International Journal of Oral Science
·
2023
·Vol. 15
·期 1
·1-14
·
IF 14.9
Wang Yushang,Wang Lihua,Sun Tianyong,Shen Song,Li Zixuan,Ma Xiaomei,Gu Xiufeng,Zhang Xiumei,Peng Ai,Xu Xin,Feng Qiang
Fusobacterium nucleatum ( F. nucleatum ) is an early pathogenic colonizer in periodontitis, but the host response to infection with this pathogen remains unclear. In this study, we built an F. nucleatum infectious model with human periodontal ligament stem cells (PDLSCs) and showed that F. nucleatum could inhibit proliferation, and facilitate apoptosis, ferroptosis, and inflammatory cytokine production in a dose-dependent manner. The F. nucleatum adhesin FadA acted as a proinflammatory virulence factor and increased the expression of interleukin(IL)-1β, IL-6 and IL-8. Further study showed that FadA could bind with PEBP1 to activate the Raf1-MAPK and IKK-NF-κB signaling pathways. Time-course RNA-sequencing analyses showed the cascade of gene activation process in PDLSCs with increasing durations of F. nucleatum infection. NFκB1 and NFκB2 upregulated after 3 h of F. nucleatum -infection, and the inflammatory-related genes in the NF-κB signaling pathway were serially elevated with time. Using computational drug repositioning analysis, we predicted and validated that two potential drugs (piperlongumine and fisetin) could attenuate the negative effects of F. nucleatum -infection. Collectively, this study unveils the potential pathogenic mechanisms of F. nucleatum and the host inflammatory response at the early stage of F. nucleatum infection.
研究领域:
微生物学
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免疫学
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分子生物学
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干细胞研究
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药理学
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PubMed
高影响因子
Food Bioscience
·
2020
·
IF 3.067
Zhaoxia Yang,Sasa Liu,Jing Lv,Zeping Sun,Wenhuan Xu,Chaofan Ji,Huipeng Liang,Shengjie Li,Chenxu Yu,Xinping Lin
Chouguiyu (stinky Mandarin fish), a traditional spontaneously fermented fish in China, is famous for its unique aroma and pleasant taste. However, the relationships between the succession of microorganisms during the fermentation and the formation of Chouguiyu 's unique aroma and taste remain to be characterized. In this study, 16S rRNA gene amplicon sequencing was done to investigate the evolving microbiota during Chouguiyu fermentation, and the volatile compounds and amino acids profiles were measured alongside with chemical characterization of the samples (e.g., determination of pH, TVB-N, TBARS , and TCA-soluble peptides). Based on the changes of the microbiota, the fermentation was categorized into two stages: early-fermentation, 1st-3rd days; and late-fermentation, 4th-7th days. Linalool, piperitone, anethole , 1-octen-3-ol, 2-methyl-3-octanone and indole were identified as characteristic volatile compounds in Chouguiyu . According to the sensory evaluation results, the flavor of the Chouguiyu was reinforced in the late-fermentation stage. Redundancy analysis showed the relationships between evolving microbiota and the formation of Chouguiyu 's aroma and taste, and Psychrilyobacter was identified to be the most important bacterial genus contributing to flavor and aroma development, followed by Fusobacterium , Arcobacter and O c eanisphaera . These genera were positively correlated with Glu, Met, Tyr, Pro, linalool, piperitone, indole, TBARS, TVB-N, and TCA , and influenced the flavor and aroma of the Chouguiyu . The results of this study provided a scientific basis to further improve Chouguiyu production.
