BIOMEDICAL CHROMATOGRAPHY
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2026
·Vol. 40
·期 9
·e70570
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IF 1.7
Yi Han,Renbin Li,Baobao Yao,Xuefeng Hou,Shixia Xu,Lizhen Yu,Jun Han,Huidan Huang,Di Cao
Inflammation is a defensive immune response to tissue damage or infection. Polygonatum cyrtonema Hua ( P . cyrtonema Hua, PCH) is bioactive on immune homeostasis due to its rich components and reportedly plays a therapeutic role in the treatment and prevention of diabetes. Flavonoids of PCH possess anti‐inflammatory properties, but their molecular mechanisms remain elusive. Here, chemical profiling of key flavonoids was conducted using UPLC‐QTOF‐MS/MS and the Global Natural Products Social Molecular Networking (GNPS) platform. Network pharmacology predicted potential targets and pathways, validated by molecular docking, surface plasmon resonance (SPR), and western blotting. Totally, 67 compounds were identified, with methylophiopogonanone B (MOB) as the key bioactive flavonoid. Although MOB's anti‐inflammatory activity has been previously noted, the present study provides the first evidence that this effect may be mediated through targeting SRC and modulating the PI3K/AKT signaling axis. Core therapeutic targets were identified as SRC, TNF, and AKT1 by topological analysis of network pharmacology. Molecular docking and SPR confirmed strong MOB‐SRC binding affinity. Western blotting revealed MOB dose‐dependently inhibited LPS‐induced phosphorylation of SRC, PI3K, and AKT1, without altering total protein levels. Furthermore, MOB significantly suppressed the phosphorylation of NF‐κB pathway proteins IκB and p65, confirming the involvement of NF‐κB as a downstream effector. In conclusion, this study integrates chemical profiling and network pharmacology with experimental validation to define the flavonoid composition of PCH, and is the first to implicate the SRC‐PI3K‐Akt pathway in MOB's anti‐inflammatory action and providing novel evidence supporting the mechanism and use of PCH in contemporary diabetes treatment.
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Translational Cancer Research
·
2026
·Vol. 15
·期 5
·378
·
IF 2.1
Zhongshun He,Aiping Huang,Jing Lv,Jing Zhou,Wenrong Lou,Biao Xu,Xuesong Wu
Background Malignant melanoma is among the most aggressive and life-threatening forms of skin cancer, and effective therapeutic treatment options remain limited. Thus, there is an urgent need to develop efficient and broadly applicable anti-melanoma drugs. Growing evidence suggests that baicalin (BAI) possesses anti-cancer potential; however, its anti-tumor mechanisms in melanoma cells remain to be fully elucidated. Therefore, this study aimed to investigate whether BAI exerts anti-melanoma effects. Methods A375 melanoma cells were treated with varying concentrations of BAI to assess its effects on cell proliferation, migration, invasion, and apoptosis. Network pharmacology analysis was then employed to predict potential molecular targets of BAI in melanoma treatment. Molecular docking was used to evaluate the binding interactions between BAI and the predicted targets. Finally, in vitro experiments were performed to investigate the regulatory effects of the potential targets on A375 cell functions. Results BAI significantly inhibited A375 cell proliferation, invasion, and migration, as well as inducing apoptosis of A375 cells in a dose-dependent manner (all P<0.05). Subsequent network pharmacology analysis identified three potential therapeutic targets of BAI, among which epidermal growth factor receptor (EGFR) exhibited strong binding affinity with BAI. Further in vitro experiments demonstrated that BAI suppressed EGFR-mediated PI3K/AKT pathway activation in a dose-dependent manner. Consistent with previous findings, EGFR overexpression exerted oncogenic effects in melanoma cells by inhibiting apoptosis. Mechanistically, BAI induced apoptosis in melanoma cells by targeting the EGFR-mediated PI3K/AKT signaling pathway. Conclusions This study demonstrates that BAI exerted cytotoxic effects on melanoma cells by targeting EGFR and inhibiting the PI3K/AKT pathway, thereby inducing apoptosis. These findings suggest that BAI may serve as a promising therapeutic candidate for the treatment of malignant melanoma.
