Frontiers in Pharmacology
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2024
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IF 4.4
Jia Yanjun,Wang Yanping,Wang Zixia,Zhang Zeyu,Zhang Ju,Zhang Jingjing,Sun Ke,Hua Yongchen,Chai Guolin,Hu Fangdi
Neurological injury, as a major pathogenic mechanism in depression, holds significant importance in the research and development of antidepressant drugs. Hemerocallis citrina Baroni (H. citrina), referred to as “Forgetting Sadness Grass,” has been confirmed to possess remarkable neuroprotective effects. Studies have identified that the total phenolics in H. citrina Baroni leaves (HLTP) consist of flavonoids and phenolic acids and numerous studies have substantiated the neuroprotective effects of them. Based on this, we propose that HLTP may possess neuroprotective properties. To confirm this hypothesis, we initially employed network pharmacology techniques to predict potential targets for the neuroprotective effects of HLTP based on the Swiss Target Prediction database. GO and KEGG analyses were conducted to predict potential pathways, and a component-target-pathway network was constructed. Molecular docking experiments were then performed to analyze the binding abilities of the selected active components with the main targets. Furthermore, we validated the neuroprotective effects of HLTP and key targets selected through network pharmacology using a corticosterone-induced PC12 neuronal cell damage model. Network pharmacology research has identified that in the HLTP, Quercetin, Rutin, Apigenin, and Isoquercitrin are potential active components that may exert neuroprotective effects by modulating key targets such as AKT1, TNF, TP53, and CASP3 through crucial pathways including PI3K/AKT and apoptosis. Molecular docking revealed that 4-O-Caffeoylquinic acid, 5-O-Caffeoylshikimic acid, 4-p-Coumaroylquinic acid, and 5-O-Feruloylquinic acid exhibit low binding energies with key targets. Particularly, 4-O-Caffeoylquinic acid forms stable binding through hydrogen bonding with residues such as LYS389, GLU49, GLN47, LYS30, ASP44, and GLU40 in AKT1. PC12 cells were stimulated with 200 μmol/L Corticosterone (Cort) for 24 h, and then treated with 50, 100 and 200 μg/mL of HLTP for 24 h. The cell viability of damaged cells were significantly increased in a dose-dependent manner by 9.50%, 10.42% and 21.25%, respectively (P < 0.01). Western blot analysis confirmed that HLTP significantly (P < 0.01) increased the protein expression of PI3K and AKT by 15.24%, 30.44%, 41.03%, and 21.78%, 43.63%, 12.86%, respectively. In addition, through biochemical method, flow cytometry and WB analysis, we found that different concentrations of HLTP can all improve cell damage by reducing ROS, MDA, Ca2+, Cyt-C, Caspase-3, TNF-α and IL-1β, and increasing SOD, CAT, MMP, Bcl-2/Bax and IL-10. In particular, the HLTP at 200 μg/mL, compared with the Model group, decreased by 140.2%, 54.66%, 51.34%, 65.26%, 40.32%, 63.87%, and 55.38%, and increased by 39.65%, 35.45%, 38.38%, 28.54%, and 39.98%, respectively. Through the above experiments, we verified that HLTP may exert neuroprotective effects by mediating the PI3K/AKT signaling pathway to counteract oxidative stress damage, improve mitochondrial dysfunction, and alleviate inflammatory injury.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Jinsheng Gao,Yousong Li,Jiaohua Chen,Wen Feng,Jianchen Bu,Zixuan Lu,Jiandong Wang
Background Emodin, a natural anthraquinone derivative isolated from the roots of Rheum officinale Baill, has many pharmacological effects including anti-inflammatory, antioxidant, antiviral, antibacterial and anti-cancer. However, little is known about the effect of emodin on acute radiation proctitis (ARP). The present study was conducted to determine its effects and elucidate its mechanisms involving AKT/MAPK/NF-κB/VEGF pathways in ARP mice. Methods Total 60 C57BL/6 mice were divided randomly into control group, ARP group, AKT inhibitor MK-2206 group, and different doses of emodin groups. ARP mice were induced by 27 Gy of 6 MV X-ray pelvic local irradiation. MK-2206 was given orally for 2 weeks on alternate days. Emodin was administered daily by oral gavage for 2 weeks. Subsequently, all mice were sacrificed on day 15. The rectal tissues were obtained for further tests. The general signs score and the pathological grade were used to evaluate the severity of ARP. The expression of NF-κB, VEGF and AQP1 were determined by immunohistochemistry and western blot. The expression of p-AKT, p-ERK, p-JNK, p-p38, Bcl-2 and Bax were assessed using western blot. Results The worse general signs and damaged tissue structure