PHYTOMEDICINE
·
2024
·
IF 6.7
Lin Chen,Xin Kong,Ruina Zhou,Jinhang Hu,Rui Zhou,Zhongxing Song,Zhishu Tang,Mei Wang
ABSTRACT Background Total flavonoids from Astragali Complanati Semen (TFACS), the main active ingredients in Astragali Complanati Semen (ACS), have been shown to have a protective effect on chronic liver injury (CLI), but the hepatoprotective targets and signalling pathways involved are unclear. Purpose The aim of our study was to identify the anti-CLI targets and signalling pathways of TFACS and to comprehensively elucidate its mechanism of action via proteomics analysis combined with in vivo and in vitro experiments. Methods A CLI mouse model was generated via intraperitoneal injection of carbon tetrachloride (CCl 4 ) (CCl 4 : olive oil = 1:4, 2 mL/kg, twice a week for 6 weeks). The hepatoprotective effect of TFACS was assessed by observing the pathological structure of the liver and analysing indicators of liver function. The key pathways and targets related to the hepatoprotective effect of TFACS were identified via 4D-label-free quantitative proteomics technology and further verified via in vivo indicator validation and in vitro cell experiments. Results TFACS administration significantly normalized the histopathological structure and function of the liver, decreased the levels of inflammatory factors and oxidative stress indicators, and reduced the iron staining area and the levels of hepcidin and iron in the liver compared with those in the CLI model. A total of 424 differentially expressed proteins (DEPs) were identified between the TFACS and model groups, and these DEPs were enriched in the focal adhesion, PI3K-Akt, and ferroptosis pathways. Akt1, Pik3ca, NF-κB p65, Itga5, Itgb5, Itga6, Prkca, Fn1, Tfrc, and Vdac3 were identified as key targets of TFACS. TFACS administration significantly reversed the changes in the gene and protein expression of the key targets compared with those in the model group. In addition, TFACS treatment significantly reduced the levels of inflammatory cytokines and inhibited Akt1, NF-κB p65 and FAK activation in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. In an erastin-induced L-O2 ferroptosis cell model, treatment with TFACS normalized the mitochondrial structure, reduced the protein levels of Tfrc and Vdac3, inhibited lipid peroxidation, and reduced the amount of Fe 2+ in the mitochondria. Conclusion TFACS protected against CLI, and its mechanism of action may be related to inhibition of the focal adhesion, PI3K/Akt and ferroptosis signalling pathways.
研究领域:
药理学
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蛋白质组学
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肝病学
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Frontiers in Pharmacology
·
2024
·
IF 4.4
Li Yan,Ge Jingping,Yin Yuanyuan,He Juan,Shang Longcheng
Background: This study aimed to explore the regulatory effect of anserine on HUVEC cell injury and thrombosis in deep venous thrombosis (DVT) rats, and to elucidate the underlying molecular mechanisms.Methods: Non-targeted metabolomics data analyses were conducted using an ultra-performance liquid chromatography system Vanquish UHPLC and mass spectrometer to detect plasma metabolism profiles. The transcriptome sequencing and gene intervention experiments were performed to verify the regulatory effect. Further in vivo and in vitro experiments were performed. Enzyme-linked immunosorbent assay was used to detect the levels of P-selectin, E-selectin, and vWF, hematoxylin-eosin (HE) staining was performed to observe thrombotic and inflammatory cell infiltration, flow cytometry and TUNEL assays were performed to detect apoptosis, and qPCR and WB assays were conducted to determine the gene and protein expression.Results: Anserine alleviated HUVECs injury, reduced adhesion molecule expression, and inflammation. It decreased P-selectin, E-selectin, vWF, THBD, TFPI levels, and apoptosis while promoting NOS3, ET-1, and NO release in HUVECs. In DVT rats, anserine reduced P-selectin, E-selectin, vWF, thrombosis, cell infiltration, apoptosis, and promoted NO release. Transcriptome sequencing and gene intervention confirmed anserine’s regulation of the PI3K-Akt pathway and coagulation via MYB. CARNMT1, a regulatory enzyme for anserine metabolism, increased anserine content, inhibiting coagulation, thrombosis, cell infiltration, and promoting NO release in rats.Conclusion: This study confirmed anserine could alleviate DVT by improving the inflammatory response, inhibiting blood agglutination, and promoting vasodilation, providing new potential therapeutic targets, important scientific evidence for the development of DVT management, and new clues for an in-depth understanding of its molecular mechanisms.
研究领域:
药理学
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分子生物学
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心血管疾病
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血栓
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PubMed
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BIOMEDICAL CHROMATOGRAPHY
·
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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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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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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Chemical Biology & Drug Design
·
2022
·Vol. 99
·期 6
·828-838
·
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
·
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
·
2017
·Vol. 15
·期 1
·1362-1372
·
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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MOLECULAR AND CELLULAR ENDOCRINOLOGY
·
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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ARCHIVES OF MICROBIOLOGY
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2024
·Vol. 206
·期 6
·1-11
·
IF 2.3
Zhuang Cuicui,Zhang Ruoqing,Bai Jiangang,Zhang Xinying,Zhao Jinhui
Escherichia coli ( E. coli ) can induce severe clinical bovine mastitis, which is to blame for large losses experienced by dairy farms. Macrophage polarization into various states is in response to pathogen infections. Lycopene, a naturally occurring hydrocarbon carotenoid, relieved inflammation by controlling M1/M2 status of macrophages. Thus, we wanted to explore the effect of lycopene on polarization states of macrophages in E. coli -induced mastitis. Macrophages were cultivated with lycopene for 24, before E. coli inoculation for 6 h. Lycopene (0.5 μmol/L) significantly enhanced cell viabilities and significantly reduced lactic dehydrogenase (LDH) levels in macrophages, whereas 2 and 3 μmol/L lycopene significantly enhanced LDH activities. Lycopene treatment significantly reduced the increase in LDH release, iNOS, CD86, TNF-α, IL-1β and phosphatase and tensin homolog (PTEN) expressions in E. coli group. 0.5 μmol/L lycopene significantly increased E. coli -induced downregulation of CD206, arginase I (ARG1), indoleamine 2,3-dioxygenase (IDO), chitinase 3-like 3 (YM1), PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR), p-mTOR, jumonji domain-containing protein-3 (JMJD3) and interferon regulatory factor 4 (IRF4) levels. Moreover, Ginkgolic acid C17:1 (a specific PTEN inhibitor), 740YPDGFR (a specific PI3K activator), SC79 (a specific AKT activator) or CHPG sodium salt (a specific NF-κB activator) significantly decreased CD206, AGR1, IDO and YM1 expressions in lycopene and E. coli -treated macrophages. Therefore, lycopene increased M2 macrophages via inhibiting NOTCH1-PI3K-mTOR-NF-κB-JMJD3-IRF4 pathway in response to E. coli infection in macrophages. These results contribute to revealing the pathogenesis of E. coli -caused bovine mastitis, providing the new angle of the prevention and management of mastitis.
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