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FREE RADICAL BIOLOGY AND MEDICINE
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2026
·
IF 8
Jiwang Liang,Boying Liu,Ming Sun,Xiao Yang,Yuejiao Zhao
Bisphenol A (BPA), a pervasive endocrine-disrupting chemical, has been increasingly implicated in thyroid carcinogenesis, yet the links between redox imbalance and metabolic alterations remain incompletely defined. Here, we combined LC-MS/MS quantification of BPA and its major conjugates with in vitro and in vivo thyroid cancer models to examine oxidative stress markers and lipid indices assessed by targeted biochemical assays and to evaluate a curcumin-modified, quercetin-loaded chitosan nanomicelle system (Que@CSNPs-Cur). We observed BPA enrichment in tumor-bearing mice, accompanied by increased lipid indices (free fatty acids, triglycerides, and total cholesterol) and elevated oxidative stress markers (ROS, TOS, and MDA), as assessed by targeted enzymatic and colorimetric assays. At the molecular level, BPA exposure was associated with reduced PTEN expression and increased PI3K/AKT phosphorylation, consistent with enhanced proliferative and invasive phenotypes in papillary thyroid carcinoma cells. Que@CSNPs-Cur restored PTEN levels, reduced PI3K/AKT activation, attenuated redox and lipid indices, and promoted caspase-3-dependent apoptosis. In xenograft mice, Que@CSNPs-Cur suppressed tumor growth, decreased oxidative stress markers and lipid indices, and reduced tumor BPA residue. Collectively, these results suggest that BPA exposure is linked to PTEN/PI3K/AKT dysregulation, oxidative stress and lipid disturbances. Que@CSNPs-Cur is a promising redox-oriented nanotherapeutic strategy for BPA-associated thyroid cancer phenotypes. Notably, the present study does not determine whether oxidative stress is upstream or downstream of PTEN suppression.
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Nanomedicine
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2026
·
IF 4.6
Jing Zhang,Dongdong Gao
Background Hepatocellular carcinoma (HCC) remains a highly aggressive malignancy with poor therapeutic outcomes due to drug resistance, systemic toxicity, and limited tumor-targeted drug delivery. This study aimed to develop dual-drug-loaded exosome nanocarrier encapsulating rapamycin (RAP) and Astragaloside IV (AST-IV) (RAP@AST-IV/EXO NC) to inhibit PI3K/Akt/mTOR signaling and enhance mitochondrial apoptosis in HCC.Methods Bone marrow mesenchymal stem cell-derived exosomes (BM-MSC-Exos) were isolated and used for co-delivery of RAP and AST-IV via sonication-assisted loading. Physicochemical properties, drug loading, and release behavior were evaluated. In vitro efficacy was assessed through cell viability, apoptosis, ROS generation, mitochondrial membrane potential, migration, and Western blot assays. In vivo therapeutic efficacy and safety were evaluated in male BALB/c mice bearing HepG2 xenografts.Results RAP@AST-IV/EXO NC showed favorable physicochemical characteristics, sustained drug release, enhanced apoptosis, increased ROS generation, mitochondrial membrane disruption, and inhibition of cancer cell migration. The RAP@AST-IV/EXO NC significantly reduced cell viability and suppressed phosphorylated PI3K, Akt, and mTOR expression while activating mitochondrial apoptotic markers. In vivo, RAP@AST-IV/EXO NC markedly inhibited tumor growth without evident systemic toxicity.Conclusion RAP@AST-IV/EXO NC represent a promising biocompatible strategy for targeted HCC therapy through combined PI3K/Akt/mTOR inhibition and mitochondrial apoptosis induction.
