Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway
Open accessAbstract
Background: Trimethylamine‐N‐oxide ( TMAO ) has recently been identified as a novel and independent risk factor for promoting atherosclerosis through inducing vascular inflammation. However, the exact mechanism is currently unclear. Studies have established a central role of nucleotide‐binding oligomerization domain–like receptor family pyrin domain–containing 3 ( NLRP 3) inflammasome in the pathogenesis of vascular inflammation. Here, we examined the potential role of the NLRP 3 inflammasome in TMAO ‐induced vascular inflammation in vitro and in vivo and the underlying mechanisms. Methods and Results: Experiments using liquid chromatography‐tandem mass spectrometry, Western blot, and fluorescent probes showed that TMAO ‐induced inflammation in human umbilical vein endothelial cells ( HUVEC s) and aortas from ApoE −/− mice. Moreover, TMAO promoted NLRP 3 and activated caspase‐1 p20 expression and caspase‐1 activity in vitro and in vivo. Notably, a caspase‐1 inhibitor ( YVAD ), an NLRP 3 inhibitor ( MCC 950), as well as NLRP 3 short interfering RNA attenuated TMAO ‐induced activation of the NLRP 3 inflammasome, subsequently leading to suppression of inflammation in HUVEC s. TMAO additionally stimulated reactive oxygen species ( ROS ) generation, in particular, mitochondrial ROS , while inhibiting manganese superoxide dismutase 2 (SOD2) activation and sirtuin 3 ( SIRT 3) expression in HUVEC s and aortas from ApoE −/− mice. TMAO ‐induced endothelial NLRP 3 inflammasome activation was ameliorated by the mitochondrial ROS scavenger Mito‐ TEMPO , or SIRT 3 overexpression in HUVEC s. Conversely, TMAO failed to further inhibit SOD2 and activate the NLRP 3 inflammasome or induce inflammation in SIRT 3 short interfering RNA –treated HUVEC s and aortas from SIRT 3 −/− mice. Conclusions: TMAO promoted vascular inflammation by activating the NLRP 3 inflammasome, and the NLRP 3 inflammasome activation in part was mediated through inhibition of the SIRT 3‐ SOD 2–mitochondrial ROS signaling pathway.
AI snapshot
Written from the paper’s full text.
TL;DR
TMAO promotes vascular inflammation by activating the NLRP3 inflammasome, mediated in part through inhibition of the SIRT3-SOD2-mtROS signaling pathway. In HUVECs and mouse aortas, TMAO increased NLRP3/caspase-1 p20 and inflammatory markers, while SIRT3 overexpression or mtROS scavenging attenuated these effects.
Key findings
- TMAO (600 μmol/L for 24 hours) increased IL-1β, ICAM-1, and MMP-9 expression and monocyte adhesion in HUVECs without significantly affecting cell viability; TMAO also promoted NLRP3 and caspase-1 p20 expression and caspase-1 activity in concentration- and time-dependent manners.
- NLRP3 inhibition with MCC950 (10 μmol/L), caspase-1 inhibition with YVAD (10 μmol/L), or NLRP3 siRNA attenuated TMAO-induced NLRP3/caspase-1 p20 and inflammatory protein expression, as well as monocyte adhesion.
- TMAO increased total ROS and mitochondrial ROS (mtROS); the mtROS scavenger Mito-TEMPO (TEMPO, 50 μmol/L) inhibited TMAO-induced NLRP3 inflammasome activation and inflammation. TMAO suppressed SOD2 activity and SIRT3 expression and increased SOD2 acetylation; SIRT3 siRNA mimicked TMAO effects, whereas SIRT3 overexpression diminished them.
- In vivo, 1% choline for 4 months in ApoE−/− mice increased plasma TMAO, atherosclerotic lesion areas in whole aorta and aortic root, and aortic NLRP3, caspase-1 p20, caspase-1 activity, IL-1β, ICAM-1, and MMP-9; SIRT3−/− mice showed similar inflammasome activation even on chow diet.
Methods
- In vitro: HUVECs were treated with TMAO (0, 150, 300, 600, 900 μmol/L) for 24 hours or 600 μmol/L for 0, 4, 12, and 24 hours; interventions included YVAD (10 μmol/L), MCC950 (10 μmol/L), TEMPO (50 μmol/L), NLRP3 siRNA, SIRT3 siRNA, and SIRT3 overexpression plasmid. Assays included Western blot, caspase-1 activity, SOD2 activity, DCFH-DA/MitoSOX ROS detection, and monocyte adhesion.
- In vivo: 8-week-old female 129/SvJ wild-type, ApoE−/−, and SIRT3−/− mice were fed standard chow or 1% choline-supplemented chow for 4 months; n=10 per group. Analyses included plasma TMAO by liquid chromatography-tandem mass spectrometry, aortic Western blot, caspase-1 and SOD2 activity, ultrasound of aortic sinus, and Oil-red O lesion quantification.
- Statistics: data presented as means±SE of 3 experiments; t test and 1-way ANOVA with Tukey-Kramer post hoc test, significance at P<0.05.
Limitations
- Stated by the paper: the 600 μmol/L TMAO concentration used for in vitro time-course and mechanism studies was higher than that in humans; the exact role of NF-κB in TMAO-induced NLRP3 inflammasome activation needs further studies.
- Evident from the text: in vivo experiments used dietary choline as a TMAO precursor rather than direct TMAO administration, and only female mice were studied; no human intervention data are presented.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 77 cited sources checked · 0 supported · 0 flagged
- Findingown data
TMAO treatment did not significantly affect endothelial cell viability.
“TMAO was tolerated by endothelial cells and exerted no significant effects on cell viability”
- Also stated in: § TMAO Induced Inflammation in Endothelial Cells · hedged
“These results indicated that TMAO triggered inflammation with no significant effects on cell viability in endothelial cells.”
Quote in the paperSubstantial claim - Also stated in: § TMAO Induced Inflammation in Endothelial Cells · hedged
- Findingown data
SIRT3 siRNA had similar effects on ICAM-1 expression as TMAO in HUVECs.
“Additionally, SIRT3 siRNA had similar effects on IL‐1β, ICAM‐1, and MMP‐9 expression as TMAO.”
Quote in the paperSubstantial claim - Findingown data
TMAO markedly increased acetylation levels of SOD2 in a dose- and time-dependent manner.
“acetylation levels of SOD2 were markedly increased by TMAO in a dose‐ and time‐dependent manner.”
Quote in the paperSubstantial claim - Findingown data
SIRT3 overexpression attenuated TMAO-induced increase in MMP-9 expression in HUVECs.
“However, the TMAO‐induced increase in IL‐1β, ICAM‐1, and MMP‐9 was markedly attenuated on transfection with SIRT3 overexpression plasmid (Figure 5G and 5H).”
Quote in the paperSubstantial claim - Findingown data
SIRT3 siRNA alone increased NLRP3 expression in HUVECs.
“Transfection with SIRT3 siRNA alone led to decreased SOD2 activity and increased total ROS and mtROS levels followed by an increase in caspase‐1 activity and NLRP3 and caspase‐1 p20 expression, similar to the results obtained with TMAO and SIRT3 siRNA cotreatment (Figure 5A through 5F).”
Quote in the paperSubstantial claim
- Findingown data
SIRT3 overexpression diminished TMAO-induced effects on SOD2 activity in HUVECs.
“Conversely, transfection with the SIRT3 overexpression plasmid significantly diminished the effects of TMAO on SOD2 activity, mtROS/ROS generation, and NLRP3 inflammasome activation (Figure 5A through 5F).”
Quote in the paperSubstantial claim - Findingown data
Choline-fed ApoE-/- mice had significantly higher atherosclerotic lesion areas in whole aorta than chow-fed ApoE-/- mice.
“Compared with chow‐fed ApoE−/− mice, the atherosclerotic lesion areas in whole aorta and aortic root, as indices of AS severity, were significantly higher in mice fed choline (Figure 6A through 6C).”
Quote in the paperSubstantial claim - Findingown data
SIRT3 siRNA alone increased total ROS levels in HUVECs.
“Transfection with SIRT3 siRNA alone led to decreased SOD2 activity and increased total ROS and mtROS levels followed by an increase in caspase‐1 activity and NLRP3 and caspase‐1 p20 expression, similar to the results obtained with TMAO and SIRT3 siRNA cotreatment (Figure 5A through 5F).”
Quote in the paperSubstantial claim - Findingown data
TMAO inhibited SOD2 activation and SIRT3 expression in aortas from ApoE−/− mice.
“TMAO additionally stimulated reactive oxygen species (ROS) generation, in particular, mitochondrial ROS, while inhibiting manganese superoxide dismutase 2 (SOD2) activation and sirtuin 3 (SIRT3) expression in HUVECs and aortas from ApoE−/− mice.”
Quote in the paperSubstantial claim - Findingown data
Choline-fed ApoE-/- mice had significantly higher atherosclerotic lesion areas in aortic root than chow-fed ApoE-/- mice.
“Compared with chow‐fed ApoE−/− mice, the atherosclerotic lesion areas in whole aorta and aortic root, as indices of AS severity, were significantly higher in mice fed choline (Figure 6A through 6C).”
Quote in the paperSubstantial claim - Findingown data
SIRT3 siRNA had similar effects on IL-1β expression as TMAO in HUVECs.
“Additionally, SIRT3 siRNA had similar effects on IL‐1β, ICAM‐1, and MMP‐9 expression as TMAO.”
Quote in the paperSubstantial claim - Findingown data
SIRT3 siRNA alone increased caspase-1 p20 expression in HUVECs.
“Transfection with SIRT3 siRNA alone led to decreased SOD2 activity and increased total ROS and mtROS levels followed by an increase in caspase‐1 activity and NLRP3 and caspase‐1 p20 expression, similar to the results obtained with TMAO and SIRT3 siRNA cotreatment (Figure 5A through 5F).”
Quote in the paperSubstantial claim - Findingown data
TMAO induced significant suppression of SOD2 activity in a dose- and time-dependent manner in human umbilical vein endothelial cells.
“TMAO induced significant suppression of SOD2 activity in a dose‐ and time‐dependent manner (Figure 4A and 4B).”
Quote in the paperSubstantial claim - Findingown data
Pretreatment with TEMPO attenuated TMAO-induced adhesion of monocytes to endothelial cells.
“as well as the adhesion of monocytes to endothelial cells (Supplementary Figure S1A and S1B), validating the requirement of mtROS for this process.”
Quote in the paperSubstantial claim - Findingown data
TMAO failed to further increase IL-1β expression when SIRT3 was suppressed by siRNA in HUVECs.
“Treatment with TMAO failed to further increase IL‐1β, ICAM‐1, and MMP‐9 expression on siRNA‐induced suppression of SIRT3.”
Quote in the paperSubstantial claim - Findingown data
Pretreatment with MCC950 or YVAD attenuated TMAO-induced increased adhesion of monocytes to endothelial cells.
“pretreatment with MCC950 (10 μmol/L) or YVAD (10 μmol/L) also attenuated the increased adhesion of monocytes to endothelial cells induced by TMAO (Supplementary Figure S1A and S1B).”
Quote in the paperSubstantial claim - Findingown data
SIRT3 overexpression attenuated TMAO-induced increase in ICAM-1 expression in HUVECs.
“However, the TMAO‐induced increase in IL‐1β, ICAM‐1, and MMP‐9 was markedly attenuated on transfection with SIRT3 overexpression plasmid (Figure 5G and 5H).”
Quote in the paperSubstantial claim - Findingown data
Reactive oxygen species and mitochondrial reactive oxygen species reached maximum levels at 24 hours after TMAO treatment.
“Time kinetic analysis revealed that ROS and mtROS reached maximum levels at 24 hours after TMAO treatment (Figure 3A through 3D).”
Quote in the paperNot a substantial claim - Findingown data
SIRT3 siRNA had similar effects on MMP-9 expression as TMAO in HUVECs.
“Additionally, SIRT3 siRNA had similar effects on IL‐1β, ICAM‐1, and MMP‐9 expression as TMAO.”
Quote in the paperSubstantial claim - Findingown data
TMAO exposure decreased SIRT3 expression in endothelial cells.
“Figure 4 Trimethylamine‐N‐oxide (TMAO) exposure decreased superoxide dismutase (SOD)2 activity and sirtuin‐3 (SIRT3) expression.”
Quote in the paperSubstantial claim - Findingown data
TMAO at 600 μmol/L for 24 hours increased adhesion of monocytes to endothelial cells.
“treatment with TMAO (600 μmol/L) for 24 hours also caused a significant increase in the adhesion of monocytes to endothelial cells (Figure S1A and S1B).”
Quote in the paperSubstantial claim - Findingown data
SIRT3 overexpression attenuated TMAO-induced increase in IL-1β expression in HUVECs.
“However, the TMAO‐induced increase in IL‐1β, ICAM‐1, and MMP‐9 was markedly attenuated on transfection with SIRT3 overexpression plasmid (Figure 5G and 5H).”
Quote in the paperSubstantial claim - Findingown data
TMAO exposure decreased SOD2 activity in endothelial cells.
“Figure 4 Trimethylamine‐N‐oxide (TMAO) exposure decreased superoxide dismutase (SOD)2 activity and sirtuin‐3 (SIRT3) expression.”
Quote in the paperSubstantial claim - Findingown data
TMAO treatment led to a significant decrease in SIRT3 expression in human umbilical vein endothelial cells.
“TMAO treatment led to a significant decrease in SIRT3 expression (Figure 4G through 4J)”
Quote in the paperSubstantial claim - Findingown data
TMAO promoted NLRP3 and caspase-1 p20 expression in a concentration- and time-dependent manner in human umbilical vein endothelial cells.
“TMAO promoted NLRP3 and caspase‐1 p20 expression in a concentration‐ and time‐dependent manner (Figure 2A through 2D).”
Quote in the paperSubstantial claim - Findingown data
SIRT3 siRNA alone decreased SOD2 activity in HUVECs.
“Transfection with SIRT3 siRNA alone led to decreased SOD2 activity and increased total ROS and mtROS levels followed by an increase in caspase‐1 activity and NLRP3 and caspase‐1 p20 expression, similar to the results obtained with TMAO and SIRT3 siRNA cotreatment (Figure 5A through 5F).”
Quote in the paperSubstantial claim - Findingown data
TMAO failed to further increase ICAM-1 expression when SIRT3 was suppressed by siRNA in HUVECs.
