Cell Death Discovery
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2025
·Vol. 11
·期 1
·1-16
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IF 7
Liang Xue,Tian Ruofei,Li Ting,Wang Hao,Qin Yifei,Qian Meirui,Fan Jing,Wang Dan,Cui Hong-Yong,Jiang Jianli
Pancreatic cancer exhibits high mortality rates with limited therapeutic options. Emerging evidence suggests that the ketogenic diet may act as adjuvant therapy by triggering ferroptosis in cancer cells, though the underlying molecular mechanisms remain unclear. This study aims to investigate the molecular mechanisms linking ketogenic metabolism and ferroptosis, with an emphasis on key regulatory proteins. We demonstrated that pancreatic adenocarcinoma (PAAD) tissues significantly enhanced ketogenic and ferroptosis phenotypes compared to normal tissues, both correlating with poorer patient prognosis. These phenotypes showed strong interdependence mediated by CAV1. In the pancreatic tumor microenvironment, CAV1 was predominantly expressed in tumor cells. Through in vitro cell experiments, we clarified that Na-OHB downregulated CAV1 expression in pancreatic cancer cells, inhibiting the transcription of the CAV1/AMPK/NRF2 downstream ferroptosis-protective genes SLC7A11 and SLC40A1. Additionally, we demonstrated the interaction between CAV1 and SLC7A11 molecules; when CAV1 was downregulated, it affected the stability of SLC7A11, leading to the ubiquitination and degradation of the translated SLC7A11 protein. Through these dual mechanisms, Na-OHB caused Fe 2+ overload, lipid peroxidation accumulation, and oxidative stress in pancreatic cancer cells, ultimately triggering ferroptosis. In ketogenic diet-fed tumor-bearing mouse models, we also observed a significant increase in lipid peroxidation and other related biomarkers, while CAV1 and SLC7A11 levels were markedly decreased compared to the normal diet group. Our findings identify CAV1 as a pivotal molecular link between ketogenic metabolism and ferroptosis in pancreatic cancer. The multi-level regulatory axis involving CAV1-mediated transcriptional regulation and post-translational modifications provides mechanistic insights into ketogenic diet-induced ferroptosis, suggesting potential therapeutic targets for pancreatic cancer adjuvant treatment.
研究领域:
肿瘤学
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分子生物学
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营养学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2023
·
IF 13.6
Bingwei Yang,Zhishuai Ye,Xiangyu Zhu,Rongchong Huang,Erqun Song,Yang Song
Further investigations are required to prove that polychlorinated biphenyls (PCBs) exposure is a cardiovascular disease risk factor. Unlike previous studies that attributed the atherogenic effect of PCBs to aryl hydrocarbon receptor activation, we illustrated a new mechanism involved in the redox reactivity of PCBs. We discover the redox reactivity of quinone moiety is the primary factor for PCB29-pQ-induced proinflammatory response, which highly depends on the status of caveolin 1 (CAV1) phosphorylation. PCB29-pQ-mediated CAV1 phosphorylation disrupts endothelial nitric oxide synthase, toll-like receptor 4, and reduces interleukin-1 receptor-associated kinase 1 binding with CAV1. Phosphorylated proteomics analysis indicated that PCB29-pQ treatment significantly enriched phosphorylated peptides in protein binding functions, inflammation, and apoptosis signaling. Meanwhile, apolipoprotein E knockout (ApoE -/- ) mice exposed to PCB29-pQ had increased atherosclerotic plaques compared to the vehicle group, while this effect was significantly reduced in ApoE -/- /CAV1 -/- double knockout mice . Thus, we hypothesis CAV1 is a platform for proinflammatory cascades induced by PCB29-pQ on atherosclerotic processes. Together, these findings confirm that the redox activity of PCB metabolite plays a role in the etiology of atherosclerosis.
