Journal of Cardiovascular Translational Research
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2024
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IF 2.4
Zhang Ning,Liu Liangju,Lv Xiaowang,Wang Yixuan,Zhang Wei,Wen Xin,Yu Fan,Zhou Tingting
Trimethylamine oxide (TMAO) is an intestinal flora metabolite associated with risk of cardiovascular diseases. Transient receptor potential vanilloid 4 (TRPV4) is a Ca 2+ -permeable ion channel that is essential for vasodilation and endothelial function. Currently, there are few studies on the effect of TMAO on TRPV4 channels. In the present study, Ca 2+ imaging of vascular tissue showed that TMAO inhibited TRPV4-mediated Ca 2+ influx into aortic endothelial cells in a dose-dependent manner. Furthermore, a whole-cell patch clamp assay showed that TMAO blocked TRPV4-mediated cation currents. Notably, results of aortic vascular tension measurement showed that TMAO impaired endothelium-dependent vasodilation in mouse aortic vessels through the TRPV4-NO pathway. Our results indicated that TMAO inhibited Ca 2+ entry in endothelial cells and impaired vasodilation through the TRPV4-NO pathway in mice. These results provide scientific evidence for novel pathogenic mechanisms underlying the role of TMAO in cardiovascular disease. Graphical Abstract TMAO impairs mouse aortic vasodilation by inhibiting TRPV4-NO pathway in endothelial cells.
研究领域:
药理学
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心血管生理学
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分子生物学
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DOI
PubMed
高影响因子
ACS Applied Polymer Materials
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2025
·
IF 4.7
Yujie Gao,Xiangyu Dang,Ahai Zhu,Zhize Chen
Hydrogels exhibiting excellent biocompatibility and resistance to foreign body response (FBR) hold significant promise in the biomedical field. In this study, we developed a photopolymerized hydrogel named poly(3,3′-((2-(2-((3-methacrylamidopropyl)amino)-2-oxoethyl)-4-((3-methacrylamidopropyl)carbamoyl)-2,4-dimethylhexanedioyl)bis(azanediyl))bis(N,N-dimethylpropan-1-amine oxide))(PIAPMANOX), whose prepolymer is based on poly(itaconic acid)(PIA) and is grafted with varying ratios of zwitterionic trimethylamine N-oxide (TMAO) derivatives and N-(3-aminopropyl)methacrylamide hydrochloride (APMA). The TMAO derivatives possess the ability to form a compact hydration layer due to their distinctive properties─namely, the minimal spacing between zwitterionic groups, the robust hydrogen bonding interactions, the smallest net charge, and the lowest dipole moment. These characteristics collectively promote the establishment of a tightly packed hydration shell that effectively inhibits nonspecific adsorption of substances such as proteins and cells. Meanwhile, APMA contributes a carbon–carbon double bond that promotes photoinitiated radical polymerization for constructing a three-dimensional hydrogel network. Among the various materials studied, the hydrogel PIAPMANOX, which incorporates the zwitterionic TMAO, demonstrates exceptional performance in terms of protein and cell rejection. The hydrogel was implanted into the peritoneal cavity of mice. Experimental results demonstrated that this hydrogel significantly reduced FBR, with no notable inflammatory reaction observed and a decrease in fibrosis. Therefore, the PIAPMANOX series introduces innovative nontoxic zwitterionic materials to the field of biomaterials.