“Treatment with TMAO failed to further increase IL‐1β, ICAM‐1, and MMP‐9 expression on siRNA‐induced suppression of SIRT3.”
Quote in the paperSubstantial claim - Findingown data
SIRT3 overexpression diminished TMAO-induced NLRP3 inflammasome activation in HUVECs.
“Conversely, transfection with the SIRT3 overexpression plasmid significantly diminished the effects of TMAO on SOD2 activity, mtROS/ROS generation, and NLRP3 inflammasome activation (Figure 5A through 5F).”
Quote in the paperSubstantial claim - Findingown data
SIRT3 siRNA alone increased caspase-1 activity in HUVECs.
“Transfection with SIRT3 siRNA alone led to decreased SOD2 activity and increased total ROS and mtROS levels followed by an increase in caspase‐1 activity and NLRP3 and caspase‐1 p20 expression, similar to the results obtained with TMAO and SIRT3 siRNA cotreatment (Figure 5A through 5F).”
Quote in the paperSubstantial claim - Findingown data
TMAO induced a marked increase in caspase-1 activity in human umbilical vein endothelial cells.
“TMAO additionally induced a marked increase in caspase‐1 activity, indicating activation of the NLRP3 inflammasome.”
Quote in the paperSubstantial claim - Findingown data
Suppression of NLRP3 via specific siRNA blocked TMAO-induced increases in NLRP3, caspase-1 p20, IL-1β, ICAM-1, and MMP9 expression in human umbilical vein endothelial cells.
“the TMAO‐induced increases in NLRP3, caspase‐1 p20, IL‐1β, ICAM‐1, and MMP9 expression were blocked on suppression of NLRP3 via transfection with specific siRNA (Figure 2I and 2J).”
Quote in the paperSubstantial claim - Findingown data
TMAO increased IL-1β, ICAM-1, and MMP-9 expression in endothelial cells.
“induced a significant increase in IL‐1β, ICAM‐1, and MMP‐9 expression in endothelial cells (Figure 1C through 1F)”
Quote in the paperSubstantial claim - Findingown data
TMAO failed to further increase MMP-9 expression when SIRT3 was suppressed by siRNA in HUVECs.
“Treatment with TMAO failed to further increase IL‐1β, ICAM‐1, and MMP‐9 expression on siRNA‐induced suppression of SIRT3.”
Quote in the paperSubstantial claim - Findingown data
TMAO increased total reactive oxygen species and mitochondrial reactive oxygen species levels in human umbilical vein endothelial cells in a dose- and time-dependent manner.
“Our results showed an increase in both ROS and mtROS levels in response to TMAO in a dose‐ and time‐dependent manner.”
Quote in the paperSubstantial claim - Findingown data
SIRT3 overexpression diminished TMAO-induced effects on mtROS/ROS generation in HUVECs.
“Conversely, transfection with the SIRT3 overexpression plasmid significantly diminished the effects of TMAO on SOD2 activity, mtROS/ROS generation, and NLRP3 inflammasome activation (Figure 5A through 5F).”
Quote in the paperSubstantial claim - Findingown data
SIRT3 siRNA alone increased mtROS levels in HUVECs.
“Transfection with SIRT3 siRNA alone led to decreased SOD2 activity and increased total ROS and mtROS levels followed by an increase in caspase‐1 activity and NLRP3 and caspase‐1 p20 expression, similar to the results obtained with TMAO and SIRT3 siRNA cotreatment (Figure 5A through 5F).”
Quote in the paperSubstantial claim - Findingown data
Choline induced a significant increase in caspase-1 activity in aorta of ApoE-/- mice.
“Choline induced a significant increase in NLRP3 and caspase‐1 p20 expression and caspase‐1 activity, followed by upregulation of IL‐1β, ICAM‐1, and MMP‐9 expression in aorta (Figure 6D through 6F).”
Quote in the paperSubstantial claim - Findingown data
Choline upregulated IL-1β expression in aorta of ApoE-/- mice.
“Choline induced a significant increase in NLRP3 and caspase‐1 p20 expression and caspase‐1 activity, followed by upregulation of IL‐1β, ICAM‐1, and MMP‐9 expression in aorta (Figure 6D through 6F).”
Quote in the paperSubstantial claim - Findingown data
In chow-fed SIRT3-/- mice compared with chow-fed WT mice, NLRP3 expression was higher in aortas.
“Compared with chow‐fed WT mice, expression of Ac‐SOD2, NLRP3, caspase‐1 p20, IL‐1β, ICAM‐1, MMP‐9, and caspase‐1 activity were higher and SOD2 activity was lower in the aortas of chow‐fed SIRT3−/− mice, similar to results that were observed in aortas from choline‐fed WT and SIRT3−/− mice (Figure 7C through 7H).”
Quote in the paperSubstantial claim - Findingown data
Choline upregulated ICAM-1 expression in aorta of ApoE-/- mice.
“Choline induced a significant increase in NLRP3 and caspase‐1 p20 expression and caspase‐1 activity, followed by upregulation of IL‐1β, ICAM‐1, and MMP‐9 expression in aorta (Figure 6D through 6F).”
Quote in the paperSubstantial claim - Findingown data
Choline inhibited SOD2 activity in ApoE-/- mice.
“As depicted in Figure 7A and 7B, choline promoted SIRT3 expression and SOD2 acetylation as well as inhibition of SOD2 activity in ApoE−/− mice.”
Quote in the paperSubstantial claim - Findingown data
In chow-fed SIRT3-/- mice compared with chow-fed WT mice, ICAM-1 expression was higher in aortas.
“Compared with chow‐fed WT mice, expression of Ac‐SOD2, NLRP3, caspase‐1 p20, IL‐1β, ICAM‐1, MMP‐9, and caspase‐1 activity were higher and SOD2 activity was lower in the aortas of chow‐fed SIRT3−/− mice, similar to results that were observed in aortas from choline‐fed WT and SIRT3−/− mice (Figure 7C through 7H).”
Quote in the paperSubstantial claim - Findingown data
Choline promoted SOD2 acetylation in ApoE-/- mice.
“As depicted in Figure 7A and 7B, choline promoted SIRT3 expression and SOD2 acetylation as well as inhibition of SOD2 activity in ApoE−/− mice.”
Quote in the paperSubstantial claim - Findingown data
In chow-fed SIRT3-/- mice compared with chow-fed WT mice, caspase-1 p20 expression was higher in aortas.
“Compared with chow‐fed WT mice, expression of Ac‐SOD2, NLRP3, caspase‐1 p20, IL‐1β, ICAM‐1, MMP‐9, and caspase‐1 activity were higher and SOD2 activity was lower in the aortas of chow‐fed SIRT3−/− mice, similar to results that were observed in aortas from choline‐fed WT and SIRT3−/− mice (Figure 7C through 7H).”
Quote in the paperSubstantial claim - Findingown data
Addition of 1% choline led to a marked increase in plasma TMAO levels in ApoE-/- mice.
“Additionally, the addition of 1% choline led to a marked increase in the levels of plasma TMAO in ApoE−/− mice (Figure 6G).”
Quote in the paperSubstantial claim - Findingown data
In chow-fed SIRT3-/- mice compared with chow-fed WT mice, Ac-SOD2 expression was higher in aortas.
“Compared with chow‐fed WT mice, expression of Ac‐SOD2, NLRP3, caspase‐1 p20, IL‐1β, ICAM‐1, MMP‐9, and caspase‐1 activity were higher and SOD2 activity was lower in the aortas of chow‐fed SIRT3−/− mice, similar to results that were observed in aortas from choline‐fed WT and SIRT3−/− mice (Figure 7C through 7H).”
Quote in the paperSubstantial claim - Findingown data
Choline induced a significant increase in NLRP3 expression in aorta of ApoE-/- mice.
“Choline induced a significant increase in NLRP3 and caspase‐1 p20 expression and caspase‐1 activity, followed by upregulation of IL‐1β, ICAM‐1, and MMP‐9 expression in aorta (Figure 6D through 6F).”
Quote in the paperSubstantial claim - Findingown data
Choline upregulated MMP-9 expression in aorta of ApoE-/- mice.
“Choline induced a significant increase in NLRP3 and caspase‐1 p20 expression and caspase‐1 activity, followed by upregulation of IL‐1β, ICAM‐1, and MMP‐9 expression in aorta (Figure 6D through 6F).”
Quote in the paperSubstantial claim - Findingown data
Choline promoted SIRT3 expression in ApoE-/- mice.
“As depicted in Figure 7A and 7B, choline promoted SIRT3 expression and SOD2 acetylation as well as inhibition of SOD2 activity in ApoE−/− mice.”
Quote in the paperNot a substantial claim - Findingown data
In chow-fed SIRT3-/- mice compared with chow-fed WT mice, SOD2 activity was lower in aortas.
“Compared with chow‐fed WT mice, expression of Ac‐SOD2, NLRP3, caspase‐1 p20, IL‐1β, ICAM‐1, MMP‐9, and caspase‐1 activity were higher and SOD2 activity was lower in the aortas of chow‐fed SIRT3−/− mice, similar to results that were observed in aortas from choline‐fed WT and SIRT3−/− mice (Figure 7C through 7H).”
Quote in the paperSubstantial claim - Findingown data
Choline induced a significant increase in caspase-1 p20 expression in aorta of ApoE-/- mice.
“Choline induced a significant increase in NLRP3 and caspase‐1 p20 expression and caspase‐1 activity, followed by upregulation of IL‐1β, ICAM‐1, and MMP‐9 expression in aorta (Figure 6D through 6F).”
Quote in the paperSubstantial claim - Findingown data
In chow-fed SIRT3-/- mice compared with chow-fed WT mice, IL-1β expression was higher in aortas.
“Compared with chow‐fed WT mice, expression of Ac‐SOD2, NLRP3, caspase‐1 p20, IL‐1β, ICAM‐1, MMP‐9, and caspase‐1 activity were higher and SOD2 activity was lower in the aortas of chow‐fed SIRT3−/− mice, similar to results that were observed in aortas from choline‐fed WT and SIRT3−/− mice (Figure 7C through 7H).”
Quote in the paperSubstantial claim - Findingown data
In chow-fed SIRT3-/- mice compared with chow-fed WT mice, MMP-9 expression was higher in aortas.
“Compared with chow‐fed WT mice, expression of Ac‐SOD2, NLRP3, caspase‐1 p20, IL‐1β, ICAM‐1, MMP‐9, and caspase‐1 activity were higher and SOD2 activity was lower in the aortas of chow‐fed SIRT3−/− mice, similar to results that were observed in aortas from choline‐fed WT and SIRT3−/− mice (Figure 7C through 7H).”
Quote in the paperSubstantial claim - Findingown data
In chow-fed SIRT3-/- mice compared with chow-fed WT mice, caspase-1 activity was higher in aortas.
“Compared with chow‐fed WT mice, expression of Ac‐SOD2, NLRP3, caspase‐1 p20, IL‐1β, ICAM‐1, MMP‐9, and caspase‐1 activity were higher and SOD2 activity was lower in the aortas of chow‐fed SIRT3−/− mice, similar to results that were observed in aortas from choline‐fed WT and SIRT3−/− mice (Figure 7C through 7H).”
Quote in the paperSubstantial claim - Findingown data
TMAO markedly suppressed SOD2 activity in vitro and in vivo.
“Data from the present study showed that TMAO markedly suppressed SIRT3 expression and SOD2 activity in vitro and in vivo.”
Quote in the paperSubstantial claim - Findingown data
TMAO treatment induced mtROS generation to a significant extent.
“As expected, TMAO treatment induced mtROS generation to a significant extent.”
Quote in the paperSubstantial claim - Findingown data
TMAO markedly suppressed SIRT3 expression in vitro and in vivo.
“Data from the present study showed that TMAO markedly suppressed SIRT3 expression and SOD2 activity in vitro and in vivo.”
Quote in the paperSubstantial claim - Findingown data
TMAO failed to further activate vascular inflammation in SIRT3 siRNA-transfected HUVECs and SIRT3-/- mice.
“Moreover, TMAO failed to further inhibit SOD2 and activate NLRP3 inflammasome and vascular inflammation in SIRT3 siRNA‐transfected HUVECs and SIRT3−/− mice.”
Quote in the paperSubstantial claim - Findingown data
TMAO failed to further inhibit SOD2 in SIRT3 siRNA-transfected HUVECs and SIRT3-/- mice.
“Moreover, TMAO failed to further inhibit SOD2 and activate NLRP3 inflammasome and vascular inflammation in SIRT3 siRNA‐transfected HUVECs and SIRT3−/− mice.”
Quote in the paperSubstantial claim - Findingown data
TMAO failed to further activate NLRP3 inflammasome in SIRT3 siRNA-transfected HUVECs and SIRT3-/- mice.
“Moreover, TMAO failed to further inhibit SOD2 and activate NLRP3 inflammasome and vascular inflammation in SIRT3 siRNA‐transfected HUVECs and SIRT3−/− mice.”
Quote in the paperSubstantial claim - Findingown data
SIRT3 overexpression downregulated inflammation caused by TMAO in endothelial cells.
“Conversely, SIRT3 overexpression significantly abrogated TMAO‐induced SOD2 inhibition and NLRP3 inflammasome activation, thereby downregulating inflammation caused by TMAO in endothelial cells.”
Quote in the paperSubstantial claim - Findingown data
SIRT3 overexpression significantly abrogated TMAO-induced NLRP3 inflammasome activation in endothelial cells.
“Conversely, SIRT3 overexpression significantly abrogated TMAO‐induced SOD2 inhibition and NLRP3 inflammasome activation, thereby downregulating inflammation caused by TMAO in endothelial cells.”
Quote in the paperSubstantial claim - Findingown data
SIRT3 overexpression significantly abrogated TMAO-induced SOD2 inhibition in endothelial cells.
“Conversely, SIRT3 overexpression significantly abrogated TMAO‐induced SOD2 inhibition and NLRP3 inflammasome activation, thereby downregulating inflammation caused by TMAO in endothelial cells.”
Quote in the paperSubstantial claim - Premisecitation
The NLRP3 inflammasome plays a central role in the pathogenesis of vascular inflammation.
“Studies have established a central role of nucleotide‐binding oligomerization domain–like receptor family pyrin domain–containing 3 (NLRP3) inflammasome in the pathogenesis of vascular inflammation.”