of ARP mice were profoundly ameliorated by emodin. The expression of p-AKT, p-ERK, NF-κB, VEGF and AQP1 were significantly increased, resulting in the inflammation-induced angiogenesis in ARP mice. However, the expression of p-JNK and p-p38 were decreased, leading to the reduction of apoptosis in ARP mice. Excitedly, emodin reversed these changes, not only inhibited inflammation-induced angiogenesis, but also promoted apoptosis. Notably, the effects of emodin were similar to that of AKT inhibitor MK-2206, suggesting the involvement of AKT signaling in the effect of emodin. Conclusion These results suggest that emodin attenuates ARP in mice, and the underlying mechanism might involve inhibition of the AKT/ERK/NF-κB/VEGF pathways and the induction of apoptosis mediated by JNK and p38.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Junxian Hu,Yibo Zhu,Xiaoxiao Li,Zeyu Pang,Xiangwei Li,Huilin Zhang,Yiyang Wang,Pei Li,Qiang Zhou
Medical and conservative treatments for intervertebral disc degeneration (IDD) primarily focus on alleviating symptoms. However, effective curative therapies that promote disc regeneration remain lacking. Recent advancements in disc repair materials offer a potential solution, but identifying effective cytokines for regeneration and developing efficient drug delivery systems are crucial for success. This study demonstrated a negative correlation between AQP3 expression levels and the extent of disc degeneration induced by mechanical overload, as evidenced in both in vivo and in vitro models, suggesting that AQP3 is a key regulator of intervertebral disc (IVD) homeostasis. Moreover, the overexpression of AQP3 or exogenous AQP3 protein significantly repaired degenerated IVDs. As a membrane protein, exogenous AQP3 is challenging for cells to recognize and internalize. To address this issue, we designed liposomes to encapsulate AQP3 and incorporated them into GelMA (AQP3-lipo@GelMA) for targeted repair of IDD resulting from high mechanical pressure. The encapsulation of AQP3 in liposomes improved cellular recognition and uptake, thereby enhancing its functionality at the cell membrane. Additionally, AQP3 within this material inhibited the binding of integrins to sialic acid-binding proteins (IBSP), which subsequently reduced the expression of the downstream integrin αVβ3. This cascade effect indirectly activated the AKT pathway, promoting the survival of NP cells. In vivo experiments, we found that AQP3-lipo@GelMA had an efficient function of repairing degenerated intervertebral disc. This study introduced AQP3-lipo@GelMA as a promising material for clinical applications in IVD repair.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2025
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IF 4.7
Shengli Quan,Jinhua Li,Shuxian Ding,Xingjie Zhuo,Yuanxiao Yang,Qin Li
Background Parkinson's disease is a progressive neurodegenerative disorder of the brain, that commonly leads to motor dysfunction and dementia. Artemether is a semi - synthetic derivative of artemisinin, which is extracted from the traditional Chinese herb Artemisia annua. And it is widely used in the treatment of malaria. Recent studies have shown that it exhibits significant neuroprotective effects and holds potential for the treatment of neurodegenerative diseases. However, its effects and mechanisms in the context of Parkinson 's disease remain unclear. Objective To explore Artemether's neuroprotective effects and mechanisms in 6-OHDA-induced PD models. Methods Network pharmacology and molecular docking were used to predict potential pathways and targets of Artemether against Parkinson's disease. PD models were established using 6-OHDA-induced PC12 cells and C57BL/6 mice to assess Artemether's effects and mechanisms. Results Through network pharmacological analysis and molecular docking verification, it was found that Artemether against Parkinson 's disease was related to apoptosis-related signaling pathways, and Artemether had good spontaneous binding activity with key targets PI3K, Akt, GSK-3β, and Bcl-2. Furthermore, the related experimental results showed that Artemether could increase the cell viability of PC12 cells induced by 6-OHDA, reduce intracellular ROS level, increase mitochondrial membrane potential and decrease apoptosis. In addition, Artemether improved motor dysfunction and cognitive dysfunction in Parkinson 's disease mice, and increased the expression of dopamine neurons in both the Substantia Nigra and Striatum. Conclusion Artemether exerted neuroprotective effects in Parkinson 's disease models in vitro and in vivo induced by 6-OHDA through the PI3K/Akt/GSK-3β signaling pathway.
