Translational Cancer Research
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2025
·Vol. 14
·期 6
·3758
·
IF 1.7
Shaojun Cai,Liyong Zhang,Tenghong Liu,Bo Wang,Shouyi Yan,Sisi Wang,Jiafan Yu,Sibin Wu,Siying Lin,Wenxin Zhao
Background Anaplastic thyroid cancer (ATC) is a rare but extremely aggressive type of thyroid cancer derived from follicular cells of the thyroid gland. Due to the rapid growth of neck masses in ATC patients, which can lead to asphyxia, multimodality therapy, including surgery, chemotherapy, and radiotherapy, is essential in the treatment of ATC. Theaflavin (TF) has anti-cancer effects; however, no study has examined whether TF inhibits the malignant progression of ATC. Therefore, this study was conducted to explore the effects of TF on ATC and to provide a preliminary exploration of its mechanism. Methods The effects of TF on the half-maximal inhibitory concentration (IC 50 ) and proliferation of 8305C cells were determined by Cell Counting Kit-8 (CCK-8) assay. The effects of TF on the invasion and migration of 8305C cells were determined by transwell assay. Cell apoptosis was evaluated by flow cytometry. Labeled 8305C cells were injected into the yolk sac of zebrafish, and the progression of the 8305C cells was observed in vivo . Fluorescence real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) were used to detect the expression of proteins related to the lipid metabolism pathway and cell apoptosis. Network pharmacology was used to study the predicted mechanisms of the TF action on 8305C cells. Results The IC 50 of TF in the treatment of 8305C cells for 48 h was 21.79 µg/mL. TF inhibited the proliferation, migration, and invasion of the 8305C cells at a concentration of 1/2 IC 50 , and induced the apoptosis of the 8305C cells. TF also inhibited the proliferation of the 8305C cells in vivo . TF significantly increased the expression of the caspase3, caspase8, and caspase9 proteins in vivo and in vitro , and significantly inhibited the expression of the survivin protein. TF also inhibited the messenger RNA (mRNA) expression of SREBP1 and PPARD , and increased the mRNA expression of HNF4 . The network pharmacology results revealed that the PI3K/AKT signaling pathway is an important pathway by which TF acts on 8305C cells, and that TF was able to inhibit the proliferation, migration, and invasion, increase the apoptosis, inhibit the mRNA expression of SREBP1 , and increase the mRNA expression of HNF4 in the 8305C cells when the PI3K/AKT signaling pathway was activated. Conclusions This study found that TF inhibits the proliferation, migration, and invasion of ATC 8305C cells, and induces 8305C cell apoptosis by regulating lipid metabolism via the PI3K/AKT signaling pathway.
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Journal of Inflammation Research
·
2025
·
IF 4.1
Jing Ma,Lu Ding,Xiaoyu Zang,Yingying Yang,Wei Zhang,Xiangyan Li,Daqing Zhao,Zepeng Zhang,Zeyu Wang,Linhua Zhao,Xiaolin Tong
Purpose Pulmonary Fibrosis (PF) is a severe interstitial lung disease currently lacking effective prevention strategies. Endothelial mesenchymal transition (EndMT), a novel mechanism for fibroblast production, is closely associated with PF. The precise mechanisms underlying the contribution of EndMT-derived fibroblasts to PF, however, remain unclear.Methods Using network pharmacology, molecular docking, and molecular dynamics, we identified the key targets and pathways through which Qimai Feiluoping decoction (QM) combats PF. EndMT and autophagy proteins were quantified in bleomycin (BLM) -induced C57BL/6 mice, human umbilical vein endothelial cells (HUVECs), and zebrafish using Western blotting (WB), quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), immunofluorescence (IF), Transwell migration assays, and transmission electron microscopy (TEM), revealing the targets and pathways through which QM mitigates PF.Results Network pharmacology, molecular docking, and molecular dynamics suggest that QM combats PF by modulating the PI3K/AKT/mTOR pathway. Observations from the study indicated that QM was found to alleviate EndMT by restoring autophagy, primarily through inhibition of the PI3K/AKT/mTOR signaling pathway in both BLM-induced C57 mice and HUVECs. Supporting evidence from zebrafish models demonstrated that QM not only counteracts EndMT but also improves a range of vascular functional disorders and remodeling issues following EndMT.Conclusion Our research validates the active compounds, core targets, and signaling pathways through which QM counters PF, providing valuable insights for its therapeutic application in PF management.
