CARBOHYDRATE POLYMERS
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2024
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IF 10.7
Shuiling Qin,Zhiwei Wen,Huajie Huang,Wei Wu
Our research aimed to enhance the oral bioavailability of doxorubicin hydrochloride (DOX·HCl) while minimizing the potential for myocardial toxicity. To achieve this goal, we developed a new method that utilizes a coating material to encapsulate the drug in liposomes, which can specifically target intestinal taurine transporter proteins. This coating material, TAU-CS, was created by combining taurine with chitosan. We characterized TAU-CS using various methods, including 1 H NMR, FT-IR, and scanning electron microscopy (SEM). The resulting liposomes exhibited a regular spherical morphology, with a particle size of 195.7 nm, an encapsulation efficiency of 91.23 %, and a zeta potential of +11.65 mV. Under simulated gastrointestinal conditions, TAU-CS/LIP@DOX·HCl exhibited good stability and slow release. Pharmacokinetic studies revealed that, compared with DOX·HCl, TAU-CS/LIP@DOX·HCl had a relative bioavailability of 342 %. Intracellular uptake, immunofluorescence imaging, and permeation assays confirmed that the taurine transporter protein mediates the intestinal uptake of these liposomes. Our study suggested that liposomes coated with TAU-CS could serve as an effective oral delivery system and that targeting the taurine transporter protein shows promise in enhancing drug absorption.
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ACS Applied Bio Materials
·
2025
·
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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CHEMISTRY-A EUROPEAN JOURNAL
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2025
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IF 3.7
Gankun Yuan,Ruyue Yang,Wenjing Wen,Zhaoyi Wei,Meiru Song,Lingyang Zhang,Kun Hou,Gaofeng Liang
Graphical Da-CD@CET@CQ NPs can accurately target tumor cells, and the ER-targeting photosensitizer CET can be used as an ICD inducer for amplifying the ICD effect. Meanwhile, the ER PDT was further strengthened by autophagy inhibition, which can achieve more effective autophagy-regulated photodynamic synergistic immunotherapy for triple-negative breast cancer. Activating immunogenic cell death (ICD) represents a promising therapeutic strategy for tumor immunotherapy. However, photodynamic therapy (PDT)-mediated ICD effect is severely limited due to the extremely short half-life and limited diffusion radius of reactive oxygen species (ROS), hindering effective endoplasmic reticulum (ER) stress induction. In addition, targeted therapy of triple-negative breast cancer (TNBC) remains hugely challenging due to the lack of expression of multiple receptors. Herein, we constructed a hierarchical targeting and controllable intelligent nanodelivery material Da-CD@CET@CQ based on poly- β -cyclodextrin with remarkable solubility and stability, loaded with a novel photosensitized ICD inducer, CET, and autophagy inhibitor chloroquine (CQ). Excitingly, Da-CD@CET@CQ NPs can accurately recognize TNBC tumor cells under the mediation of SRC protein. Moreover, CET could achieve observable enrichment in the ER and amplify the ICD effect by in situ ER PDT, which is further strengthened by the autophagy inhibition caused by CQ. All results show that Da-CD@CET@CQ NPs exhibited excellent targeting ability to tumor cells and ER and effectively enhanced synergistic immunotherapy of in situ ER PDT combined with autophagy inhibition, which significantly inhibited tumor growth and metastasis. Overall, our study provides a novel strategy and meaningful guideline for targeted-PDT-synergistic immunotherapy of TNBC.
