MOLECULES
·
2023
·Vol. 28
·期 9
·3687
·
IF 4.6
Changli Fu,Mingjin Wang,Yuan Lu,Jie Pan,Yueting Li,Yongjun Li,Yonglin Wang,Aimin Wang,Yong Huang,Jia Sun,Chunhua Liu
AlthoughPolygonum orientaleL. (PO) has a beneficial effect on treatment of myocardial ischemia (MI), its mechanism remains unclear. This study aimed to explore the pharmacological mechanism of PO against MI through MAPK signaling pathways. Firstly, the therapeutic effect of PO was evaluated for treatment of MI mice. Using Western blot and immunohistochemistry, the influence of PO on MAPK signaling pathways and cell apoptosis was investigated. Subsequently, one key pathway (ERK) of MAPK signaling pathways was screened out, on which PO posed the most obvious impact. Finally, an inhibitor of ERK1/2 was utilized to further verify the regulatory effect of PO on the MAPK/ERK signaling pathway. It was found that PO could reduce the elevation of the ST segment; injury of heart tissue; the activity of LDH, CK, NOS, cNOS and iNOS and the levels of NO, BNP, TNF-α and IL-6. It is notable that PO could significantly modulate the protein content of p-ERK/ERK in mice suffering from MI but hardly had an effect on p-JNK/JNK and p-p38/p38. Additionally, the expressions of bax, caspase3 and caspase9 were inhibited in heart tissue in the PO-treated group. To evaluate whether ERK1/2 inhibitor (PD98059) could block the effect of PO on treatment of MI, both PO and PD98059 were given to mice with MI. It was discovered that the inhibitor indeed could significantly reverse the regulatory effects of PO on the above indicators, indicating that PO could regulate p-ERK/ERK. This study provides experimental evidence that PO extenuates MI injury, cardiomyocyte apoptosis and inflammation by activating the MAPK/ERK signaling pathway.Keywords:Polygonum orientaleL.;myocardial ischemia;MAPK signaling pathway
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ORAL DISEASES
·
2022
·
IF 4.068
Minmin Sun,Yaoting Ji,Shuhui Zhou,Rourong Chen,Hantao Yao,Minquan Du
Objective The objective of the study was to determine the anti-osteoclastogenic potential of ginsenoside Rb3 for the treatment of periodontitis. Methods The anti-osteoclastogenic effect was determined using RANKL-induced RAW264.7 cells and murine bone marrow-derived macrophages followed by TRAP and phalloidin staining. Expression of osteoclastogenesis-related genes and proteins were examined by qPCR and WB. Activation of signaling pathways was detected by WB and IHC techniques. Experimental periodontitis rat model was built up by gingival injections of P. gingivalis LPS. After 21 days of Rb3 treatment, rats were sacrificed for micro-CT, IHC, H&E, and TRAP staining analyses. Results Rb3 dramatically inhibits RANKL-induced osteoclastogenesis. Nfatc1, Mmp9, Ctsk, Acp5 mRNA, and MMP9, CTSK proteins were dose-dependently downregulated by Rb3 pretreatment. WB results revealed that Rb3 suppressed activations of p38 MAPK, ERK, and p65 NF-κB, and the inhibition of ERK was most pronounced. Consistently, IHC analysis revealed that p-ERK was highly expressed in alveolar bone surface, blood vessels, odontoblasts, and gingival epithelia, which were notably suppressed by Rb3 treatment. H&E staining and micro-CT analyses showed that Rb3 significantly attenuated gingivitis and alveolar bone resorption in rats. Conclusion Rb3 inhibits RANKL-induced osteoclastogenesis and attenuates P. gingivalis LPS-induced gingivitis and alveolar bone resorption in rats via ERK/NF-κB signaling pathway.
