective effect of sclareol. Sclareol inhibits Ang II-activated MAPKs pathway to reduce inflammatory response in mouse hearts and cultured cardiomyocytes. Blockage of MAPKs in cardiomyocytes abolished the antiinflammatory effects of sclareol. In conclusion, we show that sclareol protects hearts against Ang II-induced injuries through inhibiting MAPK-mediated inflammation, indicating the potential use of sclareol in the prevention of hypertensive heart failure.
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Experimental and Therapeutic Medicine
·
2021
·Vol. 22
·期 6
·1-9
·
IF 2.447
Yue-Yuan Chen,Xiao-Jie Yan,Xiao-Hua Jiang,Feng-Lai Lu,Xue-Rong Yang,Dian-Peng Li
Aberrant destruction of the articular extracellular matrix (ECM) has been considered to be one of the pathological features of osteoarthritis (OA) which results in chondrocyte changes and articular cartilage degeneration. The MAPK signaling pathway serves a key role by releasing cartilage‑degrading enzymes from OA chondrocytes. However, the use of MAPK inhibitors for OA is hindered by their potential long‑term toxicity. Vicenin 3 is one of the major components of the Jian‑Gu injection which is effective in the clinical treatment of OA. However, its potential impact on OA remain poorly understood. Therefore, the present study aimed to assess the effects of vicenin 3 on interleukin (IL)‑1β‑treated SW1353 chondrocytes, which mimic the microenvironment of OA. These chondrocytes were pretreated with vicenin 3 (0, 5 and 20 µM) for 1 h and subsequently stimulated with IL‑1β (10 ng/ml) for 24 h. Nitric oxide (NO) production was measured using the Griess reaction, whereas the production of prostaglandin E2 (PGE2), matrix metalloproteinases (MMPs), A disintegrin‑like and metalloproteinase with thrombospondin motifs (ADAMTSs), collagen type II and aggrecan were measured using ELISA. The mRNA expression of MMPs and ADAMTSs were measured using reverse transcription‑quantitative PCR. The protein expression levels of MAPK were measured using western blotting. Vicenin 3 was found to significantly inhibit IL‑1β‑induced production of NO and PGE. Increments in the expression levels of MMP‑1, MMP‑3, MMP‑13, ADAMTS‑4 and ADAMTS‑5 induced by IL‑1β, in addition to the IL‑1β‑induced degradation of collagen type II and aggrecan, were all reversed by vicenin 3 treatment. Furthermore, vicenin 3 suppressed IL‑1β‑stimulated MAPK activation, an effect that was similar to that exerted by SB203580, a well‑known p38 MAPK inhibitor. In conclusion, vicenin 3 may confer therapeutic potential similar to that of the p38 MAPK inhibitor for the treatment of OA.
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ACTA HISTOCHEMICA
·
2025
·
IF 2.4
Xiaorui Dong,Xixi Chen,Mengling Xue,Yina Zhang,Peiyue Jiang
Background Cervical cancer (CC) is a common gynecological disease that seriously threatens women’s health. This study aims to explore key genes and pathways related to CC prognosis through bioinformatics, providing new insights for further treatment of CC. Methods CC patient data were analyzed from the public databases. The enrichment analyses explored the roles and pathways of CC-related differentially expressed genes (DEGs). A prognostic key gene was identified using Venn diagrams and subjected to survival analysis. Gene Set Enrichment Analysis (GSEA) was employed to investigate the potential pathways of key genes. Correlations between the key gene and clinical features were examined. The function of the key gene was validated through immunohistochemistry, flow cytometry, transwell, MTT, and Western blot assays in vitro and in vivo . Results Our research identified 2459 upregulated genes among DEGs between healthy and tumor cervical tissues. These DEGs were primarily enriched in the PI3K-AKT and MAPK pathways. Moreover, EFNA1 was recognized as a key prognostic gene in CC, with elevated expression compared to normal tissue. A negative correlation between EFNA1 levels and patient survival rates was corroborated by Kaplan-Meier analysis. Furthermore, EFNA1 expression correlated with the cancer stage and was linked to antigen presentation, folate synthesis, and IL-17 signaling. Knockdown of EFNA1 enhanced apoptosis and reduced migration, invasion, and proliferation in vitro and in vivo , inhibiting EMT and MAPK pathways. Conclusion This study revealed the key signaling pathways in CC progression and identified EFNA1 as a crucial prognostic biomarker, potentially impacting CC treatment.
