January 2025
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5 Reads
Atherosclerosis
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January 2025
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5 Reads
Atherosclerosis
December 2024
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12 Reads
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2 Citations
Journal of Clinical Lipidology
September 2024
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63 Reads
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1 Citation
JCI Insight
Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3'sialyllactose (3'SL) as a natural inhibitor of Toll-Like Receptor (TLR) 4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3'SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of Liver X Receptor (LXR) and Sterol Regulatory Element-binding Protein-1 (SREBP). These acute anti-inflammatory effects of 3'SL were associated with reduced histone H3K27 acetylation at a subset of lipopolysaccharide (LPS)-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), Interferon Regulatory Factor 2 (IRF2), B-cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both subcutaneous and oral administration of 3'SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3'SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.
August 2024
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67 Reads
Oxidized phosphatidylcholines (OxPC) are neurotoxic byproducts of oxidative stress elevated in the central nervous system (CNS) during progressive multiple sclerosis (P-MS). How OxPC contribute to the pathophysiology of P-MS is unclear. Here, we report that OxPC deposition in the CNS of mice induces a chronic compartmentalized lesion with pathological features similar to chronic active lesions found in P-MS. Using this new model, we found that while microglia protected the CNS from chronic neurodegeneration, they were also replaced by monocyte derived macrophages in chronic OxPC lesions. Aging, a risk factor for P-MS, altered microglial composition and exacerbated neurodegeneration in chronic OxPC lesions. Amelioration of disease pathology in caspase 1/4 deficient mice and by blockade of IL-1R1 indicate IL-1β signaling contributes to chronic OxPC accumulation and neurodegeneration. These results highlight OxPC and IL-1β as potential drivers of chronic neurodegeneration in MS and suggest that their neutralization may be effective for treating P-MS.
August 2024
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46 Reads
Arteriosclerosis Thrombosis and Vascular Biology
BACKGROUND Dyslipidemia increases cardiovascular disease risk, the leading cause of death worldwide. Under time-restricted feeding (TRF), wherein food intake is restricted to a consistent window of <12 hours, weight gain, glucose intolerance, inflammation, dyslipidemia, and hypercholesterolemia are all reduced in mice fed an obesogenic diet. LDLR (low-density lipoprotein receptor) mutations are a major cause of familial hypercholesterolemia and early-onset cardiovascular disease. METHODS We subjected benchmark preclinical models, mice lacking LDLR-knockout or ApoE knockout to ad libitum feeding of an isocaloric atherogenic diet either ad libitum or 9 hours TRF for up to 13 weeks and assessed disease development, mechanism, and global changes in hepatic gene expression and plasma lipids. In a regression model, a subset of LDLR-knockout mice were ad libitum fed and then subject to TRF. RESULTS TRF could significantly attenuate weight gain, hypercholesterolemia, and atherosclerosis in mice lacking the LDLR-knockout mice under experimental conditions of both prevention and regression. In LDLR-knockout mice, increased hepatic expression of genes mediating β-oxidation during fasting is associated with reduced VLDL (very-low-density lipoprotein) secretion and lipid accumulation. Additionally, increased sterol catabolism coupled with fecal loss of cholesterol and bile acids contributes to the atheroprotective effect of TRF. Finally, TRF alone or combined with a cholesterol-free diet can reduce atherosclerosis in LDLR-knockout mice. However, mice lacking ApoE, which is an important protein for hepatic lipoprotein reuptake do not respond to TRF. CONCLUSIONS In a preclinical animal model, TRF is effective in both the prevention and regression of atherosclerosis in LDLR knockout mice. The results suggest TRF alone or in combination with a low-cholesterol diet can be a lifestyle intervention for reducing cardiovascular disease risk in humans.
April 2024
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1 Read
April 2024
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98 Reads
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52 Citations
The New-England Medical Review and Journal
Background: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III. Methods: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis. Results: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group. Conclusions: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.).