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Microbiology Spectrum
·
2025
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IF 3.8
Xianduo Sun,Gaosheng Hu,Yuting Li,Wenjing Li,Yong Wang,Hui Yan,Guoqing Long,Long Zhao,Anhua Wang,Jingming Jia
Gut microbiota have been found to promote hypoxia-induced intestinal injury. However, the role of gut microbiota in high-altitude pulmonary edema (HAPE), the preventive effect of synbiotic on HAPE, and the mechanisms by which they might work remain unknown. In this study, we aimed to investigate the role of gut microbiota in the pathogenesis of HAPE and to explore the underlying mechanisms involved. We performed a fecal microbiome analysis and found a significant decrease in intestinal Klebsiella and Escherichia-Shigella, along with a notable increase in intestinal Bifidobacterium and Lactobacillus, as volunteers recovered from acute mountain sickness (AMS). Gavage colonization with Klebsiella pneumoniae and Escherichia coli induced plasma inflammation, increased plasma lysophosphatidylcholine (LPC) levels, and contributed to HAPE in rats at a simulated altitude of 6,500 m. Conversely, a synbiotic containing Bifidobacterium, Lactiplantibacillus, fructooligosaccharides, and isomaltose-oligosaccharides significantly reduced the severity of HAPE. Cellular experiments and molecular dynamics simulations revealed that LPCs can cause damage and permeability to human pulmonary microvascular endothelial cell (HPMEC) and human pulmonary alveolar epithelial cell (HPAEpiC) monolayers under hypoxic conditions by disrupting cell membrane integrity. In addition, tail vein injection of LPCs promoted HAPE in mice at a simulated altitude of 6,500 m. In conclusion, this study describes a gut microbiota-LPCs/inflammation-HAPE axis, an important new insight into HAPE that will help open avenues for prevention and treatment approaches.
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CELLULAR SIGNALLING
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2025
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IF 3.7
Yi-Jun Qi,Ye-Lin Jiao,Pan Chen,Qiao-Qing Zhu,Ran Guo,Dang-Rou Wu,Yu-Bo Du,Wan-Ying Li,Yue-Yue Cheng,Xiao-Shuang Wu,Meng-Xiang Li,Wei Li,Shegan Gao
Porphyromonas gingivalis ( P. gingivalis ), a keystone pathogen in adult periodontitis, is linked to an increased risk of many cancers. Although autophagy stimulated by P. gingivalis in ESCC has been reported, the molecular mechanisms and functional roles of autophagy in P. gingivalis -related ESCC progression are still unclear. P. gingivalis infection promoted the malignant progression of ESCC through autophagy, as demonstrated in both in vitro and in vivo studies. Once P. gingivalis invaded cancer cells, it induced the dephosphorylation and nuclear accumulation of YAP/TAZ, which are the effectors of Hippo pathway. In a TEAD-dependent manner, YAP/TAZ activated the miR-21-5p/RASA1/ERK signaling pathway to enhance autophagy-mediated tumor-promoting roles in the proliferation, migration, and invasion of ESCC. Additionally, P. gingivalis infection was correlated with higher levels of miR-21-5p, YAP/TAZ, and LC3, all of which were associated with shorter overall survival of patients with ESCC. Taken together, our findings reveal that the YAP/TAZ-miR-21-5p-ERK axis plays a crucial role in the P. gingivalis -infected subtype of ESCC, suggesting P. gingivalis and the autophagy pathway as promising therapeutic targets for ESCC treatment.
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FASEB JOURNAL
·
2025
·Vol. 39
·期 10
·e70670
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IF 4.2
Shushu Jiang,Shichen Bu,Xiang Kang,Yin Dong,Long Chen,Lin Yuan,Menghao Shi,Meng Du,Minglu Liang,Kai Huang,Liu Yang
Pathological cardiac hypertrophy leads to heart failure. In this study, we aimed to explore the role of transmembrane protein Tspan9 in the development of cardiac hypertrophy and failure. We found that Tspan9 was upregulated in the hearts of patients with hypertrophic cardiomyopathy (HCM), in the hearts of mice subjected to transverse aortic constriction (TAC), as well as in phenylephrine-induced hypertrophic neonatal rat cardiomyocytes (NRCMs). AAV9-mediated overexpression (OE) of Tspan9 in mouse hearts augmented TAC-induced cardiac hypertrophy and failure, while Tspan9 knockdown (KD) alleviated this effect. Tspan9-OE promotes PE-induced cardiomyocyte enlargement, whereas Tspan9-KD suppresses it. Mechanistically, we demonstrated that Tspan9 interacts with p62, a pivotal regulator of autophagy, impairs its cargo function, leading to autophagy suppression. Remarkably, the anti-hypertrophic effect of Tspan9-KD was impaired when autophagy was inactivated or p62 was knocked down. These findings suggest that Tspan9 exacerbates pressure overload-induced pathological cardiac hypertrophy and failure by suppressing cardiac autophagy through its interaction with p62. Graphical Upon pathological stimuli, Tspan9 is upregulated in the cardiomyocytes and interacts with p62. It impairs the binding of p62 to the ubiquitin chains of misfolded proteins and LC3 on phagophores. This leads to the inhibition of autophagy flux and accumulation of misfolded proteins, which ultimately results in cardiac hypertrophy and failure.
