CURRENT MOLECULAR MEDICINE
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2025
·Vol. 25
·期 3
·343-352
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IF 2.5
Weiqing Feng,Haixiong Zhang,Qing Yu,Hao Yin,Xiaowei Ou,Jie Yuan,Liang Peng
Background The emergence of treatment resistance has hindered the efficacy of targeted therapies used to treat patients with hepatocellular carcinoma (HCC). Objective This study aimed to explore the mechanism of organoids constructed from lenvatinib-resistant HCC cells. Methods Hep3B cell and human HCC organoids were cultured and identified using hematoxylin and eosin staining and Immunohistochemistry. Lenvatinib-sensitive/ resistant Hep3B cells were constructed using lenvatinib (0, 0.1, 1, and 10 μM) and lenvatinib (0, 1, 10, and 100 μM). qRT-PCR and flow cytometry were utilized to deter-mine HCC stem cell markers CD44, CD90, and CD133 expressions. Transcriptome sequencing was performed on organoids. Western blot evaluated Notch pathway-related proteins (NOTCH1 and Jagged) expressions. Furthermore, DAPT, an inhibitor of the Notch pathway, was used to investigate the effects of lenvatinib on resistance or stemness in organoids and human HCC tissues. Results The organoids were successfully cultivated. With the increase of lenvatinib concentration, sensitive cell organoids were markedly degraded and ATP activity was gradually decreased, while there was no significant change in ATP activity of resistant cell organoids. CD44 expressions were elevated after lenvatinib treatment compared with the control group. KEGG showed that lenvatinib treatment of organoids constructed from Hep3B cells mainly activated the Notch pathway. Compared with the control group, NOTCH1 and Jagged expressions elevated, and ATP activity decreased after lenvatinib treatment. However, ATP activity was notably decreased after DAPT treatment. Moreover, DAPT inhibited lenvatinib resistance and the increase in the expressions of CD44 caused by lenvatinib. Besides, 100 μM lenvatinib significantly inhibited the growth and ATP activity of human HCC organoids, and DAPT increased the inhibitory effect of lenvatinib. Conclusion Lenvatinib regulated resistance and stemness in organoids via the Notch pathway.
研究领域:
肿瘤学
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分子生物学
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转化医学
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DOI
PubMed
高影响因子
CHINESE MEDICAL JOURNAL
·
2025
·
IF 7.3
Li Na,Mao Jingwei,Tang Haiying,Tan Xiaoyan,Bi Jian,Wu Hao,Chen Xiuli,Wang Yingde
Background: Regulatory dendritic cell (DCreg) subset exhibits a unique capacity for inducing immune tolerance among the variety subsets of dendritic cells (DCs) within gut-associated lymphoid tissues (GALTs). Fms-like tyrosine kinase 3 ligand (FLT3L) is involved in the differentiation of DCregs and the subsequent expansion of regulatory T-cells (Tregs) mediated by DCregs, though the precise mechanism remains poorly understood. This study aimed to explore the expansion mechanism of Treg induced by DCreg and the role of FLT3L in this process. Methods: DCregs were distinguished from other DC subsets isolated from GALTs of BALB/c mice through a mixed lymphocyte reaction assay. The functions and mechanisms by which FLT3L promoted Treg expansion via DCregs were investigated in vitro through co-culture experiments involving DCregs and either CD4 + CD25 − T-cells or CD4 + CD25 + T-cells. Additionally, an in vivo experiment was conducted using a dextran sulfate sodium (DSS)-induced colitis model in mice. Results: CD103 + CD11b + DC exhibited DCreg-like functionality and was identified as DCreg for subsequent investigation. Analysis of Foxp3 + Treg percentages within a co-culture system of CD4 + CD25 − T-cells and DCregs, with or without FLT3L, demonstrated the involvement of the FLT3/FLT3L axis in driving the differentiation of precursor T-cells into Foxp3 + Tregs induced by DCregs. Cell migration and co-culture assays revealed that the FLT3/FLT3L axis enhanced DCreg migration toward Tregs via the Rho pathway. Additionally, it was observed that DCregs could promote Treg proliferation through the Notch pathway, as inhibition of Notch signaling by DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester) suppressed Treg expansion within the co-culture system of DCregs and CD4 + T-cells or CD4 + CD25 + T-cells. Furthermore, the FLT3/FLT3L axis influenced JAG1 expression in DCregs, indirectly modulating Treg expansion. In vivo experiments further established that FLT3L promoted DCreg expansion and restored Treg balance in DSS-induced colitis models, thereby ameliorating colitis symptoms in mice. Conclusion: The FLT3/FLT3L axis is integral to the maintenance of DCreg function in Treg expansion.