研究领域:
生物材料学
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组织工程学
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医学材料科学
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DOI
高影响因子
PHARMACOLOGICAL RESEARCH
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2021
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IF 7.658
Qiao Zhang,Xiaomin Guo,Cao Xie,Zhonglian Cao,Xin Wang,Li Liu,Ping Yang
Trimethylamine-N-oxide (TMAO) has emerged as a promising new therapeutic target for the treatment of central nervous system diseases , atherosclerosis and other diseases. However, its origin in the brain is unclear. Gynostemma pentaphyllum (Thunb.) Makino can reduce the increase of TMAO level caused by a high fat diet. But its effective chemical composition and specific mechanism have not been reported. The study confirmed that TMA was more easily to penetrate blood brain barrier than TMAO, the MAO enzyme was partly involved in the transformation of the TMA in brain, which further supplemented the choline-TMA-TMAO pathway. Based on the above metabolic pathway, using multi-omics approaches, such as microbiodiversity, metagenomics and lipidomics, it was demonstrated that the reduction of plasma TMAO levels by gypenosides did not act on FMO3 and MAO in the pathway, but remodeled the microbiota and affected the trimethylamine lyase needed in the conversion of choline to TMA in intestinal flora . At the same time, gypenosides interfered with enzymes associated with TCA and lipid metabolism, thus affecting TMAO and lipid metabolism. Considering the bidirectional transformation of phosphatidycholine and choline, lipid metabolism and TMAO metabolism could affected each other to some extent. In conclusion, our study revealed the intrinsic correlation between long-term application of gypenosides to lipid reduction and nervous system protection, and explained why gypenosides were used to treat brain diseases, even though they had a poor ability to enter the brain. Besides, it provided a theoretical basis for clinical application of gypenosides and the development of new drugs.
研究领域:
药理学
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代谢学
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神经科学
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微生物学
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生物化学
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DOI
PubMed
高影响因子
Food & Function
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2023
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IF 6.1
Huafang Ding,Jianhui Liu,Zixing Chen,Shouhe Huang,Chi Yan,Erika Kwek,Zouyan He,Hanyue Zhu,Zhen-Yu Chen
Trimethylamine-N-oxide (TMAO) is a risk factor for atherosclerosis. As a natural phenolic acid, protocatechuic acid (PCA) is abundant in various plant foods. The present study was to investigate the effect of PCA on TMAO-aggravated atherosclerosis in ApoE-/- mice. The mice were randomly divided into five groups and fed one of the following five diets for 12 weeks: namely a low-fat diet (LFD), a western diet (WD), a WD+0.2% TMAO diet (WDT), a WDT+0.5% PCA diet (WDT+LPCA), and a WDT+1.0% PCA diet (WDT+HPCA). Results demonstrated that dietary TMAO exacerbated the development of atherosclerosis by eliciting inflammation and disturbing lipid metabolism. PCA at 1% diet reduced TMAO-induced aortic plaque by 30% and decreased the levels of plasma proinflammatory cytokines. PCA also improved the lipid metabolism by up-regulating hepatic gene expression of peroxisome proliferator-activated receptor alpha (PPARα). In addition, PCA supplementation enhanced fecal excretion of fatty acids and decreased hepatic fat accumulation. PCA supplementation favorably modulated gut microbiota by increasing α-diversity with an increase in the abundance of beneficial genera (Rikenella, Turicibacter, Clostridium_sensu_stricto and Bifidobacterium) and a decrease in the abundance of adverse Helicobacter genus. In summary, PCA could alleviate the TMAO-exacerbated atherosclerosis and inflammation, improve the lipid metabolism, and modulate gut microbiota.
研究领域:
心血管疾病
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营养学
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微生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEMBRANE SCIENCE
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2021
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IF 8.742
Yang Liu,Guiliang Li,Qiu Han,Haibo Lin,Qiang Li,Gang Deng,Fu Liu
Dialysis membranes capable of preventing coagulation and inflammation and achieving high toxin clearances are highly desired for clinical hemodialysis. Here, we constructed an electro-neutral and hydrophilic surface on Polysulfone (PSf) membrane, which both improved the hemocompatibility and toxin clearance. The membrane surface was modified with trimethylamine N-oxide (TMAO) through Michael addition reaction and subsequent crosslinking with glycidyl ether oxypropyl trimethoxysilane (KH560). Saltwater fish inspired zwitterionic monomer TMAO without spacers between positive and negative headgroups is thought to generate a hydrated and net-charged layer that prevents non-specific plasma proteins and platelets adsorption and activation. Coagulation time, serine protease Factor XIIa, bradykinin (BK), kallikrein (KLK) and anaphylatoxins (C3, C5 and SC5b-9) were examined to explore blood compatibility. All results showed that the highly hydrated and electro-neutral surface could efficiently alleviate the activation of the coagulation cascade, kallikrein-kinin system (KKS) and complement system simultaneously. Furthermore, the modified PSf membrane is favorable to toxins clearance (e.g., urea, creatine, lysozyme and vitamin B12) during simulated dialysis process. It is manifested that the TMAO based surface modification is feasible for improving the hemocompatibility and toxin clearance of dialysis membranes.
