scholarly journals Berberine attenuates choline-induced atherosclerosis by inhibiting trimethylamine and trimethylamine-N-oxide production via manipulating the gut microbiome

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Xingxing Li ◽  
Chunyan Su ◽  
Zhibo Jiang ◽  
Yuxin Yang ◽  
Yue Zhang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Atherosclerotic Lesion ◽  
Chow Diet ◽  
Dose Administration ◽  
Human Volunteers ◽  
Apoe Ko Mice ◽  
Gut Microbiota Composition ◽  
Apoe Ko

AbstractTrimethylamine-N-oxide (TMAO), a derivative from the gut microbiota metabolite trimethylamine (TMA), has been identified to be an independent risk factor for promoting atherosclerosis. Evidences suggest that berberine (BBR) could be used to treat obesity, diabetes and atherosclerosis, however, its mechanism is not clear mainly because of its poor oral bioavailability. Here, we show that BBR attenuated TMA/TMAO production in the C57BL/6J and ApoE KO mice fed with choline-supplemented chow diet, and mitigated atherosclerotic lesion areas in ApoE KO mice. Inhibition of TMA/TMAO production by BBR-modulated gut microbiota was proved by a single-dose administration of d9-choline in vivo. Metagenomic analysis of cecal contents demonstrated that BBR altered gut microbiota composition, microbiome functionality, and cutC/cntA gene abundance. Furthermore, BBR was shown to inhibit choline-to-TMA conversion in TMA-producing bacteria in vitro and in gut microbial consortium from fecal samples of choline-fed mice and human volunteers, and the result was confirmed by transplantation of TMA-producing bacteria in mice. These results offer new insights into the mechanisms responsible for the anti-atherosclerosis effects of BBR, which inhibits commensal microbial TMA production via gut microbiota remodeling.

Xenogenic macrophage immunization reduces atherosclerosis in apolipoprotein E knockout mice

2007 ◽  
Vol 293 (3) ◽  
pp. C865-C873 ◽  
Author(s):  
Tomoya Yamashita ◽  
Seinosuke Kawashima ◽  
Tetsuaki Hirase ◽  
Masakazu Shinohara ◽  
Tomofumi Takaya ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Critical Role ◽  
Atherosclerotic Lesion ◽  
Plasma Lipid ◽  
Chronic Inflammatory Disease ◽  
Apolipoprotein E Knockout Mice ◽  
Apoe Ko Mice ◽  
Apoe Ko

Atherosclerosis is a complex chronic inflammatory disease in which macrophages play a critical role, and the intervention of the inflammatory process in atherogenesis could be a therapeutic strategy. In this study, we investigated the efficacy of xenogenic macrophage immunization on the atherosclerotic lesion formation in a model of murine atherosclerosis. Apolipoprotein E knockout (apoE-KO) mice were repeatedly immunized with formaldehyde-fixed cultured human macrophages (phorbol ester-stimulated THP-1 cells), using human serum albumin as a control protein or HepG2 cells as human control cells, once a week for four consecutive weeks. The vehicle phosphate-buffered saline was injected in the nonimmunized controls. THP-1 immunization induced antibodies that are immunoreactive with mouse macrophages. Although the plasma lipid levels were unchanged by the immunization, the atherosclerotic lesion area in the aortic root was significantly reduced by >50% in 16-wk-old THP-1-immunized apoE-KO mice compared with that in control mice. THP-1 immunization reduced in vivo macrophage infiltration, reduced in vitro macrophage adhesion, and changed cytokine production by macrophages to the antiatherogenic phenotype. Xenogenic macrophage immunization protects against the development of atherosclerosis in apoE-KO mice by modulating macrophage function in which antibodies induced by the immunization are likely to be involved. This method is a novel and potentially useful cell-mediated immune therapeutic technique against atherosclerosis.

scholarly journals Exogenous and endogenous HDAC inhibitor effects in Rubinstein-Taybi syndrome models

2020 ◽  
Author(s):  
Elisabetta Di Fede ◽  
Emerenziana Ottaviano ◽  
Paolo Grazioli ◽  
Camilla Ceccarani ◽  
Chiara Parodi ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Hdac Inhibitors ◽  
Clinical Signs ◽  
Microbiota Composition ◽  
Autosomal Dominant Disorder ◽  
Donor Cells ◽  
Neurodevelopmental Impairment ◽  
Gut Microbiota Composition

ABSTRACTRubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder with specific clinical signs and neurodevelopmental impairment. The two known proteins altered in the majority of RSTS patients are the histone acetylation regulators CBP and p300. For assessing possible ameliorative effects of exogenous and endogenous HDAC inhibitors (HDACi), we exploited in vivo and in vitro RSTS models. First, HDACi effects were tested on Drosophila melanogaster, showing molecular rescue. In the same model, we observed a shift in gut microbiota composition. We then studied HDACi effects in RSTS cell lines compared to healthy donor cells. We observed patients-specific molecular rescue of acetylation defects at subtoxic concentrations. Finally, we assessed commensal gut microbiota composition in a cohort of RSTS patients compared to healthy siblings. Intriguingly, we observed a significant depletion in butyrate-producing bacteria in RSTS patients. In conclusion, this study reports the possibility of modulating acetylation equilibrium by HDACi treatments and the importance of microbiota composition in a chromatinopathy.

Abstract 466: Therapeutic Immunization with an Antiglycosaminoglycan Antibody Reduces Atherosclerotic Lesion Progression in Apolipoprotein E-Deficient Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Roger Sarduy ◽  
Victor Brito ◽  
Yosdel Soto ◽  
Livan Delgado-Roche ◽  
Tania Griñán ◽  
...  
Keyword(s):  
Antibody Response ◽  
Apolipoprotein E ◽  
Chondroitin Sulfate ◽  
Atherosclerotic Lesion ◽  
Ldl Oxidation ◽  
High Cholesterol Diet ◽  
Chow Diet ◽  
Aortic Lesion

Subendothelial retention of apoB-containing lipoproteins by interaction with glycosaminoglycan-side chains of proteoglycans is considered the key initiating step of atherogenesis. Previously, we characterized the antiatherogenic properties of the chimeric mAb chP3R99, which binds sulfated GAG, inhibits LDL-chondroitin sulfate (CS) association, and abrogates LDL oxidation in vitro and in vivo. In preventive settings, rabbits and mice immunized with this mAb showed reduced atherosclerotic lesions, related with the induction of anti-chondroitin sulfate (CS) antibodies. Now we focus in define the immunization schedule which can induce in apolipoprotein E-deficient (apoE-/-) the highest anti-CS antibody response and the greater reduction of atherosclerotic lesion progression. ApoE - / - mice (6-8 wk. old) fed a chow diet received four s.c. injections of 50 or 200 μg of chP3R99 mAb. Autologous antichondroitin sulfate (CS) antibody response was evaluated in sera by ELISA. Mice who were immunized with 200 μg generated a significant higher response against CS than the ones that received 50 μg. Then, to evaluate the association of the induction of a higher anti-CS response in the atherosclerotic lesion progression, apoE-/- mice fed with a high-fat high-cholesterol diet from 4 to 18 wk. of age, received 6 doses of 50, 100 or 200 μg of the mAb starting when 5% of the aortic area was covered by lesions. Animals were sacrificed and aortas isolated to determine the presence of lesions by histologic studies. Mean aortic lesion areas of 50 and 100 μg chP3R99-treated mice were significant reduced by ~40% in comparison with mice treated with an isotype-matched control mAb. In contrast, 62% reduction in total lesion area was observed in mice treated with 200 μg of chP3R99. Again, there was an association between the level of anti-CS antibody response and the reduction of atherosclerotic lesion progression. In conclusion, this study demonstrated the dose dependence of the anti-CS antibody response and its relationship with the arresting of the atherosclerotic progression induced by chP3R99 mAb immunization. Our results also supports the potential use of this antiglycosaminoglycan antibody-based immunotherapy as a novel approach to target advanced atherosclerosis

Abstract 358: Factor Xa Deteriorates Atherosclerosis by Facilitating Inflammasome Formation via PAR-2-mediated Autophagy Suppression

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Yasuhiro Maejima ◽  
Yusuke Ito ◽  
Natsuko Tamura ◽  
Masanori Konishi ◽  
Kenzo Hirao ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Critical Role ◽  
Atherosclerotic Lesion ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Inflammasome Activation ◽  
Apoe Ko Mice ◽  
Autophagy Activity ◽  
Apoe Ko