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Acupuncture in Medicine
·
2017
·
IF 2.156
Chunxiao Wu,Chun Li,Guoping Zhou,Lu Yang,Guimei Jiang,Jing Chen,Qiushi Li,Zhulian Zhan,Xiuhong Xu,Xin Zhang
ObjectiveTo explore the effects of electroacupuncture (EA) on the phosphorylated extracellular signal regulated kinase (p-ERK) pathway of the cerebral cortex in a rat model of focal cerebral ischaemia/reperfusion (I/R).Methods160 adult Sprague-Dawley rats underwent middle carotid artery occlusion (MCAO) to establish I/R injury and were randomly divided into four groups (n=40 each) that remained untreated (I/R group) or received EA at LU5, LI4, ST36 and SP6 (I/R+EA group), the ERK inhibitor PD98059 (I/R+PD group), or both interventions (I/R+PD+EA groups). An additional 40 rats undergoing sham surgery formed a healthy control group. Eight rats from each group were sacrificed at the following time points: 2 hours, 6 hours, 1 day, 3 days and 1 week. Neurological function was assessed using neurological deficit scores, morphological examination was performed following haematoxylin-eosin staining of cortical tissues, and apoptotic indices were calculated after terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labelling. Cortical protein and mRNA expression of p-ERK and ERK were measured by immunohistochemistry and real-time quantitative PCR, respectively.ResultsCompared with the I/R group, neurological deficit scores and apoptotic indices were lower in the I/R+EA group at 1 and 3 days, whereas mRNA/protein expression of ERK/p-ERK was higher in the EA group at all time points studied.ConclusionOur results suggest that EA can alleviate neurological deficits and reduce cortical apoptosis in rats with I/R injury. These anti-apoptotic effects may be due to upregulation of p-ERK. Moreover, apoptosis appeared to peak at 1 day after I/R injury, which might therefore represent the optimal time point for targeting of EA.
研究领域:
神经科学
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分子生物学
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中医学
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ChemistryOpen
·
2024
·
IF 2.5
Wei Gao,Xiaoju Hua,Shengliang Liao,Zhikai Xiahou,Haikuan Yang,Lifang Hu,Yunyang Chi
Graphical Compound 3h has been found to show inhibitory effects on the survival of HepG2 liver cancer cells.The results show that 3h induces cell-cycle arrest in the S phase. Additionally, 3h exerts a strong pro-apoptotic effect. Specifically, compound 3h reduces the phosphorylation of PI3K, AKT, and ERK, thereby inhibiting both the MAPK/ERK and PI3K/AKT signaling pathways. 2H-pyran compound 1 synthesized from 6-methylpyridine-2,4-diol and citral, has been used for Cu-catalyzed N -arylation with a range of arylboric acids to obtain arylated pyranopyridine core structure derivatives (yield up to 77 %). Among them, compound 3 h exhibited a much better inhibitory effect on HepG2 liver cancer cells compared to citral, and the IC 50 value was 5.3 μM following exposure with the newly synthesized derivatives (herein named 3 h for short in this paper), which was lower than that of the cisplatin (6.5 μM). Meanwhile, the cell-cycle arrest of HepG2 cells occurred in the S phase, and the apoptosis of HepG2 cells was significantly increased with increasing drug concentration. In addition, real-time fluorescence quantification PCR and Western blotting experiments showed that the expression of apoptotic protein BAX was increased, while the expression of anti-apoptotic protein BCL2 was inhibited in a dose-dependent fashion. The results of these experiments indicated that apoptosis was promoted in HepG2 cells via apoptotic signaling pathway activated by 3 h . Furthermore, 3 h effectively decreased the phosphorylation levels of PI3 K, ATK and ERK, resulting in the inhibitions of MAPK/ERK and PI3 K/ATK signaling pathways. Briefly, 3 h has been found to show inhibitory effects on the survival of HepG2 liver cancer cells and may be used as anti-cancer drug in the future.
研究领域:
药理学
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肿瘤学
·
分子生物学
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MOLECULAR CARCINOGENESIS
·
2026
·
IF 3.5
Ningyi Xian,Ziwei Wang,Bingqing Wang,Xiaofei Wang,Yan Zheng
Cutaneous squamous cell carcinoma (cSCC) is a malignant skin cancer which is derived from epidermal keratinocytes, and long-term exposure to ultraviolet rays is its main risk factor. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) is a crucial gene for the formation and stability of collagen intermolecular cross-links, being vital in the development of cancer. Nevertheless, the interaction between cSCC and PLOD2 has not been elucidated. Here, we found PLOD2 upregulated in human cSCC. Its knockdown in cSCC cells suppressed proliferation, migration, invasion, and angiogenesis while inducing apoptosis and cell cycle arrest; overexpression promoted these malignant phenotypes. In mouse xenografts, PLOD2 knockdown inhibited tumor growth and collagen deposition. Furthermore, in a DMBA/TPA-induced carcinogenesis model, topical PLOD2 inhibition by minoxidil suppressed tumor development as well. Mechanistically, our studies revealed that PLOD2 acts as a key downstream effector of STAT3 to activate ERK and AKT signaling evidenced by rescue experiments. As a result, our study not only establishes the STAT3/PLOD2/ERK-AKT axis as a key driver of cSCC but also identifies the clinically approved drug minoxidil as a potent PLOD2 inhibitor, demonstrating immediate promise as a repurposed therapeutic agent.