研究领域:
食品科学
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微生物学
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化学分析
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DOI
高影响因子
ACS Nano
·
2024
·
IF 15.8
Shizhen Geng,Pengke Guo,Xinling Li,Yaru Shi,Jing Wang,Mengnian Cao,Yunya Zhang,Kaixiang Zhang,Airong Li,Haiwei Song,Zhenzhong Zhang,Jinjin Shi,Junjie Liu,Yiling Yang
Immune checkpoint blockade (ICB) therapy has been approved for breast cancer (BC), but clinical response rates are limited. Recent studies have shown that commensal microbes colonize a variety of tumors and are closely related to the host immune system response. Here, we demonstrated that Fusobacterium nucleatum (F.n), which is prevalent in BC, creates an immunosuppressive tumor microenvironment (ITME) characterized by a high-influx of myeloid cells that hinders ICB therapy. Administering the antibiotic metronidazole in BC can deplete F.n and remodel the ITME. To prevent an imbalance in the systemic microbiota caused by antibiotic administration, we designed a biomimetic nanovehicle for on-site antibiotic delivery inspired by F.n homing to BC. Additionally, ferritin-nanocaged doxorubicin was coloaded into this nanovehicle, as immunogenic chemotherapy has shown potential for synergy with ICB. It has been demonstrated that this biomimetic nanovehicle can be precisely homed to BC and efficiently eliminate intratumoral F.n without disrupting the diversity and abundance of systemic microbiota. This ultimately remodels the ITME, improving the therapeutic efficacy of the PD-L1 blocker with a tumor inhibition rate of over 90% and significantly extending the median survival of 4T1 tumor-bearing mice.
研究领域:
肿瘤学
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免疫学
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纳米技术
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微生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 2
·1469
·
IF 5.6
Fengjing Jia,Qun Yu,Ruolei Wang,Ling Zhao,Fuwen Yuan,Haidong Guo,Yunhui Shen,Feng He
Colorectal cancer (CRC) is a major health burden worldwide due to its high morbidity, mortality, and complex etiology.Fusobacterium nucleatum(Fn), a Gram-negative anaerobe found in 30% of CRC patients, promotes CRC carcinogenesis, metastasis, and chemoresistance. Effective antimicrobial treatment is an unmet need for the rising CRC burden. Antimicrobial peptides (AMPs) represent a new class of antimicrobial drugs. In our previous study, we did the structure-activity study of Jelleine-I (J-I) and identified several halogenated J-I derivatives Cl-J-I, Br-J-I, and I-J-I. To determine whether those J-I derivatives can be a new therapy for bacterial-associated CRC, here we tested the antibacterial activities of these AMPs againstFnand their effects on CRC development. We found that Br-J-I showed the highest anti-Fnactivity and Br-J-I may target membrane-associated FadA forFnmembrane disruption. More importantly,Fnpromoted the growth of CRC cells-derived xenograft tumors. Br-J-I suppressedFnload, colon inflammation, andFn-induced CRC growth. Of note, Br-J-I induced better anti-CRC effects than common antibiotic metronidazole and Br-J-I sensitized the cancer-killing effect of chemotherapy drug 5-fluorouracil. These results suggest that Br-J-I could be considered as an adjunctive agent for CRC treatment and AMPs-based combination treatment is a new strategy for CRC in the future.Keywords:colorectal cancer;fusobacterium nucleatum;antimicrobial peptides;adjunctive therapy;antimicrobial treatment
研究领域:
肿瘤学
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微生物学
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药理学
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DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2026
·Vol. 9
·期 36
·17044-17059
·
IF 5.8
Ma Jingwen,Zeng Yun,Wang Xiaoye,Liu Yuan,Xiao Dan,Zhou Bowei,Cai Na,Qiang Rong
Fusobacterium nucleatum ( F.n. ) infection is closely related to poor prognosis
and
high mortality in colorectal cancer (CRC) patients, promotes the proliferation
and migration of CRC cells, induces inflammation, and creates an immunosuppressive
tumor microenvironment. Compared with CRC cells not infected with F.n. , F.n. -infected CRC cells exhibit greater
glycolytic activity, considered as a beneficial metabolic change for
establishing a symbiotic relationship between CRC cells and F.n. In this study, the classical glycolysis inhibitors
2-deoxy- d -glucose (2-DG) and tanshinone IIA (TAN IIA) were
coloaded into zeolitic imidazolate framework-8 nanoparticles (DTZP
NPs) to suppress F.n. -infected CRC growth. TAN IIA
not only eliminated intratumoral F.n. but also acted
as a chemotherapeutic drug against F.n. -infected
CRC cells. DTZP NPs strongly inhibited both the F.n. -infected MC38 tumor model and the azoxymethane (AOM)/dextran sulfate
sodium salt (DSS)-induced spontaneous CRC model by downregulating
the NF-κB/HIF-1α/glycolysis pathway. DTZP NPs’
treatment improved the immunosuppressive tumor microenvironment, decreased
the inflammatory levels in both serum and tumor tissue, and modulated
the gut microbiota and its metabolites. In summary, we proposed combining
anti-intratumoral F.n. with adjusting the tumor metabolism
strategy, which could provide new insights into the treatment of F.n. -infected CRC in the future.
