ENZYME AND MICROBIAL TECHNOLOGY
·
2017
·
IF 2.502
Ren-Chao Zheng,Xiao-Ling Tang,Hui Suo,Li-Lin Feng,Xiao Liu,Jian Yang,Yu-Guo Zheng
Tyrosine phenol-lyase (TPL) catalyzes the reversible cleavage of l -tyrosine to phenol, pyruvate and ammonia. When pyrocatechol is substituted for phenol, l -dihydroxyphenylalanine ( l -DOPA) is produced. The TPL-catalyzed route was regarded as the most economic process for l -DOPA production. In this study, a novel TPL from Fusobacterium nucleatum ( Fn -TPL) was successfully overexpressed in Escherichia coli and screened for l -DOPA synthesis with a specific activity of 2.69 U mg −1 . Fn -TPL was found to be a tetramer, and the optimal temperature and pH for α, β-elimination of l -tyrosine was 60 °C and pH 8.5, respectively. The enzyme showed broad substrate specificity toward natural and synthetic l -amino acids. Kinetic analysis suggested that the k cat / K m value for l -tyrosine decomposition was much higher than that for l -DOPA decomposition, while Fn -TPL exhibited similar catalytic efficiency for synthesis of l -tyrosine and l -DOPA. With whole cells of recombinant E. coli as biocatalyst, l -DOPA yield reached 110 g L −1 with a pyrocatechol conversion of 95%, which was comparable to the reported highest level. The results demonstrated the great potential of Fn -TPL for industrial production of l -DOPA.
研究领域:
生物化学
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酶学
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微生物学
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DOI
高影响因子
BIOPROCESS AND BIOSYSTEMS ENGINEERING
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2018
·Vol. 41
·期 9
·1347-1354
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IF 2.139
Tang Xiao-Ling,Liu Xiao,Suo Hui,Wang Zhi-Chao,Zheng Ren-Chao,Zheng Yu-Guo
The tyrosine phenol lyase (TPL) catalyzed synthesis of L-DOPA was regarded as one of the most economic route for L-DOPA synthesis. In our previous study, a novel TPL from Fusobacterium nucleatum ( Fn -TPL) was exploited for efficient biosynthesis of L-DOPA. However, the catalytic efficiency decreased when the reaction system expanded from 100 mL to 1 L. As such, the bioprocess for scale-up production of L-DOPA was developed in this study. To increase the stability of substrate and product, as well as decrease the by-product formation, the optimum temperature and pH were determined to be 15 °C and pH 8.0, respectively. The initial concentration of pyrocatechol, pyruvate and ammonium acetate was fixed at 8, 5 and 77 g/L and a fed-batch approach was applied with sodium pyruvate, pyrocatechol and ammonium acetate fed in a concentration of 5, 5 and 3.5 g/L, respectively. In addition, L-DOPA crystals were exogenously added to inhibit cell encapsulation by the precipitated product. The final L-DOPA concentration reached higher than 120 g/L with pyrocatechol conversion more than 96% in a 15-L stirred tank, demonstrating the great potential of Fn -TPL for industrial production of L-DOPA.
研究领域:
生物化学
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微生物学
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制药工程
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2024
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IF 10.7
Pengrong Zhu,Lingtong Meng,Yue Shu,Yuqiao Xu,Weiming Liu,Yong Bi,Jian Xu,Lijuan Meng,Yanan Li
The abundance of Fusobacterium nucleatum ( F. nucleatum ) is highly associated with the development and poor prognosis of colorectal cancer (CRC), which is regarded as a promising target for CRC. However, until now, the novel strategy to clear F. nucleatum in the colon and CRC has not been well proposed. Herein, a probiotic strain Enterococcus faecium ( E. faecium , EF47) is verified to secrete various organic acids and bacteriocins to exert superior antimicrobial activity towards F. nucleatum . However, the oral delivery of EF47 is affected by the complex digestive tract environment, so we design the hyaluronic acid-inulin (HA-IN) coated EF47 for colon-targeted delivery to fight F. nucleatum . IN can protect EF47 from the harsh gastrointestinal tract environment and is degraded specifically in the colon, acting as prebiotics to further promote the proliferation of EF47. The exposed HA can also enhance the targeting effect to the tumor area via the interaction with the CD44 receptor on the tumor cells, which is confirmed to increase the adhesive ability in tumor tissues and inhibit the growth of F. nucleatum . Therefore, this colon-targeted delivery system provides a novel platform to realize high-activity and adhesive delivery of probiotics to assist the therapeutic efficiency of CRC.