- Also stated in: § Introduction · hedged
“Thus, the NLRP3 inflammasome is proposed to be a key player in the pathogenesis of vascular inflammation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Yin Y, Pastrana JL, Li XY, Huang X, Mallilankaraman K, Choi ET, Madesh M, Wang H, Yang XF. Inflammasomes: sensors of metabolic stresses for vascular inflammation. Front Biosci (Landmark Ed). 2013; 18: 638– 649. 23276949 PMC3590813 source
Not checked in the free run.
- Also stated in: § Introduction · hedged
- Premisecitation
Trimethylamine-N-oxide (TMAO) is a novel and independent risk factor for promoting atherosclerosis through inducing vascular inflammation.
“Trimethylamine‐N‐oxide (TMAO) has recently been identified as a novel and independent risk factor for promoting atherosclerosis through inducing vascular inflammation.”
- Also stated in: § Introduction · plain
“A recent metabolomics approach identified plasma trimethylamine‐N‐oxide (TMAO), a choline metabolite, as a novel and independent risk factor for promoting AS.4, 5”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [4] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472: 57– 63. 21475195 PMC3086762 source
Not checked in the free run.
- cites [5] Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013; 368: 1575– 1584. 23614584 PMC3701945 source
Not checked in the free run.
- Also stated in: § Introduction · plain
- Premisecitation
SIRT3 primarily regulates mitochondrial reactive oxygen species levels by altering acetylation of major mitochondrial antioxidant enzymes, including SOD2, isocitrate dehydrogenase 2 and glutathione peroxidase.
“SIRT3 primarily regulates mtROS levels by altering acetylation of the major mitochondrial antioxidant enzymes, including manganese superoxide dismutase 2 (SOD2), isocitrate dehydrogenase 2 and glutathione peroxidase.17”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Qiu XL, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3‐mediated SOD2 activation. Cell Metab. 2010; 12: 662– 667. 21109198 source
Not checked in the free run.
- Premisecitation
SIRT3 is the primary mitochondrial acetyllysine deacetylase that modulates various proteins to control mitochondrial function and mitochondrial reactive oxygen species homeostasis.
“Sirtuin 3 (SIRT3), an important member of the Sir2 family, has been identified as the primary mitochondrial acetylysine deacetylase that modulates various proteins to control mitochondrial function and mtROS homeostasis.16”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Bause AS, Haigis MC. SIRT3 regulation of mitochondrial oxidative stress. Exp Gerontol. 2013; 48: 634– 639. 22964489 source
Not checked in the free run.
- Premisecitation
SOD2 is mainly regulated by deacetylation of specific conserved lysines in a reaction catalyzed by SIRT3.
“because SOD2 is mainly regulated by the deacetylation of specific conserved lysines in a reaction catalyzed by the mitochondrial sirtuin SIRT3,20”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, Kim HS, Flynn CR, Hill S, Hayes McDonald W, Olivier AK, Spitz DR, Gius D. Sirt3‐mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell. 2010; 40: 893– 904. 21172655 PMC3266626 source
Not checked in the free run.
- Premisecitation
NLRP3 and activated caspase-1 p20 are considered accurate indicators of inflammasome activation.
“we investigated the expression of NLRP3 and activated caspase‐1 (p20), which are considered accurate indicators of inflammasome activation.27”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Vanaja SK, Rathinam VA, Fitzgerald KA. Mechanisms of inflammasome activation: recent advances and novel insights. Trends Cell Biol. 2015; 25: 308– 315. 25639489 PMC4409512 source
Not checked in the free run.
- Interpretationown data
The SIRT3-SOD2 pathway is required for TMAO-induced subsequent activation of the NLRP3 inflammasome in endothelial cells.
“Our data clearly indicated that the SIRT3‐SOD2 pathway was required for mtROS accumulation and subsequent activation of the NLRP3 inflammasome induced by TMAO in endothelial cells.”
Quote in the paperSubstantial claim - Interpretationown data
The SIRT3-SOD2 pathway is required for TMAO-induced mtROS accumulation in endothelial cells.
“Our data clearly indicated that the SIRT3‐SOD2 pathway was required for mtROS accumulation and subsequent activation of the NLRP3 inflammasome induced by TMAO in endothelial cells.”
- Also stated in: § TMAO Induced mtROS Accumulation via the SIRT3‐SOD2 Pathway in Endothelial Cells · plain
“Figure 5 Trimethylamine‐N‐oxide (TMAO) induced mitochondrial reactive oxygen species (mtROS) accumulation via the sirtuin‐3–superoxide dismutase‐2 (SIRT3‐SOD2) pathway in endothelial cells.”
Quote in the paperSubstantial claim - Also stated in: § TMAO Induced mtROS Accumulation via the SIRT3‐SOD2 Pathway in Endothelial Cells · plain
- Interpretationown data
Mitochondrial reactive oxygen species are required for TMAO-induced activation of the NLRP3 inflammasome in endothelial cells.
“validating the requirement of mtROS for this process.”
- Also stated in: § mtROS Played a Key Role in TMAO‐Induced Activation of the NLRP3 Inflammasome in Endothelial Cells · plain
“mtROS Played a Key Role in TMAO‐Induced Activation of the NLRP3 Inflammasome in Endothelial Cells”
Quote in the paperSubstantial claim - Also stated in: § mtROS Played a Key Role in TMAO‐Induced Activation of the NLRP3 Inflammasome in Endothelial Cells · plain
- Interpretationown data
NLRP3 inflammasome activation in TMAO-induced vascular inflammation was mediated in part through inhibition of the SIRT3-SOD2-mitochondrial reactive oxygen species signaling pathway.
“TMAO promoted vascular inflammation by activating the NLRP3 inflammasome, and the NLRP3 inflammasome activation in part was mediated through inhibition of the SIRT3‐SOD2–mitochondrial ROS signaling pathway.”
- Also stated in: § Introduction · boosted
“Our results demonstrated for the first time that TMAO promoted vascular inflammation by activating the NLRP3 inflammasome, and the NLRP3 inflammasome activation was mediated in part through inhibition of the SIRT3‐SOD2‐mtROS signaling pathway.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · boosted
- Interpretationown data
The NLRP3 inflammasome was required for TMAO-induced inflammation in endothelial cells.
“Based on these findings, we postulated that the NLRP3 inflammasome was required for TMAO‐induced inflammation in endothelial cells.”
Quote in the paperSubstantial claim - Interpretationown data
TMAO induced mitochondrial reactive oxygen species accumulation via the SIRT3-SOD2 pathway in endothelial cells.
“TMAO Induced mtROS Accumulation via the SIRT3‐SOD2 Pathway in Endothelial Cells”
- Also stated in: § TMAO Induced mtROS Accumulation via the SIRT3‐SOD2 Pathway in Endothelial Cells · plain
“revealing a suppressive effect on both expression of SIRT3 and activity of SOD2.”
Quote in the paperSubstantial claim - Also stated in: § TMAO Induced mtROS Accumulation via the SIRT3‐SOD2 Pathway in Endothelial Cells · plain
- Interpretationown data
TMAO promoted vascular inflammation by activating the NLRP3 inflammasome.
“TMAO promoted vascular inflammation by activating the NLRP3 inflammasome, and the NLRP3 inflammasome activation in part was mediated through inhibition of the SIRT3‐SOD2–mitochondrial ROS signaling pathway.”
- Also stated in: § Introduction · boosted
“Our results demonstrated for the first time that TMAO promoted vascular inflammation by activating the NLRP3 inflammasome, and the NLRP3 inflammasome activation was mediated in part through inhibition of the SIRT3‐SOD2‐mtROS signaling pathway.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · boosted
- Interpretationown data
TMAO treatment promoted cellular NLRP3 inflammasome activation in human umbilical vein endothelial cells.
“The collective results suggested that TMAO treatment promoted cellular NLRP3 inflammasome activation in HUVECs.”
Quote in the paperSubstantial claim - Interpretationown data
TMAO induced vascular inflammation via NLRP3 inflammasome activation in vivo.
“The results suggested that TMAO induced vascular inflammation via NLRP3 inflammasome activation, ultimately promoting AS in vivo.”
- Also stated in: § TMAO Induced Vascular Inflammation via NLRP3 Inflammasome Activation In Vivo · plain
“Figure 6 Trimethylamine‐N‐oxide (TMAO) induced vascular inflammation via nucleotide‐binding oligomerization domain–like receptor family pyrin domain–containing 3 (NLRP3) inflammasome activation in vivo.”
Quote in the paperSubstantial claim - Also stated in: § TMAO Induced Vascular Inflammation via NLRP3 Inflammasome Activation In Vivo · plain
- Premisecitation
Elevated TMAO levels retained a strong prognostic value for predicting incidence of adverse cardiovascular events, even after adjustment for traditional risk factors and renal function.
“Furthermore, elevated TMAO levels retained a strong prognostic value for predicting the incidence of adverse cardiovascular events, even after adjustment for traditional risk factors and renal function.5”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013; 368: 1575– 1584. 23614584 PMC3701945 source
Not checked in the free run.
- Interpretationown data
TMAO ultimately promotes AS in vivo.
“The results suggested that TMAO induced vascular inflammation via NLRP3 inflammasome activation, ultimately promoting AS in vivo.”
Quote in the paperSubstantial claim - Premisecitation
Plasma TMAO is a novel and independent risk factor for promoting AS.
“Recently, plasma TMAO was identified as a novel and independent risk factor for promoting AS.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013; 368: 1575– 1584. 23614584 PMC3701945 source
Not checked in the free run.
- Interpretationown data
SIRT3 is necessary for TMAO-induced subsequent vascular inflammation in vivo.
“Accordingly, we concluded that SIRT3 was necessary for TMAO‐induced SOD2 inhibition and NLRP3 inflammasome activation and subsequent vascular inflammation in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
TMAO triggered vascular inflammation via an NLRP3 inflammasome-dependent mechanism.
“In the present study we showed for the first time that TMAO triggered vascular inflammation via an NLRP3 inflammasome‐dependent mechanism.”
Quote in the paperSubstantial claim - Premisecitation
Within the cohort examined, the hazard ratio for TMAO was significantly higher than that for traditional risk factors such as LDL cholesterol.
“Within the cohort examined, the hazard ratio for TMAO was significantly higher than that for traditional risk factors such as LDL cholesterol.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013; 368: 1575– 1584. 23614584 PMC3701945 source
Not checked in the free run.
- Premisecitation
In a large independent clinical cohort (n=4007), elevated TMAO levels were associated with significantly increased risk for major adverse cardiovascular events (2.54 for highest versus lowest TMAO quartile; P<0.001).
“In a large independent clinical cohort (n=4007), elevated TMAO levels were associated with significantly increased risk for major adverse cardiovascular events (2.54 for highest versus lowest TMAO quartile; P<0.001).5”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013; 368: 1575– 1584. 23614584 PMC3701945 source
Not checked in the free run.
- Interpretationown data
SIRT3 is necessary for TMAO-induced NLRP3 inflammasome activation in vivo.
“Accordingly, we concluded that SIRT3 was necessary for TMAO‐induced SOD2 inhibition and NLRP3 inflammasome activation and subsequent vascular inflammation in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
SIRT3 is necessary for TMAO-induced SOD2 inhibition in vivo.
“Accordingly, we concluded that SIRT3 was necessary for TMAO‐induced SOD2 inhibition and NLRP3 inflammasome activation and subsequent vascular inflammation in vivo.”
Quote in the paperSubstantial claim - Premisecitation
Inhibition of mitochondrial complex I by rotenone or complex III by antimycin A induces robust ROS production by mitochondria, sufficient to drive NLRP3 inflammasome activation.
“Several studies have shown that inhibition of mitochondrial complex I by rotenone or of complex III by antimycin A induces robust ROS production by mitochondria, which is sufficient to drive NLRP3 inflammasome activation.39, 40”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [39] Huang LS, Cobessi D, Tung EY, Berry EA. Binding of the respiratory chain inhibitor antimycin to the mitochondrial bc1 complex: a new crystal structure reveals an altered intramolecular hydrogen‐bonding pattern. J Mol Biol. 2005; 351: 573– 597. 16024040 PMC1482829 source
Not checked in the free run.
- cites [40] Won JH, Park S, Hong S, Son S, Yu JW. Rotenone‐induced impairment of mitochondrial electron transport chain confers a selective priming signal for NLRP3 inflammasome activation. J Biol Chem. 2015; 290: 27425– 27437. 26416893 PMC4646374 source
Not checked in the free run.
- Interpretationcitation
mtROS serve as direct activators of the NLRP3 inflammasome.
“These results suggest that mtROS serve as direct activators of the NLRP3 inflammasome.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [36] Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin‐interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010; 11: 136– 140. 20023662 source
Not checked in the free run.
- cites [37] Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008; 320: 674– 677. 18403674 PMC2396588 source
Not checked in the free run.
- cites [38] Chen H, Lu Y, Cao Z, Ma Q, Pi H, Fang Y, Yu Z, Hu H, Zhou Z. Cadmium induces NLRP3 inflammasome‐dependent pyroptosis in vascular endothelial cells. Toxicol Lett. 2016; 246: 7– 16. 26809137 source
Not checked in the free run.
- Premisecitation
SIRT3 deacetylates mitochondrial proteins including SOD2, which limits accumulation of mtROS.
“SIRT3 deacetylates a number of mitochondrial proteins including SOD2, which is responsible for limiting the accumulation of mtROS.20”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, Kim HS, Flynn CR, Hill S, Hayes McDonald W, Olivier AK, Spitz DR, Gius D. Sirt3‐mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell. 2010; 40: 893– 904. 21172655 PMC3266626 source
Not checked in the free run.
- Interpretationown data
The SIRT3-SOD2 linked pathway plays a key role in TMAO-mediated mtROS production and NLRP3 inflammasome activation in HUVECs in vitro and aortas in vivo.
“Finally, our results supported a key role of the SIRT3‐SOD2 linked pathway in TMAO‐mediated mtROS production and NLRP3 inflammasome activation in HUVECs in vitro and aortas in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
TMAO-triggered NLRP3 inflammasome is mainly preceded by generation of mtROS in endothelial cells.
“These findings indicate that TMAO‐triggered NLRP3 inflammasome is mainly preceded by the generation of mtROS in endothelial cells.”
Quote in the paperSubstantial claim - Interpretationown data
TMAO-induced vascular inflammation occurs through activation of NLRP3 inflammasome.
“Overall, our findings indicated a novel mechanism of TMAO‐induced vascular inflammation through activation of the NLRP3 inflammasome.”
Quote in the paperSubstantial claim - Interpretationown data
SIRT3-SOD2 was a major signaling pathway mediating TMAO-induced NLRP3 inflammasome activation and vascular inflammation, both in vitro and in vivo.
