EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Wenkai Nie,Xuan Zhao,Yan Zhang,Cheng Zeng,Huiwen Yang,Bing Liu
Objective Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease that significantly impacts patients' quality of life. Chlorogenic acid (CGA), a polyphenol present in various dietary sources and plants, has been shown to reduce skin inflammation. However, its efficacy and mechanisms of action in AD have not been thoroughly investigated. This study aimed to evaluate the therapeutic effect of CGA on AD in mice and explored its mechanism. Methods To establish a BALB/c mouse model of AD induced by 2,4-dinitrochlorobenzene (DNCB) to evaluate the therapeutic potential of CGA. The anti-inflammatory effects of CGA were assessed by measuring IL-1β and IL-6 levels in TNF-α-stimulated HaCaT cells. The phosphorylation levels of PI3K, Akt, Akt1, NF-κB, and IκB-α were analyzed using Western blotting. Molecular docking was conducted to evaluate the binding affinity of CGA to Akt1. Results Topical application of CGA significantly reduced dermatitis scores, spleen index, epidermal thickness, mast cell infiltration, and skin fibrosis. CGA reversed DNCB-induced increases in IgE, histamine, TNF-α, IL-1β, IL-6, and IL-8 levels. Western blot analysis showed that CGA inhibited the PI3K/Akt and NF-κB signaling pathways. In vitro , CGA exerts its anti-inflammatory effects by inhibiting the Akt1/NF-κB pathway, and the Akt activator (SC79) can counteract this effect. Molecular docking and dynamics simulations suggest that CGA may inhibit Akt1 activity by interacting with specific residues (ALA-50, GLY-37, TYR-326, ASP-323). Conclusions CGA improves AD by inhibiting the Akt1/NF-κB pathway, suggesting its potential as a natural treatment for AD.
研究领域:
皮肤病学
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Yang Wang,Zhimin Chen,Fang You,Jing Sun,Hongyi Yang
Premature ovarian insufficiency (POI) is a female reproductive disorder characterized by impaired ovarian function. Protein tyrosine kinase 2 beta (PTK2B), a non-receptor tyrosine kinase, has been implicated in folliculogenesis, but its role in POI remains unknown. In this study, a rat POI model was established by intraperitoneal injection of cyclophosphamide (Cy) for 14 days. Electroacupuncture (EA) has been elicited to effectively improve ovarian function in POI. Here, mRNA sequencing (mRNA-seq) analysis found that PTK2B expression in ovarian tissues was upregulated by Cy treatment but downregulated by EA. To investigate PTK2B's role, primary rat ovarian granulosa cells (GCs) were co-treated with Cy (250 μM) and a PTK2B inhibitor PF-431396 (10 μM) for 48 h. PF-431396 inhibited Cy-induced inflammatory response and apoptosis in GCs. Further, PTK2B binds to AKT1 in GCs. PF-431396 facilitated AKT1 phosphorylation, and the inhibitory effects of PF-431396 on GC inflammatory response and apoptosis were reversed by an AKT1 inhibitor LY294002. In vivo , rats were given PF-431396 (10 mg/kg/d) by gavage for 7 days following Cy induction for 14 days. Treatment with PF-431396 increased ovarian weight, serum E2, and AMH levels, while decreased FSH and LH levels. Additionally, it could improve Cy-induced ovarian tissue injury, inhibit inflammation and apoptosis, and elevate p-AKT1 level in ovarian tissues. Together, our results unveil that PF-431396, a PTK2B inhibitor, ameliorates ovarian dysfunction in POI through promoting AKT1 phosphorylation, suggesting that PTK2B may be a therapeutic target for POI.