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Nano Today
·
2024
·
IF 13.2
Tengling Wu,Danyang Jin,Mengdi Wu,Youtao Xin,Hongyu Liu,Na Li,Feihe Ma,Yunjian Yu,Bangmao Wang,Jingwen Zhao,Jimin Zhang,Xiongwei Qu,Hui Gao
Fusobacterium nucleatum ( Fn ) adhesion to colorectal cancer (CRC) cells is a prerequisite for chemoresistance evolution. Conventional approaches for overcoming Fn -induced chemoresistance primarily rely on antimicrobial methods, which probably cause bacterial resistance and intestinal microbiome disruption. Here, we propose a non-antimicrobial strategy to counter chemotherapy resistance of Fn -resident CRC by blocking Fn adhesion to cancer cells. Taking inspiration from the natural process of Fn colonization in CRC tissue, where the Fn lectin Fap2 binds to Gal-GalNAc displayed on CRC cells, a N-acetylgalactosamine (GalNAc)-derived nanoplatform is fabricated to disrupt this critical host-pathogen interactions. The nanoplatform (OGPA/P-C) is formulated from GalNAc-modified oligopolyethyleneimine (OEI) conjugated with oxaliplatin (OxPt) and azobenzene (AZO), along with polyethylene glycol- β -Cyclodextrin (PEG-CD) through host-guest interactions. Notably, the PEG-armed OGPA/P-C demonstrates effective accumulation in CRC tumors by evading GalNAc-mediated liver targeting, while exposing GalNAc for specific Fn targeting in response to CRC-associated azo-reductase. GalNAc exposure enables robust inhibition of Fn attachment to CRC through a Fap2-dependent competitive mechanism and overcoming chemotherapy resistance to OxPt by suppressing autophagy activation, which displays exhilarating anticancer effects against Fn -associated CRC both in vitro and in vivo . Overall, this non-lethal antiadhesion strategy holds great promise for boosting the chemotherapeutic efficacy in Fn -burdened solid tumors.
研究领域:
肿瘤学
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药学
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分子生物学
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生物医学工程
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DOI
高影响因子
Acta Biomaterialia
·
2024
·
IF 9.4
Na Li,Yunjian Yu,Qixian Chen,Jiazhen Niu,Chan Gao,Xiongwei Qu,Jimin Zhang,Hui Gao
ABSTRACT Anti-angiogenesis has emerged a promising strategy against colorectal cancer (CRC). However, the efficacy of anti-angiogenic therapy is greatly compromised by the up-regulated autophagy levels resulting from the evolutionary resistance mechanism and the presence of Fusobacterium nucleatum ( F. nucleatum ) in CRC. Herein, we report a cationic polymer capable of blocking autophagic flux to deliver plasmid DNA (pDNA) encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) for enhanced anti-angiogenic therapy against F. nucleatum -associated CRC. The autophagy-inhibiting cationic polymer, referred to as PNHCQ, is synthesized by conjugating hydroxychloroquine (HCQ) into 3,3′-diaminodipropylamine-pendant poly(β-benzyl-L-aspartate) (PAsp(Nors)), which can be assembled and electrostatically interacted with sFlt-1 plasmid to form PNHCQ/sFlt-1 polyplexes. Hydrophobic HCQ modification not only boosts transfection efficiency but confers autophagy inhibition activity to the polymer. Hyaluronic acid (HA) coating is further introduced to afford PNHCQ/sFlt-1@HA for improved tumor targeting without compromising on transfection. Consequently, PNHCQ/sFlt-1@HA demonstrates significant anti-tumor efficacy in F. nucleatum -colocalized HT29 mouse xenograft model by simultaneously exerting anti-angiogenic effects through sFlt-1 expression and down-regulating autophagy levels exacerbated by F. nucleatum challenge. The combination of anti-angiogenic gene delivery and overall autophagy blockade effectively sensitizes CRC tumors to anti-angiogenesis, providing an innovative approach for enhanced anti-angiogenic therapy against F. nucleatum -resident CRC. Statement of Significance Up-regulated autophagy level within tumors is considered responsible for the impaired efficacy of clinic antiangiogenic therapy against CRC colonized with pathogenic F. nucleatum . To tackle this problem, an autophagy-inhibiting cationic polymer is developed to enable efficient intracellular delivery of plasmid DNA encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) and enhance anti-angiogenic therapy against F. nucleatum -associated CRC. HA coating that can be degraded by tumor-enriching hyaluronidase is further introduced for improved tumor targeting without compromising transfection efficiency. The well-orchestrated polyplexes achieve considerable tumor accumulation, efficient in vivo transfection, and effectively reinforce the sensitivity of CRC to the sFlt-1-derived anti-angiogenic effects by significantly blocking overall autophagy flux exacerbated by F. nucleatum challenge, thus harvesting robust antitumor outcomes against F. nucleatum -resident CRC.
