Acta Biomaterialia
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2025
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IF 9.6
Liting Lin,Qingrong Li,Yan Yang,Cong Zhang,Wenqi Wang,Fan Ni,Xianwen Wang
Ulcerative colitis (UC) is a long-term inflammatory bowel disease characterized by intense inflammation of the colorectal mucosa. Overproduction of reactive oxygen species exacerbates the progression of UC, which is linked to mitochondrial impairment and dysbiosis of the intestinal microbiota. CaGA nanozymes have demonstrated efficacy in the treatment of UC. The modulation of M1 and M2 polarization of macrophages by CaGA nanozymes has been demonstrated to be useful in reducing inflammation. Furthermore, CaGA nanozymes regulate the M1 and M2 polarization of macrophages, efficiently decreasing inflammation. The oral delivery of CaGA nanozymes resulted in their enrichment in inflamed areas of the colon and effectively reduced colonic damage in mice with DSS-induced colitis by improving the repair of the intestinal barrier. An investigation of 16S rDNA sequencing revealed that CaGA nanozymes regulate populations of both pathogenic and helpful bacteria and impact the progression of ulcerative colitis by influencing the tricarboxylic acid (TCA) cycle. Thus, CaGA nanozymes may be employed in the management of ulcerative colitis to control the intestinal milieu and improve the preservation of the intestinal barrier by decreasing the invasion of inflammatory cells and restoring mitochondrial activity. Statement of significance CaGA nanozymes exhibit multifunctional enzymatic activity, effectively eliminating cellular RONS with robust antioxidant capacity. CaGA nanoenzymes promote macrophage M1 to M2 polarization and produce anti-inflammatory effects. CaGA nanozymes increase cell viability by restoring impaired mitochondrial function, reducing reactive oxygen species (ROS) production, and restoring the ability of mitochondria to produce ATP. CaGA nanozymes modulate intestinal flora diversity and composition, potentially influencing inflammatory pathways via aromatic compound metabolism. They participate in cellular energy and biosynthesis, regulating ulcerative colitis (UC)-related intestinal function through the tricarboxylic acid (TCA) and urea cycles. Calcium ions bind to GA nanomedicine and small particles are readily absorbed by inflammatory cells, preventing diarrhea from being rapidly excreted.
研究领域:
医学
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生物化学
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免疫学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Qin Tang,Zhengcai Ma,Xiang Tang,Yan Liu,Huimin Wu,Yu Peng,Baihua Jiao,Rui Wang,Xiaoli Ye,Hang Ma,Xuegang Li
Ethnopharmacological relevance Helicobacter pylori (H. pylori) is a major pathogen colonized in the human stomach and is implicated in gastritis, peptic ulcer, and gastric carcinoma. Antibiotics are useful for eradicating H. pylori but failed for drug resistance, making it urgent to develop effective and safe drugs. Rhizoma Coptidis was reported as one of the most effective Chinese medicines to treat H. pylori -related gastrointestinal diseases, while the precise antimicrobial mechanism remains unclear. Thus, it is of great significance to study the antimicrobial ingredients and corresponding mechanisms of Rhizoma Coptidis. Aim of the study To search for the most effective alkaloid against H. pylori in Rhizoma Coptidis and illustrate the probable mechanisms . Materials and methods Five main alkaloids in Rhizoma Coptidis were isolated. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were tested to determine the most effective one. Bacterial growth experiments, Annexin V-FITC/PI staining, TUNEL staining, and transmission electron microscopy (TEM) were performed to further study the anti- H. pylori activity of coptisine (Cop) . The in vivo effect of Cop on H. pylori eradication rate and H. pylori -induced inflammation was investigated in mice . Transcriptomics was used to understand the underlying mechanism of eradicating H. pylori and reducing host inflammation. Western blot, RT-PCR, and ELISA experiments were utilized and confirmed that cagA was one of the targets of Cop. Results According to the MIC and MBC, Cop was the most effective alkaloid against H. pylori , especially with no drug resistance developed . In vitro experiments showed that Cop inhibited H. pylori by inducing DNA fragmentation, phosphatidylserine exposure, and membrane damage. Cop (150 mg/kg/day) effectively eradicated H. pylori in mice and reduced the levels of IL-2 and IL-6 to relieve gastric inflammation. Transcriptomic analysis revealed that virulence factor cagA was one of the hub genes associated with the inflammation-improving effect of Cop. That is, Cop could decrease the expression of CagA and subsequently reduce the translocation of CagA to gastric epithelial cells, thereby improving the morphology of hummingbird-like phenotype induced by CagA and alleviating inflammation . Conclusions Cop is the most effective alkaloid in Rhizoma Coptidis and might act through multiple mechanisms for H. pylori eradication along with reducing the expression of CagA to alleviate inflammation.