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Chemical Biology & Drug Design
·
2022
·Vol. 99
·期 6
·828-838
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IF 2.873
Yan Zhao,Danyao Li,Yun Han,Haohao Wang,Rui Du,Zhaowei Yan
Infantile hemangioma (IH) is a common benign endothelial cell tumor in infants and young children, sometimes accompanied by potential complications, and may develop into malignant tumors. Hemangioma endothelial cells (HemECs) are one of the main components of IH. Podophyllotoxin (PPT) has been reported to have many pharmacological activities, especially anti-tumor, but its high toxicity, poor water solubility, and serious gastrointestinal side effects limit its clinical application. In this study, we have designed and synthesized 20 ester derivatives by introducing Boc-amino acids or organic acids at the C-4 position of podophyllotoxin through esterification reactions. The cytotoxicity of these compounds was evaluated on HemECs. Changes in cell proliferation and apoptotic signaling pathways were studied by DAPI staining, colony formation assay, migration assay, measurement of reactive oxygen species (ROS) levels flow cytometry, and Western blot analysis. We found that eight of the compounds were more potent than PPT. Of these, compound V-31 was the most active (IC 50 = 0.079 ± 0.0049 µM). Further research indicated that compound V-31 inhibited its proliferation and migration, increased the level of ROS in cells, and induced apoptosis by downregulating p-PI3K, p-Akt, and Bcl-2, and upregulating cleaved caspase-3 and Bax. Our research provides the first insight into the application of PPT derivatives in HemECs, may provide an effective medicine for IH treatment.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2018
·
IF 4.816
Long Ma,Yuanyuan Meng,Chunhao Tu,Xiuqi Cao,Haiyue Wang,Yuyin Li,Shuli Man,Jin Zhou,Miao Li,Zhenxing Liu,Yanfang Su
Experiments have been undertaken and for the first time, we have identified that a new cardiac glycoside (CG) isolated from Helleborus thibetanus Franch. a plant endemic to China, bears potent anti-cancer activity. We have named it as HTF-1. By using in vitro cell models, we have found that HTF-1 induces apoptosis against several types of cancer cells in a concentration- and time-dependent manner. It is able to inhibit cancer cell in proliferation, migration and invasion. HTF-1 causes S cell cycle arrest . Further-on, we have identified that HTF-1 triggers caspase-9 dependent apoptosis pathway and double strand DNA breaks (DSBs). Additionally, HTF-1 activates JNK , but suppresses ERK and PI3K-Akt-mTOR pathways. Collectively, the above-mentioned mechanisms contribute to the anti-cancer activity of HTF-1. It is rare to discover novel anti-cancer CG during the past couple of decades. We believe that our work will enrich the understanding of CGs; also, pave the way for natural product-based anti-cancer drug development.
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JOURNAL OF NATURAL PRODUCTS
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2022
·
IF 4.803
Qi Zeng,Xu Nie,Li Li,Hui-Fang Liu,Yang-Yao Peng,Wang-Ting Zhou,Xiao-Jia Hu,Xin-Yi Xu,Xue-Li Chen
Salidroside (Sal), the major active constituent of Rhodiola rosea L., is considered as a potential pro-drug with various activities; however, its role in tumor therapy is not clear. Here, we demonstrated in vitro and in vivo that Sal enhanced the inhibitory activity of doxorubicin (DOX) in drug-resistant cancer cell lines. Our results showed that combination drug treatment (Sal and DOX) significantly decreased cell proliferation, migration, and motility. Besides biological validation, a luciferase-labeled animal tumor xenograft model and bioluminescence imaging (BLI) were applied for assessing the tumor progression. Sal combined with DOX inhibited the growth of HeLa-ADR-luc cells in vivo and downregulated the DOX-induced high expression of MDR1. Also, Sal downregulated the Bcl-2, MMP-2, MMP-9, PI3K, and AKT and upregulated BAX proteins. Sal demonstrated high safety and cardiac protection activity. We discovered that Sal enhances DOX sensitivity through the regulation of PI3K/Akt/HIF-1α and DOX-induced resistance pathways. Our results suggest that Sal could be a novel chemosensitization agent for the treatment of multi-drug-resistance tumors.
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Oncology Letters
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2017
·Vol. 15
·期 1
·1362-1372
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IF 1.39
Chun‑Yu Li,Qi Wang,Shen Shen,Xiao‑Lu Wei,Guo‑Xia Li
Epithelial‑mesenchymal transition (EMT) has been reported to play pivotal roles in tumor invasion and metastasis. Inhibition of EMT may exert beneficial effects in regulating metastasis. Oridonin (ORI), an active diterpenoid compound isolated from Rabdosia rubescens, was found to be a potent anti‑metastatic agent. However, the possible involvement of ORI in the EMT in malignant melanoma is unclear. The present study found that ORI inhibited cell migration, invasion, and adhesion in A375 and B16‑F10 melanoma cells. The transforming growth factor‑β1 (TGF‑β1)‑induced EMT was also inhibited in ORI‑treated cells, as reflected in the upregulation of E‑cadherin, and downregulation of vimentin and Snail. Similar results were observed in A375 and B16‑F10 melanoma cells treated with ORI. Furthermore, pre‑treatment with ORI blocked the TGF‑β1‑induced phosphoinositide 3‑kinase (PI3K)/AKT serine/threonine kinase (Akt)/glycogen synthase kinase (GSK)‑3β signaling pathway activation. These effects mimicked PI3 kinase inhibitor LY294002 treatment. ORI interfered with the PI3K/Akt/GSK‑3β pathway, and reversed TGF‑β1‑induced EMT, which suppressed the invasion and metastasis of melanoma cells. Taken together, the present study demonstrated that ORI inhibits melanoma cells migration, invasion, and adhesion and TGF‑β1‑induced EMT through the PI3K/Akt/GSK‑3β signaling pathway. These findings suggest that ORI is a promising anti‑metastasis agent for melanoma.
