ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
·
IF 6.6
Shan Tian,Yugang Hu,Jinhui Zou,Nan Hao,Jian Liu,Ruixue Li,Jiao Li
Nanoplastic pollution is a serious global concern, which has caused great threat to the human health. However, the relationship between nanoplastic exposure and the development and progression of ulcerative colitis (UC) is still unknown. We established a chronic dextran sulfate sodium (DSS)-induced colitis model with exposure to polystyrene nanoplastics (PS-NPs) and evaluated disease severity, gut inflammation, and intestinal barrier function. The immune microenvironment was assessed using fluorescence multiplex immunohistochemistry (mIHC), while histone lactylation modification was analyzed via western blot and Cleavage Under Targets and Tagmentation (CUT&Tag). Additionally, lipopolysaccharide (LPS)-treated RAW264.7 cells were cultured and intervened to further investigate the molecular mechanism of PS-NPs in colitis. Continuous exposure to PS-NPs exacerbated gut inflammation and damage intestinal barrier function in DSS-induced colitis. PS-NPs exposure is closely correlated with increased macrophage infiltration, enhanced the glycolysis and up-regulated the histone H3 lactylation in macrophages. CUT&Tag analysis showed that PS-NPs influenced the expression of GART via histone H3K18la lactylation. Intervention in histone H3K18la lactylation significantly altered the expression of GART and levels of inflammatory factors in LPS-treated RAW264.7 cells. Downregulating GART expression reduced inflammatory factor levels in RAW264.7 cells treated with LPS plus PS-NPs. PS-NPs exposure exacerbates colitis by upregulating histone H3 lactylation. This study reveals a novel mechanism underlying nanoplastic-exacerbated intestinal injury and provides a direction for future risk assessment of nanoplastics.
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Signal Transduction and Targeted Therapy
·
2026
·Vol. 11
·期 1
·341
·
IF 81.2
Liu Shuai,Ma Yunfeng,Zeng Yujie,Lv Dekang,Hou Zhijie,Huang Junxiu,Gong Yaqi,Feng Ruijun,Wang Zihan,Sui Ran,Huang Dan,Wu Yameng,Chen Nuo,Yao Mingzhi,Shan Ying,Huang Yuan,Wang Yuesheng,Yan Jinsong,Peng Fei,Liu Quentin,Xu Jie
Activation of quiescent or extremely slow-cycling breast cancer stem-like cells (qsBCSCs) contributes to tumor progression, yet the regulatory mechanisms involved in triple-negative breast cancer (TNBC) remain elusive. We developed a dual-reporter system combining NANOG-EGFP and H2B-mCherry pulse-chase labeling to separately identify qsBCSCs and active BCSCs (aBCSCs) in vitro and in vivo. aBCSCs display significant enrichment of glycolysis and lactylation signatures, a finding corroborated by single-cell RNA sequencing (scRNA-seq) of TNBC patient samples. Glycolytic enzyme Enolase 1 (ENO1) expression is positively correlated with elevated histone H4 lysine 12 lactylation (H4K12la) in aBCSCs. Functional studies revealed a positive feedback circuit in which ENO1-increased lactate promotes H4K12la, which in turn activates ENO1 transcription. The ENO1-lactate-H4K12la axis enhances proliferating cell nuclear antigen ( PCNA ) transcription to activate qsBCSCs. Suppression of ENO1 or H4K12la prevents PCNA upregulation and qsBCSC activation. Importantly, PCNA knockdown alone blocks the activation of qsBCSCs induced by exogenous sodium L-lactate (NALA). In orthotopic breast cancer mouse models, both genetic depletion of ENO1 and pharmacological inhibition of lactate production attenuated tumor growth by blocking qsBCSC activation. Clinically, ENO1 expression was strongly correlated with PCNA expression, with high expression predicting poor OS, RFS, and DMFS. Our results establish the ENO1-H4K12la-PCNA axis as a key metabolic‒epigenetic driver of qsBCSC activation and a therapeutic target in TNBC.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2026
·
IF 6.6
Xinying Zhao,Xiangrong Zhou,Keying Li,Qiuchen Wu,Yuqin Sha,Zhuoyi Xie,Ping Zeng,Zhipeng Qi,Qiao Niu,Wei Li,Weiyi Song
