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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产品关联
DOI
PubMed
高影响因子
Genes & Diseases
·
2024
·
IF 6.9
Nan Wang,Xiaoyu Shen,Huakun Huang,Runhan Zhao,Habu Jiwa,Zongxin Li,Pei Li,Jixing Ye,Qiang Zhou
Amyloid precursor protein (APP), especially Swedish mutant APP (APPswe), is recognized as a significant pathogenic protein in Alzheimer's disease, but limited research has been conducted on the correlation between APPswe and the osteogenic differentiation of mesenchymal stem cells (MSCs). The effects of APPswe and its intracellular and extracellular segments on the osteogenic differentiation of bone morphogenetic protein 2 (BMP2)-induced MSCs were analyzed in this study. Our analysis of an existing database revealed that APP was positively correlated with the osteogenic differentiation of MSCs but negatively correlated with their proliferation and migration. Furthermore, APPswe promoted BMP2-induced osteogenic differentiation of MSCs, while APPswe-C (APPswe without an intracellular segment) had the opposite effect; thus, the intracellular domain of APPswe may be a key factor in promoting the osteogenic differentiation of MSCs. Additionally, both APPswe and APPswe-C inhibited the proliferation and migration of MSCs. Furthermore, the intracellular domain of APPswe inhibited the activity of the Notch pathway by regulating the expression of the Notch intracellular domain to promote the osteogenic differentiation of MSCs. Finally, APPswe-treated primary rat bone marrow MSCs exhibited the most favorable bone repair effect when a GelMA hydrogel loaded with BMP2 was used for in vivo experiments, while APPswe-C had the opposite effect. These findings demonstrate that APPswe promotes the osteogenic differentiation of MSCs by regulating the Notch pathway, but its extracellular segment blocks the self-renewal, proliferation, and migration of MSCs, ultimately leading to a gradual decrease in the storage capacity of MSCs and affecting long-term bone formation.
研究领域:
生物医学
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细胞生物学
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分子生物学
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DOI
高影响因子
Advanced Science
·
2025
·
IF 14.1
Dongjian Song,Qiuliang Liu,Zechen Yan,Qi Wang,Meng Su,Hui Zhang,Longyan Shi,Yingzhong Fan,Qian Zhang,Heying Yang,Da Zhang
This study investigates the molecular mechanisms by which superparamagnetic iron oxide nanoparticles (SPIONs) loaded with the WSGC peptide (WSGC@FA@PEG/PEI-SPIONs)—a 40-amino acid polypeptide derived from apoC-III—modulate chemotherapy resistance in gastric adenocarcinoma (GA). Emphasis is placed on their role in regulating mitophagy and mitochondrial homeostasis via the Notch signaling pathway. The physicochemical properties of WSGC@FA@PEG/PEI-SPIONs are thoroughly characterized, demonstrating favorable biocompatibility, stable size distribution, and efficient peptide loading. In vitro experiments show that these nanoparticles significantly inhibit GA cell proliferation, migration, and invasion by downregulating mitophagy-associated proteins (LC3, PINK1, and Parkin), primarily through modulation of the Notch pathway. In vivo studies, using a GA nude mouse model, confirm the therapeutic potential of WSGC@FA@PEG/PEI-SPIONs, revealing marked tumor growth inhibition and increased apoptotic activity. Collectively, the findings highlight the WSGC peptide as a promising therapeutic agent for overcoming chemotherapy resistance in GA by targeting the Notch signaling pathway and suppressing mitophagy, thereby presenting a novel strategy for polypeptide-based cancer therapy.