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JOURNAL OF APPLIED TOXICOLOGY
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2024
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IF 2.7
Qianqian Wang,Yaqian Yang,Pengfei Li,Ruoyun Dong,Chenhao Sun,Guanling Song,Yan Wang
Titanium dioxide nanoparticles (TiO 2 NPs) can cause apoptosis in TM4 cells; however, the underlying mechanism has not been entirely elucidated. The purpose of this study was to investigate the effects of TiO 2 NPs on ROS, Ca 2+ level, p38/AKT/mTOR pathway, and apoptosis in TM4 cells and to evaluate the role of Ca 2+ in p38/AKT/mTOR pathway and apoptosis. After exposure to different concentrations (0, 50, 100, 150, and 200 μg/mL) of TiO 2 NPs for 24 h, cell viability, ROS, Ca 2+ level, Ca 2+ -ATPase activity, p38/AKT/mTOR pathway-related proteins, apoptosis rate, and apoptosis-related proteins (Bax, Bcl-2, Caspase 3, Caspase 9, and p53) were detected. The ROS scavenger NAC was used to determine the effect of ROS on Ca 2+ level. The Ca 2+ chelator BAPTA-AM was used to evaluate the role of Ca 2+ in p38/AKT/mTOR pathway and apoptosis. TiO 2 NPs significantly inhibited cell viability, increased ROS level, and elevated Ca 2+ level while suppressing Ca 2+ -ATPase activity. TiO 2 NPs regulated the p38/AKT/mTOR pathway via increasing p-p38 level and decreasing p-AKT and p-mTOR levels. TiO 2 NPs significantly enhanced the apoptosis. NAC attenuated Ca 2+ overload and reduction in Ca 2+ -ATPase activity caused by TiO 2 NPs. BAPTA-AM alleviated TiO 2 NPs-induced abnormal expression of p38/AKT/mTOR pathway-related proteins. BAPTA-AM assuaged the apoptosis caused by TiO 2 NPs. Altogether, this study revealed that TiO 2 NPs elevated intracellular Ca 2+ level through ROS accumulation. Subsequently, the heightened intracellular Ca 2+ level was observed to exert regulation over the p38/AKT/mTOR pathway, ultimately culminating in apoptosis. These results provides a complementary understanding to the mechanism of TiO 2 NPs-induced apoptosis in TM4 cells.