Lanthanum (La), one of the most widely used rare earth elements (REEs), is inevitably released into the environment, raising concerns about its potential health risks. Epidemiological evidence has linked La exposure to liver injury, but the mechanisms underlying chronic hepatotoxicity remain poorly understood. Here, zebrafish were exposed to environmentally relevant concentrations of LaCl 3 (0.1 and 1 μM) from 2 hours post-fertilization (hpf) to 120 days post-fertilization (dpf), and integrated histological, biochemical, metabolomic, and transcriptomic analyses to examine LaCl 3 -induced hepatic responses. We found that chronic LaCl 3 exposure caused marked hepatic steatosis and liver injury in male zebrafish, and these effects persisted after a 30-day depuration period. Multi-omics analyses revealed that LaCl 3 drives glycolysis-dependent metabolic reprogramming, which subsequently suppresses the AMPK-ULK1-LC3B axis, thereby impairing lipophagy and leading to abnormal lipid droplet accumulation. In HepG2 cells, pharmacological inhibition of glycolysis with 2-DG or activation of AMPK with AICAR effectively restored AMPK-ULK1-LC3B signaling and attenuated LaCl 3 -induced lipid accumulation. Collectively, our findings provide a previously underrecognized mechanism underlying LaCl 3 -disrupted hepatic lipid homeostasis, offering novel insights into REEs-related hepatotoxicity and supporting environmental health risk assessment.
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Frontiers in Oncology
·
2026
·
IF 3.4
Bixia Chi,Zhi Cui,Xinyue Hou,Hongfang Ding,Linjun Li,Rui Ai,Yizhuang Yang,Yue Zhao,Liyan Wang,Juan Wang
Acidic leucine-rich nuclear phosphoprotein 32A(ANP32A) is known to possess multi-functions and has been observed to exhibit different roles across various malignancies. Although the expression of ANP32A has been shown to correlate with metastatic spread and reduced survival in Hepatocellular carcinoma(HCC), the underlying mechanisms have not been fully elucidated. This study utilized univariate Cox regression, differential gene analysis, and WGCNA to identify ANP32A as closely associated with poor HCC prognosis. Our Co-IP results confirmed the interaction between ANP32A and LDHA. Additionally, silencing ANP32A inhibited HCC cell proliferation in vitro as well as in vivo, and altered glycolytic and ferroptotic pathways, with increased LDHA ubiquitination detected. These data suggested that ANP32A may play a role in HCC progression, positioning it as a highly attractive therapeutic target for advanced HCC. Silencing ANP32A augmented the susceptibility of HCC cells to ferroptosis and inhibited aerobic glycolysis, which may provide new avenues for combination therapies, offering potential for improved patient outcomes.
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INTERNATIONAL ENDODONTIC JOURNAL
·
2026
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IF 6.4
Yongjie Cai,Xiaoting Peng,Beichen Chen,Yiqing Zhao,Waruna Lakmal Dissanayaka,Yiwen Zhang,Shengyan Yang,Qiong Xu
Aim To delineate the mechanisms underlying the role of lactate-related lactylation, a novel post-translational modification, in the odontogenic differentiation of human dental pulp stem cells (hDPSCs). Methodology Dynamic levels of key glycolytic enzymes and histone lactylation along odontogenic differentiation in hDPSCs were evaluated by Western Blot and quantitative PCR (qPCR). Odontogenic differentiation was assessed via Alkaline Phosphatase and Alizarin Red S staining after treatment with sodium lactate, both with and without p300 knockdown. CUT&Tag sequencing of histone H3K18 lactylation (H3K18la) was performed, and genes identified through this analysis were subjected to pathway enrichment. WNT5A-knockdown hDPSCs were generated to elucidate the impact of both WNT5A and WNT5A/Ca 2+ signalling axis in odontogenesis. Finally, we validated the critical function of lactylation in dentine regeneration using a subcutaneous ectopic transplantation model in nude mice with and without sodium lactate via intraperitoneal injection. Results The similar dynamic trends were observed in glycolytic enzyme expression, intracellular lactate and lactylation levels in hDPSCs. Exogenous lactate dose-dependently increased H3K18 lactylation and significantly promoted hDPSC odontogenic differentiation. Mechanistically, the key lactyltransferase p300 was demonstrated to be a regulator that enhanced lactate-induced H3K18la modification and odontogenic differentiation in hDPSCs. CUT&Tag sequencing identified WNT5A as a target gene whose promoter exhibited increased H3K18la enrichment upon lactate treatment. Lactate upregulated WNT5A expression and activated the WNT5A/Ca 2+ signalling pathway via p300-mediated H3K18la, consequently accelerating the odontogenic differentiation. Further in vivo evidence revealed that lactate administration promoted pulp-like tissue regeneration, accompanied by increased hDPSC odontogenic marker expression and H3K18la levels in nude mice with subcutaneously transplanted dentine slices. Conclusions The lactate-driven mechanism acts through the p300-mediated H3K18la-WNT5A/Ca 2+ signalling axis to promote the odontogenic differentiation of hDPSCs. The crosstalk between metabolism, epigenetic modifications and signalling pathways of hDPSCs might offer novel strategies for dental pulp regeneration.