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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2026
·
IF 4
Chen Xiaohui,Liang Gang,Wang Liangwei,Xie Zhilang,Li Zhongpan,Xiang Yulin,Li Rongzhu,Zhao Fulan,Chen Xiaojun,Huang Rui
This study leverages modern nanotechnology and molecular biological approaches to elucidate the scientific rationale underlying the traditional aqueous decoction practice of Lycopodium japonicum Thunb. (LJT) for knee osteoarthritis (KOA), establishing that the spontaneously formed nanoparticles may contribute to the pharmacologically active material foundation, and demonstrating that they confer therapeutic benefits predominantly through modulation of the MAPK/ERK inflammatory pathway, thereby positioning LJT-NPs as a potentially biocompatible, plant-derived nanotherapeutic candidate. LJT constituents were profiled by ultrahigh-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HR-MS) during aqueous decoction, and their self-assembly into supramolecular nanoparticles was observed by transmission electron microscopy (TEM). After optimization, LJT-derived nanoparticles (LJT-NPs) were prepared and biosafety was assessed in vivo . Systems pharmacology predicted the main pathway, and anti-osteoarthritic efficacy was validated in papain-induced KOA rat models and in vitro cellular assays. UPLC-HR-MS analysis indicated that lycopodium alkaloids were the primary components of LJT-NPs. In vivo profiling suggested that this endogenous nanosystem exhibits preliminary biosafety. Systems pharmacology revealed MAPK/ERK as the primary regulatory pathway, and experiments showed attenuated phosphorylation of RAF, MEK, ERK, and ELK1 in vivo and in vitro . Additionally, LJT-NPs ameliorated KOA at low doses via local joint injection. LJT-NPs showed therapeutic potential in KOA models, associated with attenuation of MAPK/ERK pathway hyperactivation. This positions LJT-NPs as a botanical-origin nanotherapeutic candidate with good safety and efficacy profiles. Graphical
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·Vol. 74
·期 29
·22784-22797
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IF 6.7
Cheng Xin,Wang Jiaxing,Tan Haoyang,Ji Yaxin,Yu Xiaoqing,Hu Jiahuan,Li Siyao,Kang Huijie,Zhang Shuai,Xuanpan Ding,Jiao Wenjing,Fan Honggang,Zhao Yuan
Chronic
stress (CS) represents a pivotal environmental trigger
for depression. It induces depression-like behaviors primarily by
disrupting hypothalamic–pituitary–adrenal (HPA) axis
homeostasis and impairing hippocampal synaptic plasticity. Flavonoids
are abundant in human diet and possess significant neuroprotective
potential. We screened a library of 339 flavonoid compounds. Daidzein
(DAI) was identified as the lead compound. Subsequently, in rats subjected
to chronic restraint stress (CRS), DAI administration effectively
ameliorated depression-like behaviors, and attenuated hippocampal
histopathological damage. Network pharmacology and molecular docking
analyses suggested that ERK-related signaling may be involved in the
protective effects of DAI, and molecular dynamics simulations supported
the stability of the DAI-ERK2 complex. Furthermore, DAI activated
the ERK/CREB/BDNF signaling cascade, an effect that was partially
reversed by ERK inhibitor intervention. Notably, DAI also enhanced
dendritic complexity and spine density in hippocampus. In summary,
our study demonstrates that DAI alleviates stress-induced synaptic
plasticity damage through the ERK/CREB/BDNF signaling pathway.