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International Journal of Genomics
·
2025
·Vol. 2025
·期 1
·9710652
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IF 1.9
Jin Cai,Shuang Shi,Yuhang Wang,Xiangdong Zhang,Xinghua Wei,Yanjing Wu,Yunlong Shi,Bin Li,Daorong Hou
Purpose This research sought to investigate the impact and underlying mechanisms of growth hormone (GH) on atherosclerosis (AS) based on the analysis of single-cell RNA sequencing (scRNA-seq) data. Methods We analyzed the impact of GH on arterial vascular smooth muscle cells (VSMCs) by utilizing scRNA-seq data obtained from both atherosclerotic and healthy vascular tissues in mice. AS was induced in C57BL/6 and ApoE −/− mice through hypophysectomy performed via the parapharyngeal approach, followed by a high-fat diet (HFD), resulting in the C57-Hx and ApoE −/− -Hx models. AS was evaluated by measuring arterial lipid deposition, plaque progression, collagen loss, vascular inflammation, and oxidative stress. Serum metabolite alterations were assessed using liquid chromatography-mass spectrometry (LC-MS). RNA sequencing was employed to examine the underlying mechanisms of GH in the context of AS treatment, with findings further confirmed through western blot analysis. In vitro experiments involved treating VSMCs with oxidized low-density lipoprotein (ox-LDL) to simulate atherosclerotic injury. The formation of foam cells was evaluated by measuring lipid accumulation, inflammatory responses, apoptosis, and the expression levels of foam cell-related markers. Finally, the PI3K/AKT inhibitor LY294002 confirmed that GH alleviates AS via the PI3K/AKT signaling pathway. Results scRNA-seq data analysis showed that growth hormone signaling was reduced in VSMCs of atherosclerotic arteries. HFD led to elevated levels of serum total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), accompanied by increased lipid deposition, inflammatory responses, and oxidative stress. In contrast, high-density lipoprotein cholesterol (HDL-C) and insulin-like growth factor 1 (IGF-1) levels were lower in C57-Hx mice. GH treatment improved HFD-induced AS in ApoE −/− -Hx mice. LC-MS analysis revealed that GH altered lipid metabolism in serum samples from C57-sham, C57-Hx, ApoE −/− -Hx, and ApoE −/− -Hx-GH(3) mice. GH maintained lipid balance by increasing 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), PE-NMe2(18:1(9z)/18:1(9z)) (DMPE), and 4-chloro-2-nitrobenzylalcohol levels and decreasing 1-heptadecanoyl-sn-glycerol-3-phosphocholine. RNA sequencing showed significant gene expression differences in the aortas of C57-sham and C57-Hx mice. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that GH inhibited the progression of AS by modulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, a finding that was validated through western blotting. Further in vitro studies demonstrated that GH exerted protective effects on VSMCs against ox-LDL-induced damage through activation of the PI3K/AKT pathway, as evidenced by experiments using the specific PI3K inhibitor LY294002. Conclusion GH alleviates the development of AS through the activation of the PI3K/AKT pathway. The findings of this research emphasize the therapeutic potential of GH in inhibiting AS and highlight the importance of the PI3K/AKT pathway as a promising target for clinical intervention.