“Our findings provided preliminary evidence that SIRT3‐SOD2 was a major signaling pathway mediating TMAO‐induced NLRP3 inflammasome activation and vascular inflammation, both in vitro and in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
The SIRT3-SOD2-mtROS signaling pathway plays a critical role in modulating TMAO-mediated NLRP3 inflammasome activation.
“Moreover, the SIRT3‐SOD2‐mtROS signaling pathway played a critical role in modulating TMAO‐mediated NLRP3 inflammasome activation (Figure 8).”
Quote in the paperSubstantial claim
- May combine two claims. 27
- Classified as probably not a substantial claim. 34
May combine two claims.
Findingown dataTMAO induced inflammation in human umbilical vein endothelial cells and aortas from ApoE−/− mice.
“Experiments using liquid chromatography‐tandem mass spectrometry, Western blot, and fluorescent probes showed that TMAO‐induced inflammation in human umbilical vein endothelial cells (HUVECs) and aortas from ApoE−/− mice.”
- Also stated in: § TMAO Induced Inflammation in Endothelial Cells · hedged
“These results indicated that TMAO triggered inflammation with no significant effects on cell viability in endothelial cells.”
Quote in the paperSubstantial claim- Also stated in: § TMAO Induced Inflammation in Endothelial Cells · hedged
May combine two claims.
Findingown dataPretreatment with MCC950 or YVAD markedly inhibited TMAO-induced NLRP3 and caspase-1 p20 expression and decreased IL-1β, ICAM-1, and MMP9 expression in endothelial cells.
“Pretreatment with MCC950 (10 μmol/L) or YVAD (10 μmol/L) markedly inhibited TMAO‐induced NLRP3 and caspase‐1 p20 expression, followed by decreased expression of IL‐1β, ICAM‐1, and MMP9 in endothelial cells (Figure 2G and 2H).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPretreatment with TEMPO markedly inhibited TMAO-induced activation of the NLRP3 inflammasome and decreased IL-1β, ICAM-1, and MMP-9 expression in human umbilical vein endothelial cells.
“pretreatment with TEMPO (50 μmol/L) markedly inhibited TMAO‐induced activation of the NLRP3 inflammasome followed by decreased expression of IL‐1β, ICAM‐1, and MMP‐9 (Figure 3E and 3F)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTMAO-induced endothelial NLRP3 inflammasome activation was ameliorated by the mitochondrial reactive oxygen species scavenger Mito-TEMPO or by SIRT3 overexpression in human umbilical vein endothelial cells.
“TMAO‐induced endothelial NLRP3 inflammasome activation was ameliorated by the mitochondrial ROS scavenger Mito‐TEMPO, or SIRT3 overexpression in HUVECs.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTMAO failed to further inhibit manganese SOD2 and activate the NLRP3 inflammasome or induce inflammation in SIRT3 siRNA-treated human umbilical vein endothelial cells and aortas from SIRT3−/− mice.
“Conversely, TMAO failed to further inhibit magnesium SOD2 and activate the NLRP3 inflammasome or induce inflammation in SIRT3 short interfering RNA–treated HUVECs and aortas from SIRT3−/− mice.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTMAO promoted NLRP3 and activated caspase-1 p20 expression and caspase-1 activity in aortas from ApoE−/− mice.
“Moreover, TMAO promoted NLRP3 and activated caspase‐1 p20 expression and caspase‐1 activity in vitro and in vivo.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationThe most well-characterized mechanism underlying activation of the NLRP3 inflammasome is reactive oxygen species, particularly mitochondrial reactive oxygen species, generation.
“Following decades of research, the most well‐characterized mechanism underlying activation of the NLRP3 inflammasome is reactive oxygen species (ROS), particularly mitochondrial ROS (mtROS), generation.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [14] Zhou RB, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011; 469: 221– 225. 21124315 source
Not checked in the free run.
- cites [15] Alfonso‐Loeches S, Urena‐Peralta JR, Morillo‐Bargues MJ, Oliver‐De La Cruz J, Guerri C. Role of mitochondria ROS generation in ethanol‐induced NLRP3 inflammasome activation and cell death in astroglial cells. Front Cell Neurosci. 2014; 8: 216– 234. 25136295 PMC4118026 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOxidized low-density lipoprotein and cholesterol crystals activate the NLRP3 inflammasome, leading to processing and secretion of IL-1β and IL-18 and triggering vascular inflammation via upregulation of adhesion molecules.
“Oxidized low‐density lipoprotein and cholesterol crystals activate the inflammasome, thereby leading to the processing and secretion of the proinflammatory cytokines IL‐1β and IL‐18 and ultimately triggering vascular inflammation via upregulation of adhesion molecules.9, 10”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [9] Yin Y, Pastrana JL, Li XY, Huang X, Mallilankaraman K, Choi ET, Madesh M, Wang H, Yang XF. Inflammasomes: sensors of metabolic stresses for vascular inflammation. Front Biosci (Landmark Ed). 2013; 18: 638– 649. 23276949 PMC3590813 source
Not checked in the free run.
- cites [10] Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010; 464: 1357– 1361. 20428172 PMC2946640 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationAtherosclerosis is the result of prolonged and excessive inflammatory processes in the vascular wall, often beginning with inflammatory changes in the endothelium and characterized by expression of adhesion molecules.
“Accumulating evidence indicates that AS is the result of a prolonged and excessive inflammatory processes in the vascular wall, which often begins with inflammatory changes in the endothelium and is characterized by the expression of adhesion molecules.2, 3”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2] Maskrey BH, Megson IL, Whitfield PD, Rossi AG. Mechanisms of resolution of inflammation: a focus on cardiovascular disease. Arterioscler Thromb Vasc Biol. 2011; 31: 1001– 1006. 21508346 source
Not checked in the free run.
- cites [3] Wong BW, Meredith A, Lin D, McManus BM. The biological role of inflammation in atherosclerosis. Can J Cardiol. 2012; 28: 631– 641. 22985787 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationAblation of NLRP3 protects endothelial cells from inflammatory damage, leading to attenuation of atherosclerosis.
“Several studies have suggested that ablation of NLRP3 protects endothelial cells from inflammatory damage, leading to attenuation of AS.12, 13”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [12] Wu JJ, Xu XS, Li Y, Kou JP, Huang F, Liu BL, Liu K. Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3‐mediated inflammation and apoptosis with regulation of AMPK in endothelial cells. Eur J Pharmacol. 2014; 745: 59– 68. 25446924 source
Not checked in the free run.
- cites [13] Chen Y, Wang L, Pitzer AL, Li X, Li PL, Zhang Y. Contribution of redox‐dependent activation of endothelial NLRP3 inflammasomes to hyperglycemia‐induced endothelial dysfunction. J Mol Med. 2016; 94: 1335– 1347. 27783111 PMC5512566 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationSOD2 is the primary mitochondrial oxidative scavenger and plays a crucial role in regulation of mitochondrial reactive oxygen species.
“In view of the finding that SOD2, the primary mitochondrial oxidative scavenger, plays a crucial role in regulation of mtROS,29”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Tao R, Vassilopoulos A, Parisiadou L, Yan Y, Gius D. Regulation of MnSOD enzymatic activity by SIRT3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis. Antioxid Redox Signal. 2014; 20: 1646– 1654. 23886445 PMC3942696 source
Not checked in the free run.
May combine two claims.
PremisecitationTMAO promotes vascular inflammation, leading to atherosclerosis.
“More recently, TMAO has been shown to promote vascular inflammation, leading to AS.7”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Seldin MM, Meng YH, Qi HX, Zhu WF, Wang ZE, Hazen SL, Lusis AJ, Shih DM. Trimethylamine N‐oxide promotes vascular inflammation through signaling of mitogen‐activated protein kinase and nuclear factor‐κB. J Am Heart Assoc. 2016; 5: e002767. DOI: 10.1161/JAHA.115.002767. PMC4802459 26903003 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThe NLRP3 inflammasome plays a key role in the pathogenesis of diverse inflammatory diseases, including atherosclerosis, type 2 diabetes mellitus, and gout.
“The NLRP3 inflammasome plays a key role in the pathogenesis of diverse inflammatory diseases, including AS, type 2 diabetes mellitus, and gout.9”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Yin Y, Pastrana JL, Li XY, Huang X, Mallilankaraman K, Choi ET, Madesh M, Wang H, Yang XF. Inflammasomes: sensors of metabolic stresses for vascular inflammation. Front Biosci (Landmark Ed). 2013; 18: 638– 649. 23276949 PMC3590813 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTMAO promotes vascular inflammation through mitogen-activated protein kinase and nuclear factor-κB signaling.
“In 2016, Seldin and co‐workers7 showed that TMAO promotes vascular inflammation through signaling of mitogen‐activated protein kinase and nuclear factor‐κB (NF‐κB).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Seldin MM, Meng YH, Qi HX, Zhu WF, Wang ZE, Hazen SL, Lusis AJ, Shih DM. Trimethylamine N‐oxide promotes vascular inflammation through signaling of mitogen‐activated protein kinase and nuclear factor‐κB. J Am Heart Assoc. 2016; 5: e002767. DOI: 10.1161/JAHA.115.002767. PMC4802459 26903003 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAtheroprone flow induces the NLRP3 inflammasome in endothelium through SREBP2 activation.
“Xiao et al11 additionally reported that atheroprone flow induces the NLRP3 inflammasome in endothelium through serol regulatory element binding protein 2 activation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Xiao H, Lu M, Lin TY, Chen Z, Chen G, Wang WC, Marin T, Shentu TP, Wen L, Gongol B, Sun W, Liang X, Chen J, Huang HD, Pedra JHF, Johnson DA, Shyy JYJ. Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic‐induced atherosclerosis susceptibility. Circulation. 2013; 128: 632– 642. 23838163 PMC3798034 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTMAO partially contributes to the development of atherosclerosis by regulating the major pathway of cholesterol metabolism and the bile acid synthetic pathway.
“Previous studies suggest that TMAO partially contributes to the development of AS by regulating the major pathway of cholesterol metabolism and the bile acid synthetic pathway.4, 5, 6”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472: 57– 63. 21475195 PMC3086762 source
Not checked in the free run.
- cites [5] Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013; 368: 1575– 1584. 23614584 PMC3701945 source
Not checked in the free run.
- cites [6] Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of l‐carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013; 19: 576– 585. 23563705 PMC3650111 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationSOD2 activity is tightly regulated via acetylation at its lysine residues.
“SOD2 activity is known to be tightly regulated via acetylation at its lysine residues.20”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, Kim HS, Flynn CR, Hill S, Hayes McDonald W, Olivier AK, Spitz DR, Gius D. Sirt3‐mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell. 2010; 40: 893– 904. 21172655 PMC3266626 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIncreased innate immunity in endothelium synergizes with hyperlipidemia to cause topographical distribution of atherosclerotic lesions.
“This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographical distribution of atherosclerotic lesions.11”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Xiao H, Lu M, Lin TY, Chen Z, Chen G, Wang WC, Marin T, Shentu TP, Wen L, Gongol B, Sun W, Liang X, Chen J, Huang HD, Pedra JHF, Johnson DA, Shyy JYJ. Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic‐induced atherosclerosis susceptibility. Circulation. 2013; 128: 632– 642. 23838163 PMC3798034 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationMitoSOX Red is a highly selective fluorescent probe for detection of superoxide generated within mitochondria.
“mtROS levels were evaluated using MitoSOX™ Red, a highly selective fluorescent probe for detection of O2∙− generated within mitochondria.28”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Chowdhury SK, Dobrowsky RT, Fernyhough P. Nutrient excess and altered mitochondrial proteome and function contribute to neurodegeneration in diabetes. Mitochondrion. 2011; 11: 845– 854. 21742060 PMC3375692 source
Not checked in the free run.
May combine two claims.
PremisecitationThe majority of NLRP3 activators increase mitochondrial reactive oxygen species levels, and chemical scavengers of mitochondrial reactive oxygen species effectively inhibit NLRP3 activation.
“The majority of NLRP3 activators increase mtROS levels, and chemical scavengers of mtROS effectively inhibit NLRP3 activation.14, 15”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [14] Zhou RB, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011; 469: 221– 225. 21124315 source
Not checked in the free run.
- cites [15] Alfonso‐Loeches S, Urena‐Peralta JR, Morillo‐Bargues MJ, Oliver‐De La Cruz J, Guerri C. Role of mitochondria ROS generation in ethanol‐induced NLRP3 inflammasome activation and cell death in astroglial cells. Front Cell Neurosci. 2014; 8: 216– 234. 25136295 PMC4118026 source
Not checked in the free run.
May combine two claims.
PremisecitationSIRT3 can directly bind and deacetylate SOD2, leading to increased SOD2 activity and subsequently exerting significant effects on mitochondrial reactive oxygen species homeostasis and NLRP3 inflammasome activation.
“More importantly, SIRT3 can directly bind and deacetylate SOD2, leading to increased SOD2 activity and subsequently exerting significant effects on mtROS homeostasis and NLRP3 inflammasome activation.18, 19, 20”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [18] Zhao WY, Zhang L, Sui MX, Zhu YH, Zeng L. Protective effects of sirtuin 3 in a murine model of sepsis‐induced acute kidney injury. Sci Rep. 2016; 6: 33201. 27620507 PMC5020492 source
Not checked in the free run.
- cites [19] Traba J, Kwarteng‐Siaw M, Okoli TC, Li J, Huffstutler RD, Bray A, Waclawiw MA, Han K, Pelletier M, Sauve AA, Siegel RM, Sack MN. Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects. J Clin Invest. 2015; 125: 4592– 4600. 26529255 PMC4665779 source
Not checked in the free run.
- cites [20] Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, Kim HS, Flynn CR, Hill S, Hayes McDonald W, Olivier AK, Spitz DR, Gius D. Sirt3‐mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell. 2010; 40: 893– 904. 21172655 PMC3266626 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningImage parameters remained constant throughout the ultrasound experiment to reduce variability.
“To reduce variability, image parameters remained constant throughout the experiment.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe study was approved by the ethics review board at the Third Military Medical University, and informed consent was obtained from all patients before participation.
“The ethics review board at the Third Military Medical University approved this study, and informed consent was obtained from all patients before participation.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenUltrasound examinations were performed by an experienced operator, and all measurements were repeated 3 times at the same site.