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高影响因子
Cancers
·
2022
·Vol. 14
·期 2
·345
·
IF 6.575
Hui Chen,Han Zhang,Lixing Cao,Jinling Cui,Xuan Ma,Chong Zhao,Shutao Yin,Hongbo Hu
Simple SummarySelenite, a representative inorganic form of selenium, is preferentially accumulated in tumors. The therapeutic potential of sodium selenite in tumors has received significant attention. However, the effect of sodium selenite in the treatment of established tumors is hampered by its systemic toxicities. In this study, we found selenite exerted a stronger lethality to the cancer cells under the condition of glucose limitation in vitro and an enhanced inhibitory effect on tumor growth when combined with intermittent fasting in vivo. In addition, this treatment showed no obvious toxicity to normal cells and mice. The findings of the present study provide an effective and practical approach for increasing the therapeutic window of selenite and imply that combination of selenite and fasting holds promising potential to be developed a clinically useful regimen for treating certain types of cancer.AbstractCombination of intermittent fasting and chemotherapy has been drawn an increasing attention because of the encouraging efficacy. In this study, we evaluated the anti-cancer effect of combination of glucose limitation and selenite (Se), a representative inorganic form of selenium, that is preferentially accumulated in tumors. Results showed that cytotoxic effect of selenite on cancer cells, but not on normal cells, was significantly enhanced in response to the combination of selenite and glucose limitation. Furthermore, in vivo therapeutic efficacy of combining selenite with fasting was dramatically improved in xenograft models of lung and colon cancer. Mechanistically, we found that SLC7A11 expression in cancer cells was up-regulated by selenite both in vitro and in vivo. The elevated SLC7A11 led to cystine accumulation, NADPH depletion and the conversion of cystine to cysteine inhibition, which in turn boosted selenite-mediated reactive oxygen species (ROS), followed by enhancement of selenite-mediated cytotoxic effect. The findings of the present study provide an effective and practical approach for increasing the therapeutic window of selenite and imply that combination of selenite and fasting holds promising potential to be developed a clinically useful regimen for treating certain types of cancer.Keywords:selenite;glucose limitation;SLC7A11;NADPH;ROS
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Advanced Healthcare Materials
·
2021
·Vol. 11
·期 2
·2101926
·
IF 9.933
Wenjie Feng,Wanrui Shi,Shuwei Liu,Huiwen Liu,Yi Liu,Pengfei Ge,Hao Zhang
Most of the antitumor chemotherapeutic drugs execute the therapeutic performance upon eliciting tumor cell apoptosis, which may cause chemoresistance of tumors. Design of novel drugs to eradicate apoptosis-resistant tumors via non-apoptotic cell death pathways is promising for improving the long-term chemotherapeutic efficacy. Herein, a Fe(III)-Shikonin metal-polyphenol-coordinated supramolecular nanomedicine for combined therapy of tumor via ferroptosis and necroptosis is designed. The construction of the nanomedicine based on the coordinated self-assembly between Fe 3+ and Shikonin not only overcomes the shortcomings of Shikonin including its low bioavailability and high toxicity toward normal tissues, but also integrates the theranostics functions of Fe ions. Under the exposure of the high concentration of glutathione (GSH) in tumor cells, the as-prepared nanomedicine will disassemble into Fe 2+ and Shikonin, followed by stimulating the tumor cell death through ferroptosis and necroptosis. In addition, benefiting from the stealth effect of polyethylene glycol (PEG) and the targeting ability of cyclo(Arg-Gly-Asp- d -Phe-Lys) (cRGD) to α v β 3 -integrin, NH 2 -PEG-cRGD-modified nanomedicine exhibits a GSH-responsive therapy toward 4T1 tumor in vivo and self-enhanced longitudinal relaxation (T 1 )-weighted imaging property. Since the self-assembly of natural Shikonin and human body-necessary Fe element is facile and feasible, the work may provide a promising supramolecular nanomedicine for next-generation chemotherapeutic applications.