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Pharmaceutics
·
2026
·Vol. 18
·期 1
·102
·
IF 5.5
Yujing Huangfu,Wei Chen,Dandan Guo,Peiyao Wang,Aifang Li,Yi Yang,Shuxuan Li,Qianfang Wang,Baiyan Wang,Shuying Feng
Background: As a widely used chemotherapeutic agent, cisplatin frequently induces acute kidney injury (AKI), which severely compromises patient survival and limits its clinical use. While the natural flavonoid diosmetin (Dio) shows promise in mitigating cisplatin-induced nephrotoxicity, its clinical translation is challenged by poor solubility, low bioavailability, and incompletely elucidated mechanisms. This study aimed to overcome these limitations by developing a novel drug delivery system using the microalgae Dunaliella salina ( D. salina , Ds ) to load Dio ( Ds -Dio), thereby enhancing its efficacy and exploring its therapeutic potential. Methods: We first characterized the physicochemical properties of Ds and Dio, and then Ds -Dio complex was synthesized via co-incubation. Its nephroprotective efficacy and safety were systematically evaluated in a cisplatin-induced mouse AKI model by assessing renal function (serum creatinine, blood urea nitrogen), injury biomarkers, histopathology, body weight, and organ index. The underlying mechanism was predicted by network pharmacology and subsequently validated experimentally. Results: The novel Ds -Dio delivery system has been successfully established. In the AKI model, Ds -Dio significantly improved renal function and exhibited a superior protective effect over Dio alone; this benefit is attributed to the enhanced bioavailability provided by Ds carrier. In addition, Ds -Dio also demonstrated safety performance, with no evidence of toxicity to major organs. Network pharmacology analysis predicted the involvement of PI3K/AKT pathway, which was experimentally verified. Specifically, we confirmed that Ds -Dio alleviates AKI by modulating the PI3K/AKT pathway, resulting in concurrent suppression of NF-κB-mediated inflammation and activation of NRF2-dependent antioxidant responses. Conclusions: This study successfully developed a microalgae-based drug delivery system, Ds -Dio, which significantly enhances the nephroprotective efficacy of Dio against cisplatin-induced AKI. The nephroprotective mechanism is associated with modulation of the PI3K/AKT pathway, resulting in the simultaneous attenuation of oxidative stress and inflammation.
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Pharmaceuticals
·
2026
·Vol. 19
·期 6
·965
·
IF 5.7
Mei Mei,Huawei Sun,Kai Zhang,Feng Zhang,Shiqing Sun,Enbin Yu,Yu Zhang
Background:To investigate the protective effects ofPhellodendron amurenseRupr. polysaccharides (PAP), alkaloids, and flavonoids in alleviating diabetic kidney disease (DKD) and to elucidate the role of the PI3K/AKT/GSK-3β/Nrf2 signaling pathway.Methods:Active components were extracted and quantified. In vitro, high-glucose (HG)-induced human kidney-2 (HK-2) cells were used to screen the optimal fraction via CCK-8, reactive oxygen species (ROS), TdT-mediated dUTP Nick-End Labeling (TUNEL), and Western Blot (WB) assays. In vivo, a DKD rat model was established using 2% Streptozotocin (STZ) and a high-fat with high-sugar diet. Rats were treated with PAP and LY294002. Renal damage and signaling pathway proteins were evaluated using histological staining and WB.Results:Among the tested components, PAP conferred the most pronounced cytoprotection against HG-induced injury in HK-2 cells. PAP significantly reduced glomerular damage, collagen deposition, and glycogen accumulation in the kidneys of DKD rats. Mechanistically, PAP activated the PI3K/AKT/GSK-3β/Nrf2 pathway, upregulating HO-1 and NQO1, while inhibiting the TGF-β1/Smad2 pathway and Bcl-2/Bax-mediated apoptosis. These protective effects were significantly attenuated by LY294002.Conclusions:Among the tested fractions under the present experimental conditions, PAP exhibited the most pronounced protective activity. These protective effects were partially mediated through the PI3K/AKT/GSK-3β/Nrf2 pathway, which enhanced antioxidant capacity while reducing fibrosis and apoptosis.