“All examinations were performed by an experienced operator, and all measurements were repeated 3 times at the same site.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAnimal experiments were approved by the Animal Care and Use Committee of the Third Military Medical University.
“Animal experiments were carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health and approved by the Animal Care and Use Committee of the Third Military Medical University (Chongqing, China; Approval SYXC‐2014‐00112).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationTMAO plays a role in activation of inflammatory pathways in cells of the vasculature, leading to endothelial cell leukocyte recruitment and AS.
“These results support a role for TMAO in the activation of inflammatory pathways in cells of the vasculature, leading to endothelial cell leukocyte recruitment and AS.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Seldin MM, Meng YH, Qi HX, Zhu WF, Wang ZE, Hazen SL, Lusis AJ, Shih DM. Trimethylamine N‐oxide promotes vascular inflammation through signaling of mitogen‐activated protein kinase and nuclear factor‐κB. J Am Heart Assoc. 2016; 5: e002767. DOI: 10.1161/JAHA.115.002767. PMC4802459 26903003 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIL-1β is a major atheroprone factor that promotes development of lipid plaques and destabilizes plaques by upregulating adhesion molecules including VCAM-1 and ICAM-1.
“IL‐1β is a major atheroprone factor that plays a significant role in promoting the development of lipid plaques and destabilizing plaques by upregulating adhesion molecules, including vascular cell adhesion molecule‐1 and ICAM‐1.31, 32, 33”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [31] De Nardo D, Latz E. NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol. 2011; 32: 373– 379. 21733753 PMC3151541 source
Not checked in the free run.
- cites [32] Connat JL. [ Inflammasome and cardiovascular diseases]. Ann Cardiol Angeiol (Paris). 2011; 60: 48– 54. 20800829 source
Not checked in the free run.
- cites [33] Alcocer‐Gomez E, Cordero MD. NLRP3 inflammasome: common nexus between depression and cardiovascular diseases. Nat Rev Cardiol. 2017; 14: 124. 28054580 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSREBP2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced AS susceptibility.
“Moreover, recent studies have demonstrated that sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic‐induced AS susceptibility,11”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Xiao H, Lu M, Lin TY, Chen Z, Chen G, Wang WC, Marin T, Shentu TP, Wen L, Gongol B, Sun W, Liang X, Chen J, Huang HD, Pedra JHF, Johnson DA, Shyy JYJ. Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic‐induced atherosclerosis susceptibility. Circulation. 2013; 128: 632– 642. 23838163 PMC3798034 source
Not checked in the free run.
May combine two claims.
PremisecitationAS is decreased in several rodent models lacking NLRP3 or IL-1 molecules, whereas mice deficient in IL-1 receptor antagonist show increased AS.
“AS is decreased in several rodent models lacking NLRP3 or IL‐1 molecules, whereas in contrast, mice deficient in the IL‐1 receptor antagonist show increased AS.10”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010; 464: 1357– 1361. 20428172 PMC2946640 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPhysiological levels of TMAO can induce expression of cytokines and adhesion molecules, at least in part via the NF-κB signaling pathway in vascular endothelial and smooth muscle cells, both in vivo and in vitro.
“Recent studies have shown that physiological levels of TMAO can induce expression of cytokines and adhesion molecules, at least in part via the NF‐κB signaling pathway in vascular endothelial and smooth muscle cells, both in vivo and in vitro.7”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Seldin MM, Meng YH, Qi HX, Zhu WF, Wang ZE, Hazen SL, Lusis AJ, Shih DM. Trimethylamine N‐oxide promotes vascular inflammation through signaling of mitogen‐activated protein kinase and nuclear factor‐κB. J Am Heart Assoc. 2016; 5: e002767. DOI: 10.1161/JAHA.115.002767. PMC4802459 26903003 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTMAO contributes to the development of AS, in part, by affecting cholesterol metabolism through regulating the major pathway for cholesterol elimination from the body and the bile acid synthetic pathway at multiple levels.
“Researchers have confirmed that TMAO contributes to the development of AS, in part, by affecting cholesterol metabolism through regulating the major pathway for cholesterol elimination from the body and the bile acid synthetic pathway at multiple levels.4, 6”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [4] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472: 57– 63. 21475195 PMC3086762 source
Not checked in the free run.
- cites [6] Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of l‐carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013; 19: 576– 585. 23563705 PMC3650111 source
Not checked in the free run.
May combine two claims.
PremisecitationAblation of NLRP3 protects endothelial cells from inflammatory damage, subsequently attenuating AS.
“whereas ablation of NLRP3 protects endothelial cells from inflammatory damage, subsequently attenuating AS.12, 13”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [12] Wu JJ, Xu XS, Li Y, Kou JP, Huang F, Liu BL, Liu K. Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3‐mediated inflammation and apoptosis with regulation of AMPK in endothelial cells. Eur J Pharmacol. 2014; 745: 59– 68. 25446924 source
Not checked in the free run.
- cites [13] Chen Y, Wang L, Pitzer AL, Li X, Li PL, Zhang Y. Contribution of redox‐dependent activation of endothelial NLRP3 inflammasomes to hyperglycemia‐induced endothelial dysfunction. J Mol Med. 2016; 94: 1335– 1347. 27783111 PMC5512566 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe NLRP3 inflammasome is an IL-1β family cytokine-activating protein complex consisting of NLRP3, apoptotic speck-like protein, and inactive pro-caspase-1, and involved in regulation of innate immunity and inflammatory response.
“The NLRP3 inflammasome is an IL‐1β family cytokine‐activating protein complex consisting of the pattern recognition receptor NLRP3, adaptor protein apoptotic speck‐like protein, and inactive pro‐caspase‐1, and involved in the regulation of innate immunity and inflammatory response.30”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Gross O, Thomas CJ, Guarda G, Tschopp J. The inflammasome: an integrated view. Immunol Rev. 2011; 243: 136– 151. 21884173 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrimed macrophages secrete large amounts of IL-1β in response to cholesterol crystals in an NLRP3 inflammasome-dependent manner in mouse and human cells.
“Primed macrophages secrete large amounts of IL‐1β in response to cholesterol crystals in an NLRP3 inflammasome‐dependent manner in mouse and human cells.34, 35”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [34] Rajamaki K, Lappalainen J, Oorni K, Valimaki E, Matikainen S, Kovanen PT, Eklund KK. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010; 5: e11765. 20668705 PMC2909263 source
Not checked in the free run.
- cites [35] Abdul‐Muneer PM, Alikunju S, Mishra V, Schuetz H, Szlachetka AM, Burnham EL, Haorah J. Activation of NLRP3 inflammasome by cholesterol crystals in alcohol consumption induces atherosclerotic lesions. Brain Behav Immun. 2017; 62: 291– 305. 28232172 PMC6378699 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSeveral endogenous metabolic stress molecules (e.g., oligomers of islet amyloid polypeptide, glucose, ceramid, oxidized LDL, cholesterol crystals) are sensed by NLRP3, stimulating NLRP3 inflammasome complex assembly, leading to activation of caspase-1 and processing/secretion of IL-1β and IL-18.
“Several endogenous metabolic stress molecules, such as oligomers of islet amyloid polypeptide, glucose, ceramid, oxidized LDL, and cholesterol crystals, are sensed by NLRP3, stimulating NLRP3 inflammasome complex assembly and, in turn, leading to activation of caspase‐1 and ultimately to the processing and secretion of the proinflammatory cytokines IL‐1β and IL‐18.9”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Yin Y, Pastrana JL, Li XY, Huang X, Mallilankaraman K, Choi ET, Madesh M, Wang H, Yang XF. Inflammasomes: sensors of metabolic stresses for vascular inflammation. Front Biosci (Landmark Ed). 2013; 18: 638– 649. 23276949 PMC3590813 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationInflammation participates centrally in all stages of AS from initial lesion to end-stage thrombotic complications.
“Inflammation participates centrally in all stages of AS from the initial lesion to end‐stage thrombotic complications.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] Maskrey BH, Megson IL, Whitfield PD, Rossi AG. Mechanisms of resolution of inflammation: a focus on cardiovascular disease. Arterioscler Thromb Vasc Biol. 2011; 31: 1001– 1006. 21508346 source
Not checked in the free run.
- cites [3] Wong BW, Meredith A, Lin D, McManus BM. The biological role of inflammation in atherosclerosis. Can J Cardiol. 2012; 28: 631– 641. 22985787 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationmtROS-dependent activation of endothelial NLRP3 inflammasome by hyperglycemia may be an important initiating mechanism for endothelial dysfunction.
“It has also been found that the mtROS‐dependent activation of the endothelial NLRP3 inflammasome by hyperglycemia may be an important initiating mechanism for endothelial dysfunction,13”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Chen Y, Wang L, Pitzer AL, Li X, Li PL, Zhang Y. Contribution of redox‐dependent activation of endothelial NLRP3 inflammasomes to hyperglycemia‐induced endothelial dysfunction. J Mol Med. 2016; 94: 1335– 1347. 27783111 PMC5512566 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationZhao and colleagues demonstrated a protective role of SIRT3 against mitochondrial damage in kidney through activating SOD2 and decreasing ROS production, subsequently inhibiting NLRP3 inflammasome and downregulating IL-1β and IL-18.
“Recently, Zhao and colleagues18 demonstrated a protective role of SIRT3 against mitochondrial damage in the kidney through activating SOD2 and decreasing ROS production, subsequently inhibiting the NRLP3 inflammasome and downregulating IL‐1β and IL‐18.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Zhao WY, Zhang L, Sui MX, Zhu YH, Zeng L. Protective effects of sirtuin 3 in a murine model of sepsis‐induced acute kidney injury. Sci Rep. 2016; 6: 33201. 27620507 PMC5020492 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSirtuins are NAD+-dependent enzymes implicated in AS, diabetes, cancer, longevity, neurodegeneration through deacetylation of numerous substrates.
“Sirtuins are NAD+‐dependent enzymes implicated in a range of physiological and pathophysiological conditions, including AS, diabetes mellitus, cancer, longevity, and neurodegeneration, through deacetylation of numerous substrates.42”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010; 5: 253– 295. 20078221 PMC2866163 source
Not checked in the free run.
May combine two claims.
PremisecitationTraba et al. confirmed that a 24-hour fast in human subjects activates SIRT3 biology, increasing SOD2 activity, conferring resistance to NLRP3 inflammasome activation via blunting mtROS level.
“Traba et al19 additionally confirmed that a 24‐hour fast in human subjects activates SIRT3 biology, thereby increasing SOD2 activity, in turn conferring resistance to NLRP3 inflammasome activation via blunting of the mtROS level.19”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Traba J, Kwarteng‐Siaw M, Okoli TC, Li J, Huffstutler RD, Bray A, Waclawiw MA, Han K, Pelletier M, Sauve AA, Siegel RM, Sack MN. Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects. J Clin Invest. 2015; 125: 4592– 4600. 26529255 PMC4665779 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTreatment with ROS inhibitors suppresses cadmium-, silica-, and asbestos-induced NLRP3 inflammasome activation.
“Conversely, treatment with ROS inhibitors has been shown to suppress cadmium‐, silica‐, and asbestos‐induced NLRP3 inflammasome activation.37, 38”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [37] Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008; 320: 674– 677. 18403674 PMC2396588 source
Not checked in the free run.
- cites [38] Chen H, Lu Y, Cao Z, Ma Q, Pi H, Fang Y, Yu Z, Hu H, Zhou Z. Cadmium induces NLRP3 inflammasome‐dependent pyroptosis in vascular endothelial cells. Toxicol Lett. 2016; 246: 7– 16. 26809137 source
Not checked in the free run.
May combine two claims.
PremisecitationSIRT3 directly binds and deacetylates SOD2, increasing SOD2 activity and affecting mtROS homeostasis, which plays a key protective role in high glucose-, angiotensin II-, and hypoxia-induced endothelial dysfunction.
“Specifically, SIRT3 directly binds and deacetylates SOD2, thereby increasing SOD2 activity and subsequently leading to a significant effect on mtROS homeostasis, which plays a key protective role in high glucose–,43 angiotensin II–,44 and hypoxia45‐induced endothelial dysfunction.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [43] Liu G, Cao M, Xu Y, Li Y. SIRT3 protects endothelial cells from high glucose‐induced cytotoxicity. Int J Clin Exp Pathol. 2015; 8: 353– 360. 25755722 PMC4348913
Not checked in the free run.
- cites [44] Liu H, Chen T, Li N, Wang S, Bu P. Role of SIRT3 in angiotensin II‐induced human umbilical vein endothelial cells dysfunction. BMC Cardiovasc Disord. 2015; 15: 81– 88. 26223796 PMC4520206 source
Not checked in the free run.
- cites [45] Tseng AH, Wu LH, Shieh SS, Wang DL. SIRT3 interactions with FOXO3 acetylation, phosphorylation and ubiquitinylation mediate endothelial cell responses to hypoxia. Biochem J. 2014; 464: 157– 168. 25162939 source
Not checked in the free run.
May combine two claims.
Interpretationown dataTMAO activated the NLRP3 inflammasome and IL-1β release, subsequently causing inflammation, both in vitro in cultured HUVECs and in vivo in aortas from ApoE-/- mice, and ultimately promoting AS.
“Data from the present study showed that TMAO activated the NLRP3 inflammasome and IL‐1β release, subsequently causing inflammation, both in vitro in cultured HUVECs and in vivo in aortas from ApoE−/− mice, and ultimately promoting AS.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationSIRT3 serves as a primary regulator of mitochondrial protein acetylation, involved in regulation of energy production and mtROS homeostasis.
“SIRT3, a mitochondrial sirtuin, serves as a primary regulator of mitochondrial protein acetylation, which is involved in the regulation of energy production and mtROS homeostasis.16”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Bause AS, Haigis MC. SIRT3 regulation of mitochondrial oxidative stress. Exp Gerontol. 2013; 48: 634– 639. 22964489 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEndothelial senescence could be mediated through mtROS and NLRP3 inflammasome signaling pathways.
“and endothelial senescence could be mediated through mtROS and NLRP3 inflammasome signaling pathways.41”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Sun C, Fan S, Wang X, Lu J, Zhang Z, Wu D, Shan Q, Zheng Y. Purple sweet potato color inhibits endothelial premature senescence by blocking the NLRP3 inflammasome. J Nutr Biochem. 2015; 26: 1029– 1040. 26164602 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationInflammasome activators such as uric acid crystals enhance ROS production, promoting association of thioredoxin-interacting protein with NLRP3 and activation of inflammasome.
