INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2023
·Vol. 24
·期 2
·1469
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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
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
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微生物学
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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
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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
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分子生物学
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口腔健康
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干细胞研究
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产品关联
DOI
PubMed
高影响因子
ACS Infectious Diseases
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2024
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IF 4
Zhao Liu,Yijie Wang,Chen Zhang,Yongshuai Yang,Junfeng Zhang
Antimicrobial peptides (AMPs) are becoming next-generation alternative antibacterial agents because of the rapid increase in resistance in bacteria against existing antibiotics, which can also be attributed to the formation of resilient biofilms. However, their widespread use is limited because of their poor absorption, higher dosage requirements, and delayed onset of the bioactivity to elicit a desired response. Here we developed a short AMP that specifically targeted Fusobacterium nucleatum. We conjugated 23R to a statherin-derived peptide (SDP) through rational design; this conjugate binds to FomA, a major porin protein of F. nucleatum. The SDP-tagged 23R exhibited rapid and highly specific bactericidal efficacy against F. nucleatum. Further, IC50 values were in the nanomolar range, and they were 100-fold lower than those obtained with unconjugated 23R. In a human gut microbiota model, 0.1 nM SDP–23R achieved 99% clearance of F. nucleatum ATCC 25586 without markedly altering resident microbiota. Here we demonstrated that binding-peptide-coupled AMPs show increased killing efficacy and specificity for the target pathogen without affecting the resident microbiota.
研究领域:
微生物学
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药理学
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生物技术
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DOI
PubMed
高影响因子
Frontiers in Microbiology
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2025
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IF 4.5
Yuqi Wang,Jun Ma,Haoyu Wang,Jingzheng Yi,Yuxin Bai,Min Hu,Jiaqing Yan
Introduction: Periodontitis and inflammatory bowel disease are chronic inflammatory diseases with shared epidemiological, biological, and therapeutic associations. Given the similarities in their pathogenic factors, this study hypothesized that mesalazine, a key treatment agent for inflammatory bowel disease, could also be effective in managing periodontitis.Methods: The antimicrobial effect of mesalazine on Porphyromonas gingivalis was investigated in vitro, including observations of morphological changes on the surface of P. gingivalis. Additionally, the impact of mesalazine on both the formation and established plaque biofilms was examined. The antimicrobial mechanism was elucidated by assessing the expression of P. gingivalis virulence genes and by determining the disruptive effect on P. gingivalis cell membranes. An in vivo rat model of periodontitis was constructed to evaluate mesalazine’s efficacy and its influence on the periodontal bacterial flora in the context of periodontitis.Results and discussion: Our results demonstrated that mesalazine concentrations ranging from 0.5 to 2 mg/mL significantly inhibited P. gingivalis proliferation over 72 h. Flow cytometry revealed a marked reduction in the number of viable cells following mesalazine treatment. At the nanometer scale, mesalazine induced crumpling and rupture of the P. gingivalis surface, compromising cell membrane integrity. Mesalazine not only suppressed the formation of plaque biofilms by P. gingivalis and polymicrobial communities but also disrupted pre-existing biofilms. The data also suggested that mesalazine could disrupt the integrity of the P. gingivalis cell membrane and inhibit the expression of virulence factors. An animal model of periodontitis in rats was successfully constructed in vivo. Mesalazine treatment inhibited alveolar bone resorption, alleviated inflammation of periodontal tissues, and improved the composition of the periodontal flora to a healthier state. This study establishes that mesalazine can treat periodontitis through modulation of the periodontal flora and its anti-inflammatory properties, thus broadening its classical therapeutic applications.
研究领域:
牙科
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微生物学
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药理学
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感染病学
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DOI
PubMed
高影响因子
Metabolites
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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
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分子生物学
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医学研究
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DOI
PubMed
高影响因子
International Journal of Oral Science
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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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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL MICROBIOLOGY
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2024
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IF 2.3
Wang Minyu,Chu Weihua
Oral opportunistic pathogen Fusobacterium nucleatum can participate in various disease processes through the metabolite hydrogen sulfide, such as halitosis and colorectal cancer. The object of this study is to identify inhibitor capable of suppressing Fn1220, which is the principal hydrogen sulfide-producing enzyme in F . nucleatum . Through this inhibition, we aim to reduce the hydrogen sulfide production of F . nucleatum , consequently diminishing its virulence. Employing molecular docking techniques for inhibitor screening, we identified dencichine as the monomeric compound from Chinese medicine exhibiting the lowest binding energy to Fn1220 among a set of 27,045 candidates, and evaluated in vitro the ability of dencichine to inhibit hydrogen sulfide production using bismuth chloride method. Additionally, we investigated its impact on key virulence factors, including biofilm formation, hemolysis, and adhesion factors of F . nucleatum , using the crystalline violet method, sheep blood method, and RT-qPCR, respectively. Furthermore, we assessed the influence of dencichine on the lifespan of Caenorhabditis elegans . Results showed that dencichine was a suitable inhibitor of the Fn1220 of F . nucleatum , which significantly inhibited the production of virulence factors, e.g., biofilm, hemolysin, FadA, and Fap2 of F . nucleatum and improved the survival of C . elegans . We successfully identified the inhibitor of the enzyme Fn1220, dencichine, which inhibited the production of hydrogen sulfide and attenuated the virulence of F . nucleatum and holds promise as a potential therapeutic avenue for addressing oral diseases, e.g., halitosis in the future.