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Cell Death & Disease
·
2021
·Vol. 12
·期 1
·1-18
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IF 8.469
Fang Shaohong,Wan Xin,Zou Xiaoyi,Sun Song,Hao Xinran,Liang Chenchen,Zhang Zhenming,Zhang Fangni,Sun Bo,Li Hulun,Yu Bo
Inducing autophagy and inhibiting apoptosis may provide a therapeutic treatment for atherosclerosis (AS). For the treatment of progressive AS, arsenic trioxide (ATO) has been used to coat vascular stents. However, the effect of ATO on autophagy of macrophages is still unknown. Therefore, the aims of this study were to characterize the effects and the mechanism of actions of ATO on autophagy in macrophages. Our results showed that ATO-induced activation of autophagy was an earlier event than ATO-induced inhibition of the expression of apoptosis markers in macrophages and foam cells. Nuclear transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy and promoting lysosomal biogenesis. Here, we report that ATO triggered the nuclear translocation of TFEB, which in turn promoted autophagy and autophagosome-lysosome fusion. Both the latter events were prevented by TFEB knockdown. Moreover, ATO decreased the p-AKT and p-mTOR in the PI3K/AKT/mTOR signaling pathway, thus inducing autophagy. Correspondingly, treatment with the autophagy inhibitor 3-methyladenine (3-MA) abolished the autophagy-inducing effects of ATO. Meanwhile, PI3K inhibitor (LY294002) and mTOR inhibitor (rapamycin) cooperated with ATO to induce autophagy. Furthermore, reactive oxygen species (ROS) were generated in macrophages after treatment with ATO. The ROS scavenger N-acetyl-1-cysteine (NAC) abolished ATO-induced nuclear translocation of TFEB, as well as changes in key molecules of the AKT/mTOR signaling pathway and downstream autophagy. More importantly, ATO promoted autophagy in the aorta of ApoE −/− mice and reduced atherosclerotic lesions in early AS, which were reversed by 3-MA treatment. In summary, our data indicated that ATO promoted ROS induction, which resulted in nuclear translocation of TFEB and inhibition of the PI3K/AKT/mTOR pathway. These actions ultimately promoted macrophage autophagy and reduced atherosclerotic lesions at early stages. These findings may provide a new perspective for the clinical treatment of early-stage atherosclerosis and should be further studied.