研究领域:
生殖生物学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Anatomical Record-Advances in Integrative Anatomy and Evolutionary Biology
·
2018
·Vol. 301
·期 6
·1115-1125
·
IF 1.373
Hui Wang,Xiaoguang Dong,Zengxun Liu,Shaowei Zhu,Haili Liu,Wenchuang Fan,Yanlai Hu,Tao Hu,Yonghui Yu,Yizhao Li,Tianwei Liu,Chengjia Xie,Qing Gao,Guibao Li,Jing Zhang,Zhaoxi Ding,Jinhao Sun
Rotenone is a common pesticide and has been reported as one of the risk factors for Parkinson disease. Rotenone can cause neuronal death or apoptosis through inducing oxidative injury and inhibiting mitochondrial function. As a natural polyphenolic compound, resveratrol possesses the antioxidant capacity and neuroprotective effect. However, the mechanism underlying the neuroprotective effect of resveratrol against rotenone-induced neurotoxicity remains elusive. Here, we treated PC12 cells with rotenone to induce neurotoxicity, and the neurotoxic cells were subjected to resveratrol treatment. The CCK8 and LDH activity assays demonstrated that resveratrol could suppress neurotoxicity induced by rotenone ( P < 0.01). The DCFH-DA assay indicated that resveratrol reduced the production of reactive oxygen species (ROS). JC-1 and Hoechst 33342/PI staining revealed that resveratrol attenuated mitochondrial dysfunction and cell apoptosis. Moreover, resveratrol reversed rotenone-induced decrease in SIRT1 expression and Akt1 phosphorylation ( P < 0.05). Furthermore, when the SIRT1 and Akt1 activity was inhibited by niacinamide and LY294002, respectively, the neuroprotective effect of resveratrol was remarkably attenuated, which implied that SIRT1 and Akt1 could mediate this process and may be potential molecular targets for intervening rotenone-induced neurotoxicity. In summary, our study demonstrated that resveratrol reduced rotenone-induced oxidative damage, which was partly mediated through activation of the SIRT1/Akt1 signaling pathway. Our study launched a promising avenue for the potential application of resveratrol as a neuroprotective therapeutic agent in Parkinson disease. Anat Rec, 301:1115–1125, 2018. © 2018 Wiley Periodicals, Inc.
研究领域:
神经科学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Li Hu,Haiping Liu,Haixiang Ma,Xingyue Zeng,Yongkai Cao,Bing Liu,Huijun Li,Xiaohan Zhang
AKT, also known as protein kinase B (PKB), serves as a crucial regulator of numerous biological functions, including cell growth, metabolism, and tumorigenesis. Increasing evidence suggests that the kinase activity of AKT is regulated via ubiquitination by various E3 ligase enzymes in response to different stimuli. However, the molecular mechanisms underlying insulin-induced AKT ubiquitination are not yet fully understood. Here, we show that activation of the insulin receptor (IR) leads to enhanced ubiquitination of AKT1 at K8 and K14 residues, facilitated by the cytosolic E3 ubiquitin ligase enzyme, TRAF6. Further investigation using AKT1 mutants with modified nucleocytoplasmic shuttling properties reveals that TRAF6-mediated AKT1 ubiquitination occurs within the nucleus in a β-Arr2-dependent manner. The nuclear entry of TRAF6 depends on importin β1, while β-Arr2 regulates this process by facilitating the interaction between TRAF6 and importin β1. Additionally, the ubiquitination of AKT1 is essential for its translocation to the activated IR on the plasma membrane, where it plays a functional role in recruiting Glut4 and facilitating glucose uptake. This study uncovers the cellular components and processes involved in insulin-induced ubiquitination and activation of AKT1, providing insights and detailed strategies for manipulating AKT1.