Background: It is known that an endogenous blood coagulation factor Xa (FXa) plays a critical role in facilitating atherosclerosis by activating protease-activated receptor-2 (PAR-2). However, the precise mechanism how FXa-mediated PAR-2 activation promotes atherogenesis remains to be elucidated. Purpose: The aim of this study is to explore how FXa promotes atherosclerosis through PAR-2-associated signaling pathway. Methods & Results: Administration of direct FXa inhibitor rivaroxaban (Riv; 120 mg/kg/day) to the mice significantly suppressed the plasma FXa activity compared with untreated mice. Administration of Riv to ApoE knockout mice fed with high fat diet (ApoE-KO-HFD) significantly reduced atherosclerotic area in the aorta compared with those in the untreated ApoE-KO-HFD. The plaque size of ApoE-KO mice crossed with PAR-2 knockout mice fed with HFD was similar to those of Riv-treated ApoE-KO-HFD. Ultrastructural examinations of atherosclerotic lesions revealed that the number of autophagosomes in the plaque-resident macrophages of Riv-treated ApoE-KO-HFD was significantly smaller than those of the untreated ApoE-KO-HFD. Immunostaining of NLRP3 revealed that Riv attenuated the inflammasome formation in the atherosclerotic lesion in ApoE-KO-HFD. In vitro experiments demonstrated that treatment of 7-ketocholesterol (7KC) markedly enhanced autophagy activity in the murine macrophages. The addition of FXa significantly promoted mTOR (Ser 2448 ) phosphorylation and blocked autophagy activity induced by 7KC, which was reversed in the presence of Riv (1 μM). Furthermore, immunoblot analyses demonstrated that FXa administration significantly accelerated inflammasome formation induced by 7KC, which was blocked in the presence of Riv. On the other hand, treatment with FXa failed to inhibit 7KC-induced autophagy and inflammasome activation in PAR-2-KO mice-derived macrophages. Conclusion: These results suggest that FXa worsens atherogenesis through PAR-2-mediated pathway by inhibiting macrophage autophagy which, in turn, promoting inflammasome activation.

Abstract 164: Endothelial Gab1 Limits Vascular Remodeling and Atherosclerosis Through Inhibition of Endothelial Inflammation

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Suowen Xu ◽  
Meimei Yin ◽  
Jingjing Zhao ◽  
Marina Koroleva ◽  
Zheng Gen Jin
Keyword(s):  
Adhesion Molecule ◽  
Vascular Remodeling ◽  
Fluid Shear Stress ◽  
Atherosclerotic Lesion ◽  
Monocyte Adhesion ◽  
Disturbed Flow ◽  
Apoe Ko Mice ◽  
Apoe Ko

Objective: We have previously shown that docking protein Grb2-associated binder 1 (Gab1) is a mechano-effector protein in response to fluid shear stress and regulates postnatal angiogenesis. The aim of this study was to determine the in vivo role of endothelial Gab1 in flow-mediated vascular remodeling and atherosclerosis and explore the underlying mechanisms. Methods and Results: To determine the role of endothelial Gab1 in disturbed flow-induced vascular remodeling in vivo, we performed partial carotid artery ligation in Gab1 endothelium-restricted knockout (Gab1-ecKO) mice and wild-type (WT) littermates, and we observed that Gab1-ecKO mice resulted in increased intima-media thickness. To examine the role of endothelial Gab1 in atherosclerosis, we next crossed Gab1-ecKO mice with ApoE KO mice. After partial ligation, Gab1-ecKO;ApoE KO mice under high fat diet showed increased atherosclerotic lesion size compared to Gab1-WT;ApoE KO mice. The levels of proatherogenic genes intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and leukocyte infiltration were all increased in Gab1-ecKO;ApoE KO mice. Using loss- and gain-of-function studies in cultured human endothelial cells (ECs), we found that Gab1 depletion by siRNA augmented monocyte adhesion to ECs by increasing ICAM-1 and VCAM-1 expression in response to the proinflammatory cytokine TNF-α. Conversely, adenoviral overexpression of Gab1 inhibited TNFα-induced monocyte adhesion to ECs and upregulation of ICAM-1 and VCAM-1 in ECs. Conclusions: These results demonstrate that endothelial Gab1 represses disturbed flow-induced vascular remodeling and atherogenesis through inhibition of vascular inflammation. Our findings suggest that Gab1 activation might represent novel approaches for the treatment of vascular diseases, including intimal hyperplasia and atherosclerosis.

Plant polyphenols alter a pathway of energy metabolism by inhibiting fecal Bacteroidetes and Firmicutes in vitro

2016 ◽  
Vol 7 (3) ◽  
pp. 1501-1507 ◽  
Author(s):  
Bin Xue ◽  
Jinli Xie ◽  
Jiachen Huang ◽  
Long Chen ◽  
Lijuan Gao ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Gut Microbiota ◽  
Microbiota Composition ◽  
Faecal Microbiota ◽  
Plant Polyphenols ◽  
Gut Microbiota Composition

This study investigated the effect of plant polyphenols on faecal microbiota metabolizing oligosaccharides. The results show that plant polyphenols can change the pathway of degrading FOS or even energy metabolism in vivo by altering gut microbiota composition.