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ACS Applied Bio Materials
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2025
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IF 4.7
Dong Fan,Zhongyu Wang,Xingyi Yuan,Shixue Luo,Runsi Zhan,Weiyu Hu,Huitong Chen,Weiwen Wang,Jing Liu,Zongming Wang,Xin Wang
Aims Nonfunctioning pituitary adenomas (NFPAs) are a common intracranial tumor in clinical practice, and currently available treatments for NFPA include surgical resection and radiotherapy. However, this is due to the relatively high risk of recurrence and persistent side effects of these therapies. As a local treatment, photodynamic therapy (PDT) shows promise in solid tumors through spatiotemporally controlled cytotoxicity. The aim of this study was to investigate the mechanism of action of photosensitizer Ru2 in NFPA. Materials and methods [Ru(tpy)(tpy-Br)] (PF6)2 was synthesized from Ru(tpy)Cl3, and further synthesized into Ru2. Cell viability of Light+Ru2 or Dark+Ru2 was assayed using the CCK-8 assay and live–dead cell staining. RNA-seq of Light+Ru2-treated PDFS cells yielded differentially expressed genes. The expression of PI3K/ATK/P53 was detected using qPCR, Western blot. PI3K agonist 740Y–P and AKT agonist SC79 were added for further pathway validation. The effect of PDT on PDFS cell viability by 3D multicellular tumor spheroids (MCTSs) was evaluated. Key findings We untangle that Ru2-PDT specifically activates the p53 pathway and inhibits PI3K/AKT phosphorylation in PDFS cells. Under 595 nm illumination, Ru2 activates p53 and induces cell cycle arrest in the G0/G1 phase. Simultaneously, Ru2-PDT significantly suppressed the phosphorylation of the PI3K/AKT signaling pathway. Further investigation reveals that the PI3K/AKT agonist treatment partially inhibits p53 expression, alleviates Ru2-PDT-induced apoptosis, and reverses its inhibitory effects on PDFS cell migration and invasion. Significance This study, for the first time, elucidates the molecular mechanism of Ru2-PDT targeting the PI3K/AKT/p53 signaling axis, providing a theoretical basis for the clinical treatment of nonfunctioning pituitary adenomas.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Leisheng Wang,Yifei Fu,Shiwei Xu,Enhong Chen,Shuo Zhang,Dongjie Yang,Youzhao He,Yuanlong Gu,Yong Mao,Fenglai Yuan,Hao Hu
6PPD-quinone (6PPDQ), a derivative of the antioxidant 6PPD used in the rubber industry, has been implicated in environmental and public health risks. To explore its impact on metabolic and cognitive functions, we orally administered 6PPDQ to mice and assessed its effects. Our results show that 6PPDQ induces a dose-dependent increase in body weight, elevated fasting blood glucose, insulin resistance, and other hallmarks of metabolic syndrome. Furthermore, cognitive tests revealed significant impairments in learning and memory in 6PPDQ-treated mice. Transcriptomic and Western blot analyses suggest that 6PPDQ disrupts insulin signaling through inhibition of the PI3K-AKT pathway, leading to metabolic and cognitive dysfunction. Notably, treatment with the PI3K-AKT agonist SC79 partially alleviated these effects. These findings highlight the health risks of 6PPDQ exposure and suggest potential avenues for preventive and therapeutic strategies.