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MATERIALS & DESIGN
·
2026
·
IF 8.2
Jiali Deng,Xiaoqiong Huang,Yang Yang,Linjuan Li,Jiaqi Shen,Wenyi Zeng,Xiaolin Yu,Feilong Deng,Ruogu Xu,Zhengchuan Zhang
Ti‑preconditioned exosomes suppress macrophage inflammation via autophagy activation. • Lyophilized exosome–loaded biomimetic periosteum was successfully constructed. • The delivery system promotes M2 macrophage polarization to facilitate angiogenic osteogenesis. Critical-sized bone defects remain a clinical challenge due to dysregulated inflammation that impairs angiogenesis. Here, we developed a cell-free biomaterial system consisting of a decellularized biomimetic periosteum (DBP) loaded with engineered exosomes derived from nanoporous titanium–preconditioned mesenchymal stem cells (Ti–Exos). We further demonstrated that Ti-Exos significantly attenuated LPS-induced macrophage inflammation by enhancing autophagy through the inhibition of the PI3K/AKT/mTOR pathway, thereby promoting M1-to-M2 macrophage polarization and anti‑inflammatory cytokine secretion. The bilayer DBP scaffold enabled sustained release of Ti-Exos and mimicked key functions of natural periosteum. In a rat critical-sized calvarial defect model, DBP/Ti-Exos facilitated the early macrophage transition from the M1 to M2 phenotype, reduced inflammatory infiltration, stimulated angiogenesis, and ultimately enhanced the formation of mature and mineralized bone. Collectively, this study demonstrates that the engineered exosomes integrated within a biomimetic periosteum can synergistically orchestrate immunomodulation and angiogenesis, offering a promising cell–free therapeutic strategy for vascularized bone regeneration of critical-sized bone defects. This study introduces an engineered exosome–based cell–free strategy that orchestrates the local immune microenvironment to accelerate vascularized bone repair. Specifically, nanoporous Ti-preconditioned exosomes (Ti-Exos) were fabricated and proven to attenuate LPS-induced macrophage inflammation by inhibiting PI3K/AKT/mTOR to activate autophagy. Lyophilized Ti-Exos-loaded decellularized biomimetic periosteum (DBP/Ti-Exos) was constructed and exhibited uniform distribution of Ti-Exos. DBP/Ti-Exos was demonstrated to drive M1-to-M2 macrophage polarization, and promote angiogenic osteogenesis in rat calvarial defects. Download: Download high-res image (182KB) Download: Download full-size image
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KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
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2026
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IF 3.1
Shan-Shan Wang,Hong-Cheng Wei,Lin Jiang,Yi-Sen Shao
Tongue squamous cell carcinoma, the most aggressive subtype of oral squamous cell carcinoma, which is associated with high mortality, frequent recurrence, and early lymph-node metastasis. Triptolide, a bioactive diterpenoid from Tripterygium wilfordii , exhibits broad anticancer activity. Although its inhibitory action on OSCC has been established, its specific molecular regulatory mechanisms in TSCC, a distinct and aggressive subtype, remain largely underexplored. The present study investigates the regulatory role of triptolide in the PI3K–AKT signaling pathway, which is a critical axis intimately linked to tumor survival and metastasis. A network-pharmacology workflow was used to intersect triptolide putative targets with TSCC-related genes. Core hubs were identified with Cytoscape; KEGG and GO analyses highlighted the PI3K–AKT axis as the top enriched pathway. Binding kinetics were quantified by molecular docking and surface plasmon resonance (SPR). Cellular assays (CCK-8, Transwell, wound-healing, Western blot and immunofluorescence) validated the predictions. We retrieved 389 common targets and shortlisted eight key nodes (JUN, MAPK1, MAPK3, AKT1, TP53, BCL2, STAT3, MYC). SPR revealed high-affinity binding of triptolide to AKT1 and PI3K. Functionally, triptolide dose-dependently suppressed TSCC cell proliferation, invasion, and migration, downregulated PI3K–AKT signaling proteins, and reduced the colocalization and phosphorylation levels of p-PI3K and p-AKT. This study is the first to demonstrate the pivotal role of the PI3K–AKT signaling pathway in mediating the antitumor effects of triptolide in tongue squamous cell carcinoma. Our findings thereby provide a novel theoretical foundation for the development of traditional Chinese medicine-based therapeutic strategies targeting this malignancy.