研究领域:
癌症生物学
·
分子生物学
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药学
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生物医学工程
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PubMed
高影响因子
Metabolites
·
2023
·Vol. 13
·期 3
·451
·
IF 4.1
Fujian Qin,Jiankang Li,Tianxiao Mao,Shuo Feng,Jing Li,Maode Lai
2-hydroxybutyric acid (2HB) serves as an important regulatory factor in a variety of diseases. The circulating level of 2HB in serum is significantly higher in multiple diseases, such as cancer and type 2 diabetes (T2D). However, there is currently no systematic study on 2HB-producing bacteria that demonstrates whether gut bacteria contribute to the circulating 2HB pool. To address this question, we used BLASTP to reveal the taxonomic profiling of 2HB-producing bacteria in the human microbiome, which are mainly distributed in the phylum Proteobacteria and Firmicutes. In vitro experiments showed that most gut bacteria (21/32) have at least one path to produce 2HB, which includes Aspartic acid, methionine, threonine, and 2-aminobutyric acid. Particularly,Fusobacterium nucleatumhas the strongest ability to synthesize 2HB, which is sufficient to alter colon 2HB concentration in mice. Nevertheless, neither antibiotic (ABX) norFusobacterium nucleatumgavage significantly affected mouse serum 2HB levels during the time course of this study. Taken together, our study presents the profiles of 2HB-producing bacteria and demonstrates that gut microbiota was a major contributor to 2HB concentration in the intestinal lumen but a relatively minor contributor to serum 2HB concentration.Keywords:2-hydroxybutyric acid;gut microbiota;HMP;taxonomic identification;Fusobacterium nucleatum
研究领域:
微生物学
·
分子生物学
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医学研究
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Shuang Xie,Li Wei,Yuan Liu,Jie Meng,Wenxiong Cao,Bo Qiu,Xiaohong Li
Bacteria play important roles in tumor formation, growth and metastasis through downregulating immune response and initiating drug resistance. Herein, size-tunable nanogels (NGs) have been developed to address the existing size paradox in tumor accumulation, intratumoral penetration and intracellular release of therapeutics for the treatment of Fusobacterium nucleatum ( F. nucleatum )-infected colorectal cancer . Zinc-imidazolate frameworks with doxorubicin (DOX) loading and folate grafting (f-ZIF D ) were mixed with metronidazole (MET) and encapsulated in NGs through thiol-ene click crosslinking of sulfhydryl hyaluronan , sulfhydryl alginate and 4-arm poly(ethylene glycol) acrylate . Hyaluronidase-initiated matrix degradation causes NG swelling to release sufficient MET and maintains a large size for an extended time period, and the gradually discharged f-ZIF D nanoparticles (NPs) from NGs exhibit acid-responsive intracellular release of DOX after folate-mediated internalization into tumor cells. The encapsulation into NGs significantly enhances the bioavailability and increases half-lives of MET and DOX by around 20 times. In the F. nucleatum -infected tumor model, the extended retention of swollen NGs and the efficient tumor infiltration and cellular uptake of the discharged f-ZIF D NPs cause 6 times higher DOX levels in tumors than that of free DOX administration. F. nucleatum promotes tumor cell proliferation and tumor growth, and the cascaded releases of MET and f-ZIF D NPs eliminate F. nucleatum to effectively inhibit tumor growth with a significant extension of animal survival. Thus, the hyaluronidase-mediated NG expansion and dual-responsive cascaded drug release have overcome challenges in the release regimen and size paradox of drug delivery carriers to combat bacteria-infected cancer.