研究领域:
微生物学
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药理学
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分子生物学
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传染病学
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口腔健康
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产品关联
DOI
PubMed
高影响因子
Nano Today
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2021
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IF 20.722
Zhao-Xia Chen,Jiang-Lan Li,Pei Pan,Peng Bao,Xuan Zeng,Xian-Zheng Zhang
Gut microbiota is closely related to the tumorigenesis and progression of colorectal cancer (CRC), especially Fusobacterium nucleatum ( Fn ) could promote colorectal tumor growth and cause chemoresistance. Here, we developed a tumor-triggered release drug delivery gel to inhibit CRC cell growth in situ by intestinal perfusion . Antibiotic metronidazole (MTZ) and 5-fluorouracil (5-FU), the first-line chemotherapy drug of CRC, are individually incorporated into metal polyphenol network-coated mesoporous silica nanoparticle (MSN), and then blended with carboxymethyl cellulose (CMC) to obtain an anti-CRC gel, AB-Gel. In vivo studies showed that AB-Gel could efficiently inhibit the growth and metastasis of CRC in an orthotopic mouse model attributing to the MTZ-induced modulation in the CRC-related microbiota. Chemotherapy efficacy against orthotopic CRC was significantly enhanced by the elimination of Fn . This strategy based on the combination of gut microbiota modulation and chemotherapy would be considered as an enhanced strategy for CRC treatment with potential use in the clinic.
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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癌症治疗
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产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Renchuan Liang,Feng Lin,Xuezhong Mo,Jie Long,Weizhong Tang,Tao Luo,Yunxi Huang
The susceptibility of colorectal cancer (CRC) cells to Fusobacterium nucleatum (F. nucleatum) infection pose significant challenges to CRC treatment and prevention. This study addresses these challenges by mobilizing cGAS/STING axis activation and F. nucleatum-specific targeting, thereby achieving a multimodal treatment strategy for reversing the immunosuppressive microenvironment (ITM) and achieving targeted anti-F. nucleatum therapy. Specifically, a hybrid nanoplatform CuPpIX@HM was engineered using Escherichia coli and tumor cell membranes encapsulating ultrasound (US) stimulation-responsive copper protoporphyrin IX (CuPpIX). This design enables the precise accumulation of the nanoplatform at tumor sites following oral administration. Notably, upon US activation, CuPpIX generates a high level of reactive oxygen species (ROS), selectively eradicating F. nucleatum and exerting potent antitumor effects. Meanwhile, bacterial membrane components activate the cGAS/STING signaling pathway, effectively reversing the ITM, enhancing systemic antitumor immunity. Importantly, CuPpIX@HM exerts minimal disruption to healthy intestinal microbiota and remarkably increases the level of probiotics. In both orthotopic and liver metastasis, CRC models demonstrated that this strategy could significantly inhibit tumor growth and metastasis. Collectively, our study presents a highly targeted multimodal nanotherapy that holds strong potential to improve CRC treatment outcomes through the precision modulation of F. nucleatum and immune activation.
研究领域:
纳米医学
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免疫治疗
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微生物学
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肿瘤学
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生物工程
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产品关联
DOI
PubMed
高影响因子
Nano Today
·
2024
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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
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2024
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IF 4.9
Yuan Tian,Yunjia Song,Jialin Liu,Suli Lan,Bo Chen,Ying Li,Jianmin Han
Periodontitis is a bacteria-induced infectious disease that can lead to tooth loss and contribute to various systemic conditions. Current nonsurgical therapies, such as mechanical debridement with antibiotics administration, face significant challenges, including limited access to bacteria hard-to-reach areas and the risk of antibiotic resistance. To address these issues, we developed Zinc Phthalocyanine-loaded Mesoporous Polydopamine (ZnPc-MPDA) nanoparticles, which demonstrate excellent photothermal (PTT) and photodynamic (PDT) properties. ZnPc-MPDA nanoparticles penetrate deep into periodontal lesions, effectively eliminating dental biofilms and killing bacteria under light irradiation without inducing antibiotic resistance. In vitro , ZnPc-MPDA showed good biocompatibility with fibroblasts at an optimal concentration of 100 μg/mL. Antibacterial rates against periodontitis-associated bacteria Fusobacterium nucleatum ( F. nucleatum ) and Streptococcus gordonii ( S. gordonii ) were 99.96 % and 99.94 %, respectively, under successive irradiation with 808 nm and 635 nm lasers. Additionally, biofilm survival rates of F. nucleatum and S. gordonii after ZnPc-MPDA treated were 17.5 % and 13.7 %, respectively. The superior antibacterial efficacy of ZnPc-MPDA can be attributed to the synergistic effects of PTT and PDT. In a rat periodontitis model, ZnPc-MPDA demonstrated light-activated, safe, and efficient antibacterial activity with mild photothermal effects, reducing alveolar bone resorption, inflammation, and collagen degradation. Overall, this study presents a promising photothermal/photodynamic synergistic strategy for the treatment of periodontitis.
研究领域:
牙科学
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纳米技术
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治疗学
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细菌学
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材料科学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）