研究领域:
生物医学工程
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材料科学
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血液学
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产品关联
DOI
高影响因子
Food & Function
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2023
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IF 6.1
Zouyan HE,Hanyue Zhu,Jianhui Liu,Erika Kwek,Ka Ying Ma,Zhen-Yu Chen
Trimethylamine-N-oxide (TMAO), originating from dietary trimethylamine-containing nutrients such as choline, has been recognized as a risk factor for atherosclerosis. Mangiferin is a bioactive xanthone initially extracted from mango (Mangifera indica). The present study aimed to investigate the effect of mangiferin on TMAO-induced atherogenesis in mice fed a high-choline diet. Female ApoE-/- mice were randomly divided into three groups and fed either a control diet, a high-choline diet with 1% free choline, or an experimental diet with 1% free choline plus 0.5% mangiferin for 15 weeks. Our results showed that a high-choline diet elevated plasma TMAO level, accelerated atherogenesis, promoted cholesterol accumulation, and reduced the generation of short-chain fatty acids (SCFAs) by gut microbes. Mangiferin alleviated inflammation, and lowered plasma total cholesterol level by facilitating the elimination of neutral and acidic sterols in feces, resulting in a 16.7-29.0% reduction in aortic atherosclerotic lesions. Notably, mangiferin could favorably remodel the composition of gut microbiota by fostering the growth of the beneficial taxa Akkermansia, Parabacteroides, and Bifidobacteriaceae, while reducing the relative abundance of the pathogenic genus Helicobacter. This modulation led to a decrease in plasma lipopolysaccharide level, enhanced production of total SCFAs by gut microbes, and reduced susceptibility to atherosclerosis. In conclusion, mangiferin exhibited its ability to alleviate TMAO-induced atherosclerosis through its anti-inflammatory, cholesterol-lowering, and gut microbial modulatory activities.
研究领域:
心血管疾病
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营养学
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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
Probiotics and Antimicrobial Proteins
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2024
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IF 4.4
Zheng Xiumei,Zhang Zhe,Shan Tianhu,Zhao Maozhen,Lu Haiyan,Zhang Lanwei,Liang Xi
Atherosclerosis is a major cause of cardiovascular disease (CVD). The trimethylamine (TMA)-trimethylamine N-oxide (TMAO) pathway is a key crossover pathway highly associated with diet, gut microbiome, and atherosclerosis. The Bifidobacterium animalis subsp. lactis F1-3–2 ( Bif. animalis F1-3–2, No. CCTCCM2020832) was screened through in vitro and in vivo experiments in the early stage of this study with excellent lipid-lowering and anti-inflammatory function. By building an atherosclerosis model and focusing on TMAO, the specific mechanism of Bif. animalis F1-3–2 to improve atherosclerosis was explored. The study found that Bif. animalis F1-3–2 effectively improved the accumulation of aortic plaque in atherosclerotic mice. The strain improved lipid metabolism in serum and liver. It decreased the serum TMA and TMAO, regulated bile acid composition, participated in the farnesoid X receptor (FXR) pathway to improve lipid metabolism, and further reduced the aortic macrophage foam cell accumulation. In addition, the strain could improve the structure of the intestinal microbiome and reduce the proportion of Firmicutes and Bacteroidetes. The abundance of Turicibacter , Clostridium sensu stricto_1 , and Romboutsia was reduced at the genus level. The differential microbiota is highly correlated with bile acid metabolism, which is speculated to be involved in ameliorating atherosclerotic lipid metabolism disorders. Graphical abstract