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Chemical Biology & Drug Design
·
2024
·Vol. 104
·期 4
·e70003
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IF 3.2
Xiang Yu,Di Zhang,Chengming Hu,Zejun Yu,Yang Li,Cheng Fang,Yinsheng Qiu,Zhinan Mei,Lingyun Xu
Hepatocellular carcinoma (HCC) is the sixth most prevalent malignant tumor. Hepatocellular carcinogenesis is closely linked to apoptosis, autophagy, and inflammation. Diosmetin and chrysin, are two flavonoid compounds, exhibit anti-inflammatory and anticancer properties. In this study, the TCGA database was utilized to identify differentially expressed genes between normal subjects and HCC patients. Molecular docking and molecular dynamics analyses were employed to assess the binding affinity of chrysin and diosmetin to key proteins in the PI3K/AKT/mTOR/NF-κB signaling pathway. Western blotting and RT-qPCR were used to measure the protein and gene expression within this pathway. The results indicated that HCC patients had elevated levels of PI3K, AKT, mTOR, and P65 proteins compared to normal subjects, which adversely affected patient survival. Molecular docking and dynamics studies demonstrated that diosmetin and chrysin are effectively bound to these four proteins. In vitro experiments revealed that the combination of diosmetin and chrysin could induce apoptosis, enhance autophagy, reduce inflammatory mediator production, and improve the tumor cell microenvironment by inhibiting the PI3K/AKT/mTOR/NF-κB signaling pathway. Notably, the synergy score for the combination of diosmetin (25 μM) and chrysin (10 μM) was 16. Thus, the diosmetin–chrysin combination shows promise as an effective therapeutic approach for hepatocellular carcinoma due to its strong synergistic effect.
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MOLECULAR AND CELLULAR ENDOCRINOLOGY
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2025
·
IF 3.6
Lei Wei,Zonggang Feng,Qian Dou,Genhong Mao,Hu Zhao,Xinghua Zhao,Bin Hao
Male reproductive disorders are responsible for approximately 50% of infertility cases. Bis (2-ethylhexyl) phthalate (DEHP) is a common environmental pollutant known for its reproductive toxicity. Oxidative stress is a key mechanism in response to DEHP exposure. Glutathione S-transferase A2 (GSTA2), a member of the glutathione S-transferase family, has the capacity to detoxify environmental toxins. However, its role in regulating DEHP-induced male reproductive disorders remains unexplored. Next, male mice aged 3 weeks were orally administered with DEHP (500 mg/kg/day) for 14 days to induce male reproductive disorders. We observed a decrease in the GSTA2 expression in the testicular tissues of DEHP-treated mice. To investigate the role of GSTA2 in DEHP exposure, lentiviral vectors carrying GSTA2 sequences (1 × 10 7 TU/mL, 20 μL) were given to mice on the first day of DEHP treatment. GSTA2 overexpression was found to alleviate testicular damage induced by DEHP, as well as to inhibit oxidative stress and subsequent cell apoptosis. In addition, the PI3K/AKT signaling pathway, which is associated with oxidative stress and DEHP exposure, was activated in DEHP-exposed mice following GSTA2 overexpression. Subsequently, mouse spermatocyte GC-2spd cells with DEHP treatment were used to mimic male reproductive disorders in vitro . Consistently, the GSTA2 expression was decreased in GC-2spd cells with DEHP treatment. GSTA2 overexpression inhibited oxidative stress and cell apoptosis in DEHP-treated GC-2spd cells by activating the PI3K/AKT signaling pathway. Moreover, we discovered that GSTA2 overexpression significantly altered the metabolic profiles of DEHP-treated GC-2spd cells. Collectively, our results suggest that GSTA2 overexpression alleviates DEHP-induced male reproductive disorders by suppressing oxidative stress-mediated cell apoptosis via the PI3K/AKT signaling pathway, providing a novel insight into mitigating reproductive toxicity caused by DEHP exposure.