“Inflammasome activators, such as uric acid crystals, enhance ROS production, thereby promoting association of thioredoxin‐interacting protein with NLRP3 and activation of the inflammasome.36”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin‐interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010; 11: 136– 140. 20023662 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationROS generation is the most common pathway in inflammasome assembly.
“Previous studies have ascertained that ROS generation is the most common pathway in inflammasome assembly.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin‐interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010; 11: 136– 140. 20023662 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe process of AS often begins with inflammatory changes in the endothelium, characterized by expression of adhesion molecules.
“The process often begins with inflammatory changes in the endothelium, characterized by expression of adhesion molecules.2, 3”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] Maskrey BH, Megson IL, Whitfield PD, Rossi AG. Mechanisms of resolution of inflammation: a focus on cardiovascular disease. Arterioscler Thromb Vasc Biol. 2011; 31: 1001– 1006. 21508346 source
Not checked in the free run.
- cites [3] Wong BW, Meredith A, Lin D, McManus BM. The biological role of inflammation in atherosclerosis. Can J Cardiol. 2012; 28: 631– 641. 22985787 source
Not checked in the free run.
May combine two claims.
InterpretationcitationThe NLRP3 inflammasome plays a key role in the pathogenesis of vascular inflammation, thereby contributing to AS development.
“These results clearly indicate that the NLRP3 inflammasome plays a key role in the pathogenesis of vascular inflammation, thereby contributing to AS development.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [10] Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010; 464: 1357– 1361. 20428172 PMC2946640 source
Not checked in the free run.
- cites [11] Xiao H, Lu M, Lin TY, Chen Z, Chen G, Wang WC, Marin T, Shentu TP, Wen L, Gongol B, Sun W, Liang X, Chen J, Huang HD, Pedra JHF, Johnson DA, Shyy JYJ. Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic‐induced atherosclerosis susceptibility. Circulation. 2013; 128: 632– 642. 23838163 PMC3798034 source
Not checked in the free run.
- cites [12] Wu JJ, Xu XS, Li Y, Kou JP, Huang F, Liu BL, Liu K. Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3‐mediated inflammation and apoptosis with regulation of AMPK in endothelial cells. Eur J Pharmacol. 2014; 745: 59– 68. 25446924 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNF-κB-mediated signaling is involved in NLRP3 inflammasome activation by regulating transcription of inflammasome-related components, including inactive NLRP3, pro-IL-1β, and pro-IL-18.
“Additionally, it has been demonstrated that NF‐κB–mediated signaling is also involved in the NLRP3 inflammasome activation by regulating the transcription of inflammasome‐related components, including inactive NLRP3, pro‐IL‐1β, and pro‐IL‐18.46”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Shao BZ, Xu ZQ, Han BZ, Su DF, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015; 6: 262– 271. 26594174 PMC4633676 source
Not checked in the free run.
The authors state this as an assumption.
Lower concentrations of TMAO would have some impact, although it may be hard to detect experimentally.
“AS is a chronic disease that develops over many years, and one can assume that lower concentrations of TMAO would have some impact, although it may be hard to detect experimentally.”
The paper relies on this without support.
Mitochondria are the major source of cellular ROS.
“Importantly, mitochondria are the major source of cellular ROS.”
The paper relies on this without support.
Blood levels of TMAO are causatively linked to AS risk.
“Given that blood levels of TMAO are causatively linked to AS risk, the next obvious question is the mechanism by which circulating TMAO promotes AS, which is under active investigation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
There is convincing evidence suggesting an association between TMAO and inflammation.
“nowadays there is convincing evidence suggesting an association between TMAO and inflammation [8,9,10,11,12]”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [9]
In HUVEC and mice, TMAO administration activates NLRP3 inflammasome through inhibition of the SIRT3-SOD2-mitochondrial ROS signalling pathway.
“Other experiments performed in HUVEC and mice also revealed a link between TMAO administration and inflammation by activation of NLRP3 inflammasome. One of these studies suggests that this activation occurs through the inhibition of SIRT3-SOD2-mitochondrial ROS signalling pathway.”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [9]
Trimethylamine N-oxide has been shown to promote platelet reactivity and thrombosis potential, vascular inflammation and inflammasome activation, and heightened heart failure and chronic kidney disease related phenotypes in animal models.
“It has also been shown to promote platelet reactivity and thrombosis potential14, 83–85, vascular inflammation and inflammasome activation86–88, heightened heart failure89–91 and CKD92–95 related phenotypes in animal models (Figure 2).”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [87]
TMAO can impact inflammation via priming and activation of the NLRP3 inflammasome in endothelial cells and the arterial vascular wall in mice, involving mitochondrial ROS production, TXNIP, and lysosomal destabilization.
“Recent investigations have suggested TMAO can impact inflammation via priming and activation of the NLRP3 inflammasome in endothelial cells, as well as the arterial vascular wall in mice, involving mitochondrial reactive oxygen species (ROS) production, thioredoxin interacting protein (TXNIP) and lysosomal destabilization87, 130, 131.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [87]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Opposite effects on SIRT3 expression reported in vivo
MinorThe Results state that choline promoted SIRT3 expression in ApoE−/− mice, whereas the Discussion states that TMAO suppressed SIRT3 expression in vivo. These are opposite directions for a result central to the proposed mechanism.
“choline promoted SIRT3 expression and SOD2 acetylation as well as inhibition of SOD2 activity in ApoE−/− mice.”
“Data from the present study showed that TMAO markedly suppressed SIRT3 expression and SOD2 activity in vitro and in vivo.”
Cell-viability time points differ between Methods and Results
MinorThe Results include a 48-hour cell-viability measurement, but the corresponding Methods list no 48-hour measurement and instead include a 0-hour measurement.
“a fixed dose of TMAO (600 μmol/L) at different time points (4, 8, 12, 24, 36, 48, and 72 hours), following which cell viability was determined.”
“a fixed concentration (600 μmol/L) for the indicated time periods (0, 4, 8, 12, 24, 36, and 72 hours).”
Cites
A role for mitochondria in nlrp3 inflammasome activation
Zhou, R., Yazdi, A. S., Menu, P., & Tschopp, J. (2011) · Nature · doi:10.1038/nature09663 · Cited by 5,602 · see citing works
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597 · see citing works
Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study
Murray, C. J., & Lopez, A. D. (1997) · The Lancet · doi:10.1016/s0140-6736(96)07495-8 · Cited by 4,492 · cited 1× · see citing works
“T he incidence of cardiovascular diseases such as atherosclerosis (AS) is increasing globally, creating a serious and expensive public health issue.(1) Accumulating evidence indicates that AS is the result of a prolonged and”
BackgroundIntestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis
Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., Britt, E. B., Fu, X., Wu, Y., Li, L., et al. (2013) · Nature Medicine · doi:10.1038/nm.3145 · Cited by 4,386 · see citing works
NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
Duewell, P., Kono, H., Rayner, K. J., Sirois, C. M., Vladimer, G., Bauernfeind, F. G., Abela, G. S., Franchi, L., Nuñez, G., Schnurr, M., et al. (2010) · Nature · doi:10.1038/nature08938 · Cited by 4,026 · see citing works
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk
Tang, W. H. W., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., Wu, Y., & Hazen, S. L. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1109400 · Cited by 3,402 · cited 9× · see citing works
“001).(5) Within the cohort examined, the hazard ratio for TMAO was significantly higher than that for traditional risk factors such as LDL cholesterol.”
BackgroundInfluentialThioredoxin-interacting protein links oxidative stress to inflammasome activation
Zhou, R., Tardivel, A., Thorens, B., Choi, I., & Tschopp, J. (2010) · Nature Immunology · doi:10.1038/ni.1831 · Cited by 2,708 · see citing works
Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica
Dostert, C., Pétrilli, V., Van Bruggen, R., Steele, C., Mossman, B. T., & Tschopp, J. (2008) · Science · doi:10.1126/science.1156995 · Cited by 2,658 · see citing works
Mammalian Sirtuins: Biological Insights and Disease Relevance
Haigis, M. C., & Sinclair, D. A. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092250 · Cited by 2,085 · see citing works
Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation
Qiu, X., Brown, K., Hirschey, M. D., Verdin, E., & Chen, D. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.11.015 · Cited by 1,310 · see citing works
Rajamäki, K., Lappalainen, J., Öörni, K., Välimäki, E., Matikainen, S., Kovanen, P. T., & Eklund, K. K. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011765 · Cited by 1,039 · see citing works
Quantitative assessment of atherosclerotic lesions in mice
Paigen, B. J., Morrow, A., Holmes, P. A., Mitchell, D., & Williams, R. A. (1987) · Atherosclerosis · doi:10.1016/0021-9150(87)90202-4 · Cited by 952 · see citing works
Inflammasomes and Their Roles in Health and Disease
Lamkanfi, M., & Dixit, V. M. (2012) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-101011-155745 · Cited by 935 · cited 1× · see citing works
“Nucleotide-binding oligomerization domain–like receptor family pyrin domain containing 3 (NLRP3) inflammasome is an interleukin (IL)-1b family cytokine-activating protein complex involved in regulation of innate immune and inflammatory responses.(8) The NLRP3 inflammasome plays a key role in the pathogenesis of divers…”
BackgroundSeldin, M. M., Meng, Y., Qi, H., Zhu, W., Wang, Z., Hazen, S. L., Lusis, A. J., & Shih, D. M. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.115.002767 · Cited by 911 · see citing works
Tao, R., Coleman, M. C., Pennington, J. D., Ozden, O., Park, S.-H., Jiang, H., Kim, H.-S., Flynn, C. R., Hill, S., Hayes McDonald, W., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.12.013 · Cited by 899 · see citing works
NLRP3 inflammasome and its inhibitors: a review
Shao, B.-Z., Xu, Z.-Q., Han, B.-Z., Su, D.-F., & Liu, C. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00262 · Cited by 836 · cited 1× · see citing works
“Additionally, it has been demonstrated that NF-jB–mediated signaling is also involved in the NLRP3 inflammasome activation by regulating the transcription of inflammasome-related components, including inactive NLRP3, pro-IL-1b, and pro-IL-18.(46) More recently, TMAO has been found to induce phosphorylation of the NF-j…”
BackgroundWang, Y., Xu, C.-F., Liu, Y.-J., Mao, Y.-F., Lv, Z., Li, S.-Y., Zhu, X.-Y., & Jiang, L. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000477112 · Cited by 825 · see citing works
Self-citationThe inflammasome: an integrated view
Gross, O., Thomas, C. J., Guarda, G., & Tschopp, J. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01046.x · Cited by 778 · see citing works
Chen, M.-L., Yi, L., Zhang, Y., Zhou, X., Ran, L., Yang, J., Zhu, J.-D., Zhang, Q.-Y., & Mi, M.-T. (2016) · mBio · doi:10.1128/mbio.02210-15 · Cited by 754 · see citing works
Self-citationMechanisms of inflammasome activation: recent advances and novel insights
Vanaja, S. K., Rathinam, V. A. K., & Fitzgerald, K. A. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.12.009 · Cited by 499 · see citing works
NLRP3 inflammasomes link inflammation and metabolic disease
De Nardo, D., & Latz, E. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.05.004 · Cited by 425 · see citing works
Wang, D., Xia, M., Xiao, Y., Li, D., Wang, L., Xu, Y., Jin, T., & Ling, W. (2012) · Circulation Research · doi:10.1161/circresaha.112.266502 · Cited by 315 · see citing works
SIRT3 regulation of mitochondrial oxidative stress
Bause, A. S., & Haigis, M. C. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2012.08.007 · Cited by 311 · see citing works
Huang, L.-S., Cobessi, D., Tung, E. Y., & Berry, E. A. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.05.053 · Cited by 304 · see citing works
Chen, M., Yi, L., Jin, X., Liang, X., Zhou, Y. G., Zhang, T., Xie, Q., Zhou, X., Chang, H., Fu, Y., et al. (2013) · Autophagy · doi:10.4161/auto.26336 · Cited by 267 · see citing works
Self-citationAlfonso-Loeches, S., Ureña-Peralta, J. R., Morillo-Bargues, M. J., Oliver-De La Cruz, J., & Guerri, C. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00216 · Cited by 265 · see citing works
Xiao, H., Lu, M., Lin, T. Y., Chen, Z., Chen, G., Wang, W.-C., Marin, T., Shentu, T.-P., Wen, L., Gongol, B., et al. (2013) · Circulation · doi:10.1161/circulationaha.113.002714 · Cited by 257 · see citing works
Tao, R., Vassilopoulos, A., Parisiadou, L., Yan, Y., & Gius, D. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5482 · Cited by 194 · see citing works
Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects
Traba, J., Kwarteng-Siaw, M., Okoli, T. C., Li, J., Huffstutler, R. D., Bray, A., Waclawiw, M. A., Han, K., Pelletier, M., Sauve, A. A., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci83260 · Cited by 180 · see citing works
Mechanisms of Resolution of Inflammation: A Focus on Cardiovascular Disease
Maskrey, B. H., Megson, I. L., Whitfield, P. D., & Rossi, A. G. (2011) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.110.213850 · Cited by 177 · see citing works
The Biological Role of Inflammation in Atherosclerosis
Wong, B. W., Meredith, A., Lin, D., & McManus, B. M. (2012) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2012.06.023 · Cited by 168 · see citing works
Cadmium induces NLRP3 inflammasome-dependent pyroptosis in vascular endothelial cells
Chen, H., Lu, Y., Cao, Z., Ma, Q., Pi, H., Fang, Y., Yu, Z., Hu, H., & Zhou, Z. (2016) · Toxicology Letters · doi:10.1016/j.toxlet.2016.01.014 · Cited by 165 · see citing works
Won, J.-H., Park, S., Hong, S., Son, S., & Yu, J.-W. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.667063 · Cited by 142 · see citing works
Inflammasomes: sensors of metabolic stresses for vascular inflammation
Yang, X.-F. (2013) · Frontiers in Bioscience · doi:10.2741/4127 · Cited by 134 · see citing works
Wu, J., Xu, X., Li, Y., Kou, J., Huang, F., Liu, B., & Liu, K. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.09.046 · Cited by 125 · see citing works
Tseng, A. H.-H., Wu, L.-H., Shieh, S.-S., & Wang, D. L. (2014) · Biochemical Journal · doi:10.1042/bj20140213 · Cited by 114 · see citing works
Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury
Zhao, W.-Y., Zhang, L., Sui, M.-X., Zhu, Y.-H., & Zeng, L. (2016) · Scientific Reports · doi:10.1038/srep33201 · Cited by 114 · see citing works
Chen, Y., Wang, L., Pitzer, A. L., Li, X., Li, P.-L., & Zhang, Y. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1481-5 · Cited by 108 · see citing works
Chowdhury, S. K. R., Dobrowsky, R. T., & Fernyhough, P. (2011) · Mitochondrion · doi:10.1016/j.mito.2011.06.007 · Cited by 82 · see citing works
Chen, C.-Y., Yi, L., Jin, X., Zhang, T., Fu, Y.-J., Zhu, J.-D., Mi, M.-T., Zhang, Q.-Y., Ling, W.-H., & Yu, B. (2011) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-011-9216-2 · Cited by 61 · see citing works
Self-citationNiu, L., Qian, M., Yang, W., Meng, L., Xiao, Y., Wong, K. K. L., Abbott, D., Liu, X., & Zheng, H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076880 · Cited by 48 · see citing works
Sun, C., Fan, S., Wang, X., Lu, J., Zhang, Z., Wu, D., Shan, Q., & Zheng, Y. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2015.04.012 · Cited by 43 · see citing works
Role of SIRT3 in Angiotensin II-induced human umbilical vein endothelial cells dysfunction
Liu, H., Chen, T., Li, N., Wang, S., & Bu, P. (2015) · BMC Cardiovascular Disorders · doi:10.1186/s12872-015-0075-4 · Cited by 36 · see citing works
Abdul Muneer, P. M., Alikunju, S., Mishra, V., Schuetz, H., Szlachetka, A. M., Burnham, E. L., & Haorah, J. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2017.02.014 · Cited by 33 · see citing works
SIRT3 protects endothelial cells from high glucose-induced cytotoxicity.