研究领域:
微生物学
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心血管疾病
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营养学
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代谢组学
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DOI
PubMed
高影响因子
Scientific Reports
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2021
·Vol. 11
·期 1
·1-13
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IF 4.38
Wang Zijing,Ma Peng,Wang Yisa,Hou Biyu,Zhou Can,Tian He,Li Bowen,Shui Guanghou,Yang Xiuying,Qiang Guifen,Yin Chengqian,Du Guanhua
Endoplasmic reticulum (ER) stress is a cellular state that results from the overload of unfolded/misfolded protein in the ER that, if not resolved properly, can lead to cell death. Both acute lung infections and chronic lung diseases have been found related to ER stress. Yet no study has been presented integrating metabolomic and transcriptomic data from total lung in interpreting the pathogenic state of ER stress. Total mouse lungs were used to perform LC–MS and RNA sequencing in relevance to ER stress. Untargeted metabolomics revealed 16 metabolites of aberrant levels with statistical significance while transcriptomics revealed 1593 genes abnormally expressed. Enrichment results demonstrated the injury ER stress inflicted upon lung through the alteration of multiple critical pathways involving energy expenditure, signal transduction, and redox homeostasis. Ultimately, we have presented p-cresol sulfate (PCS) and trimethylamine N-oxide (TMAO) as two potential ER stress biomarkers. Glutathione metabolism stood out in both omics as a notably altered pathway that believed to take important roles in maintaining the redox homeostasis in the cells critical for the development and relief of ER stress, in consistence with the existing reports.
研究领域:
生物学
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生物化学
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分子生物学
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药理学
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医学研究
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产品关联
DOI
PubMed
高影响因子
PHYSIOLOGICAL RESEARCH
·
2026
·Vol. 75
·期 1
·89
·
IF 2.8
Qian CHEN,Zhaoxu QIU,Yaobo ZHAO,Lu BAI,Yuhong CHEN,Sheng JIN,Fenfen MA,Jing DAI
The present study was aimed to investigate whether trimethylamine-N-oxide (TMAO) contributed to kidney aging by activating necroptosis. Male C57BL/6J mice were randomly divided into Control group (3 months old) and Old group (18 months old), compared to 3-month-old controls, 18-month-old male C57BL/6J mice showed significant increases in plasma creatinine (Cre) and blood urea nitrogen (BUN) ( P <0.05), enhanced renal fibrosis ( P <0.001), elevated plasma TMAO ( P <0.01), and upregulation of senescence markers p53, p21, and p16 ( P <0.05, P <0.01, and P <0.001, respectively). In order to investigate the effects of TMAO on kidney aging, the mice were intraperitoneally injected with TMAO for one to three months, mice showed time-dependent increases in Cre and BUN ( P <0.05, respectively), progressive fibrosis, and gradual upregulation of senescence markers, ZBP1, and phosphorylation of RIPK3 and MLKL ( P <0.05, respectively). In addition, three months of DMB treatment (inhibitor for TMAO formation) significantly reduced the plasma Cre and BUN levels ( P <0.001 and P <0.05), downregulated the senescence markers expression, and improved kidney fibrosis ( P <0.001 or P <0.05, respectively). In conclusion, our studies revealed that TMAO induced kidney aging by activating ZBP1-mediated necroptosis. Moreover, the inhibition of TMAO generation might be a potential treatment for kidney aging.