研究领域:
纳米医学
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肿瘤学
·
分子生物学
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药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
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2022
·Vol. 13
·期 11
·1-13
·
IF 9.685
Chen Shiyu,Cai Kun,Zheng Dijie,Liu Yanqing,Li Lin,He Zhiwei,Sun Chengyi,Yu Chao
Pancreatic cancer (PC) is one of the most malignant types of cancer, and is characterized by early metastasis, limited response to chemotherapeutics, and poor prognosis. Therefore, there is an urgent need to explore new therapeutic strategies for PC treatment. Human rhomboid-like 2 (RHBDL2) is differentially expressed in cervical and breast cancer. However, the correlation between RHBDL2 and PC remains unclear. We found that RHBDL2 is highly expressed in human PC cells and tissues and is significantly associated with distant metastasis and poor survival of patients with PC. Gain- and loss-of-function assays indicated that RHBDL2 could accelerate PC cell proliferation and mobility in vitro and in vivo. The RNA-Seq results suggest that RHBDL2 may be involved in the activation of Notch signaling pathway. IMR-1 could restore the proliferation and metastatic capacity of PC cells mediated by RHBDL2. RHBDL2 interacted with and cleaved Notch1, resulting in the release of N1ICD. RHBDL2 decreased the ubiquitination level of N1ICD and collaborated with Ovarian tumor domain-containing 7B (OTUD7B) to stabilize N1ICD via the ubiquitin-proteasome pathway. RHBDL2 facilitated PC cell proliferation and mobility by stabilizing the N1ICD via the OTUD7B and activating the Notch signaling pathway. Thus, targeting this novel pathway may be a potential therapeutic strategy for PC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2022
·
IF 7.419
Xi Luo,Yi Zheng,Yong-rui Bao,Shuai Wang,Tian-jiao Li,Jia-peng Leng,Xian-sheng Meng
Colitis-associated cancer (CAC) is the colorectal cancer (CRC) subtype that is difficult to treat, and shows high mortality. The consumption of flavonoid-rich fructus aurantii extracts (FAE) has been associated with multiple beneficial effects including anti-inflammatory and anti-cancer properties, but the potential effects on the colitis-associated carcinogenesis have not been thoroughly investigated. Recent clinical data show that, as yet, few agents clearly inhibited CRC development in long-standing inflammatory bowel diseases. Here, we identified that FAE showed significant efficiency to inhibit HT-29 cell proliferation. The potential of FAE in vivo was further evaluated in an AOM/DSS-induced CAC mouse model. Intriguingly, FAE diminished the number of polyps in mice. Furthermore, FAE inhibited CAC by regulating the gene expression of Notch/ NF-κB/IL-1 signaling pathways. Collectively, these results were indicative of FAE has great potential in CAC prevention and treatment.
研究领域:
肿瘤学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2023
·
IF 13.6
Weike Shaoyong,Hongli Jin,Xiao Jiang,Bocheng Xu,Yalin Liu,Yizhen Wang,Mingliang Jin
The adsorption of toxic substances on polystyrene microplastics (PSMPs) can modify their biological toxicity and exacerbate the threat to human health. The effects of benzo [ a ] pyrene (B ( a ) P)-loaded aged PSMPs on colonic barrier integrity remains unclear. Here, we showed that binding environmentally relevant concentrations of B ( a ) P alteredl̥ the physicochemical features and markedly enhanced the toxicity of PSMPs. Compared to pristine PSMP, [email protected] ( a ) P promoted colonic barrier degradation, body weight loss, colon length shortening, oxidative stress (OS), autophagy, inflammation, and bacterial translocation. Microplastic (MP) exposure induced injury to the colon barrier, including tight junction (TJ) and mucosal barriers, via overactivation of the Notch signalling pathway under increased OS in mice and intestinal organoids. Notably, [email protected] ( a ) P exposure exacerbated damage to TJ and the mucosal barrier via the overproduction of reactive oxygen species (ROS), which could be related to the release of B ( a ) P from [email protected] ( a ) P induced by the acidic environment of autophagosomes, which in turn exert synergistic toxic effects with PSMPs. Our study elucidates some of the potential molecular mechanisms by which B ( a ) P enhances PSMP-related intestinal toxicity, which provides a potential therapeutic approach for diseases caused by [email protected] ( a )P and PSMP pollution.
研究领域:
环境科学
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毒理学
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分子生物学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 10
·1-15
·
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
Foods
·
2025
·Vol. 14
·期 21
·
IF 5.1
Junxia Ma,Yingshan Jiang,Yue Teng,Ting Ren,Yanchao Xing,Aoyun Li,Zhongmei He,Weijia Chen,Ying Zong,Rui Du
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and current treatments are limited by significant side effects. Deer bone, which is rich in proteins and various active compounds, possesses anti-inflammatory and bone-health-promoting properties. However, its fermented product’s effects on RA treatment remain unexplored. In this study, we evaluated the therapeutic effects of probiotic-fermented deer bone aqueous extract (BbF) in an adjuvant arthritis (AA) rat model, combined with LPS-stimulated RAW264.7 macrophage models. In vivo experiments showed that BbF significantly reduced paw swelling, arthritis index, and improved bone mineral density. BbF also alleviated synovial hyperplasia and inflammatory cell infiltration. It suppressed pro-inflammatory cytokines (TNF-α, IL-1β, etc.) and inhibited macrophage migration and invasion. Transcriptomic analysis revealed significant enrichment of the Notch signaling pathway, and Western blot confirmed the downregulation of Notch3, Notch4, DLL4, and Jagged1 proteins. BbF also restored gut microbiota homeostasis, increasing beneficial bacteria such asFirmicutesandClostridia, while decreasing potential pathogens likeProteobacteria,Gammaproteobacteria, andEscherichia-Shigella. Furthermore, BbF enhanced short-chain fatty acids (SCFCs) production, including butyrate and caproic acid. These results indicate that BbF alleviates RA by inhibiting the Notch signaling pathway and regulating gut microbiota, providing new insights for the development of functional foods with immune-modulatory properties.