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Translational Oncology
·
2025
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IF 4.1
Chunyang Zhu,Shuming Chen,Yangyang Lu,Jialin Song,Shasha Wang,Jing Guo,Xiaoxi Han,YuanYuan Fang,Siyi Zhang,Wensheng Qiu,Weiwei Qi
Background : Gastric cancer (GC) is a prevalent malignant tumor worldwide, with limited treatment targets. Timosaponin AIII (Tim AIII) is the naturally steroid saponin isolated from Anemarrhena, while this study initially confirms the anti-GC effect of Tim AIII. Methods : MTT assay, cell cycle analysis, and wound healing assay were used to evaluate the inhibitory effects of Tim AIII on GC cells (AGS and HGC27). Evaluate the oxidative stress (OS) by measuring reactive oxygen species (ROS) and malondialdehyde (MDA), as well as the Kelch-like ECH-associated protein 1 (Keap1) - Nuclear factor erythroid-derived 2-like 2 (Nrf2) pathway. RNA sequencing and proteomics analysis were utilized to investigate deeper molecular mechanisms. To track the autophagic flux using transmission electron microscope, detecting changes in autophagy-related pathway proteins, staining with LC3B and lysosome. Experiments related to cell viability, OS, and autophagy levels were performed on normal gastric mucosal epithelial cells (GES-1) as parallel controls. Finally, Nude mouse subcutaneous tumor model to evaluate the anti-GC ability in vivo. Results : Tim AIII inhibits the viability, proliferation, and migration of GC cells. Tim AIII causes OS in GC cells by the increasing intracellular ROS and MDA levels and inhibiting the Keap1-Nrf2 pathway. RNA sequencing and proteomics analysis mainly focused on the autophagy-associated pathways and lysosome in GC cells. Tim AIII activates autophagy, as indicated by an increase in the number of autophagosomes, inhibition of the PI3K-AKT pathway, and activation of the AMPK pathway in GC cells. However, Tim AIII inhibits autophagy-lysosome fusion and impairs lysosomal function, which results in autophagic flux blockage in GC cells. The Tim AIII concentration that significantly inhibited GC cells in this study was applied to GES-1 cells. The results showed that at this concentration, Tim AIII exhibited no significant cytotoxic effects on GES-1 cells, did not induce OS, and had no impact on autophagy. Finally, Tim AIII also has the ability to inhibit tumor growth in vivo. Significance : In summary, the results of our study indicate Tim AIII as a novel late-stage autophagy inhibitor, which may provide novel medical possibilities for GC.
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Advanced Science
·
2025
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IF 14.1
Yiwen Zhou,Lili Chen,Miaomiao Han,Peixiang Zhu,Yanyi Wang,Xuanxuan Yu,Tingyu Reng,Huijuan Wang,Baochao Li,Caixia Zhang,Ziwei Huang,Shuang Lin,Guoyun Wang,Jie Ge,Baosheng Guo,Huang Li
Maxillary underdevelopment is a critical component of skeletal Class III malocclusion, closely linked to altered biomechanical signaling. Mechanical stimulation through early facemask protraction can effectively promote maxillary growth, yet the underlying mechanotransduction mechanisms remain unclear. In this study, fibroblast growth factor 9 (FGF9) is identified as a key biomechanical responder in maxillary development. Secreted predominantly by osteocytes, FGF9 interacts with fibroblast growth factor receptor 2 (FGFR2) on preosteoblasts to inhibit osteogenic differentiation. Mechanical stress reduces FGF9 secretion from osteocytes, thereby relieving its inhibitory effect and enhancing osteogenesis. Mechanistically, FGF9 promotes nuclear translocation of FGFR2 in preosteoblasts, which modulates transcription factors ATF5 and NR2F1 to suppress bone formation. In vivo, targeted overexpression of FGF9 in bone tissue led to significant maxillary growth impairment, underlying the pathological impact of disrupted mechanical signaling. These findings reveal a novel osteocyte–preosteoblast axis regulated by FGF9–FGFR2 signaling in response to mechanical stimulation and provide mechanistic insight into how biomechanical forces shape craniofacial development. This pathway offers new mechanistic insights and potential therapeutic targets for correcting craniofacial skeletal abnormalities.
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BIOMATERIALS
·
2025
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IF 12.9
Jingchuan He,Tingting Li,Xiaoqin Pan,Zhihua Deng,Jifu Huang,Xiaocheng Mo,Xiaoju Shen,Xiumei Qin,Xingye Yang,Ming Gao,Jie Yang
Combination therapy is a promising strategy for lung adenocarcinoma (LUAD), due to the advantages of overcoming drug resistance, side effects, and tumor heterogeneity. Herein, we report a novel dual-targeting bimetallic nanozyme (MH-iRGD) consisting of nanosized manganese ferrite (MF) after encapsulating with dopamine and methacrylic anhydride to modify hyaluronic acid, followed by integrin receptor targeting peptide (HS-PEG3400-iRGD) modification for LUAD targeted therapy. Our study confirmed that MH-iRGD combined with near-infrared irradiation (NIR) possessed dramatic photothermal effects and reactive oxygen species (ROS) production and GSH depletion abilities. Importantly, MH-iRGD possessed dual-targeting capacities for LUAD cells overexpressed CD44 and αV-integrin receptors owing to hyaluronic acid coating and iRGD modification. Inhibitors of CD44 and integrins could impair the uptake of MH-iRGD in LUAD cells. Moreover, MH-iRGD+NIR displayed excellent anti-LUAD effects as a result of the production of intracellular ROS, consumption of glutathione (GSH) and mitochondrial dysfunction. Mechanistically, NIR robustly strengthened MH-iRGD-induced ferroptosis and apoptosis by down-regulating SLC7A11, GPX4, Bcl-2 levels while up-regulating Bax level. Specifically, ferroptosis and apoptosis were increased while the LUAD progression was inhibited after intravenous injection of MH-iRGD+NIR in xenograft mouse models. Taken together, our results indicate that MH-iRGD+NIR serves as a promising targeted therapy for LUAD, which broadens the applications of highly active dual-targeting bimetallic nanozymes.
