Cell Host & Microbe
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2022
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IF 31.316
Jie Gao,Xinmei Zhao,Shixian Hu,Zhenhe Huang,Mengyao Hu,Shaoqin Jin,Bingyun Lu,Kai Sun,Zhang Wang,Jingyuan Fu,Rinse K. Weersma,Xiaolong He,Hongwei Zhou
Summary The pattern-recognition receptor NOD2 senses bacterial muropeptides to regulate host immunity and maintain homeostasis. Loss-of-function mutations in NOD2 are associated with Crohn’s disease (CD), but how the variations in microbial factors influence NOD2 signaling and host pathology is elusive. We demonstrate that the Firmicutes peptidoglycan remodeling enzyme, DL-endopeptidase, increased the NOD2 ligand level in the gut and impacted colitis outcomes. Metagenomic analyses of global cohorts (n = 857) revealed that DL-endopeptidase gene abundance decreased globally in CD patients and negatively correlated with colitis. Fecal microbiota from CD patients with low DL-endopeptidase activity predisposed mice to colitis. Administering DL-endopeptidase, but not an active site mutant, alleviated colitis via the NOD2 pathway. Therapeutically restoring NOD2 ligands with a DL-endopeptidase-producing Lactobacillus salivarius strain or mifamurtide, a clinical analog of muramyl dipeptide, exerted potent anti-colitis effects. Our study suggests that the depletion of DL-endopeptidase contributes to CD pathogenesis through NOD2 signaling, providing a therapeutically modifiable target.
研究领域:
免疫学
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微生物学
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胃肠病学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
DRUG RESISTANCE UPDATES
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2023
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IF 24.3
Wei Zhang,Yibao Fan,Jinze Zhang,Dan Shi,Jiahui Yuan,Milad Ashrafizadeh,Wei Li,Man Hu,A.M. Abd El-Aty,Ahmet Hacimuftuoglu,Michael Linnebacher,Yongxian Cheng,Weiguang Li,Shuo Fang,Peng Gong,Xianbin Zhang
Aims Multidrug resistance in pancreatic cancer poses a significant challenge in clinical treatment. Bufalin (BA), a compound found in secretions from the glands of toads, may help overcome this problem. However, severe cardiotoxicity thus far has hindered its clinical application. Hence, the present study aimed to develop a cell membrane-camouflaged and BA-loaded polylactic-co-glycolic acid nanoparticle (CBAP) and assess its potential to counter chemoresistance in pancreatic cancer. Methods The toxicity of CBAP was evaluated by electrocardiogram, body weight, distress score, and nesting behavior of mice. In addition, the anticarcinoma activity and underlying mechanism were investigated both in vitro and in vivo . Results CBAP significantly mitigated BA-mediated acute cardiotoxicity and enhanced the sensitivity of pancreatic cancer to several clinical drugs, such as gemcitabine, 5-fluorouracil, and FOLFIRINOX . Mechanistically, CBAP directly bound to nucleotide-binding and oligomerization domain containing protein 2 (NOD2) and inhibited the expression of nuclear factor kappa-light-chain-enhancer of activated B cells. This inhibits the expression of ATP-binding cassette transporters, which are responsible for chemoresistance in cancer cells. Conclusions Our findings indicate that CBAP directly inhibits NOD2. Combining CBAP with standard-of-care chemotherapeutics represents a safe and efficient strategy for the treatment of pancreatic cancer.
研究领域:
肿瘤学
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药学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-15
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IF 16.6
Gao Jie,Wang Lei,Jiang Jing,Xu Qian,Zeng Nianyi,Lu Bingyun,Yuan Peibo,Sun Kai,Zhou Hongwei,He Xiaolong
Secreted proteins are one of the direct molecular mechanisms by which microbiota influence the host, thus constituting a promising field for drug discovery. Here, through bioinformatics-guided screening of the secretome of clinically established probiotics from Lactobacillus , we identify an uncharacterized secreted protein (named LPH here) that is shared by most of these probiotic strains (8/10) and demonstrate that it protects female mice from colitis in multiple models. Functional studies show that LPH is a bi-functional peptidoglycan hydrolase with both N-Acetyl-β-D-muramidase and DL-endopeptidase activities that can generate muramyl dipeptide (MDP), a NOD2 ligand. Different active site mutants of LPH in combination with Nod2 knockout female mice confirm that LPH exerts anti-colitis effects through MDP-NOD2 signaling. Furthermore, we validate that LPH can also exert protective effects on inflammation-associated colorectal cancer in female mice. Our study reports a probiotic enzyme that enhances NOD2 signaling in vivo in female mice and describes a molecular mechanism that may contribute to the effects of traditional Lactobacillus probiotics.