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产品关联
DOI
PubMed
高影响因子
Foods
·
2025
·Vol. 14
·期 2
·214
·
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
·
微生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Ningjie Chen,Doudou Chai,Liping Gao,Wei Zhang,Haitao Wang,Jincun Yang,Xiuxiang Yu,Shuang Yan,Qingpeng Xu,Siqing Wang
Exosomes have promising applications in accelerating wound healing; however, it remains a challenge for exosomes to effectively promote healing of damaged wounds such as diabetic foot ulcers. The aim of this study was to produce an exosome that promotes wound healing in diabetic foot ulcers and to investigate its potential mechanism. Firstly, graphene oxide/alginate gel loaded with platelet-rich plasma-derived exosomes (GO/Alg + Exo) was prepared and characterized, and then the cytotoxicity and function of the gel were detected in vitro by cell survival, immunofluorescence and scratch test. In vitro experiments were performed to investigate the molecular mechanism of GO/Alg + Exo in promoting diabetic wound healing. Finally, an animal model of diabetic foot ulcer was prepared to study the bioactivity of the gel and the molecular mechanism in vivo. GO/Alg + Exo can promote skin fibrosis, enhance cell proliferation, reduce apoptosis, and promote neoangiogenesis to promote the skin repair of diabetic chronic wounds. In addition, in vitro and in vivo experiments demonstrated that GO/Alg + Exo could promote cell proliferation and angiogenesis by regulating the Notch 1 signaling pathway. GO/Alg + Exo promotes the healing of diabetic foot ulcer wounds by inhibiting the Notch 1 signaling pathway.
研究领域:
纳米医学
·
再生医学
·
糖尿病研究
·
组织工程
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2022
·
IF 5.895
Jiuyan Zhang,Yuan Zhao,Ning Sun,Manyu Song,Yongping Chen,Lin Li,Hailin Cui,Haotian Yang,Chuqiao Wang,Haiyang Zhang,Honggang Fan
Chronic stress induction in immunosuppression and splenocyte apoptosis is commonly associated with increased susceptibility to various diseases. Lycopene (LYC) is a member of the carotenoid family with immune restoration and anti-apoptotic function. However, little is known about the mechanisms underlying the protective roles of LYC against spleen injury induced by chronic stress. Herein, male Wistar rats were undergoing chronic restraint stress and/or administered LYC (10 mg/kg) for 21 days. The effective model establishment was validated by open-field tests and levels of corticosterone in serum. Histopathological staining observation displayed that LYC could reduce chronic stress-induced spleen structure damage. Furthermore, LYC treatment significantly reduced the number of apoptotic-positive splenocytes caused by chronic stress via the death receptor apoptotic pathway. We detected the interleukin 4 and interferon γ levels in serum and spleen to determine the ratio of Th1 and Th2 and found that LYC can alleviate the immunosuppression induced by chronic stress. Notably, western blot and real-time polymerase chain reaction indicated that LYC can reduce the expression of the Notch-pathway-related proteins and mRNA in rats exposed to chronic stress. Further study of the potential mechanisms by adding the Notch pathway inhibitor DAPT revealed that LYC alleviates the structure damage, apoptosis, and immunosuppression caused by chronic stress via the suppression of the Notch pathway. Overall, this study presents a strong rationale to target LYC as a treatment strategy to relieve chronic stress-induced spleen injury.
研究领域:
免疫学
·
药理学
·
分子生物学
·
应激生理学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Yue Xiong,Chao He,Xun Lin,Ke Cheng,Fumei He,Jingxin Zhao,Mengjie Yang,Hong Gao,Fangjie He,Xiaopei Zhang,Zeqi Liu,Gan Liu,Wenbin Deng
Black phosphorus nanosheet (BPNS) has recently demonstrated intrinsic anti-tumor bioactivity, but its underlying molecular mechanism remains unclear, limiting its potential applications in biomedicine. In this study, we investigated the impact of BPNS on glioblastoma cells and observed a significant dose-dependent inhibition of invasion and migration. RNA sequencing analysis revealed downregulation of genes associated with the WNT/β-catenin and NOTCH signaling pathways, both linked to invasion and migration. Mechanistically, BPNS directly binds to CSNK2A2, reducing its kinase activity, which indirectly enhances GSK-3β kinase activity. As a result, GSK-3β increases the phosphorylation level of β-catenin, leading to its degradation and subsequent inhibition of downstream molecules in the WNT/β-catenin signaling pathway. Our study uncovers the inherent biological activity of BPNS in hindering glioblastoma invasion and migration and sheds light on the molecular mechanisms, offering new directions for the nanomaterial’s biomedical applications.
研究领域:
生物医学工程
·
癌症生物学
·
分子生物学
·
纳米技术
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）