研究领域:
微生物学
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药学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Nano Today
·
2025
·
IF 10.9
Shengke Zhao,Yunjian Yu,Youtao Xin,Hegang Lu,Xiaohui Li,Shuyu Wang,Feihe Ma,Hui Gao
The gut microbiota plays a crucial role in host immune modulation and maintaining homeostasis. An abnormal increase in certain pathogens such as Fusobacterium nucleatum ( Fn ) can break homeostasis and drive the progression of various intestinal diseases. Supplementing probiotics can partially counteract these effects without flora disturbance. However, broad-spectrum antibacterial treatments are not compatible with probiotic therapy in a therapeutic system due to their non-selective damage on both probiotics and the overall gut microbiota. Herein, we screen and identify lauric acid (LA)-derived lipid, S12, from a combinatorial library of 12 chemically diverse lipids for its selective antibacterial activity against Fn over probiotic Clostridium butyricum ( Cb ). This lipid is then utilized as a single-cell carrier to orally deliver Cb ( Cb @S12) for enhanced treatment of Fn -associated intestinal diseases. The surface arming of S12 effectively protects Cb from simulated gastric and intestinal fluids, thus significantly prolonging its intestinal retention in mice. Oral administration of Cb @S12 has demonstrated impressive therapeutic outcomes against Fn -aggravated inflammatory bowel disease and orthotopic colorectal cancer by selectively eliminating Fn while preserving the probiotic activity of Cb . This study introduces a robust approach using selectively antibacterial lipids for probiotic encapsulation, offering an antibiotic-free “probiotic-antagonistic” combination therapeutic strategy for intestinal diseases.
研究领域:
微生物学
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医学
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药理学
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DOI
高影响因子
Microbiology Spectrum
·
2023
·Vol. 11
·期 6
·
IF 3.7
Minyu Wang,Zheng Wang,Duncan James Lessing,Min Guo,Weihua Chu
Fusobacterium nucleatum is a harmful bacterium that produces hydrogen sulfide by metabolizing sulfur-containing amino acids, both of which have been shown to promote/initiate the development of various cancers, such as colorectal cancer, liver cancer, as well as lung cancer. However, few studies have reported how F. nucleatum acts on gut microbiota, influences the autophagy process, and promotes the development of colorectal cancer through the metabolite hydrogen sulfide. It was found that HCT116 cells secreted more inflammatory factors and showed higher survival as well as migration rate when given a pathological concentration of hydrogen sulfide. Using cellular transcriptome sequencing, it could be seen that after giving HCT116 cells F. nucleatum or F. nucleatum with L-cysteine, many inflammation-related signaling pathways, including autophagic pathways, were elevated compared to the control group. In vivo, the mice in the model groups displayed cancer progression, and the expression of some of the autophagy-related genes, DRAM1, NBR1, ATG7, MAP1LC3A were also increased in mice given F. nucleatum or F. nucleatum with L-cysteine when compared to the untreated control mice. The number of certain probiotic bacteria and fungi in the mice given F. nucleatum or F. nucleatum and L-cysteine decreased significantly; in contrast, the number of potentially pathogenic bacteria and fungi increased. These findings suggest that F. nucleatum and its metabolite hydrogen sulfide can modulate intestinal microbiota and autophagy as well as promote the development and progression of colorectal cancer.
研究领域:
微生物学
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癌症生物学
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分子生物学
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胃肠病学
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DOI
高影响因子
Cell Host & Microbe
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2025
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IF 18.7
Jing Yu,Yuxuan Liang,Qingrong Zhang,Hui Ding,Minghao Xie,Jingjing Zhang,Wenyan Hu,Sihua Xu,Yiyuan Xiao,Sha Xu,Rong Na,Baixing Wu,Jiaming Zhou,Haitao Chen
Intratumoral microbiota plays a crucial role in cancer progression. However, the relationship between host genetics and intratumoral microbiota, as well as their interaction in colorectal cancer (CRC) progression, remains unclear. With 748 Chinese CRC patients enrolled from three cohorts, we find that the single nucleotide polymorphism (SNP) rs2355016, located in the intron of ATP-sensitive inward rectifier potassium channel 11 ( KCNJ11 ), is significantly associated with the abundance of Fusobacterium . Compared with the rs2355016 GG genotype, patients carrying the A allele exhibit downregulation of KCNJ11 and enrichment of Fusobacterium , which corresponds to accelerated proliferation and progression. Low expression of KCNJ11 can increase the level of galactose-N-acetyl-d-galactosamine (Gal-GalNAc) on the surface of CRC cells, thereby facilitating the binding of the Fap2 protein from F. nucleatum to Gal-GalNAc. This further enhances the adhesion and invasion of F. nucleatum and promotes CRC growth. Our study explores the interaction between intratumoral microbiota and SNPs in CRC patients, which will enhance our understanding of CRC proliferation.