研究领域:
免疫学
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分子生物学
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医学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Hongtao Duan,Rui Zhang,Aiminuer Asikaer,Liang Pan,Shui Wang,Kuilong Huang,Deshuai Lou,Yuanqiang Wang,Zhihua Lin,Yan Shen
Background & Aims: Acute pancreatitis (AP) is a life-threatening condition, and hypertriglyceridemia (HTG) is recognized as a factor exacerbating AP and impeding pancreatic regeneration. Nicotinamide mononucleotide (NMN), a precursor in the biosynthesis of nicotinamide adenine dinucleotide (NAD + ), is extensively utilized to restore NAD + levels. However, the impact of NMN on HTG-AP has not been previously addressed, which prompted our investigation into its effects and underlying mechanisms in this study. Methods & Results: Here, through bioinformatics analysis and in vivo experiments, we identified abnormalities in the thioredoxin system. In vitro studies revealed that NMN rescued oleic acid (OA)- and palmitic acid (PA)-induced mitochondrial dysfunction and cellular injury in pancreatic acinar cells by suppressing thioredoxin-interacting protein (TXNIP) through NAD + /sirtuin 1 (SIRT1) signaling. Repeated administration of NMN significantly ameliorated P407 and caerulein (CER)-induced pancreatic injury and dysfunction in mice. Consistently, NMN exhibited the potential to reduce inflammatory responses, lower serum lipid levels, and mitigate the accumulation of reactive oxygen species (ROS). More importantly, sustained NMN treatment inhibited the NOTCH pathway and promoted M2-type macrophage dominance during the pancreatic repair phase, influencing early or late macrophage polarization, which significantly enhanced inflammation resolution. As expected, in vitro models using mouse bone marrow-derived macrophage (BMDM), RAW 264.7, and THP-1 cells confirmed that NMN influences macrophage phenotype through the NOTCH pathway. Conclusions: Therefore, NMN ameliorates pancreatic acinar cell injury via NAD + /SIRT1-mediated TXNIP suppression and may influence macrophage polarization by inhibiting NOTCH activation, offering a novel therapeutic strategy for the treatment and repair of HTG-AP.