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SOUTH AFRICAN JOURNAL OF BOTANY
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2025
·
IF 2.7
Jingxin Chen,Jian Shi,Wenting Gu,Weiye Li,Ruiyin Lyu,Xueping Wu,Junming Wang,Chunhong Liu
Depression is a worldwide affliction that seriously compromises social adaptation and physical well-being. Citrus medica L. var. sarcodactylis Swingle (also known as Bergamot) is a citrus plant in the Rutanceae family. Bergamot essential oil, a naturally derived product, has been reported to possess neuroprotective effects. The present study aimed to reveal the neuroprotective mechanisms of bergamot essential oil in PC12 cells, and compare its efficacy with that of its predominant constituent, D-limonene. To confirm the target of action, this study sought to use PI3K inhibitor LY294002 to validate the mechanism in modulating autophagy and apoptosis of bergamot essential oil. By constructing a corticosterone-induced PC12 cell model of depression in vitro , we observed that bergamot essential oil stimulated the PI3K/AKT/mTOR signaling cascade, reducing autophagy markers LC3-II and p62 approximately by 22 % and 37 % respectively, and decreasing apoptosis rates by 37 %. Bergamot essential oil intervention also upregulated 5-HT levels and played a positive role in the BDNF/TrkB pathway which associated with synaptic plasticity. D-limonene (56.6 % of bergamot essential oil) was demonstrated to be a key contributor to these mechanisms. It exhibited protective effects comparable to bergamot essential oil against autophagy and BDNF/5-HT signaling activation, however, bergamot essential oil showed better efficacy in alleviating apoptosis. This study provides in vitro mechanistic evidence supporting the potential application of bergamot essential oil in the treatment of depression.
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Pharmaceuticals
·
2025
·Vol. 18
·期 6
·791
·
IF 4.8
Xiaojie Wang,Miaomiao Chang,Kun Feng,Qingyue Wang,Bowen Li,Weijuan Gao
Background:Chronic atrophic gastritis precancerous lesions (PL-CAG) are characterized by the atrophy of gastric mucosal glands, often accompanied by intestinal metaplasia or dysplasia. Timely intervention and treatment can effectively reverse its malignant progression and prevent the onset of gastric cancer. Bombyx Batryticatus (BB) exhibits a range of pharmacological effects, including anticoagulation, antiepileptic properties, anticancer activity, and antibacterial effects. However, the pharmacological basis and mechanisms underlying BB’s efficacy in treating PL-CAG remain unclear.Methods:A three-factor modeling approach was implemented to develop a rat PL-CAG model, while the MNNG-induced PLGC (precancerous lesions of gastric cancer) cell model was served as a cell PL-CAG model. UPLC-QE-Orbitrap-MS/MS (Ultra performance liquid chromatography-quadrupole-electrostatic field orbital trap high-resolution mass spectrometry) was utilized to perform an in-depth analysis of the components in the plasma extract of BB. Leveraging network pharmacology, molecular docking analyses, and experimental validation, we initially elucidated the potential mechanisms through which BB mediates its therapeutic effects on PL-CAG at both in vivo and in vitro levels.Results:Prototype compounds of 42 blood-entering components were identified by UPLC-QE-Orbitrap-MS/MS analysis. Network pharmacology analysis and molecular docking studies indicate that the core targets are primarily enriched in the PI3K-Akt signaling pathway, and the key components, including Nepitrin, Quercetin 3-O-neohesperidoside, Rutin, and others, exhibited stable docking conformations with the first eleven pivotal targets. Both in vivo and in vitro experiments validated that BB may effectively treat PL-CAG via modulation of the PI3K-Akt signaling pathway.Conclusions:The therapeutic efficacy of BB in the management of PL-CAG may be achieved through the synergistic interaction of multiple components and targets, which may be more closely related to the inhibition of the PI3K/AKT signaling pathway. This approach will establish a solid experimental foundation and provide essential data for the clinical application of BB in treating PL-CAG, while also facilitating further research initiatives.
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