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MOLECULES
·
2023
·Vol. 28
·期 8
·3395
·
IF 4.6
Yi Ou,Zonglin You,Min Yao,Yingfan Cao,Xiu Xue,Min Chen,Rihui Wu,Lishe Gan,Dongli Li,Panpan Wu,Xuetao Xu,Wingleung Wong,Vincent Kam Wai Wong,Wenfeng Liu,Jiming Ye,Jingwei Jin
Naproxen is widely used for anti-inflammatory treatment but it can lead to serious side effects. To improve the anti-inflammatory activity and safety, a novel naproxen derivative containing cinnamic acid (NDC) was synthesized and used in combination with resveratrol. The results showed that the combination of NDC and resveratrol at different ratios have a synergistic anti-inflammatory efficacy in RAW264.7 macrophage cells. It was indicated that the combination of NDC and resveratrol at a ratio of 2:1 significantly inhibited the expression of carbon monoxide (NO), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), induced nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) and reactive oxygen species (ROS) without detectable side effects on cell viability. Further studies revealed that these anti-inflammatory effects were mediated by the activation of nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) signaling pathways, respectively. Taken together, these results highlighted the synergistic NDC and resveratrol anti-inflammatory activity that could be further explored as a strategy for the treatment of inflammatory disease with an improved safety profile.Keywords:naproxen derivative;resveratrol;synergistic;anti-inflammatory;mechanism
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BIOORGANIC CHEMISTRY
·
2023
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IF 5.1
Ren-Fen Ma,Hu Liu,Xue-Chun Zhao,Peipei Shan,Ping Sun,Jun-Juan Xue,Guodong Wei,Hua Zhang
Phytochemical investigation into the leaves and branches of Daphne genkwa afforded 25 meroterpenoids ( 1 – 16 ) including nine pairs of enantiomers ( 1a / 1b − 8a / 8b and 12a / 12b ), among which 20 compounds have been reported in the present work for the first time. The structures with absolute configurations of the new molecules (excluding 10 – 13 ) were established via comprehensive spectroscopic analyses especially electronic circular dichroism (ECD) and Mosher’s methods. A preliminary in vitro cell viability assay revealed remarkable cytotoxicities of selective compounds against A549 (lung), Hela (cervical), MDA-MB231 (breast) and MCF-7 (breast) cancer cells, and compound 8a showed the best inhibitory activity with IC 50 values in the range of 3.12–4.67 μM toward the four cell lines. Subsequent in vitro antitumor evaluation of 8a disclosed that it could inhibit the proliferation and metastasis, as well as induce significant apoptosis and cycle arrest, of A549 cells. Further mechanistic investigations revealed that 8a could exert its antitumor activity via inhibiting the PI3K/Akt/mTOR signaling pathway.