研究领域:
药理学
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微生物学
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分子生物学
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民族药理学
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产品关联
DOI
PubMed
高影响因子
Virulence
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2024
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IF 5.5
Xiaofei Ji,Qianwen Wu,Xinying Cao,Shuzhen Liu,Jianhui Zhang,Si Chen,Jiangfan Shan,Ying Zhang,Boqing Li,Huilin Zhao
CagA is a significant oncogenic factor injected into host cells by Helicobacter pylori, which is divided into two subtypes: East Asian type (CagAE), characterized by the EPIYA-D motif, and western type (CagAW), harboring the EPIYA-C motif. CagAE has been reported to have higher carcinogenicity than CagAW, although the underlying reason is not fully understood. SHIP2 is an intracellular phosphatase that can be recruited by CagA to perturb the homeostasis of intracellular signaling pathways. In this study, we found that SHIP2 contributes to the higher oncogenicity of CagAE. Co-Immunoprecipitation and Pull-down assays showed that CagAE bind more SHIP2 than CagAW. Immunofluorescence staining showed that a higher amount of SHIP2 recruited by CagAE to the plasma membrane catalyzes the conversion of PI(3,4,5)P3 into PI(3,4)P2. This alteration causes higher activation of Akt signaling, which results in enhanced IL-8 secretion, migration, and invasion of the infected cells. SPR analysis showed that this stronger interaction between CagAE and SHIP2 stems from the higher affinity between the EPIYA-D motif of CagAE and the SH2 domain of SHIP2. Structural analysis revealed the crucial role of the Phe residue at the Y + 5 position in EPIYA-D. After mutating Phe of CagAE into Asp (the corresponding residue in the EPIYA-C motif) or Ala, the activation of downstream Akt signaling was reduced and the malignant transformation of infected cells was alleviated. These findings revealed that CagAE hijacks SHIP2 through its EPIYA-D motif to enhance its carcinogenicity, which provides a better understanding of the higher oncogenic risk of H. pylori CagAE.
研究领域:
微生物学
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分子生物学
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肿瘤学
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细胞生物学
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DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2025
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IF 4.2
Huilin Zhao,Shuzhen Liu,Jiangfan Shan,Juan Zhang,Qianwen Wu,Jianhui Zhang,Zekun Sun,Xinying Cao,Shu Chen,Mingzhu Feng,Yinuo Zhang,Xiang Cheng,Boqing Li,Xiaofei Ji
CagA, one of the key virulence factors of Helicobacter pylori , plays a significant role in H. pylori -associated gastric cancer by actively participating in neoplastic transformation. Among CagA variants, East Asian type CagA (CagA E ) bearing the EPIYA-D motif exhibits a higher risk than the Western-type (CagA W ) with EPIYA-C motifs. In this study, we investigated the interactions of CagA E and CagA W and host intracellular Grb2 and found a pronouncedly greater recruitment of Grb2 by CagA E compared to CagA W . Our findings revealed the phosphorylated tyrosine in the EPIYA motif is very important for the binding of CagA to Grb2. Phe at Y + 5 position in EPIYA-D, which interacts with Trp 121 in SH2 domain of Grb2, established the higher affinity than the interaction of EPIYA-C and Grb2-SH2. The substitute of Phe to Asp/Ala in CagA E EPIYA-D reduced the recruitment of Grb2 by CagA E , and neutralized the stronger induced malignant characteristics of the recipient cells. These findings provide additional insights into the distinct regulatory mechanisms employed by CagA E and CagA W , contributing to a better understanding of the higher oncogenic risk associated with H. pylori CagA E .
研究领域:
微生物学
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分子生物学
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癌症生物学
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传染病学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
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IF 14.3
Lijiao He,Xiao Zhang,Shengwei Zhang,Yi Wang,Weichao Hu,Jie Li,Yunyi Liu,Yu Liao,Xue Peng,Jianjun Li,Haiyan Zhao,Liting Wang,Yang-Fan Lv,Chang-Jiang Hu,Shi-Ming Yang
Persistent H. pylori infection triggers the repair program of the mucosa, such as spasmolytic polypeptide-expressing metaplasia (SPEM). However, the mechanism underlying the initiation of SPEM in gastric tissues by H. pylori remains unclear. Here, an increase in telomerase reverse transcriptase (TERT) protein expression is observed in chief cells upon infection with cagA -positive H. pylori . Tert knockout significantly ameliorated H. pylori -induced SPEM and single-cell RNA sequencing demonstrated that the Wnt/β-Catenin pathway is suppressed in gastric cells with Tert knockout. Mechanism study revealed that CagA elevated TERT abundance by disrupting the interaction between TERT and its novel E3 ligase, SYVN1. Interestingly, Nitazoxanide effectively relieved SPEM via inhibition of the Wnt/β-Catenin signaling in vivo. This results clarified the mechanism underlying which CagA activated the TERT/Wnt/β-Catenin pathway, thus promoting the dedifferentiation of chief cells and the occurrence of SPEM in gastric mucosa. This highlights a molecular basis for targeting CagA-activated Wnt signaling in chief cells for the treatment of gastric precancerous lesions.
研究领域:
胃肠病学
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分子生物学
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肿瘤学
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病理学
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DOI
PubMed
高影响因子
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