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BRITISH JOURNAL OF CANCER
·
2025
·
IF 6.8
Pu Yamin,Xu Fuyan,He Anqi,Li Ru,Wang Xiangxiu,Zhou Liang,Sun Hongbao,Zhang Yiwen,Xia Yong
Background Triple-negative breast cancer (TNBC) presents significant challenges due to its aggressive nature and high propensity for brain metastasis, often exhibiting resistance to standard treatments. In this study, we conducted a preliminary screening of potential therapeutic agents and identified chlorpromazine (CPZ) as a promising candidate for treating TNBC and its brain metastases. Methods The inhibitory activities of CPZ and its combination with several standard treatment drugs were evaluated in preclinical TNBC models. The mechanism of CPZ on TNBC was elucidated using TMT-labeled quantitative proteomics analysis. Results In vivo experiments demonstrated that CPZ robustly suppressed tumor growth and metastasis, particularly in lung and brain models. Importantly, CPZ enhanced the efficacy of standard therapeutic agents such as vinorelbine (NVB) and anti-PD-1 antibody. Mechanistically, CPZ induced G2/M phase arrest and triggered mitochondria-mediated intrinsic apoptosis in TNBC cells. Furthermore, CPZ triggered incomplete autophagy and activated PINK1-Parkin-mediated mitophagy. Inhibiting autophagy/mitophagy augmented CPZ’s anticancer effects, indicating these processes may have cell protective roles. Conclusions Our study highlights the dual function of CPZ in suppressing TNBC growth and metastasis, positioning it as a promising candidate for treating this aggressive cancer. Additionally, targeting autophagy/mitophagy may serve as an effective strategy to enhance anticancer therapies against TNBC.
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CARBOHYDRATE POLYMERS
·
2025
·
IF 12.5
Jinyan Gu,Mouming Zhao,Lijun You,Lianzhu Lin
Rhamnogalacturonan-I type pectin polysaccharide from wolfberry has immunity activity, but its intestinal immunity activity and structure-activity relationship in the small intestine was still unclear. This study comparatively investigated the intestinal immune activity of wolfberry-derived high and low branched Rhamnogalacturonan-I type pectin polysaccharides (H-LBP and L-LBP) and explored the interaction mechanism with mechanical barrier. In the normal mechanical barrier model, both H-LBP and L-LBP could cross mechanical barrier with transport rates of 23.2 % and 25 %, thereby directly enhancing macrophage viability and phagocytic ability after crossing the mechanical barrier. The transport mechanism of H-LBP in mechanical barrier included the clathrin- and caveolin-mediated pathways. In the damaged mechanical barrier model, H-LBP could significantly enhance mechanical barrier integrity, reduce the production of neurotransmitter (NO) and inflammatory cytokine (TNF-α), thereby exerting indirectly intestinal immune activity. Transcriptome analysis showed that the interaction mechanism between H-LBP and damaged mechanical barrier mainly involved signaling pathway regulating cell growth and survival (PI3K-AKT). Western blot experiment and molecular docking simulation confirmed that H-LBP could reduce the expression of p-PI3K, p-AKT and cleaved Caspase3. H-LBP had stronger directly and indirectly intestinal immune activity than L-LBP. These findings were useful for the application of H-LBP in improving intestinal immunity oral formulations.
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