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OncoTargets and Therapy
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2022
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IF 4.345
Ping Chen,Xiaoyong Zhao,Hui Wang,Mengdan Zheng,Qinghua Wang,Wenjuan Chang
Purpose LncRNAs are important regulators in cancers. In this study, we investigated the role of lncRNA PCAT18 in gastric cancer (GC).Patients and Methods The level of PCAT18 in GC tissues and cells was determined by qRT-PCR. The cellular behaviors of GC cells with knockdown or overexpression of PCAT18 were respectively detected by CCK-8 assays, colony formation assays, flow cytometry and Western blot. A GC mice model was established by subcutaneous injection of MGC-803 and HGC-27 cells with the knockdown or overexpression of PCAT18. The tumor size and weight were measured, and IHC was performed to determine ki-67 level. Predicted by bioinformatics software and confirmed by dual-luciferase reporter assay, PCAT18 was involved in miR-107/PTEN axis, thus, the expression of and relationship among PCAT18, miR-107 and PTEN pathway were explored in clinical cases and GC cell lines. Rescue assay was performed in GC cells by co-transfection with miR-107 mimic or PCAT18. The PTEN/PI3K/AKT pathway was then detected by Western blot.Results PCAT18 was down-regulated in GC tissues and cells, and it had a significant diagnostic value for GC. The expression of PCAT18 was highly associated with tumor size, and PCAT18 was found to inhibit GC growth in vitro and in vivo. It was also found that PCAT18 was involved in PTEN/PI3K/AKT signaling pathway through targeting miR-107.Conclusion PCAT18 inhibits the progression of GC via miR-107/PTEN/PI3K/AKT signaling pathway. Additionally, PCAT18 is possibly a promising target for treatment of GC.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2022
·
IF 8.025
Lulu Wang,Mingkui Shen,Qiaodan Hou,Zimei Wu,Jing Xu,Lin Wang
Diabetic individuals are frequently associated with increased fracture risk and poor bone healing capacity, and the treatment of diabetic bone defects remains a great challenge in orthopedics. In this study, an antioxidant hydrogel was developed using reduced glutathione grafted gelatine methacrylate (GelMA-g-GSH), followed by 3D printing to form a tissue engineering scaffold, which possessed appropriate mechanical property and good biocompatibility. In vitro studies displayed that benefitting from the sustained delivery of reduced glutathione, GelMA-g-GSH scaffold enabled to suppress the overproduction of reactive oxygen species (ROS) and reduce the oxidative stress of cells. Osteogenic experiments showed that GelMA-g-GSH scaffold exhibited excellent osteogenesis performance, with the elevated expression levels of osteogenesis-related genes and proteins. Further, RNA-sequencing revealed that activation of PI3K/Akt signaling pathway of MC3T3-E1 seeded on GelMA-g-GSH scaffold may be the underlying mechanism in promoting osteogenesis. In vivo, diabetic mice calvarial defects experiment demonstrated enhanced bone regeneration after the implantation of GelMA-g-GSH scaffold, as shown by micro-CT and histological analysis. In summary, 3D-printed GelMA-g-GSH scaffold can not only scavenge ROS, but also promote proliferation and differentiation of osteoblasts by activating PI3K/Akt signaling pathway, thereby accelerating bone repair under diabetes.
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Materials Today Bio
·
2022
·
IF 10.761
Lili Liu,Xianjing Li,Wenhuan Bu,Nianqiang Jin,Yuan Meng,Yi Wang,Duan Wang,Xiaowei Xu,Ding Zhou,Hongchen Sun
Pulp injury is one of the most common clinical diseases, and severe cases are usually associated with the functional loss of the tooth, while the current clinical treatment modality is only a cavity filling procedure without the regeneration of the dentin-pulp complex, thus leading to a devitalized and brittle tooth. In this study, carbon dots (CDots) with excellent biocompatibility are prepared from ascorbic acid and polyethyleneimine via a hydrothermal method. The as-prepared CDots can enhance extracellular matrix (ECM) secretion of human dental pulp stem cells (DPSCs), giving rise to increased cell adhesion on ECM and a stronger osteogenic/odontogenic differentiation capacity of DPSCs. Further, the mechanism underlying CDots-enhanced ECM secretion is revealed by the transcriptome analysis, Western blot assay and molecular dynamics simulation, identifying that the pharmacological activities of CDots are originated from a reasonable activation of the autophagy, which is mediated by regulating phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Based on the abundant CDots-induced ECM and thereby the reinforcement of the cell-ECM adhesion, an intact dental pulp stem cell sheet can be achieved, which in return promote in vivo the efficient regeneration of dentin-pulp complex as well as blood vessels.
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