研究领域:
肿瘤学
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生物信息学
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分子生物学
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2017
·
IF 3.154
Fujie Yan,Yunyun Yang,Lushuang Yu,Xiaodong Zheng
Main components of Apios americana leaves extract (ALE) were flavonoid C-glycosides, including vitexin (46.7%), schaftoside (18.9%), and orientin (4.32%). In vitro, ALE restored glucose consumption, glucose uptake, and glycogen content in glucose-induced hepatic cells. Exposure of HepG2 cells to high glucose resulted in reactive oxygen species and O2– accumulation, while ALE alleviated these increases by 47 ± 0.68 and 68 ± 0.74%, respectively. Glucose increased c-Jun N-terminal kinase (JNK) and decreased extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 phosphorylation, while ALE reduced p-JNK and p-p38 but not p-ERK1/2, accompanied by nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1, and NAD(P)H quinine oxidoreductase 1 downregulation. In vivo, the lifespan of Caenorhabditis elegans was more violently shortened by paraquat under hyperglycemia, while ALE protected this damage in N2 worms (2.6 times extension) but not in daf-16 mutants. Furthermore, p38/PMK-1 and Nrf2/SKN-1 expressions in worms were suppressed by glucose, which were reversed by ALE treatment. These results suggest that ALE prevents glucose-induced damage via regulating specific mitogen-activated protein kinases and Nrf2 pathways.
研究领域:
药理学
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分子生物学
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ACS Applied Materials & Interfaces
·
2014
·
IF 5.9
Yang Liu,Xin Wang,Chun-Yang Sun,Jun Wang
Hepatocellular carcinoma (HCC) is one of the most common malignant human tumors worldwide, but no effective therapeutic options are currently available. The cancer stem cell (CSC) has proven to play a central role in the development, metastasis, and recurrence of HCC. In this study, we report a dual functional mitogen-activated protein kinase inhibitor (U0126)-based therapy for treating both bulk HCC and HCC CSCs, using poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PLA) nanoparticles as the drug carrier. It is demonstrated that nanoparticle encapsulation enhanced the cell uptake of U0126 in HCC CSCs and that enhanced endocytosis lead to augmented cytotoxicity of U0126 in HCC CSCs. Moreover, the nanoparticle encapsulation increased the inhibition of self-renewal capability, prolonged the circulation time, and increased the tumor accumulation of U0126 when compared with the use of the free inhibitor. The systemic delivery of U0126 remarkably enhanced the suppression of tumor development with decreased CSCs in the HepG2 xenograft simultaneously with reduced systemic toxicity.
研究领域:
肿瘤学
·
药理学
·
生物医学工程
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CHEMICO-BIOLOGICAL INTERACTIONS
·
2026
·
IF 5.2
Gongqing Wu,Xiaoyin Zhong,Xintong Feng,Yunhong Yi
Chloroxylenol (PCMX), a widely used phenolic disinfectant, is an emerging aquatic pollutant whose immunotoxicity remains poorly understood. This study employed zebrafish models to evaluate PCMX toxicity across a concentration range (0.25–7.5 mg/L) spanning environmentally detectable levels to higher, toxicologically informative concentrations. Acute exposure caused dose-dependent developmental defects, oxidative stress, and apoptosis in both embryos and adults. Embryonic toxicological assessment revealed a 96-h LC 50 of 3.98 mg/L for larvae, with significant hatching reduction at ≥2 mg/L and malformation elevation at ≥0.5 mg/L. PCMX disrupted innate immunity by depleting neutrophils while paradoxically expanding macrophages, RNA-seq revealed 353 dysregulated genes in adult kidney, with KEGG enrichment identifying the MAPK pathway as a central hub. Network toxicology and molecular docking predicted moderate binding of PCMX to MAPK nodes (TGFBR1, GRB2, AKT1; −6.66 to −4.5 kcal/mol), corroborated by qPCR validation of MAPK and hematopoietic regulators ( optn, atf3, irak3, prkcba, tgfbr2a, spi1a, c1qb, fosab ). We propose that PCMX-induced oxidative stress converges on MAPK disruption, driving immune dysregulation and biased hematopoiesis, though this causal model is inferred from correlative evidence and requires functional validation. Despite the concentration gap, these findings show that PCMX, even at sublethal doses, can disrupt conserved immune and hematopoietic pathways, raising concern for aquatic organisms.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Jie Pang,Tingfang Chen,Hong Shen,Weihao Jiang,Yongzhen Tan,Zhiming Zhang,Juan Xu,Feifei Yang,Li Liu,Yanlin Li