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EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2021
·
IF 4.384
Yuping Wei,Caiying Zhang,Man Zhang,Qionghong Niu,Fengli Hui,Zi Liu,Xia Xu
In our previous study, a novel cell penetrating peptide (CPP) R7 (Arg-Arg-Arg-Arg-Arg-Trp-Trp, RRRRRWW) has been developed to help cellular internalization of paclitaxel (PTX) through the non-covalent interaction with CPP. However, the facilitation mechanism of R7 mediated PTX translocation is not clear. Here the uptake pathways of R7 and R7-PTX were investigated by in vitro test and molecular simulations. In vitro experiments reveal that both R7 and R7-PTX complex translocate through the direct translocation and clathrin mediated endocytosis and associate with the macropinocytosis pathway at high CPP concentration. The translocation of R7(0.1 mM)-PTX complex further involves the lipid raft/caveolae mediated endocytosis. The simulation results show that the synergistic effect between R7 and PTX not only changes the penetration energy barrier but also activates the macropinocytosis and lipid raft/caveolae mediated pathway, resulting in the improvement in the translocation. The presence of heparin also improves the R7 and R7-PTX translocation. These studies provide a theoretical basis for understanding PTX delivery facilitated by the synergistic effect between CPP and cargo and paves a way for CPP design.
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BIOMATERIALS
·
2021
·
IF 12.479
Yeneng Dai,Zhiquan Sun,Honghai Zhao,Dashan Qi,Xiangyu Li,Diya Gao,Meixing Li,Quli Fan,Qingming Shen,Wei Huang
Photothermal therapy (PTT) is hampered by limited light penetration depth and cell thermoresistance induced by over-expressed heat shock proteins (HSPs). Herein, we proposed a tumor-specific enhanced NIR-II PTT through the starvation mediated thermal sensitization strategy. A semiconducting polymer with superior NIR-II fluorescence imaging (FI) performance and NIR-II PTT efficacy was synthesized and encapsulated into folate modified liposomes , together with a glycolysis inhibitor, 2-deoxy- d -glucose (2DG). Upon specifically targeting folate receptors and guidance of NIR-II FI, spatiotemporal 2DG release could be achieved by the trigger of NIR-II photothermal effect. The released 2DG could not only deplete the energy supply of tumor cells by inhibiting tumor anaerobic glycolysis , but also decrease the ATP levels and hamper the production of HSPs, ultimately enhancing the tumor thermal sensitivity toward PTT. Owing to the sensitization effect of 2DG, tumor cells with overexpressed folate receptors could be significantly damaged by NIR-II PTT with an enhanced therapeutic efficiency. The work provided a promising strategy for specific starvation/NIR-II PTT synergistic therapy towards tumors.