scholarly journals Fermentation properties and potential prebiotic activity of Bimuno®galacto-oligosaccharide (65 % galacto-oligosaccharide content) onin vitrogut microbiota parameters

2016 ◽  
Vol 116 (3) ◽  
pp. 480-486 ◽  
Author(s):  
Roberta Grimaldi ◽  
Jonathan R. Swann ◽  
Jelena Vulevic ◽  
Glenn R. Gibson ◽  
Adele Costabile
Keyword(s):  
Gut Microbiota ◽  
Time Course ◽  
Microbiota Composition ◽  
Small Molecular Weight ◽  
Food Industries ◽  
H Nmr ◽  
Prebiotic Oligosaccharides ◽  
Gut Microbiota Composition

AbstractPrebiotic oligosaccharides have the ability to generate important changes in the gut microbiota composition that may confer health benefits to the host. Reducing the impurities in prebiotic mixtures could expand their applications in food industries and improve their selectivity and prebiotic effect on the potential beneficial bacteria such as bifidobacteria and lactobacilli. This study aimed to determine thein vitropotential fermentation properties of a 65 % galacto-oligosaccharide (GOS) content Bimuno®GOS (B-GOS) on gut microbiota composition and their metabolites. Fermentation of 65 % B-GOS was compared with 52 % B-GOS in pH- and volume-controlled dose–response anaerobic batch culture experiments. In total, three different doses (1, 0·5 and 0·33 g equivalent to 0·1, 0·05 and 0·033 g/l) were tested. Changes in the gut microbiota during a time course were identified by fluorescencein situhybridisation, whereas small molecular weight metabolomics profiles and SCFA were determined by1H-NMR analysis and GC, respectively. The 65 % B-GOS showed positive modulation of the microbiota composition during the first 8 h of fermentation with all doses. Administration of the specific doses of B-GOS induced a significant increase in acetate as the major SCFA synthesised compared with propionate and butyrate concentrations, but there were no significant differences between substrates. The 65 % B-GOS in syrup format seems to have, in all the analysis, an efficient prebiotic effect. However, the applicability of such changes remains to be shown in anin vivotrial.

Angiotensin II injures the arterial wall causing increased aortic stiffening in apolipoprotein E-deficient mice

2002 ◽  
Vol 283 (6) ◽  
pp. R1442-R1449 ◽  
Author(s):  
Doris M. Tham ◽  
Baby Martin-McNulty ◽  
Yi-Xin Wang ◽  
Valdeci Da Cunha ◽  
Dennis W. Wilson ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Arterial Wall ◽  
Ang Ii ◽  
Internal Elastic Lamina ◽  
Arterial Stiffening ◽  
Functional Changes ◽  
Apoe Ko Mice ◽  
Apoe Ko

Cardiovascular diseases, such as atherosclerosis and hypertension, are associated with arterial stiffening. Previous studies showed that ANG II exacerbated atherosclerosis and induced hypertension and aneurysm formation in apolipoprotein E-deficient (apoE-KO) mice. The aim of the present study was to examine the effects of chronic treatment of ANG II on the arterial elastic properties in apoE-KO mice. We hypothesized that ANG II will injure the arterial wall resulting in increased arterial stiffening. Male apoE-KO mice were infused with either ANG II (1.44 mg · kg−1 · day−1) or vehicle (PBS) for 30 days. ANG II treatment accelerated atherosclerosis in the carotid artery by sixfold ( P < 0.001) and increased blood pressure by 30% ( P < 0.05). Additionally, our data demonstrated that ANG II increased arterial stiffening using both in vivo and in vitro methods. ANG II significantly increased pulse wave velocity by 36% ( P< 0.01) and decreased arterial elasticity as demonstrated by a more than 900% increase in maximal stiffening (high strain Young's modulus) compared with vehicle ( P < 0.05). These functional changes were correlated with morphological and biochemical changes as demonstrated by an increase in collagen content (60%), a decrease in elastin content (74%), and breaks in the internal elastic lamina in the aortic wall. In addition, endothelium-independent vasorelaxation to sodium nitroprusside was impaired in the aortic rings of ANG II-treated mice compared with vehicle. Thus, the present data indicate that ANG II injures the artery wall in multiple ways and arterial stiffening may be a common outcome of ANG II-induced arterial damage.

scholarly journals Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
KyeongJin Kim ◽  
Jin Ku Kang ◽  
Young Hoon Jung ◽  
Sang Bae Lee ◽  
Raffaela Rametta ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Whole Body ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Ph Domain ◽  
Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

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