研究领域:
医学
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生物化学
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分子生物学
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DOI
PubMed
高影响因子
Cell Death & Disease
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2024
·Vol. 15
·期 10
·1-15
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IF 8.1
Chen Zi-Xiong,Mu Mao-Yuan,Yang Guang,Qi Han,Fu Xiao-Bo,Wang Gui-Song,Jiang Wei-Wei,Huang Bi-Jun,Gao Fei
Denticleless E3 ubiquitin protein ligase homolog (DTL), the substrate receptor of the CRL4A complex, plays a central role in genome stability. Even though the oncogenic function of DTL has been investigated in several cancers, its specific role in hepatocellular carcinoma (HCC) still needs further elucidation. Data from a clinical cohort ( n = 209), RNA-sequencing, and public database (TCGA and GEO) were analyzed, indicating that DTL is closely related to patient prognosis and could serve as a promising prognostic indicator in HCC. Functionally, DTL promoted the proliferation, metastasis, and sorafenib resistance of HCC in vitro. In the orthotopic tumor transplantation and tail vein injection model, DTL promoted the growth and metastasis of HCC in vivo. Mechanically, we revealed for the first time that DTL was transcriptionally activated by hypoxia-inducible factor 1α (HIF-1α) under hypoxia and functioned as a downstream effector molecule of HIF-1α. DTL promotes the ubiquitination of SAFB-like transcription modulator (SLTM) and subsequently relieves the transcriptional repression of Notch1. These results suggested that DTL may be a potential biomarker and therapeutic target for HCC.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
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产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
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2022
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IF 4.319
Xiangtian Ling,Xinqi Ma,Xielan Kuang,Yuxiu Zou,Han Zhang,Han Tang,Han Du,Binbin Zhu,Hao Huang,Qing Xia,Minghao Chen,Danyi Mao,Dongli Chen,Huangxuan Shen,Jianhua Yan
Purpose To assess the cellular and molecular effects of lidocaine on muscles/myoblasts.Methods Cultured myogenic precursor (C2C12) cells were treated with varying concentrations of lidocaine.Results Cell viability of C2C12 cells was inhibited by lidocaine in a concentration-dependent manner, with concentrations ≥0.08%, producing a dramatic reduction in cell viability. These ≥0.08% concentrations of lidocaine arrested cell cycles of C2C12 cells in the G0/G1 phase. Moreover, lidocaine inhibited cell migration and myogenic processes in C2C12 cells at low concentrations. Results from QRT-PCR assays revealed that following treatment with lidocaine, Notch1, Notch2, Hes1, Csl and Dll4 all showed higher levels of expression, while no changes were observed in Mmal1, Hey1, Dll1 and Jag1.Conclusion This work provides the first description of the effects of lidocaine upon the regeneration of muscles and maintenance of satellite cells at the cellular and molecular levels. In specific, we found that the Dll4-Notch-Csl-Hes1 axis was up-regulated suggesting that the Notch signaling pathway was involved in producing these effects of lidocaine. These findings provide a new and important foundation for future investigations into the effects of drug therapies in muscle diseases.
研究领域:
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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DOI
PubMed
高影响因子
Cell Metabolism
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2024
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IF 27.7
Yu Jiang,Yawen Wang,Guofeng Chen,Fei Sun,Qijing Wu,Qiong Huang,Dongqiang Zeng,Wenjun Qiu,Jiao Wang,Zhiqi Yao,Bishan Liang,Shaowei Li,Jianhua Wu,Na Huang,Yuanyuan Wang,Jingsong Chen,Xiaohui Zhai,Li Huang,Beibei Xu,Masami Yamamoto,Tetsuya Tsukamoto,Sachiyo Nomura,Wangjun Liao,Min Shi
Immune checkpoint blockade has led to breakthroughs in the treatment of advanced gastric cancer. However, the prominent heterogeneity in gastric cancer, notably the heterogeneity of the tumor microenvironment, highlights the idea that the antitumor response is a reflection of multifactorial interactions. Through transcriptomic analysis and dynamic plasma sample analysis, we identified a metabolic “face-off” mechanism within the tumor microenvironment, as shown by the dual prognostic significance of nicotinamide metabolism. Specifically, macrophages and fibroblasts expressing the rate-limiting enzymes nicotinamide phosphoribosyltransferase and nicotinamide N-methyltransferase, respectively, regulate the nicotinamide/1-methylnicotinamide ratio and CD8+ T cell function. Mechanistically, nicotinamide N-methyltransferase is transcriptionally activated by the NOTCH pathway transcription factor RBP-J and is further inhibited by macrophage-derived extracellular vesicles containing nicotinamide phosphoribosyltransferase via the SIRT1/NICD axis. Manipulating nicotinamide metabolism through autologous injection of extracellular vesicles restored CD8+ T cell cytotoxicity and the anti-PD-1 response in gastric cancer.