Liu, G., Cao, M., Xu, Y., & Li, Y. (2015) · Europe PMC (PubMed Central) · Cited by 25 · see citing works
NLRP3 inflammasome: common nexus between depression and cardiovascular diseases
Alcocer-Gómez, E., & Cordero, M. D. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2016.214 · Cited by 20 · see citing works
Rôle de l’inflammasome dans les pathologies cardiovasculaires
Connat, J.-L. (2011) · Annales de Cardiologie et d'Angéiologie · doi:10.1016/j.ancard.2010.07.011 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Gut microbiota and cardiovascular disease.
Witkowski, M., Weeks, T. L., & Hazen, S. L. (2020) · Circulation Research · doi:10.1161/circresaha.120.316242 · Cited by 1,051 · see citing works
Gut Microbiota as a Trigger for Metabolic Inflammation in Obesity and Type 2 Diabetes
Scheithauer, T. P. M., Rampanelli, E., Nieuwdorp, M., Vallance, B. A., Verchere, C. B., van Raalte, D. H., & Herrema, H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.571731 · Cited by 694 · see citing works
Janeiro, M., Ramírez, M., Milagro, F., Martínez, J., & Solas, M. (2018) · Nutrients · doi:10.3390/nu10101398 · Cited by 631 · see citing works
How the immune system shapes atherosclerosis: roles of innate and adaptive immunity
Roy, P., Orecchioni, M., & Ley, K. F. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00584-1 · Cited by 584 · see citing works
Intestinal Microbiota in Cardiovascular Health and Disease
Tang, W. H. W., Bäckhed, F., Landmesser, U., & Hazen, S. L. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.03.024 · Cited by 508 · see citing works
Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target
Zhang, J., Xiang, H., Liu, J., Chen, Y., He, R.-R., & Liu, B. (2020) · Theranostics · doi:10.7150/thno.45922 · Cited by 503 · see citing works
Gut microbiota derived metabolites in cardiovascular health and disease
Wang, Z., & Zhao, Y. (2018) · Protein & Cell · doi:10.1007/s13238-018-0549-0 · Cited by 475 · see citing works
The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease
Vogt, N. M., Romano, K. A., Darst, B. F., Engelman, C. D., Johnson, S. C., Carlsson, C. M., Asthana, S., Blennow, K., Zetterberg, H., Bendlin, B. B., et al. (2018) · Alzheimer's Research & Therapy · doi:10.1186/s13195-018-0451-2 · Cited by 471 · see citing works
Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction
Chen, S., Henderson, A., Petriello, M. C., Romano, K. A., Gearing, M., Miao, J., Schell, M., Sandoval-Espinola, W. J., Tao, J., Sha, B., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.08.021 · Cited by 427 · see citing works
Immune Cells in the BBB Disruption After Acute Ischemic Stroke: Targets for Immune Therapy?
Qiu, Y., Zhang, C., Chen, A., Wang, H.-L., Zhou, Y., Li, Y., & Hu, B. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.678744 · Cited by 405 · see citing works
Precision Nutrition and the Microbiome, Part I: Current State of the Science
Mills, S., Stanton, C., Lane, J. A., Smith, G., & Ross, R. P. (2019) · Nutrients · doi:10.3390/nu11040923 · Cited by 406 · see citing works
Wu, K., Yuan, Y., Yu, H., Dai, X., Wang, S., Sun, Z., Wang, F., Fei, H., Lin, Q., Jiang, H., et al. (2020) · Blood · doi:10.1182/blood.2019003990 · Cited by 345 · see citing works
Li, R., Xin, T., Li, D., Wang, C., Zhu, H., & Zhou, H. (2018) · Redox Biology · doi:10.1016/j.redox.2018.07.011 · Cited by 353 · see citing works
Yang, S., Li, X., Yang, F., Zhao, R., Pan, X., Liang, J., Tian, L., Li, X., Liu, L., Xing, Y., et al. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01360 · Cited by 347 · see citing works
Mirji, G., Worth, A., Bhat, S. A., El Sayed, M., Kannan, T., Goldman, A. R., Tang, H.-Y., Liu, Q., Auslander, N., Dang, C. V., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abn0704 · Cited by 327 · see citing works
Haghikia, A., Li, X. S., Liman, T., Bledau, N., Schmidt, D., Zimmermann, F., Kränkel, N., Widera, C., Sonnenschein, K., Haghikia, A., et al. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.311023 · Cited by 315 · see citing works
TMAO: how gut microbiota contributes to heart failure
Zhang, Y., Wang, Y., Ke, B., & Du, J. (2020) · Translational research · doi:10.1016/j.trsl.2020.08.007 · Cited by 306 · see citing works
Zhang, X., Li, Y., Yang, P., Liu, X., Lu, L., Chen, Y., Zhong, X., Li, Z., Liu, H., Ou, C., et al. (2020) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.119.313414 · Cited by 291 · see citing works
Self-citationBrunt, V. E., Gioscia‐Ryan, R. A., Casso, A. G., VanDongen, N. S., Ziemba, B. P., Sapinsley, Z. J., Richey, J. J., Zigler, M. C., Neilson, A. P., Davy, K. P., et al. (2020) · Hypertension · doi:10.1161/hypertensionaha.120.14759 · Cited by 285 · see citing works
Livshits, G., & Kalinkovich, A. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100980 · Cited by 239 · see citing works
Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin II–induced hypertension
Jiang, S., Shui, Y., Cui, Y., Tang, C., Wang, X., Qiu, X., Hu, W., Fei, L., Li, Y., Zhang, S., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102115 · Cited by 237 · see citing works
Liu, Y., & Dai, M. (2020) · Mediators of Inflammation · doi:10.1155/2020/4634172 · Cited by 232 · see citing works
Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia
Connell, E., Le Gall, G., Pontifex, M. G., Sami, S., Cryan, J. F., Clarke, G., Müller, M., & Vauzour, D. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00548-6 · Cited by 208 · see citing works
Brunt, V. E., LaRocca, T. J., Bazzoni, A. E., Sapinsley, Z. J., Miyamoto-Ditmon, J., Gioscia-Ryan, R. A., Neilson, A. P., Link, C. D., & Seals, D. R. (2021) · GeroScience · doi:10.1007/s11357-020-00257-2 · Cited by 197 · see citing works
Interactions between polysaccharides and gut microbiota: A metabolomic and microbial review
Zhang, D., Liu, J., Cheng, H., Wang, H., Tan, Y., Feng, W., & Peng, C. Y. (2022) · Food Research International · doi:10.1016/j.foodres.2022.111653 · Cited by 200 · see citing works
Zheng, J., Shi, L., Liang, F., Xu, W., Li, T., Gao, L., Sun, Z., Yu, J., & Zhang, J. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00414 · Cited by 173 · see citing works
Trimethylamine N-Oxide (TMAO), Diet and Cardiovascular Disease
Thomas, M. S., & Fernández, M. L. (2021) · Current Atherosclerosis Reports · doi:10.1007/s11883-021-00910-x · Cited by 182 · see citing works
Wang, D., Cao, L., Zhou, X., Wang, G., Ma, Y., Hao, X., & Fan, H. (2022) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2022.129381 · Cited by 186 · see citing works
Wang, K., Lv, Q., Miao, Y., Qiao, S., Dai, Y., & Wei, Z. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.07.039 · Cited by 179 · see citing works
Corcoran, S. E., Halai, R., & Cooper, M. A. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000171 · Cited by 179 · see citing works
SIRT3: A New Regulator of Cardiovascular Diseases
Sun, W., Liu, C., Chen, Q., Liu, N., Yan, Y., & Liu, B. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/7293861 · Cited by 170 · see citing works
Lifestyle modifications for preventing and treating heart failure
Aggarwal, M., Bozkurt, B., Panjrath, G., Aggarwal, B., Ostfeld, R. J., Barnard, N. D., Gaggin, H., Freeman, A. M., Allen, K., Madan, S., et al. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.08.2160 · Cited by 162 · see citing works
Benson, T. W., Conrad, K. A., Li, X. S., Wang, Z., Helsley, R. N., Schugar, R. C., Coughlin, T. M., Wadding-Lee, C., Fleifil, S., Russell, H., et al. (2023) · Circulation · doi:10.1161/circulationaha.122.060573 · Cited by 166 · see citing works
Trimethylamine N-Oxide Exacerbates Cardiac Fibrosis via Activating the NLRP3 Inflammasome
Li, X., Geng, J., Zhao, J., Ni, Q., Zhao, C., Zheng, Y., Chen, X., & Wang, L. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00866 · Cited by 161 · see citing works
Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice
Zhang, W., Miikeda, A., Zuckerman, J. E., Jia, X., Charugundla, S., Zhou, Z., Kaczor‐Urbanowicz, K. E., Magyar, C. E., Guo, F., Wang, Z., et al. (2021) · Scientific Reports · doi:10.1038/s41598-020-80063-0 · Cited by 148 · see citing works
Saaoud, F., Liu, L., Xu, K., Cueto, R., Shao, Y., Lu, Y., Sun, Y., Snyder, N. W., Wu, S., Yang, L., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.158183 · Cited by 153 · see citing works
Sirtuins and Insulin Resistance
Zhou, S., Tang, X., & Chen, H. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00748 · Cited by 143 · see citing works
Reactive oxygen species in hypertension
Camargo, L. L., Rios, F. J. O., Montezano, A. C. I., & Touyz, R. M. (2024) · Nature Reviews Cardiology · doi:10.1038/s41569-024-01062-6 · Cited by 154 · see citing works
Li, P., & Chang, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147688 · Cited by 141 · see citing works
Cheng, H., Liu, J., Tan, Y., Feng, W., & Peng, C. Y. (2021) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2021.10.003 · Cited by 137 · see citing works
Yu, L., Meng, G., Huang, B. S., Zhou, X., Stavrakis, S., Wang, M., Li, X., Zhou, L., Wang, Y., Wang, M., et al. (2018) · International Journal of Cardiology · doi:10.1016/j.ijcard.2017.11.071 · Cited by 131 · see citing works
Man, A. W. C., Zhou, Y., Xia, N., & Li, H. (2020) · Nutrients · doi:10.3390/nu12103054 · Cited by 136 · see citing works
Role and Effective Therapeutic Target of Gut Microbiota in Heart Failure
Jia, Q., Li, H., Zhou, H., Zhang, X., Zhang, A., Xie, Y., Li, Y., Lv, S., & Zhang, J. (2019) · Cardiovascular Therapeutics · doi:10.1155/2019/5164298 · Cited by 118 · see citing works
The role of the gut microbiota in health and cardiovascular diseases
Wang, L., Wang, S., Zhang, Q., He, C., Fu, C., & Wei, Q. (2022) · Molecular Biomedicine · doi:10.1186/s43556-022-00091-2 · Cited by 124 · see citing works
Microbial Metabolites and Gut Immunology
Takeuchi, T., Nakanishi, Y., & Ohno, H. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-090222-102035 · Cited by 130 · see citing works
Xu, L., Zhang, Y., Li, X., Li, C., Hu, H., Hu, J., Liu, M., Yang, Q. Z., Gu, P., Li, J., et al. (2025) · iMeta · doi:10.1002/imt2.270 · Cited by 138 · see citing works
Ren, P., Wu, D., Appel, R., Zhang, L., Zhang, C., Luo, W., Robertson, A. A. B., Cooper, M. A., Coselli, J. S., Milewicz, D. M., et al. (2020) · Journal of the American Heart Association · doi:10.1161/jaha.119.014044 · Cited by 123 · see citing works
Zhang, Y., Bai, X., Shen, K., Luo, L., Zhao, M., Xu, C., Jia, Y., Xiao, D., Li, Y., Gao, X., et al. (2022) · Cells · doi:10.3390/cells11162568 · Cited by 121 · see citing works
Fang, Q., Zheng, B., Liu, N., Liu, J., Liu, W., Huang, X., Zeng, X., Chen, L., Li, Z., & Ouyang, D. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.682482 · Cited by 116 · see citing works
Penna, C. R. R., & Pagliaro, P. (2025) · Antioxidants · doi:10.3390/antiox14030256 · Cited by 134 · see citing works
“TMAO causes increased production of ROS at the mitochondrial level, inhibition of SOD2 and SIRT3 in ECs with consequent ED and inflammatory state following activation of the NLPR3 inflammasome (Figure 2) [194].”