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高影响因子
Cell Communication and Signaling
·
2025
·Vol. 24
·期 1
·6
·
IF 8.9
Yang Xinyi,Ning Tingting,Zhang Wanru,Hou Songyuan,Su Jiayi,Li Wenkun,Wu Jing
Background Gastric microbiota dysbiosis is closely linked to chronic inflammation and carcinogenesis. Fusobacterium nucleatum ( Fn ), an opportunistic gastrointestinal pathogen, is implicated in perturbing the immune system and form an inflammatory microenvironment that fuels the occurrence and progression of gastric cancer (GC). However, the underlying mechanisms remain elusive. We aimd to investigate the impacts of Fn on GC cells and the crosstalk between GC cells and mast cells (MCs). Methods Fn abundance and MC infiltration were assessed in clinical GC tissues. Cell-based functional experiments, including wound healing, transwell, and ELISA, were performed using conditioned medium-based co-culture systems to explore how Fn influenced GC cell migration and the crosstalk with MC. A murine lung metastasis model was employed to evaluate Fn -driven metastasis and the effects of metronidazole and Reparixin. Results We showed that Fn and MCs were enriched and positively correlated in clinical GC tissues compared to paracancerous tissues. Fn and MCs exhibited tumor-promoting properties by facilitating GC cell migration. Besides, Fn and GC cells can recruit MCs and facilitate its activation. This crosstalk between GC cells and MCs was further enhanced by Fn , thereby amplifying this positive feedback loop between them. The production of CXCL8 in response to Fn stimulation was a significant mediator. Suppression of CXCL8 in GC cells weakened Fn ’s promoting effects on GC cell migration, MC recruitment and activation. Similarly, knocking down CXCL8 in MCs reversed the Fn -induced feedback effect of MCs on the highly invasive phenotype of GC cells. Mechanistically, the exoprotein Gbp of Fn activated CypA-NF-κB pathway in both GC cells and MCs, leading to the upregulation of CXCL8 expression. In addition, the in vivo assays substantiated Fn ’s ability to enhance tumor progression by facilitating cell migration, upregulating CXCL8 expression, and inducing MC infiltration and activation. However, these effects were reversed by metronidazole, a highly Fn -susceptible antibiotic, and Reparixin. Conclusions In summary, this study suggests that Fn contributes to GC progression by promoting tumor cell migration, MCs recruitment and activation. Simultaneously, the enhanced CXCL8-mediated crosstalk between GC cells and MCs plays a vital role in the pro-cancer effect of Fn.