研究领域:
医学
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遗传学
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微生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL MICROBIOLOGY
·
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
Nature Microbiology
·
2026
·
IF 18.7
Zhang Yue,Zhao Ying,Zhang Lu,Xuan Baoqin,Wang Zhenyu,Yu Bin,Li Weixun,Huang Xiaowen,Zhou Yilu,Ning Lijun,Ding Jinmei,Jiang Yi,Hu Muni,Shao Yuqi,Li Lingxi,Gao Xiang,Chen Shengliang,Chen Haoyan,Wang Fei,Cui Zhe,Fang Jing-Yuan,Hong Jie
Gut dysmotility is a common long-term effect of enterotoxigenic Bacteroides fragilis (ETBF) colonization but the underlying mechanisms are not clear. Here, using mouse colonization models, we found that ETBF-secreted B. fragilis toxin (BFT) causes loss of colonic myenteric neurons, which are crucial regulators of intestinal motility. BFT induced apoptosis in these neurons through the NOD1–RIPK2–CASP9–CASP3 pathway, leading to gut dysmotility that persisted even after the clearance of ETBF. Analyses of human inflammatory bowel disease and colorectal cancer patient cohorts showed a positive correlation between ETBF and Fusobacterium nucleatum abundance. In mice, F. nucleatum -derived 2-hydroxybutyric acid enhanced BFT production in ETBF by alleviating RprY-mediated suppression and aggravated neurotoxicity and dysmotility. This enteric neuron loss and dysmotility enhanced susceptibility to dextran sulfate sodium-induced colitis in mice. Therapeutically, a Bifidobacterium -based probiotic attenuated neuron toxicity and improved intestinal motility. Our findings reveal bacterial interactions regulating intestinal function and a potential clinical therapeutic approach to preventing outcomes of ETBF colonization.
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DOI
高影响因子
International Journal of Nanomedicine
·
2026
·
IF 8.7
Tan Wu,Xuejie Fei,Dan Xu,Qian Chen,Yang Zhang,Yuqin Jin,Yang Yang,Huanlong Qin,Fengzhou Du,Cheng Li
Purpose This study aimed to develop a nanocatalytic-microbial therapeutic platform for colorectal cancer (CRC) that simultaneously eliminates the tumor-associated pathobiont Fusobacterium nucleatum (F. nucleatum) and enhances catalytic tumor therapy.Methods An iron-based metal-organic framework (NH2-MIL-88B(Fe) composed of Fe3+ clusters and 2-aminoterephthalic acid, BDC-NH2) loaded with silver nanoparticles (NH2-MIL-88B(Fe)@Ag, denoted as MA) was constructed to integrate antibacterial activity with reactive oxygen species (ROS)-mediated tumor killing. The physicochemical properties, catalytic activity, and antibacterial performance of MA were characterized. Extracellular and intracellular ROS generation, cellular uptake, and cytotoxicity were evaluated in CRC cells. In vivo antitumor efficacy and biosafety were further assessed in a CT26 mouse colon cancer cells (CT26) subcutaneous tumor model with or without F. nucleatum inoculation.Results MA exhibited enhanced Fenton-like catalytic activity and generated more hydroxyl radicals than MOF alone in the presence of H2O2, indicating that Ag nanoparticles amplified ROS production. MA also showed potent antibacterial activity against F. nucleatum, enabling concurrent disruption of intratumoral bacteria and tumor cells. In vitro, MA induced pronounced ROS accumulation and significantly reduced CRC cell viability. In vivo, MA markedly suppressed tumor growth, with superior therapeutic efficacy in F. nucleatum-colonized tumors, demonstrating that bacterial elimination contributed substantially to tumor inhibition. No evident systemic toxicity was observed during treatment.Conclusion MA is a promising nanocatalytic platform for CRC therapy that combines direct antibacterial action against F. nucleatum with amplified ROS-mediated tumor cell killing. This dual-target strategy offers an effective and biocompatible approach for CRC treatment by integrating microbiota intervention with nanocatalytic therapy.