研究领域:
细胞生物学
·
分子生物学
·
内分泌学
·
信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2021
·
IF 5.34
Xiaohan Wei,Baoping Zhang,Xiao Liang,Changshun Liu,Ting Xia,Yingjie Xie,Xue Deng,Xiaomei Tan
ABSTRACT Background Allergic rhinitis (AR) is an inflammatory, immunoglobulin E (IgE)-mediated disease characterized by the typical symptoms of sneezing, rhinorrhea , nasal itching , and congestion. Higenamine (HG) is a plant-based alkaloid, possesses a wide range of activities, including vascular and tracheal relaxation, antioxidative, antiapoptotic , anti-inflammatory, and immunomodulatory activities. So far, the effect and the underlying mechanism of HG on AR have not been studied. Hypothesis/Purpose The purpose of this study was to evaluate the effects of HG on AR and investigate its underlying mechanism. Methods The effects of HG on AR were evaluated in an ovalbumin-induced AR mouse model. Network pharmacology-based methods such as target prediction, protein-protein interaction (PPI) network analysis, pathway analysis, and molecular docking were used to identify the likely HG targets. Finally, we validated the mechanism of action of HG through its effects on these targets in human nasal epithelial cells (HNEpCs). Results Oral administration of 30, 60, and 120 mg/kg HG significantly alleviated rubbing and sneezing in AR mice and attenuated histopathological changes in the lung and nasal tissues . Additionally, HG reduced the levels of IgE, histamine, and IL-4 in the serum of AR mice, and regulated imbalance in Th1/Th2 cells. Using network pharmacology-based methods, we identified 29 HG targets related to AR. These targets are mainly involved in the PD-L1, relaxin, estrogen, HIF-1, Th1 and Th2 cell differentiation , T cell receptor , and the Th17 cell differentiation signaling pathways . Molecular docking showed that HG may well be suited to the receptor binding pockets of key target AKT1 , EGFR, c-Jun, NOS2 , and JAK2 . In HNEpCs, HG inhibited the histamine-induced mRNA expression and secretion of interleukin (IL)-6, and IL-8, as well as the expression of MUC5AC and the phosphorylation of NF-κB. Moreover, HG affected the changes of AKT1, EGFR, c-Jun, iNOS, and JAK2 induced by histamine. Conclusion Overall, our results suggest that HG may alleviate AR by activating AKT1 and suppressing the EGFR/JAK2/c-JUN signaling. HG, therefore, has great potential as a therapeutic agent for the treatment of AR.
研究领域:
免疫学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Yiren Yang,Pengyu Liu,Yue Jin,Huilin Zhu,Miao Wang,Xiaowen Jiang,Huiyuan Gao
Background Conventional chemotherapy medications are inadequate for managing the primary or acquired drug resistance, high toxicity, and adverse effects of colorectal cancer (CRC) treatment. Ursolic acid (UA) and Solasodine (Sol) are natural compounds found in a wide variety of traditional medicinal plants, as well as in many fruits and vegetables, such as Actinidia arguta (Sieb. & Zucc) Planch and Solanum nigrum L.. These compounds exhibit significant anti-tumor activity. Recent investigations have demonstrated that a combination strategy using natural products exhibits greater potential in CRC treatment compared to a single-drug strategy. Purpose This study aimed to elucidate the potential of UA-Sol synergy against CRC and to investigate the mechanism of action involved in inducing apoptosis and inhibiting metastasis through the AKT1/ERK1/2-GSK-3 β - β -catenin axis. Methods The optimal ratio of UA-Sol and its synergistic effects were explored using an MTT assay combined with the technique of Chou Talalay. The effects of UA-Sol on the apoptosis, autophagy, and metastasis of CRC cells were assessed using Annexin V-FITC/PI, TUNEL, Immunofluorescence, Wound healing, Transwell migration, and western blotting. The core mechanism of action of UA-Sol against CRC was investigated employing network pharmacology prediction combined with CETSA and plasmid transfection. Finally, in vivo validation was conducted using mouse xenograft tumor and lung metastasis models. Results The combination of UA and Sol synergistically inhibited CRC cell viability