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MOLECULES
·
2020
·Vol. 25
·期 23
·5778
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IF 3.267
Yangke Wanyan,Xixi Xu,Kehang Liu,Huidan Zhang,Junai Zhen,Rong Zhang,Jumei Wen,Ping Liu,Yuqing Chen
Inhibition of the glycolytic pathway is a critical strategy in anticancer therapy because of the role of aerobic glycolysis in cancer cells. The glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) has shown potential in combination with other anticancer agents. Buforin IIb is an effective antimicrobial peptide (AMP) with broad-spectrum anticancer activity and selectivity. The efficacy of combination treatment with 2-DG and buforin IIb in prostate cancer remains unknown. Here, we tested the efficacy of buforin IIb as a mitochondria-targeting AMP in the androgen-independent human prostate cancer cell line DU145. Combining 2-DG with buforin IIb had a synergistic toxic effect on DU145 cells and mouse xenograft tumors. Combination treatment with 2-DG and buforin IIb caused stronger proliferation inhibition, greater G1 cell cycle arrest, and higher apoptosis than either treatment alone. Combination treatment dramatically decreased L-lactate production and intracellular ATP levels, indicating severe inhibition of glycolysis and ATP production. Flow cytometry and confocal laser scanning microscopy results indicate that 2-DG may increase buforin IIb uptake by DU145 cells, thereby increasing the mitochondria-targeting capacity of buforin IIb. This may partly explain the effect of combination treatment on enhancing buforin IIb-induced apoptosis. Consistently, 2-DG increased mitochondrial dysfunction and upregulated Bax/Bcl-2, promoting cytochrome c release to initiate procaspase 3 cleavage induced by buforin IIb. These results suggest that 2-DG sensitizes prostate cancer DU145 cells to buforin IIb. Moreover, combination treatment caused minimal hemolysis and cytotoxicity to normal WPMY-1 cells. Collectively, the current study demonstrates that dual targeting of glycolysis and mitochondria by 2-DG and buforin IIb may be an effective anticancer strategy for the treatment of some advanced prostate cancer.Keywords:buforin IIb;2-Deoxy-d-glucose;mitochondria;glycolysis;prostate cancer
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International Journal of Peptide Research and Therapeutics
·
2020
·Vol. 26
·期 4
·2285-2296
·
IF 1.5
Chen Xiaolong,Hu Cuihua,Zhang Yanan,Hao Wenjing,He Xu,Li Qing,Huang Yuxi,Huang Yibing,Chen Yuxin
Conjugation of cell-penetrating peptides to anticancer peptides is an effective strategy to enhance tumor treatment. The hybrid peptide, kla-TAT, by attaching the TAT peptide to the C-terminus of the pro-apoptotic peptide kla exhibited strong anticancer activity when co-administration with other peptide, but the systematic mechanism was not clear. In this study, the mechanisms of action of kla-TAT including the uptake pathway, distribution in cytoplasm, apoptosis-inducing ability and micro-morphology were investigated. The results indicated that the hybrid peptide internalized into A549 cells through two transmembrane mechanisms: endocytosis mediated by the clathrin-mediated endocytosis route and the rapid membrane disruption mechanism. Peptides that were endocytosed could interact with the mitochondrial membrane, while peptides internalized by disrupting the cell membrane caused disruption of the mitochondrial membrane. Thus, the hybrid kla-TAT peptide transfers through the cell membrane, inducing apoptosis by destroying the mitochondrial membrane and causethe expression of cyclin-D1 down-regulation. Meanwhile, the changes of the micro-morphology of the cancer cells was detected using atomic force microscope (AFM) and scanning electron microscope (SEM), which provided the visualized evidence for the mechanism of the peptides.
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APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
·
2020
·Vol. 104
·期 15
·6767-6777
·
IF 3.53
Yan Zhiyu,Wu Xiangli,Zhao Mengran,Zhang Jinxia
High temperature is a major threat to Pleurotus ostreatus cultivation. In this study, a potential mechanism by which P. ostreatus mycelia growth is inhibited under heat stress was explored. Lactate, as a microbial fermentation product, was found unexpectedly in the mycelia of P. ostreatus under heat stress, and the time-dependent accumulation and corresponding inhibitory effect of lactate on mycelial growth was further confirmed. The addition of a glycolysis inhibitor, 2 -deoxy- d -glucose (2DG), reduced the lactate content in mycelia and slightly restored mycelial growth under high-temperature conditions, which indicated the accumulation of lactate can be inhibited by glycolysis inhibition. Further data revealed mitochondrial dysfunction under high-temperature conditions, with evidence of decreased oxygen consumption and adenosine triphosphate (ATP) synthesis and increased reactive oxygen species (ROS). The removal of ROS with ascorbic acid decreased the lactate content, and mycelial growth recovered to a certain extent, indicating lactate accumulation could be affected by the mitochondrial ROS. Moreover, metabolic data showed that glycolysis and the tricarboxylic acid cycle were enhanced. This study reported the accumulation of lactate in P. ostreatus mycelia under heat stress and the inhibitory effect of lactate on the growth of mycelia, which might provide further insights into the stress response mechanism of edible fungi. Key Points • Lactate can accumulate in Pleurotus ostreatus mycelia under heat stress and inhibit its growth. • The accumulation of lactate may be due to the acceleration of glycolysis and the dysfunction of mitochondria of P. ostreatus mycelia under high-temperature stress. • The glycolysis and tricarboxylic acid cycle of P. ostreatus mycelia were accelerated under high-temperature stress.
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