Ethnopharmacological relevance Guizhi-Shaoyao-Zhimu Decoction (GSZD), derived from Synopsis of the Golden Chamber, has been used for over two thousand years to treat joint swelling and pain disorders such as "Lijie Feng" (arthralgia due to cold-dampness). It is one of the most representative traditional Chinese medicine (TCM) formulas for treating rheumatoid arthritis (RA). However, its modern pharmacological mechanism lacks systematic elaboration, and new research will better explore the underlying mechanism of its action. Research objectives With the collagen-induced arthritis (CIA) mouse model as the core experimental platform, this study first performed comprehensive chemical composition identification and quality control of GSZD via ultra-high performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) to clarify its pharmacodynamic material basis, combined transcriptomic profiling with network pharmacology approaches, and further implemented in vitro and in vivo experimental validation including lipopolysaccharide (LPS)-stimulated macrophages and IL-17RA blockade with Brodalumab to clarify whether GSZD exerts anti-rheumatoid arthritis (RA) activity by targeting the interleukin-17 receptor (IL-17R)-MAPK signaling axis. Materials and methods Sixty male SPF-grade DBA/1 mice were randomly divided into five groups: Sham, CIA, low-dose GSZD (13.24 g crude drug/kg·d), high-dose GSZD (26.48 g crude drug/kg·d), and leflunomide (10 mg/kg). Intragastric administration began 7 days after the secondary immunization and continued for 28 days. Body weight, paw thickness, and arthritis scores were monitored; spleen and thymus indices were calculated. Serum and joint tissues were collected for ELISA, qPCR, Western blot, immunohistochemistry, and histopathological staining. The chemical profile of GSZD was established by UPLC-HRMS and matched against the LuMet-TCM database. Transcriptome sequencing was performed on knee joint homogenates (CIA vs. GSZD-H, n = 3 per group) and integrated with network pharmacology (TCMSP, SwissTargetPrediction, OMIM, GeneCards, STRING, Metascape) to predict core targets. RAW264.7 macrophages were pretreated with GSZD (10–100 μg/mL) for 2 h and then stimulated with LPS (100 ng/mL) for 24 h. For IL-17RA blockade, cells were pre-incubated with Brodalumab (10 μg/mL, 30 min), followed by GSZD (100 μg/mL, 1 h) and LPS (1 μg/mL, 24 h). Molecular docking (AutoDock Vina) was used to evaluate the binding of major components to IL-17R. Results UPLC-HRMS identified 979 constituents in GSZD. Network pharmacology and transcriptomic analyses jointly predicted the IL-17R-MAPK axis as a central target. In vivo, GSZD dose-dependently attenuated arthritis symptoms, reduced spleen and thymus indices, and alleviated synovial hyperplasia and macrophage activation (decreased F4/80 and CD11b). GSZD lowered pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and chemokines (CCL2, CCL7) in serum and joints, suppressed matrix metalloproteinases (MMP3, MMP9), and reduced cartilage/bone erosion. Immunohistochemistry confirmed that GSZD inhibited IL-17RA, ERK1/2, and phosphorylated p38 in joint tissues. In vitro, GSZD suppressed IL-17R expression and the phosphorylation of p38, ERK, and JNK in LPS-stimulated macrophages. IL-17RA blockade with Brodalumab completely abrogated the inhibitory effect of GSZD on MAPK phosphorylation and IL-1β production, confirming IL-17RA dependency. Molecular docking showed that multiple GSZD components bind directly to IL-17R. Conclusion This study demonstrates that GSZD, a multi-component formula characterized by UPLC-HRMS, alleviates synovial inflammation and osteoarticular destruction by blocking the IL-17R-MAPK cascade in an IL-17RA-dependent fashion. These findings provide modern scientific evidence for the clinical application of GSZD in treating RA.
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Food & Function
·
2021
·Vol. 12
·期 23
·12127-12141
·
IF 5.396
Yue Ge,Huibin Chen,Jilite Wang,Guishan Liu,Steve W. Cui,Ji Kang,Yumei Jiang,Hao Wang
Naringenin (NN) is one of the most abundant flavonoids in citrus and grapefruits and has been shown to have antioxidant properties in vitro. The purpose of the study is to examine the antioxidant and anti-aging activities of NN in C. elegans, and to further explore the molecular mechanism. The results showed that NN enhanced the lifespan under normal and oxidative stress induced by H2O2. After treatment with NN, locomotion capability was improved and aging pigment accumulation was suppressed. NN also delayed the paralysis and reversed the defective chemotaxis behavior induced by Aβ protein. Meanwhile, the treatment with NN enhanced the activities of antioxidant enzymes and reduced the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA) content. The possible targets and pathways interacting with NN were predicted by network pharmacology. Real-time PCR analysis indicated that NN upregulated the expression levels of daf-16, sek-1 and skn-1, downregulated the expression levels of daf-2, age-1 and akt-1, and further activated sod-3, ctl-1, ctl-2, gst-4 and mtl-1. Moreover, the selected mutant strains were used and molecular docking was conducted to further suggest that IIS and MAPK pathways could be involved in the NN-mediated longevity-promoting effect.
研究领域:
老年学
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分子生物学
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药理学
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