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Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 31
·6912-6924
·
IF 5.344
Lei Liu,Xianling Gao,Xiaoyu Li,Guanglin Zhu,Nanying Li,Xuetao Shi,Yingjun Wang
Bioceramic–biopolymer composites have been used extensively as bone tissue engineering scaffolds due to their bioactive properties. However, composite scaffolds are insufficient in inducing osteogenic differentiation of stem cells. In this study, a strategy for the local delivery of bioactive factors by coating calcium alendronate (ALC) on the surface of composite scaffolds was systematically evaluated for the first time. The coated ALC not only displayed excellent cytocompatibility and cell adhesion properties but also resulted in the significant upregulation of osteogenic related gene expression, osteogenic related protein levels, alkaline phosphatase (ALP) activity and calcium deposition of ADSCs. Furthermore, our results suggested that the molecular mechanism of ADSC osteogenic differentiation induced by the constructed ALC may be related to the integrin binding and the activation of FAK/ERK signalling pathways. These findings suggested that ALC-coated composite scaffolds can serve as bone tissue engineering scaffolds, providing a simple and universal method to improve the osteogenic differentiation of ADSCs by calcium phosphate-containing composite materials.
研究领域:
组织工程
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生物材料
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干细胞生物学
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JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Dong-mei Li,Fu-cui Zhu,Jie Wei,Jia-xiu Xie,Jun-hui He,Dong-mei Wei,Yi Li,Ke-dao Lai,Li-min Liu,Qi-biao Su,Gui-ning Wei,Bin Wang,Yan-cheng Liu
Ethnopharmacological relevance Polyrhachis vicina Roger ( P. vicina ), a traditional Chinese medicinal animal, has been used to treat rheumatoid arthritis , hepatitis, cancer, and other conditions. Due to its anti-inflammatory properties, our previous pharmacological investigations have demonstrated that it is effective against cancer, depression, and hyperuricemia . Nevertheless, the key active components and targets of P. vicina in cancers are still unexplored. Aim of the study The study aimed to evaluate the pharmacological treatment mechanism of the active fraction of P. vicina (AFPR) in treating colorectal cancer (CRC) and to further reveal its active ingredients and key targets. Methods To examine the inhibitory impact of AFPR on CRC growth, tumorigenesis assays, cck-8 assays, colony formation assays, and MMP detection were utilized. The primary components of AFPR were identified by GC-MS analysis. The network pharmacology , molecular docking, qRT-PCR, western blotting , CCK-8 assays, colony formation assay, Hoechst staining, Annexin V-FITC/PI double staining, and MMP detection were performed to pick out the active ingredients and potential key targets of AFPR. The function of Elaidic acid on necroptosis was investigated through siRNA interference and the utilization of inhibitors. Elaidic acid's effectiveness to suppress CRC growth in vivo was assessed using a tumorigenesis experiment. Results Studies confirmed that AFPR prevented CRC from growing and evoked cell death. Elaidic acid was the main bioactive ingredient in AFPR that targeted ERK. Elaidic acid greatly affected the ability of SW116 cells to form colonies, produce MMP, and undergo necroptosis. Additionally, Elaidic acid promoted necroptosis predominantly by activating ERK/RIPK1/RIPK3/MLKL. Conclusion According to our findings, Elaidic acid is the main active component of AFPR, which induced necroptosis in CRC through the activation of ERK. It represents a promising alternative therapeutic option for CRC. This work provided experimental support for the therapeutic application of P. vicina Roger in the treatment of CRC.
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Frontiers in Bioengineering and Biotechnology
·
2023
·
IF 5.7
Song Baiyang,Fang Li,Mao Xufeng,Ye Xianwang,Yan Zejun,Ma Qi,Shi Zewen,Hu Yiwei,Zhu Yabin,Cheng Yue
Introduction: The repair of a diseased ureter is an urgent clinical issue that needs to be solved. A tissue-engineered scaffold for ureteral replacement is currently insufficient due to its incompetent bioactivity, especially in long-segment abnormalities. The primary reason is the failure of urothelialization on scaffolds.Methods: In this work, we investigated the ability of gelatin-grafted tubular scaffold in ureteral repairment and its related biological mechanism. We designed various porous asymmetric poly (L-lactic acid) (PLLA)/poly (L-lactide-co-e-caprolactone) (PLCL) tubes with a thermally induced phase separation (TIPS) method via a change in the ratio of solvents (named PP). To regulate the phenotype of urothelial cells and ureteral reconstruction, gelatin was grafted onto the tubular scaffold using ammonolysis and glutaraldehyde crosslinking (named PP-gel). The in vitro and in vivo experiments were performed to test the biological function and the mechanism of the scaffolds.Results and Discussion: The hydrophilicity of the scaffold significantly increased after gelatin grafting, which promoted the adhesion and proliferation of urothelial cells. Through subcutaneous implantation in rats, PP-gel scaffolds demonstrated good biocompatibility. The in vivo replacement showed that PP-gel could improve urothelium regeneration and maintain renal function after the ureter was replaced with an ∼4 cm-long PP-gel tube using New Zealand rabbits as the experimental animals. The related biologic mechanism of ureteral reconstruction was detected in detail. The gelatin-grafted scaffold upgraded the integrin α6/β4 on the urothelial cell membrane, which phosphorylates the focal adhesion kinase (FAK) and enhances urothelialization via the MAPK/Erk signaling pathway.Conclusion: All these results confirmed that the PP46-gel scaffold is a promising candidate for the constitution of an engineered ureter and to repair long-segment ureteral defects.