研究领域:
微生物学
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免疫学
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药物发现
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胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
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IF 5.6
Enkang Tong,Xiaofei Dong,Yifan Ren,Lingxue Gong,Cuicui Zhao,Rongrong Nie,Xiangfeng Meng
Objective This study aimed to investigate the effects and mechanisms of artesunate (AS) on inflammation and osteogenic differentiation under Staphylococcus aureus ( S. aureus )-induced inflammatory conditions. Methods Alkaline phosphatase staining, Western Blotting, quantitative real-time polymerase chain reaction, and immunofluorescence staining were employed to assess the effects of AS on inflammation and osteogenic differentiation in rat bone marrow mesenchymal stem cells (rBMSCs) under S. aureus -induced inflammation. The rat models of chronic suppurative mandibular osteomyelitis were established, and mandibles were assessed by histology and micro-computed tomography after treatment with AS and/or cefuroxime axetil. RNA sequencing and the NOD2 agonist muramyl dipeptide (MDP) were used to explore mechanisms. Results In vitro, AS reduced the expression of pro-inflammatory factors and increased the expression of anti-inflammatory and osteogenic factors in rBMSCs. In vivo, AS promoted anti-inflammatory responses and new bone formation in rats, with enhanced effects when combined with cefuroxime axetil. Moreover, AS decreased NOD2 and p-p65 expression while MDP reversed the anti-inflammatory and pro-osteogenic effects of AS. Conclusion AS attenuated inflammation and promoted osteogenic differentiation in rBMSCs by inhibiting the NOD2/p65 pathway. In vivo, AS facilitated the healing of chronic suppurative mandibular osteomyelitis in rats.
✓ 已验证
产品关联
DOI
高影响因子
Advanced Science
·
2024
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IF 14.3
Ruopeng Yin,Tao Wang,Jingzu Sun,Huanqin Dai,Yuting Zhang,Ningning Liu,Hongwei Liu
Prolonged alcohol consumption disrupts the gut microbiota and the immune system, contributing to the pathogenesis of alcohol-associated liver disease (ALD). Probiotic-postbiotic intervention strategies can effectively relieve ALD by maintaining gut homeostasis. Herein, the efficacy of heat-killed Lactobacillus johnsonii (HKLJ) in mitigating alcoholic liver damage is demonstrated in mouse models of ALD. The gut-liver axis is identified as a pivotal pathway for the protective effects of L. johnsonii against ALD. Specifically, HKLJ is found to upregulate the expression of intestinal lysozymes, thereby enhancing the production of immunoregulatory substances from gut bacteria, which subsequently activated the Nucleotide-binding oligomerization domain 2 (NOD2)-interleukin (IL-23)-IL-22 innate immune axis. The elevated IL-22 upregulated the antimicrobial peptide synthesis to maintain intestinal homeostasis and moreover activated the Signal transducer and activator of Transcription3 (STAT3) pathway in the liver to facilitate the repair of hepatic injuries. The heat-killed L. johnsonii provoked immunity helps correct the gut microbiota dysbiosis, specifically by reversing the reduction of butyrate-producing bacteria (such as Faecalibaculum rodentium ) and the expansion of opportunistic pathogens (such as Helicobacter sp. and Pichia kudriavzevii ) induced by ethanol. The findings provide novel insights into the gut microbiota-liver axis that may be leveraged to enhance the treatment of ALD.
研究领域:
微生物学
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免疫学
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肝病学
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胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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