Tan, Y., Sheng, Z., Zhou, P., Liu, C., Zhao, H., Song, L., Li, J., Zhou, J., Chen, Y., Wang, L., et al. (2019) · Circulation: Cardiovascular Interventions · doi:10.1161/circinterventions.118.007281 · Cited by 113 · see citing works
Simó, C., & García‐Cañas, V. (2020) · Food & Function · doi:10.1039/d0fo01237h · Cited by 110 · see citing works
Witkowski, M., Witkowski, M., Friebel, J., Buffa, J. A., Li, X. S., Wang, Z., Sangwan, N., Li, L., DiDonato, J. A., Tizian, C., et al. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab263 · Cited by 116 · see citing works
Gut microbiota-derived metabolites in CRC progression and causation
Dalal, N., Jalandra, R., Bayal, N., Yadav, A. K., Harshulika, Sharma, M., Makharia, G. K., Kumar, P., Singh, R. K., Solanki, P. R., et al. (2021) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-021-03729-w · Cited by 102 · see citing works
Dietary Strategies for Management of Metabolic Syndrome: Role of Gut Microbiota Metabolites
Croci, S., D'Apolito, L. I., Gasperi, V., Catani, M. V., & Savini, I. (2021) · Nutrients · doi:10.3390/nu13051389 · Cited by 108 · see citing works
Praveenraj, S. S., Sonali, S., Anand, N., Hediyal, T. A., Vichitra, C., Kalyan, M., Kanna, P. V., Chandana, K. A., Paneyala, S., Mahalakshmi, A. M., et al. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02990-5 · Cited by 112 · see citing works
Progress in Nonalcoholic Fatty Liver Disease: SIRT Family Regulates Mitochondrial Biogenesis
Zeng, C., & Chen, M. (2022) · Biomolecules · doi:10.3390/biom12081079 · Cited by 108 · see citing works
Self-citationGut Metabolite Trimethylamine-N-Oxide in Atherosclerosis: From Mechanism to Therapy
Wang, B., Qiu, J., Lian, J., Yang, X., & Zhou, J. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.723886 · Cited by 108 · see citing works
Zhang, J., Liang, R., Wang, L., & Yang, B. (2018) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2018.10.004 · Cited by 95 · see citing works
Chan, C. W. H., Law, B. M. H., Waye, M. M. Y., Chan, J. Y., So, W. K. W., & Chow, K. M. (2019) · Journal of Cancer · doi:10.7150/jca.31737 · Cited by 96 · see citing works
Gut Microbiota and Atherosclerosis—Focusing on the Plaque Stability
Shen, X., Li, L., Sun, Z., Zang, G., Zhang, L., Shao, C., & Wang, Z. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.668532 · Cited by 99 · see citing works
Gut-Heart Axis: The Role of Gut Microbiota and Metabolites in Heart Failure
Snelson, M., Muralitharan, R. R., Liu, C., Markó, L., Forslund, S. K., Marques, F. Z., & Tang, W. H. W. (2025) · Circulation Research · doi:10.1161/circresaha.125.325516 · Cited by 106 · see citing works
Lee, Y., Nemet, I., Wang, Z., Lai, H. T. M., Otto, M. C. D. O., Lemaître, R. N., Fretts, A. M., Sotoodehnia, N., Budoff, M. J., DiDonato, J. A., et al. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.120.020646 · Cited by 91 · see citing works
Mosterd, C. M., Kanbay, M., van den Born, B. H., van Raalte, D. H., & Rampanelli, E. (2021) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2021.101484 · Cited by 94 · see citing works
Gut microbiota and microbiota-derived metabolites in cardiovascular diseases
Chen, X., Zhang, H., Ren, S., Ding, Y.-N., Remex, N. S., Bhuiyan, M. S., Qu, J.-H., & Tang, X. (2023) · Chinese Medical Journal · doi:10.1097/cm9.0000000000002206 · Cited by 98 · see citing works
“In contrast, suppression of NLRP3 reverses the proin ammatory and proatherogenic phenotype of TMAO.”
BackgroundShanmugham, M., Bellanger, S., & Leo, C. H. (2023) · Pharmaceuticals · doi:10.3390/ph16040504 · Cited by 96 · see citing works
Bai, R., Lang, Y., Shao, J., Deng, Y., Refuhati, R., & Cui, L. (2021) · ASN NEURO · doi:10.1177/17590914211018100 · Cited by 85 · see citing works
Wang, Q., Guo, M., Liu, Y., Xu, M., Shi, L., Li, X., Zhao, J., Zhang, H., Wang, G., & Chen, W. (2022) · Nutrients · doi:10.3390/nu14061222 · Cited by 95 · see citing works
TMAO as a potential biomarker and therapeutic target for chronic kidney disease: A review
Ye, Z., Lulu, C., Xiangchang, Z., Fang, Q., Binjie, Z., Chunyang, L., Rao, T., & Dongsheng, O. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.929262 · Cited by 90 · see citing works
Serum levels of Trimethylamine-N-oxide in patients with ischemic stroke
Rexidamu, M., Li, H., Jin, H., & Huang, J. (2019) · Bioscience Reports · doi:10.1042/bsr20190515 · Cited by 84 · see citing works
Emerging role of SIRT3 in mitochondrial dysfunction and cardiovascular diseases
Wu, J., Zeng, Z., Zhang, W., Deng, Z., Wan, Y., Zhang, Y., An, S. L., Huang, Q., & Chen, Z. (2018) · Free Radical Research · doi:10.1080/10715762.2018.1549732 · Cited by 83 · see citing works
Zhou, Y., Zhang, Y., Jin, S., Lv, J., Li, M., & Feng, N. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117031 · Cited by 92 · see citing works
Intestinal microbial metabolites in human metabolism and type 2 diabetes
Herrema, H., & Niess, J. H. (2020) · Diabetologia · doi:10.1007/s00125-020-05268-4 · Cited by 79 · see citing works
Wang, M., Wang, Z., Lee, Y., Lai, H. T. M., Otto, M. C. D. O., Lemaître, R. N., Fretts, A. M., Sotoodehnia, N., Budoff, M. J., DiDonato, J. A., et al. (2022) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.121.316533 · Cited by 81 · see citing works
Yang, L., Zhang, H., & Chen, P. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.09.005 · Cited by 70 · see citing works
Trimethylamine-N-Oxide (TMAO) as a Rising-Star Metabolite: Implications for Human Health
Caradonna, E., Abate, F., Schiano, E., Paparella, F., Ferrara, F., Vanoli, E., Difruscolo, R., Goffredo, V. M., Amato, B., Setacci, C., et al. (2025) · Metabolites · doi:10.3390/metabo15040220 · Cited by 88 · see citing works
“Xiaolei Sun et al. demonstrated that in human umbilical vein endothelial cells, trimethylamine-N-oxide (TMAO) induces inflammation and endothelial dysfunction by activating the inflammasome thioredoxin-interacting protein-associated NLRP3 (TXNIP-NLRP3) [41].”
Nanto-Hara, F., Kanemitsu, Y., Fukuda, S., Kikuchi, K., Asaji, K., Saigusa, D., Iwasaki, T., Ho, H., Mishima, E., Suzuki, T., et al. (2019) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfz126 · Cited by 76 · see citing works
Trimethylamine N -oxide: heart of the microbiota–CVD nexus?
Naghipour, S., Cox, A. J., Peart, J. N., Toit, E. F. D., & Headrick, J. P. (2020) · Nutrition Research Reviews · doi:10.1017/s0954422420000177 · Cited by 75 · see citing works
Role of the Microbiome in Gut-Heart-Kidney Cross Talk
Glorieux, G., Nigám, S. K., Vanholder, R. C., & Verbeke, F. (2023) · Circulation Research · doi:10.1161/circresaha.123.321763 · Cited by 75 · see citing works
Role of the Gut Microbiome in the Development of Atherosclerotic Cardiovascular Disease
Samarraie, A. A., Pichette, M., & Rousseau, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065420 · Cited by 76 · see citing works
Oktaviono, Y. H., Lamara, A. D., Saputra, P. B. T., Arnindita, J. N., Pasahari, D., Saputra, M. E., & Suasti, N. M. A. (2023) · Biomolecules and Biomedicine · doi:10.17305/bb.2023.8893 · Cited by 87 · see citing works
Microbiota in Gut‐Heart Axis: Metabolites and Mechanisms in Cardiovascular Disease
Kondapalli, N. B., Katari, V., Dalal, K. K., Paruchuri, S. M., & Thodeti, C. K. (2025) · Comprehensive physiology · doi:10.1002/cph4.70024 · Cited by 93 · see citing works
Inflammation and gut dysbiosis as drivers of CKD–MBD
Evenepoel, P., Stenvinkel, P., Shanahan, C. M., & Pacifici, R. (2023) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00736-7 · Cited by 78 · see citing works
Zhou, S., Xue, J., Shan, J., Hong, Y., Zhu, W., Nie, Z., Zhang, Y., Ji, N., Luo, X., Zhang, T., et al. (2022) · Nutrients · doi:10.3390/nu14163338 · Cited by 72 · see citing works
Chan, M. M.-Y., Yang, X., Wang, H., Saaoud, F., Sun, Y., & Fong, D. (2019) · Nutrients · doi:10.3390/nu11081821 · Cited by 68 · see citing works
Roles of Gut Microbial Metabolites in Diabetic Kidney Disease
Fang, Q., Liu, N., Zheng, B., Guo, F., Zeng, X., Huang, X., & Ouyang, D. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.636175 · Cited by 69 · see citing works
Dong, X., He, Y., Feng, Y., Zhao, Y., Cheng, J. S., Xiao, J., Yu, W., Zhao, J., Sai, Y., Dan, G., et al. (2021) · Clinical and Translational Medicine · doi:10.1002/ctm2.312 · Cited by 61 · see citing works
Self-citationIlyas, A., Wijayasinghe, Y. S., Khan, I., Samaloty, N. M. E., Adnan, M., Dar, T. A., Poddar, N. K., Singh, L. R., Sharma, H., & Khan, S. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.964624 · Cited by 71 · see citing works
Gut microbiota in dementia. Critical review of novel findings and their potential application
Łuc, M., Misiak, B., Pawłowski, M., Stańczykiewicz, B., Zabłocka, A., Szcześniak, D. M., Pałęga, A., & Rymaszewska, J. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110039 · Cited by 69 · see citing works
Shih, D. M., Zhu, W., Schugar, R. C., Meng, Y., Jia, X., Miikeda, A., Wang, Z., Zieger, M., Lee, R., Graham, M., et al. (2019) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.119.312592 · Cited by 67 · see citing works
Yang, G., Lin, C., Yang, Y., Li, Y., Wang, P., Wen, X., Pan, M., Zhao, H., Ho, C., & Li, S. (2019) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.9b01270 · Cited by 66 · see citing works
Wu, J., Deng, Z., Sun, M., Zhang, W., Yang, Y., Zeng, Z., Wu, J., Zhang, Q., Liu, Y., Chen, Z., et al. (2019) · Laboratory Investigation · doi:10.1038/s41374-019-0332-8 · Cited by 62 · see citing works
Targeting Trimethylamine N-Oxide: A New Therapeutic Strategy for Alleviating Atherosclerosis
Jing, L., Zhang, H., Xiang, Q., Shen, L., Guo, X., Zhai, C., & Hu, H. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.864600 · Cited by 66 · see citing works
Wang, N., Hao, Y., & Fu, L. (2022) · Nutrients · doi:10.3390/nu14193955 · Cited by 64 · see citing works
Balancing the Equation: A Natural History of Trimethylamine and Trimethylamine-N-oxide
Loo, R. L., Chan, Q. M., Nicholson, J. K., & Holmes, E. C. (2022) · Journal of Proteome Research · doi:10.1021/acs.jproteome.1c00851 · Cited by 60 · see citing works
Macpherson, M. E., Hov, J. R., Ueland, T., Dahl, T. B., Kummen, M., Otterdal, K., Holm, K., Berge, R. K., Mollnes, T. E., Trøseid, M., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.574500 · Cited by 60 · see citing works
Elevated plasma trimethylamine-N-oxide levels are associated with diabetic retinopathy
Liu, W., Wang, C., Xia, Y., Xia, W. T., Liu, G., Ren, C., Gu, Y., Li, X., & Lu, P. (2020) · Acta Diabetologica · doi:10.1007/s00592-020-01610-9 · Cited by 64 · see citing works
Mitochondrial dysfunction and oxidative stress in diabetic wound
Jiang, G., Jiang, T., Chen, J., Yao, H., Mao, R., Yang, X., Chen, Z., & Li, W. (2023) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.23407 · Cited by 64 · see citing works
The Nutritional Supplement L-Alpha Glycerylphosphorylcholine Promotes Atherosclerosis
Wang, Z., Hazen, J. E., Jia, X., Org, E., Zhao, Y., Osborn, L. J., Nimer, N. A., Buffa, J. A., Culley, M. K., Krajcik, D., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413477 · Cited by 52 · see citing works
The dietary source of trimethylamine N-oxide and clinical outcomes: an unexpected liaison
Evans, M., Dai, L., Avesani, C. M., Kublickiene, K. R., & Stenvinkel, P. (2023) · Clinical Kidney Journal · doi:10.1093/ckj/sfad095 · Cited by 65 · see citing works
- Authors
- Chen, M., Zhu, X., Ran, L., Lang, H., Yi, L., & Mi, M.
- Affiliations
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, China
- Army Medical University (CN)
- Venue
- Journal of the American Heart Association
- Published
- 2017-09-22
- Volume
- 6
- Issue
- 9
- ISSN
- 2047-9980 (ISSN-L)
- PMC
- PMC5634285
- OpenAlex
- W2751157908
- Cited by
- 600
- References
- 47
- Citations by year
- 2026: 80 · 2025: 86 · 2024: 70 · 2023: 82 · 2022: 88 · 2021: 82 · 2020: 54 · 2019: 32 · 2018: 25 · 2015: 1
- FWCI
- 12.40
- Type
- journal article
- Language
- en
- Update notices
- correction (2017-11-08)
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- trimethylamine N-oxide, vascular inflammation, NLRP3 inflammasome, SIRT3, manganese superoxide dismutase, mitochondrial reactive oxygen species, caspase-1, endothelial cells, atherosclerosis, ApoE-deficient mice, MitoTEMPO, gut microbiota metabolites
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Mice, Knockout, ApoE, Superoxide Dismutase 2, Animals, Antioxidants, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Humans, Methylamines, Mitochondria, Phenotype, Superoxide Dismutase, Time Factors, Transfection, Vasculitis, Signal Transduction, Reactive Oxygen Species, Inflammation Mediators, Genetic Predisposition to Disease, RNA Interference, Atherosclerosis, Apoptosis Regulatory Proteins, Sirtuin 3, Mice, 129 Strain, Inflammasomes, Human Umbilical Vein Endothelial Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