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LIFE SCIENCES
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2025
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IF 5.1
Fangdi Wang,Li Hu,Xingyue Zeng,Wenbin You,Huijun Li,Bing Liu,Xiaohan Zhang
AKT is a pivotal kinase involved in diverse cellular processes, including tumorigenesis and glycogen metabolism. Ubiquitination modification of AKT has been reported as a critical cellular event that regulates its kinase activity and membrane translocation; however, the molecular mechanisms involved in AKT ubiquitination remain elusive. Here, we employed loss-of-function approaches and mutants of PDK1 with altered phosphorylation and modified nucleocytoplasmic shuttling behaviors to identify the functional roles of PDK1 on the ubiquitination of AKT. Our findings reveal that the nuclear entry of PDK1 in an importin7-dependent manner is required for insulin-induced TRAF6-mediated ubiquitination of AKT, which has been previously shown to occur in the nucleus. Moreover, the phosphorylation of PDK1 at S241 and the PI3K-mediated phosphorylation of PDK1 at S396 both regulate AKT ubiquitination by controlling nuclear entry of PDK1. These results provide new insights into the control of AKT signaling and suggest potential avenues for developing targeted AKT-modulating therapeutics.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2025
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IF 5.4
Huanqi Zhang,Ziyan Liu,Jing Cheng,Yiming Jiang,Xiaoli Zheng,Chong Zhang,Yangling Li
Glioblastoma (GBM), the most aggressive primary brain tumor, presents significant therapeutic challenges owing to limited treatment options beyond the cornerstone chemotherapy temozolomide (TMZ) and its intrinsic chemoresistance. This study elucidates additional mechanisms of the multimodal antidepressant vortioxetine in GBM, extending beyond the reported PI3K/Akt pathway modulation. RNA-sequencing analysis identified five potential vortioxetine-responsive targets in GBM cells: SCN5A , HTR1D , SLC6A9 , KIF11 , and ADRB2 . Notably, only HTR1D overexpression correlated with poor disease-free survival in GBM patients. Vortioxetine-mediated HTR1D suppression suggests its potential role as an HTR1D inhibitor in GBM progression. HTR1D-overexpressing GBM cells exhibited enhanced proliferative and migratory capacities. LinkedOmics database analysis revealed the HTR1D regulation on PI3K/Akt axis, a dominant signaling pathway showing significant positive correlation with TMZ resistance. Crucially, HTR1D knockdown enhanced TMZ sensitivity in GBM cells. Moreover, the TMZ-vortioxetine combination demonstrated marked synergistic anti-tumor effects concomitant with HTR1D suppression. In vivo , the TMZ-vortioxetine combination more effectively suppressed GBM proliferation than either agent alone. Collectively, these findings identify HTR1D as a novel vortioxetine target in GBM that modulates proliferation, metastasis, and TMZ resistance via PI3K/Akt signaling. This study provides convincing preclinical evidence for TMZ-vortioxetine combination therapy, proposing both a new therapeutic target and a viable strategy to circumvent TMZ resistance in GBM.
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ONCOGENE
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2025
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IF 7.3
Li Honghao,Wu Junfeng,Dai Hua,Li Jiaming,Bai Xiaoyan,Sun Yueli,Lin Jiaxin,Li Yangsi,Li Peng,Shi Lingchao,Wang Zhen,Tu Haiyan,Ke Ee
Indolent lung cancer is characterized by slow progression, and the patient may die of other causes before it becomes symptomatic. The increasing usage of lung cancer screening technologies has increased the detection of early-stage cancers, improved survival, and reduced mortality, but it also brings overdiagnosis or overtreatment for indolent lung cancer patients. In this study, we performed high-throughput whole-exome sequencing in lung adenocarcinoma (LUAD) patients with a tumor doubling time of more than 600 days (the indolent group) and another group with a tumor doubling time of less than 30 days (the aggressive group). We identified a novel germline variation in PDZRN4 , rs74955204 (p.G121E, c.362 G > A) in the indolent group. The rs74955204 variant resulted in upregulated PDZRN4 expression and was positively correlated with the survival of LUAD patients. We confirmed that overexpression of PDZRN4 inhibits the ubiquitylation of HIF-1A mediated by TRIM28, thus activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, restricting lung cancer cell growth in vitro and in vivo. With the EGFR L858R -driven lung cancer mouse model as an example, we found that PDZRN4 knockout promoted, whereas PDZRN4 overexpression suppressed LUAD growth in vivo. In addition, recombinant PDZRN4 or screened small molecules retinoic acid showed potent inhibitory effects on EGFR-driven LUAD growth and amelioration of osimertinib resistance. Overall, our findings suggest that targeted PDZRN4 is a potential therapeutic strategy for treating LUAD. Examination of PDZRN4 rs74955204 variant may be an effective approach for the early detection of indolent lung cancer and to avoid overdiagnosis. Graphical : Germline variation rs74955204 (p.G121E, c.362 G > A) in PDZRN4 significantly upregulated PDZRN4 expression and resulted in indolent growth of LUAD. Overexpressed PDZRN4 inhibits the ubiquitylation of HIF-1A by TRIM28, activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, thus restricting lung cancer cell growth.