研究领域:
心血管疾病
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毒理学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Cell Reports Methods
·
2024
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IF 4.3
Jinli Geng,Yaxiong Yang,Boying Li,Zhen Yu,Shuang Qiu,Wen Zhang,Shixin Gao,Nan Liu,Yi Liu,Bo Wang,Yubo Fan,Chengfen Xing,Xiaodong Liu
Genetically encoded inhibitors of Ca V 1 channels that operate via C-terminus-mediated inhibition (CMI) have been actively pursued. Here, we advance the design of CMI peptides by proposing a membrane-anchoring tag that is sufficient to link the inhibitory modules to the target channel as well as chemical and optogenetic modes of system control. We designed and implemented the constitutive and inducible CMI modules with appropriate dynamic ranges for the short and long variants of Ca V 1.3, both naturally occurring in neurons. Upon optical (near-infrared-responsive nanoparticles) and/or chemical (rapamycin) induction of FRB/FKBP binding, the designed peptides translocated onto the membrane via FRB-Ras, where the physical linkage requirement for CMI could be satisfied. The peptides robustly produced acute, potent, and specific inhibitions on both recombinant and neuronal Ca V 1 activities, including Ca 2+ influx-neuritogenesis coupling. Validated through opto-chemogenetic induction, this prototype demonstrates Ca 2+ channel modulation via membrane-assisted molecular linkage, promising broad applicability to diverse membrane proteins.
研究领域:
神经科学
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分子生物学
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生物工程
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DOI
PubMed
高影响因子
Journal of Functional Foods
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2026
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IF 3.9
Wei Wei,Shuai Wang,Qiming Wu,Xinyong Zheng,Fuguo Liu
Walnut is a nutrient-rich food resource, yet the utilization of its high-quality plant proteins remains inefficient. Advanced processing strategies are therefore needed to develop walnut-based functional foods. In this study, walnut peptides were prepared by sequential hydrolysis with alcalase and papain, leading to the identification of a novel antioxidant peptide, IRALPEEVL. In vitro , IRALPEEVL increased the viability of PC12 cells under H 2 O 2 -induced oxidative stress. In vivo , it ameliorated cognitive and memory dysfunctions in zebrafish exposed to the environmental toxicant bisphenol AF. Proteomic analysis indicated that the neuroprotective effects of IRALPEEVL were associated with caveolin-1 (Cav1)-dependent penetration of the blood-brain barrier, regulating the AMPK-PI3K/Akt signaling, and inhibiting neuronal apoptosis. These findings highlight the potential of value-added walnut processing and support the application of walnut-derived peptides as functional food ingredients for health promotion.
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高影响因子
RAPID COMMUNICATIONS IN MASS SPECTROMETRY
·
2026
·Vol. 40
·期 16
·e70106
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IF 1.8
Xing Hong,Yuxin Wen,Benjiang Xiao,Qi Jiang,Meng Chen,Pengyu Chen,Rui Qian,Qiong Wang,Jingjing Li,Fang Huang,Zhuang Huang,Lintao Han
Objective This study aimed to investigate the therapeutic mechanisms of CY in treating UC using an integrated metabolomics and proteomics approach. Methods A murine UC model was induced using dextran sulfate sodium (DSS). The therapeutic efficacy of CY was evaluated via histological examination (H&E staining) of colon tissues to assess inflammation, epithelial necrosis, and crypt abscesses. Serum and colon tissues were collected for ELISA, immunofluorescence, Western blotting, metabolomics, and proteomics analyses. Additionally, an in vitro intestinal epithelial barrier model was established using LPS-induced Caco-2 cells. Cell viability, barrier function (TEER and FITC-Dextran permeability), cell damage (LDH), and inflammatory cytokine levels (IL-6 and IL-1β) were measured. The expression and distribution of tight junction proteins (ZO-1 and occludin) and signaling proteins (FAK, p-FAK, paxillin, and p-paxillin) were analyzed via immunofluorescence and Western blotting. Results CY treatment significantly reduced the Disease Activity Index (DAI) and suppressed the levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in UC mice. Proteomic analysis identified Caveolin-1 (CAV1) and the focal adhesion pathway as key therapeutic targets and signaling pathways. Metabolomic profiling revealed 17 endogenous metabolites, highlighting tryptophan metabolism and butyrate metabolism as critical pathways. Furthermore, CY intervention modulated arachidonic acid and linoleic acid metabolism. Mechanistically, CY upregulated the expression of CAV1 and FAK while downregulating AKT and paxillin phosphorylation. In vitro experiments demonstrated that CY-containing serum restored the barrier function of LPS-induced Caco-2 cells by regulating FAK/paxillin phosphorylation, upregulating tight junction proteins, and mitigating inflammatory responses. Conclusion CY involvement in colonic mucosal healing attenuates inflammation and enhances intestinal barrier function in DSS-induced colitis, likely through the modulation of the CAV1/FA axis. These findings provide a theoretical basis for the clinical application of CY and offer novel insights for the development of therapeutic agents for UC.