研究领域:
肿瘤学
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免疫学
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代谢学
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癌症生物学
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DOI
PubMed
高影响因子
Foods
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2025
·Vol. 14
·期 2
·214
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IF 5.1
Mengge Duan,Yuting Wang,Shiyu Chen,Jiawen Lu,Ruihong Dong,Qiang Yu,Jianhua Xie,Yi Chen
Bisphenol A (BPA) and diisobutyl (DIBP) phthalate are widely used as typical plasticizers in food packaging. Plasticizers can be released from polymers, migrate into food, and be ingested by humans, leading to various health problems. However, little research has investigated the combined toxicity of BPA and DIBP, particularly their intestinal toxicity. Our goal is to analyse the combined toxicity of BPA (50 mg/kg) and DIBP (500 mg/kg) on the intestines of KM mice. Additionally, we tried to find natural products that can inhibit or prevent the combined toxicity of BPA and DIBP. The results indicated that the combination of BPA and DIBP exposure resulted in a reduction of beneficial flora, an increase in D-Lac levels (136 ± 14 μmol/L), an increase in intestinal permeability, activation of the notch pathway, and a decline in intestinal stem cells (ISCs) to goblet cells, compared to single-exposure sources. Nevertheless,Rubus chingiiHu phenolic extract (RHPE) (200, 400 and 600 mg/kg) ameliorated the BPA and DIBP-induced intestinal microbiota disruption and intestinal mucosal barrier impairment by inhibiting the overactivation of the notch pathway. The results of this study highlight the potential risks to human health posed by the combination of BPA and DIBP and may help explain the potential pathways of enterotoxicity caused by combined ingestion.
研究领域:
毒理学
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胃肠病学
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微生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2019
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IF 4.527
Gaofeng Cui,Haiqi Yuan,Zhiyan Jiang,Jing Zhang,Zhipeng Sun,Guohua Zhong
The widely distributed β-carboline alkaloids exhibit promising psychopharmacological and biochemical effects. Harmine, a natural β-carboline, can inhibit insect growth and development with unclear mechanisms. In this study, harmine (at 0-200 mg/L) showed a dose-dependent inhibitory effect on the pupal weight, length, height, pupation rate and eclosion rate of fruit flies Drosophila melanogaster , which was similar to the inhibition induced by the well-known botanical insect growth regulator azadirachtin . Moreover, the expression levels of major regulators from the developmental signaling network were down-regulated during the pupal stage except Numb , Fringe , Yorkie and Pten . The Notch, Wnt, Hedgehog and TGF-β pathways mainly played vital roles in coping with harmine exposure in pupae stage, while the Hippo, Hedgehog and TGF-β elements were involved in the sex differences. Notch , Hippo , Hedgehog , Dpp and Armadillo were proved to be suppressed in the developmental inhibition with fly mutants, while Numb and Punt were increased by harmine. In conclusion, harmine significantly inhibited the development of Drosophila by negatively affecting their developmental signaling network during different stages. Our results establish a preliminary understanding of the developmental signaling network subjected to botanical component-induced growth inhibition and lay the groundwork for further application.
研究领域:
昆虫学
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分子生物学
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发育生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2019
·
IF 4.527
Shaojun Liang,Shengxian Liang,Hui Zhou,Nuoya Yin,Francesco Faiola
2′,2′,4,4′-tetrabromo diphenyl ether (BDE-47), one of the most abundant congeners of commercial pentaBDE utilized as flame retardants , has been phased out of production due to its potential neural toxicity and endocrine disrupting activities, and yet still present in the environment. Several alternatives to BDE-47, including tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), tetrachlorobisphenol A (TCBPA) and decabromodiphenyl ether (BDE-209), are presently employed without restrictions and their potential toxic effects on human neural development are still unclear. In this study, we utilized a human neural stem cell (hNSC)-based system to evaluate the potential developmental neurotoxic effects of the above-mentioned five chemicals, at environment and human exposure relevant concentrations. We found that those compounds slightly altered the expression of hNSC identity markers ( SOX2 , SOX3 and NES ), without impairing cell viability or proliferation, in part by either modulating glycogen synthase kinase 3 beta (GSK3β) signaling (TBBPS, TCBPA and BDE-47), and slightly disturbing the NOTCH pathway (TBBPA, TBBPS and TCBPA). Moreover, the five chemicals seemed to alter hNSC differentiation by perturbing triiodothyronine (T3) cellular signaling. Thus, our findings suggest that the five compounds, especially TBBPS, TCBPA, and BDE-47, may affect hNSC self-renewal and differentiation abilities and potentially elicit neural developmental toxicity.