✓ 已验证
DOI
PubMed
高影响因子
PHYSIOLOGICAL RESEARCH
·
2026
·
IF 2.8
Q Chen,Z Qiu,Y Zhao,L Bai,Y Chan,S Jin,F Ma,J Dai
The present study was aimed to investigate whether trimethylamine-N-oxide (TMAO) contributed to kidney aging by activating necroptosis. Male C57BL/6J mice were randomly divided into Control group (3 months old) and Old group (18 months old), compared to 3-month-old controls, 18-month-old male C57BL/6J mice showed significant increases in plasma creatinine (Cre) and blood urea nitrogen (BUN) (P<0.05), enhanced renal fibrosis (P<0.001), elevated plasma TMAO (P<0.01), and upregulation of senescence markers p53, p21, and p16 (P<0.05, P<0.01, and P<0.001, respectively). In order to investigate the effects of TMAO on kidney aging, the mice were intraperitoneally injected with TMAO for one to three months, mice showed time-dependent increases in Cre and BUN (P<0.05, respectively), progressive fibrosis, and gradual upregulation of senescence markers, ZBP1, and phosphorylation of RIPK3 and MLKL (P<0.05, respectively). In addition, three months of DMB treatment (inhibitor for TMAO formation) significantly reduced the plasma Cre and BUN levels (P<0.001 and P<0.05), downregulated the senescence markers expression, and improved kidney fibrosis (P<0.001 or P<0.05, respectively). In conclusion, our studies revealed that TMAO induced kidney aging by activating ZBP1-mediated necroptosis. Moreover, the inhibition of TMAO generation might be a potential treatment for kidney aging. Key words Kidney aging " Trimethylamine-N-oxide " ZBP1 " Necroptosis " DMB.
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产品关联
DOI
PubMed
高影响因子
Cannabis and Cannabinoid Research
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2023
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IF 3.8
Mengxue He,Aiyang Liu,Jiachen Shi,Yong-Jiang Xu,Yuanfa Liu
Introduction: Cannabidiol (CBD) has important pharmacological activity, which includes antispasmodic, antioxidant, antithrombotic, and antianxiety properties. CBD has been applied as a health supplement to atherosclerosis. However, CBDs effect on gut microbiota and metabolic phenotype is unclear.Materials and Methods: We constructed a high production of cardiovascular risk factors, such as trimethylamine-N-oxide (TMAO) and phenylacetylglutamine (PAGln), in a mouse model using Clostridium sporogenes colonization. We used 16S ribosomal RNA (rRNA) gene sequencing and ultra-high performance liquid chromatography-quadrupole time-of flight mass spectrometry-based metabolomics to evaluate the effect of CBD on gut microbiota and plasma metabolites.Results: CBD decreased the levels of creatine kinase (CK), alanine transaminase (ALT), and low-density lipoprotein cholesterol and markedly increased high-density lipoprotein cholesterol. Furthermore, CBD treatment increased the abundance of beneficial bacteria, which include Lachnospiraceae_NK4A136 and Blautia in the gut, but it decreased the levels of TMAO and PAGln in the plasma.Conclusion: CBD might have beneficial effects for cardiovascular protection.
研究领域:
药理学
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微生物组学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
Polymer Chemistry
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2026
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IF 3.9
Xiangyu Dang,Chongyu Zhu,Zhize Chen
The foreign body reaction (FBR) induced by the host immune system leads to fibrous encapsulation, which significantly impairs the functionality of implanted medical devices and can trigger complications. Zwitterionic polymers derived from trimethylamine N-oxide (TMAO) demonstrate particularly remarkable hydrophilicity and antifouling capabilities due to the direct connection between their positive and negative charges. In this study, based on the unique molecular structure of TMAO, a polysiloxane with TMAO and carbon–carbon double bonds as side chains was designed and synthesized. Subsequently, under the combined action of a photoinitiator and ultraviolet (UV) irradiation, a hydrogel with a Si–O–Si backbone was fabricated. In vitro tests demonstrated that the trimethylamine N-oxide-grafted silicone (TMAO-Si) hydrogel exhibits excellent resistance to protein adsorption and cell adhesion, while also exhibiting good biocompatibility. Building on these findings, we implanted the hydrogel in mice. The results indicated a significant reduction in the adhesion of inflammatory cells to the surface of the TMAO-Si hydrogel, with collagen fiber deposition thickness markedly lower than that observed in PEG hydrogels, thereby demonstrating superior anti-fibrotic encapsulation effects. Consequently, the TMAO-Si hydrogel shows promising potential as an implant material that minimizes interference from FBRs, offering a new technical approach for the development of long-lasting in vivo implant materials.
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DOI
高影响因子
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