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DOI
PubMed
高影响因子
Journal of Tissue Engineering
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2023
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IF 8.2
Weifeng Li,Pinghui Zhou,Bomin Yan,Meiyao Qi,Yedan Chen,Lijun Shang,Jianzhong Guan,Li Zhang,Yingji Mao
Modulating a favorable inflammatory microenvironment that facilitates the recovery of degenerated discs is a key strategy in the treatment of intervertebral disc (IVD) degeneration (IDD). More interestingly, well-mechanized tissue-engineered scaffolds have been proven in recent years to be capable of sensing mechanical transduction to enhance the proliferation and activation of nucleus pulposus cells (NPC) and have demonstrated an increased potential in the treatment and recovery of degenerative discs. Additionally, existing surgical procedures may not be suitable for IDD treatment, warranting the requirement of new regenerative therapies for the restoration of disc structure and function. In this study, a light-sensitive injectable polysaccharide composite hydrogel with excellent mechanical properties was prepared using dextrose methacrylate (DexMA) and fucoidan with inflammation-modulating properties. Through numerous in vivo experiments, it was shown that the co-culture of this composite hydrogel with interleukin-1β-stimulated NPCs was able to promote cell proliferation whilst preventing inflammation. Additionally, activation of the caveolin1-yes-associated protein (CAV1-YAP) mechanotransduction axis promoted extracellular matrix (ECM) metabolism and thus jointly promoted IVD regeneration. After injection into an IDD rat model, the composite hydrogel inhibited the local inflammatory response by inducing macrophage M2 polarization and gradually reducing the ECM degradation. In this study, we propose a fucoidan-DexMA composite hydrogel, which provides an attractive approach for IVD regeneration.
研究领域:
组织工程
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生物医学材料
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再生医学
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骨科
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炎症生物学
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DOI
PubMed
高影响因子
Artificial Cells Nanomedicine and Biotechnology
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2020
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IF 3.343
Gang Wang,Yang Yu,Yu-Zhu Wang,Pei-Hao Yin,Ke Xu,Heng Zhang
In this study, isoliquiritigenin (ISL) incorporated nanoliposomes were prepared and their effects on colorectal cancer (CRC) cell lines were investigated. Herein, we sought to explore the anti-cancer mechanisms of ISL loaded nanoliposomes (ISL-NLs) on AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathways mediated glycolysis. Also, the key targets such as caveolin 1 (CAV1), glucose transporters and Akt/mTOR that promote glycolysis, and are activated via the induction of α-enolase (ENO1), fructose bisphosphate aldolase A (ALDOA) and monocarboxylate transporter 4 (MCT4) expressions were also investigated. It was shown that ISL-NLs significantly suppressed the proliferation and glucose uptake of CRC cell by potentially regulating the glycolysis and lactate targets as well as pathways that formed the basis of the anti-CRC effects of ISL-NLs. The mechanism underlying this effect was further validated via the regulation of some key targets such as ENO1, ALDOA, lactate dehydrogenase A (LDHA) and MCT4 in glycolysis coupled with cellular myelocytomatosis oncogene (c-myc), hypoxia-inducible factor 1-alpha (HIF-1α) in protein kinase B/mTOR (Akt/mTOR) pathways. Moreover, the AMPK proteins were identified to be up-regulated while the lactic acid production was suppressed by ISL-NLs in the CRC cells, indicating that ISL-NLs had an inhibitory effect on AMPK mediated glycolysis and lactate production. Altogether, these results have provided insights into the mechanism underlying the key role that liposomal ISL played in the multiple inhibition of AMPK and Akt/mTOR mediated glycolysis and lactate generation, which may be regulated as the alternative metabolic pathways of CRC as well as serve as adjuvant therapy for the disease.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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