at a molar ratio of 6:24. UA-Sol induced the expression of pro-apoptotic and autophagy genes such as Bax/Bcl-2 and LC3, ultimately leading to apoptosis and autophagy in CRC cells in vitro . In addition, this combination inhibited MMP-9 and promoted the expression of the adhesion protein E-cadherin, thereby inhibiting CRC cell metastasis. Mechanistically, UA-Sol regulated the expression of a downstream protein GSK-3 β by targeting AKT1 and ERK1/2 inhibition. This induced a cross-talk between the MAPK cascade pathway and the PI3K/AKT pathway, thereby inhibiting the nuclear translocation of β -catenin and participating in the regulation of CRC cell processes. Conclusion UA-Sol inhibited the AKT1/ERK1/2-GSK-3 β - β -catenin axis to induce apoptosis, autophagy and anti-metastasis by targeting AKT1 and ERK1/2 inhibition. This dual-target drug combination strategy provides promising insights into the development of novel, safe, and efficient drugs for the treatment of CRC.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Genomics
·
2023
·
IF 2.9
Yi Zhu,Xiaofeng Tian,Yan Wang,Chengxiang Wang,Naiquan Yang,Lianghong Ying,Hongyan Niu
Vascular smooth muscle cells (VSMCs) are critical elements of the vascular wall and play a crucial role in the genesis and development of atherosclerosis (AS). Increasingly, studies have indicated that long noncoding RNAs (lncRNAs) regulate VSMC proliferation, apoptosis, and other biological processes. Nevertheless, the role of lncRNA NFIA-AS1 (hereinafter referred to as NFIA-AS1) in VSMCs and AS remains unclear. Quantitative real-time PCR (qRT-PCR) was performed to analyze the messenger RNA (mRNA) levels of NFIA-AS1 and miR-125a-3p. CCK-8 and EdU staining were performed to detect VSMC proliferation. VSMC apoptosis was evaluated by flow cytometry. The expression of various proteins was detected using western blotting. The levels of inflammatory cytokines secreted by VSMCs were measured by enzyme linked immunosorbent assay (ELISA). The binding sites of NFIA-AS1 and miR-125a-3p, as well as miR-125a-3p and AKT1, were analyzed using bioinformatics methods and validated using a luciferase reporter assay. The function of NFIA-AS1/miR-125a-3p/AKT1 in VSMCs was clarified through loss- and gain-of-functional experiments. We confirmed that NFIA-AS1 was highly expressed in AS tissues and VSMCs induced by oxidized low-density lipoprotein (Ox-LDL). Knockdown of NFIA-AS1 restrained the exceptional growth of Ox-LDL-induced VSMCs, promoted their apoptosis, and decreased the secretion of inflammatory factors and expression of adhesion factors. In addition, NFIA-AS1 regulated the proliferation, apoptosis, and inflammatory response of VSMCs through the miR-125a-3p/AKT1 axis, suggesting that NFIA-AS1 may be a potential therapeutic target for AS.
研究领域:
心血管疾病
·
分子生物学
·
细胞生物学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 6
·
IF 7.7
Longchang Bai,Ruocen Liao,Yu Zhang,Yongshi Jia,Lei Shi,Hongen Xu,Liang Liang,Yu Feng,Chenfang Dong
Aberrant AKT1 activation is a hallmark of cancer, yet the molecular mechanisms regulating its activity remain incompletely understood. Here, we report that AKT1 undergoes glutarylation at evolutionarily conserved lysines K179 and K289. Mechanistically, AKT1 glutarylation is regulated by the metabolic enzymes GCDH and DHTKD1, which modulate glutaryl-CoA levels, and reversed by the deglutarylase SIRT5. Glutarylation at K179 disrupts the K179-E198 salt bridge and AKT1-ATP interactions, whereas K289 glutarylation perturbs ATP coordination and reduces PDK1-mediated phosphorylation, collectively inactivating AKT1. Functionally, AKT1 glutarylation inhibits cell proliferation and tumor growth, whereas GCDH promotes these oncogenic functions by suppressing glutarylation. Notably, pharmacological MYC inhibition, which downregulates GCDH and elevates AKT1 glutarylation, synergizes with the AKT inhibitor afuresertib to suppress gastric cancer cell growth, revealing a potential therapeutic vulnerability. These findings link lysine metabolism to AKT-driven cancer progression and suggest therapeutic strategies targeting glutarylation dynamics.