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EXPERIMENTAL DERMATOLOGY
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2020
·Vol. 30
·期 7
·932-942
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IF 3.368
Aimin Liu,Buxin Zhang,Wei Zhao,Yuanhui Tu,Qingxing Wang,Jing Li
Psoriasis is a chronic inflammatory disease characterized by abnormal hyperproliferation and differentiation. The object of this study is to explore the role of microRNA-215-5p in psoriasis-like inflammation. The expression of miR-215-5p was found to be down-regulated in pro-inflammatory factor-stimulated HaCaT cells and imiquimod (IMQ)-treated skin tissues. Overexpression of miR-215-5p suppressed the proliferation and cell cycle progression of HaCaT cells. Further, miR-215-5p agomir alleviated the disease severity, pathological features and Ki67 positive cells in IMQ-treated mice. Luciferase assay confirmed that miR-215-5p could bind to the 3′UTR of DYRK1A. The in vitro and in vivo results showed that miR-215-5p negatively regulates DYRK1A, which further inhibited EGFR and its downstream signalling pathways, AKT and ERK. Collectively, our results provide evidence that overexpression of miR-215-5p inhibits the proliferation of HaCaT cells and alleviates psoriasis-like inflammation partly by DYRK1A mediated inhibition of the EGFR signalling pathway. miR-215-5p may serve as a novel small molecule for therapeutic intervention in psoriasis.
研究领域:
分子生物学
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皮肤科
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炎症性疾病
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微小RNA研究
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Qiqi Yang,Yuan Yao,Junping Wang,Mengdi Pang,Jinyan Wu,Fusheng Yin,Jun He,Yanyan Wang,Weidong Chen
Non-small cell lung cancer (NSCLC) is characterized by a complex pathogenesis and high mortality. Targeted drug therapy represents a precise method of treatment. However, Improving sensitivity to targeted agents is currently a major challenge in clinical tumor therapy. Neogambogic acid (NGA), a bioactive compound isolated from the Traditional Chinese Medicine (TCM) Gamboge, has shown potential in NSCLC treatment. Nonetheless, the mechanism by which NGA enhances the sensitivity of NSCLC to the targeted drug Almonertinib remains unclear. This study aimed to elucidate the mechanisms underlying the ability of NGA to enhance the sensitivity of NSCLC to Almonertinib, revealing the synergistic effect exerted by the combination therapy. We established a subcutaneous grafted tumor model of mouse lung cancer by injecting Lewis cells, and evaluated the therapeutic efficacy in vivo . The study demonstrated that NGA combined with Almonertinib effectively suppressed NSCLC tumor growth by promoting cancer cell apoptosis and reducing serum tumor marker levels. In vitro experiments revealed that this combination synergistically inhibited lung cancer cell proliferation and induced apoptosis. Mechanistically, NGA demonstrated the ability to bind to Pregnane X receptor (PXR), regulating the expression of drug-metabolizing enzymes and transporters. We further validated this effect using PXR agonists and inhibitors in A549 cells. Additionally, the combination of NGA with Almonertinib significantly inhibited aberrant EGFR activation and downstream PI3K/AKT signaling, leading to enhanced apoptosis. This study demonstrated that the combination of NGA and Almonertinib inhibited the expression of CYP3A4, P-gp, and BCRP via PXR modulation. Meanwhile, it inhibited the EGFR/PI3K/AKT pathway and enhanced the sensitivity of NSCLC to Almonertinib, exerting synergistic anti-tumor effects. Our findings suggest a promising strategy for integrating active TCM components with targeted therapy in NSCLC management.
研究领域:
肿瘤学
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药理学
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分子生物学
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