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DOI
PubMed
高影响因子
ACS Infectious Diseases
·
2024
·
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
·
药理学
·
生物技术
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Tengling Wu,Fuping Zhang,Hongyu Liu,Feihe Ma,Yunjian Yu,Daxi Sun,Jujin Ren,Wentao Wang,Mahmoud Elsabahy,Hui Gao
Targeted eradication of Fusobacterium nucleatum ( Fn )-dominated biofilms within the colorectal cancer (CRC) microenvironment emerges as a promising strategy to overcome bacterial resistance and reverse immunosuppression. Herein, pH-responsive biofilm-targeting polymeric micelles (ERPNPs) are developed to disrupt biofilm-immune crosstalk for CRC immunotherapy. The ERPNPs are constructed by co-loading rifampicin (RIF) and epigallocatechin gallate (EGCG, a biofilm-dispersing agent) into self-assembled polymeric micelles incorporating a FadA-targeting peptide (Pep) for specific biofilm recognition. At physiological pH, the polyethylene glycol shell facilitates efficient tumor accumulation of ERPNPs, while in the acidic tumor microenvironment, protonation of poly(β-amino ester) (PAE) segments trigger conformational switching, exposing the Pep for specific recognition of Fn biofilms through FadA-Pep ligand-receptor interactions, accompanied by pH-responsive release of RIF and EGCG. In vitro experiments demonstrate that ERPNPs can efficiently scavenge Fn biofilms via pH-dependent and FadA-Pep-mediated targeted adhesion. In vivo studies further reveal their excellent biocompatibility, robust biofilm-scavenging, and anti-tumor activities. Mechanistically, ERPNPs eradicate Fn biofilms and reduce immunosuppressive polyamine metabolites, thereby eliciting systemic immune responses characterized by M1 macrophage polarization, suppressed recruitment of myeloid-derived suppressor cells (MDSCs), and enhanced T-cell infiltration, ultimately potentiating anti-tumor efficacy. Overall, this study provides an innovative strategy for targeted elimination of intra-tumoral pathogens and reversal of CRC-related immunosuppression.
研究领域:
肿瘤学
·
微生物组研究
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免疫治疗
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纳米医学
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药物递送
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Gut Microbes
·
2024
·
IF 12.2
Fangfang Chen,Songhe Guo,Yiqiu Li,Yongfan Lu,Le Liu,Shengxin Chen,Jun An,Ge Zhang
The intracellular bacterium Fusobacterium nucleatum (Fn) mediates tumorigenesis and progression in colorectal cancer (CRC). However, the origin of intratumoral Fn and the role of Fn-infected immunocytes in the tumor microenvironment remain unclear. Here, we observed that Fn-infected neutrophils/macrophages (PMNs/MΦs), especially PMNs, accumulate in tumor tissues and fecal Fn abundance correlates positively with an abundance of blood PD-L1+ PMNs in CRC patients. Moreover, Fn accumulates in tumor tissues of tumor-bearing mice via intragingival infection and intravenous injection. Mechanistically, Fn can survive inside PMNs by reducing intracellular ROS levels and producing H2S. Specifically, the lysozyme inhibitor Fn1792 as a novel virulence factor of Fn suppressed apoptosis of phagocytes by inducing CX3CR1 expression. Furthermore, Fn-driven CX3CR1+PD-L1+ phagocytes transfer intracellular Fn to tumor cells, which recruit PMNs/MΦs through the CXCL2/8-CXCR2 and CCL5/CCR5 axes. Consequently, CX3CR1+PD-L1+ PMNs infiltration promotes CRC metastasis and weakens the efficacy of immunotherapy. Treatment with the doxycycline eradicated intracellular Fn, thereby reducing the CX3CR1+PD-L1+ PMNs populations and slowing Fn-promoted tumor growth and metastasis in mice. These results suggest phagocytes as Fn-presenting cells use mutualistic strategies to home to tumor tissues and induce immunosuppression, and treatment with ROS-enhanced antibiotics can inhibit Fn-positive tumor progression.
研究领域:
肿瘤学
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免疫学
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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
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