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Jinqi Hu,Jiexin Zhang,Xiaomei Ge,Suyu Li,Xudong Li,Tianrui Zhang,Xiang Li,Meng He,Guanbin Gao,Taolei Sun
SAA improves liver function and reduces fibrosis in a CCl 4 -induced mouse model. • SAA suppresses the phosphorylation of AKT1 in hepatic fibrosis. • SAA decreases inflammation and HSC activation by inhibiting the AKT1/NF-κB axis. • SAA might be a potential therapeutic agent for hepatic fibrosis. Hepatic fibrosis (HF) is a crucial and reversible stage, yet there is a paucity of effective clinical antifibrotic drugs. Salvianic acid A (SAA) has shown antifibrotic potential in preliminary studies; however, its molecular mechanisms and potential targets remain incompletely understood. To evaluate the therapeutic efficacy and mechanisms of SAA in mitigating HF, we employed a carbon tetrachloride (CCl 4 )-induced HF mouse model. In parallel, we used transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 cells and primary mouse hepatic stellate cells (HSCs) for in vitro studies. In CCl 4 -induced mice, SAA markedly improved liver function and suppressed HF, as evidenced by significant reduction in α-smooth muscle actin and collagen I expression and alleviation of inflammatory response. Similar antifibrotic and anti-inflammatory effects were observed in vitro . To investigate the targets and mechanism of SAA in HF, we employed network pharmacology, molecular docking, molecular dynamics simulations, and microscale thermophoresis. We found that SAA was predicted to interact with the allosteric pocket of RAC-alpha serine/threonine-protein kinase 1 (AKT1), accompanied by inhibition of AKT1 phosphorylation and the downstream nuclear factor-kappa B (NF-κB) signaling. To further explore the involvement of AKT1 in SAA's antifibrotic effects, we used the AKT activator SC79. In CCl 4 -induced mice, SC79 partly reversed the antifibrotic effects of SAA. Consistently, we observed that SC79 partially restored the inflammatory and fibrotic markers in TGF-β1-simulated HSCs, counteracting the inhibitory efficacy of SAA. Our findings suggest that SAA exerts antifibrotic effects in part through suppression of the AKT1/NF-κB axis and may represent a promising therapeutic candidate for HF. Download: Download high-res image (435KB) Download: Download full-size image
✓ 已验证
DOI
高影响因子
Biomed Research International
·
2022
·
IF 3.246
Shisheng Jiang,Chaoming Huang,Shulin Wang,Biyun Huang,Dan Wu,Guodong Zheng,Yi Cai
Objective. Through a network pharmacology method, we screened the main active compounds of Citri Reticulatae Pericarpium (CRP), constructed a drug-ingredient-disease-target network, explored the molecular mechanism of its treatment of myocardial hypertrophy, and validated it by using molecular biology approach. Methods. Traditional Chinese Medicine Systems Pharmacology (TCMSP) and GeneCards were utilised to collect the effective component in CRP and the targets of CRP and myocardial hypertrophy. The STRING database constructed the protein interaction network. The drug-ingredient-disease-target network was outlined by the Cytoscape 3.9.0 software. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the Metascape database. Real-time PCR (RT-PCR) and Western blotting were utilised to determine the mRNA and protein level of the critical targets of CRP therapy for myocardial hypertrophy. Results. We found that five practical components of CRP exerted therapeutic effects on myocardial hypertrophy by modulating 41 targets. Further analysis revealed that naringenin was the essential active compound in CRP that regulated myocardial hypertrophy. In addition, we showed that the active compounds of CRP might exert antihypertrophy effects via regulating essential target proteins such as AKT1-, MAPK3-, PPARA-, PPARG-, and ESR1-mediated signaling pathways such as cell proliferation, nuclear receptor activation, and oxidative stress. The molecular biology experiments demonstrated that naringenin inhibited the mRNA level of NPPA and NPPB induced by Ang II and regulated related targets such as AKT1, MAPK3, PPARA, PPARG, and ESR1. Conclusion. CRP could inhibit myocardial hypertrophy through multitarget and multiapproach.