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BIOCHEMICAL PHARMACOLOGY
·
2020
·
IF 4.96
Nan Wang,Jue Wang,Yongjing Zhang,Yingnan Zeng,Shiling Hu,Haoyun Bai,Yajing Hou,Cheng Wang,Huaizhen He,Langchong He
Background Allergic asthma is a common inflammatory lung disease associated with complex pathogenesis. Mast cell (MC) is one of the key drivers of allergic asthma, Mas-related G protein-coupled receptor X2 (MRGPRX2) on the MC could mediate MC activation and trigger a pseudo-allergic reaction. Imperatorin (IMP), the main active compound of Radix Angelicae Dahuricae , has been reported to exert various pharmacological effects. In this study, we focused on the therapeutical mechanism of IMP on MRGPRX2-induced pseudo-allergy and allergic asthma. Methods We examined the effect of IMP on MRGPRX2 related mast cell activation in mouse peritoneal MC (MPMC), Human Laboratory of Allergic Disease 2 MCs (LAD2 cells) and Mrgprx2 -expressing HEK293 cells. Molecular docking and Surface plasmon resonance (SPR) were taken to reveal the binding character between IMP and MRPGRX2. MRGPRX2 downstream proteins were also detected by western blotting . IgE-independent responses was evaluated by using passive cutaneous anaphylaxis (PCA) and active systemic anaphylaxis (ASA) models. The therapeutic effect of IMP on asthma was evaluated by a lung inflammation mouse model which was induced by ovalbumin (OVA). Results IMP was found to reduce substance P (SP) induced calcium flux and suppressed degranulation of MC. SP can promote the phosphorylation of ERK and CamKII, which regulates the synthesis of inflammatory factors such as MIP-2 and TNF-α in MC. In vivo assays revealed that IMP can mitigate SP-induced mouse PCA and ASA. IMP could also mitigate lung inflammation in an OVA induced mice model by inhibiting MC activation in the lung tissue. Furthermore, IMP binds well to MRGPRX2 protein. The binding constant ( K D ) is 4.48 ± 0.49 × 10 −7 M. The data suggeste that IMP is a novel inhibitor of MRGPRX2 to treat allergic asthma.
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BIOORGANIC & MEDICINAL CHEMISTRY
·
2023
·
IF 3.5
Lu Liu,Zhendong Song,Guangjin Fan,Linlin Lou,Yuanxiang Wang,Xiaolei Zhang,Xiao-Feng Xiong
KRAS serves as a vital regulator for cellular signaling and drives tumor pathogenesis after mutation. Despite extensive research efforts spanning several decades, targeting KRAS is still challenging due to the multiple KRAS mutations and the emergence of drug resistance. Interfering the interactions between KRAS and SOS1 is one of the promising approaches for modulating KRAS functions. Herein, we discovered small-molecule SOS1 agonists with novel indazole scaffold. Through structure-based optimization, compound 11 was identified with high SOS1 activation potency (p-ERK EC 50 = 1.53 μM). In HeLa cells, compound 11 enhances cellular RAS-GTP levels and exhibits biphasic modulation of ERK1/2 phosphorylation through an on-target mechanism and presents the therapeutic potential to modulate RAS signaling by activating SOS1.
研究领域:
肿瘤学
·
分子生物学
·
药物化学
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