研究领域:
神经科学
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毒理学
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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
Asian Journal of Pharmaceutical Sciences
·
2024
·
IF 10.7
Yingqi Chen,Zuocheng Qiu,Xueling Hu,Tiehua Wang,Guoqing Li,Ziling Tang,Chongzhou Fang,Weibei Sheng,Jin Zhao,Fei Yu,Jian Weng,Anjaneyulu Udduttula,Geetha Manivasagam,Hui Zeng
In clinical settings, regenerating critical-sized calvarial bone defects presents substantial problems owing to the intricacy of surgical methods, restricted bone growth medications, and a scarcity of commercial bone grafts. To treat this life-threatening issue, improved biofunctional grafts capable of properly healing critical-sized bone defects are required. In this study, we effectively created anti-fracture hydrogel systems using spongy-like metal-organic (magnesium-phosphate) coordinated chitosan-modified injectable hydrogels (CPMg) loaded with a bioinspired neobavaisoflavone (NBF) component. The CPMg-NBF hydrogels showed outstanding anti-fracture capabilities during compression testing and retained exceptional mechanical stability even after 28 d of immersion in phosphate-buffered saline. They also demonstrated prolonged and stable release profiles of Mg 2+ and NBF. Importantly, CPMg-NBF hydrogels revealed robust biphasic mineralization and were non-toxic to MC3T3-E1 cells. To better understand the underlying mechanism of Mg 2+ and NBF component, as well as their synergistic effect on osteogenesis, we investigated the expression of key osteogenic proteins in the p38 MAPK and NOTCH pathways. Our results showed that CPMg-NBF hydrogels greatly increased the expression of osteogenic proteins (Runx2, OCN, OPN, BMPS and ALP). In vivo experiments showed that the implantation of CPMg-NBF hydrogels resulted in a significant increase in new bone growth within critical-sized calvarial defects. Based on these findings, we expect that the CPMg-NBF supramolecular hydrogel has tremendous promise for use as a therapeutic biomaterial for treating critical-sized calvarial defects.
研究领域:
生物材料
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组织工程
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骨科
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生物医学工程
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药学
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产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2023
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IF 11.2
Shisuo Jing,Huayuan Chen,Ergang Liu,Meng Zhang,Feng Zeng,Huan Shen,Yuefei Fang,Bahtiyor Muhitdinov,Yongzhuo Huang
Inflammatory bowel disease (IBD) is a chronic, life quality-reducing disease with no cures available yet. To develop an effective medication suitable for long-term use is an urgent but unmet need. Quercetin (QT) is a natural dietary flavonoid with good safety and multifaceted pharmacological activities against inflammation. However, orally administrated quercetin yields unproductive outcomes for IBD treatment because of its poor solubility and extensive metabolism in the gastrointestinal tract . In this work, a colon-targeted QT delivery system (termed COS-CaP-QT) was developed, of which the pectin (PEC)/Ca 2+ microspheres were prepared and then crosslinked by oligochitosan (COS). The drug release profile of COS-CaP-QT was pH-dependent and colon microenvironment-responsive, and COS-CaP-QT showed preferential distribution in the colon. The mechanism study showed that QT triggered the Notch pathway to regulate the proliferation of T helper 2 (Th2) cells and group 3 innate lymphoid cells (ILC3s) and the inflammatory microenvironment was remodeled. The in vivo therapeutic results revealed that COS-CaP-QT could relieve the colitis symptoms and maintain the colon length and intestinal barrier integrity.
研究领域:
药剂学
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药理学
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胃肠病学
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免疫学
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产品关联
DOI
PubMed
高影响因子
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