研究领域:
药理学
·
分子生物学
·
中医药学
·
心脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR BIOLOGY REPORTS
·
2026
·Vol. 53
·期 1
·1271
·
IF 3.2
Luan Haiyan,Li Jingyuan,Gao Lili,Li Mengyu,Liu Ying,Liu Xingyuan
Background Cardiac remodeling induced by continuous pressure overload exacerbates heart failure (HF), yet effective treatments remain limited. This study investigates the therapeutic efficacy and underlying mechanisms of paeoniflorin (Pae) in the treatment of HF. Methods A transverse aortic constriction (TAC)-induced HF model in male Sprague-Dawley (SD) rats was used to evaluate four groups: Sham, TAC, TAC + Pae (10 mg/kg/day, i.p.), and TAC + fosinopril (5 mg/kg/day, p.o.). Cardiac function, morphology, and biomarker expression were assessed via echocardiography, hemodynamics, histology, ELISA, Western blot, and qPCR. Therapeutic targets were identified using network pharmacology, molecular docking, pull-down, and cellular thermal shift assays. Additionally, in vitro rescue assays were performed using Ang II-treated H9c2 cells and the AKT1 agonist SC79. Results Pae improved cardiac function, characterized by enhanced myocardial contractility and decreased serum NT-proBNP levels. Pae treatment decreased cardiomyocyte cross-sectional area (CSA), collagen deposition, and the expression of ANP , BNP , and β-MHC . Mechanistic studies identified AKT1 as a key binding partner of Pae. Pae binding to AKT1 inhibited its phosphorylation, thereby suppressing the downstream NF-κB inflammatory pathway and reducing the expression of pro-inflammatory cytokines ( IL-1β , IL-6 , and TNF-α ). Pae reversed Ang II-induced hypertrophy, fibrosis, and NF-κB nuclear translocation in H9c2 cells. Furthermore, the protective effects of Pae against hypertrophy, fibrosis, and inflammation were abolished by SC79. Pae demonstrated an excellent safety profile. Conclusion Pae alleviates HF by targeting the AKT1/NF-κB signaling axis to mitigate pathological remodeling and inflammation, presenting a safe and promising therapeutic candidate for heart failure management.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MICROCHEMICAL JOURNAL
·
2025
·
IF 5.1
Xinyue Lin,Luxi Zhou,Lingfang Chen,Qiyue Chen,Zhuming Jin,Peixi Zhu,Ni Yang
Houttuynia cordata Thunb. is a perennial herb with a distinct “fishy” flavour, commonly used in Asian cuisine and traditional medicine. To overcome the compound identification challenges in the composite formula of its mixture, a comprehensive two-dimensional ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (2D UHPLC-QTOF-MS) method was developed and identified 293 chemical compounds. Given the herb’s strong anti-inflammatory properties, network pharmacology was employed to predict potential targets, revealing TNF, AKT1, MMP9, and PTGS2 as key theoretical targets for its anti-inflammatory effects. Molecular docking showed strong binding energies between these targets and the top 10 compounds (8,13-dihydroxy-9,11-octadecadienoic acid, neobaicalein, chrysin, apigenin, genistein, chrysoeriol, norwogonin, cirsiliol, luteolin and deoxyandrographolide), with genistein exhibiting the highest affinity for AKT1 (−10.4 kcal/mol). This innovative approach, combining advanced 2D UHPLC-QTOF-MS with network pharmacology, offers great potential for screening active components in herbs and their complex mixtures.
研究领域:
中药学
·
分析化学
·
药理学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）