研究领域:
肿瘤学
·
微生物组学
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免疫肿瘤学
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分子肿瘤学
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炎症与癌症
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信号转导
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PubMed
高影响因子
BMC CANCER
·
2023
·Vol. 23
·期 1
·1-14
·
IF 3.8
Lau Hui-Ching,Yuan Xiaohui,Huang Huiying,Zhang Ming,Hsueh Chi-Yao,Gong Hongli
Background To investigate how Fusobacterium nucleatum (Fn) promotes oxidative stress and mediates proliferation and autophagy in hypopharyngeal squamous cell carcinoma (HPSCC).Methods The prognosis for 82 HPSCC cases was retrospectively analyzed. HPSCC cell line FaDu was co-cultured with Fn. Knockdown of NUDT1 (shNUDT1 group) was done after observing DNA damage response. CCK8 and tumorigenesis assays for proliferation observation, mitochondria ROS (MitoROS) measurement to examine intracellular oxidative stress, and ELISA to analyze concentration of 8-oxo-2’-deoxyguanosine (8-oxo-dG) in cells. Dual-luciferase reporter assays clarified miR-361-3p connection with NUDT1. Autophagy flow was observed using electron microscopy and related proteins.Results Fn was highly associated with NUDT1. The shNUDT1 group experienced lower proliferation compared with normal FaDu (NC group) in vivo and in vitro. The shNUDT1 group showed 8-oxo-dG and γH2AX to be elevated. Intracellular ROS decreased in shNUDT1Fn group when compared to Fn group. Upregulating miR-361-3p could suppress NUDT1 expression and downstream proliferation and autophagy. Fn modulated miR-361-3p via OH−, which could be proven by H2O2 assay and N-acetylcysteine.Conclusion sHigher Fn in HPSCC patients suggests poorer prognosis. NUDT1 might affect cell proliferation and autophagy and modulate DNA damage response. The oxidative stress induced miR-361-3p/NUDT1 axis is first introduced in microbiome-carcinoma research.
研究领域:
肿瘤学
·
微生物学
·
分子生物学
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DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2025
·Vol. 23
·期 1
·1-18
·
IF 7.5
Dong Rui,Li Meihui,Gu Xiu Feng,Gao Haiting,Wei Ziyi,Qi Houbao,Zhang Jun,Feng Qiang
Background Periodontitis is a chronic inflammatory disease that significantly impacts periodontal bone regeneration, yet the distinct biological features of osteoblasts in this condition remain poorly understood. This study aims to elucidate the cellular and molecular mechanisms underlying osteoblast dysfunction in periodontitis, with a focus on the role of Fusobacterium nucleatum (Fn) and its effector protein, D-galactose-binding periplasmic protein (Gbp).MethodSingle-cell RNA sequencing (scRNA-seq) data from human gingival tissues of periodontitis patients (PD) and healthy controls (HC) were analyzed to identify cellular heterogeneity and molecular pathways. An experimental periodontitis model in mice and primary osteoblast cultures were used to investigate the effects of Fn and Gbp on osteogenic differentiation. Transcriptomic analysis, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks were employed to explore the underlying mechanisms.Results scRNA-seq revealed a reduction in mesenchymal stem cells (MSCs) and osteoblastic lineage cells in PD tissues, with significant downregulation of osteogenic pathways such as Wnt signaling. Fn infection induced alveolar bone destruction in vivo and inhibited osteoblast proliferation, differentiation, and mineralization in vitro. Gbp, an Fn adhesin, similarly impaired osteogenic differentiation by downregulating key osteogenic genes and pathways. Transcriptomic analysis identified shared inflammatory and osteogenic pathways affected by Fn and Gbp, with NF-κB signaling activated and Wnt/β-catenin signaling inhibited. Mechanistically, Gbp interacted with the host protein ANXA2, disrupting the ANXA2/GSK3β complex and inhibiting Wnt/β-catenin signaling, a pivotal route for osteoblast differentiation. ANXA2 knockdown mitigated the Fn/Gbp-induced suppression of osteogenic activity, emphasizing its role in Fn-induced bone loss.Conclusion This study demonstrates that Fn and its effector Gbp disrupt osteogenic differentiation by inactivating the Wnt/β-catenin pathway binding to ANXA2.
研究领域:
微生物学
·
分子生物学
·
口腔健康
·
干细胞研究
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）