April 2024
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26 Reads
Journal of the American College of Cardiology
February 2024
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83 Reads
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26 Citations
The New-England Medical Review and Journal
November 2023
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46 Reads
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2 Citations
Macrophages detect invading microorganisms via pattern recognition receptors that recognize pathogen-associated molecular patterns, or via sensing the activity of virulence factors that initiates effector-triggered immunity (ETI). Tissue damage that follows pathogen encounter leads to the release of host-derived factors that participate to inflammation. How these self -derived molecules are sensed by macrophages and their impact on immunity remain poorly understood. Here we demonstrate that, in mice and humans, host-derived oxidized phospholipids (oxPLs) are formed upon microbial encounter. oxPL blockade restricts inflammation and prevents the death of the host, without affecting pathogen burden. Mechanistically, oxPLs bind and inhibit AKT, a master regulator of immunity and metabolism. AKT inhibition potentiates the methionine cycle, and epigenetically dampens Il10 , a pluripotent anti-inflammatory cytokine. Overall, we found that host-derived inflammatory cues act as “ self ” virulence factors that initiate ETI and that their activity can be targeted to protect the host against excessive inflammation upon microbial encounter.
... It has been well demonstrated in rodents using 2'-FL [20]. 3′-SL mitigates inflammation through a transcriptional pathway, hence diminishing the progression of atherosclerosis in the context of cardiovascular illness [21]. ...
September 2024
JCI Insight
... The therapeutic potential of E06 lies in its capacity to neutralize OxPC bioactivity, and there are multiple recent reports of therapeutic properties, including anti-inflammatory, anti-atherogenic, and anti-nociceptive effects, as well as promoting inflammation resolution. Examples include decreased infarct size with intracoronary E06 in a porcine model of ischemia/reperfusion injury [64], increased macrophage uptake of oxidized lipids and lower lung inflammatory markers with intranasal E06 in cigarette smoke-exposed mice [60], and reduced OxPC-induced pain inflammation and hypersensitivity with local E06 application [26,36]. Transgenic mice that express high levels of the single-chain variable fragment of E06 (E06-scFv, a functional E06 component responsible for binding to OxPCs) in plasma are resistant to OxPC-induced inflammatory signaling in atherosclerosis, aortic stenosis, and hepatic steatosis [37]. ...
November 2021
Circulation
... Two important clinical trials have recently been published with olezarsen. The first, called BALANCE [68], was a double-blind, randomized, 52-week, phase III trial of 66 adults with FCS, of whom 22 were assigned to the olezarsen 80-mg group, 21 to the olezarsen 50-mg group, and 23 to the placebo group. Plasma TG levels at 6 months were significantly reduced with the olezarsen 80-mg dose by 43.5%, but not with the 50-mg dose. ...
April 2024
The New-England Medical Review and Journal
... The above three studies, which were not individually powered to detect an effect on pancreatitis risk, were subsequently meta-analyzed together [65]. This revealed that 2% of patients randomized to volanesorsen had incident pancreatitis events compared with 10% of those randomized to placebo, a significant 82% reduction in pancreatitis risk (odds ratio, 0.18; 95% CI 0.04-0.82). ...
February 2024
The New-England Medical Review and Journal
... The preprint from Di Gioia et al. [4] investigated the potential role of a host-derived DAMP, oxidized phospholipids (oxPLs) that result from non-enzymatic oxidation of phosphocholine-containing phospholipids. These oxPLs can be recognized by the innate immune system by a variety of PRRs and have established roles in driving atherosclerosis and non-alcoholic steatohepatitis, but their function in the context of infection is still disputed [5,6]. ...
November 2023
... There are two types: endocytic receptors, which bind to lipoproteins and mediate their internalization and subsequent lysosomal delivery, such as those of the LDLr family; and receptors, which bind to lipoproteins but transfer the lipid molecules directly to the plasma membrane without the cellular absorption of other component molecules of lipoproteins, such as type B scavenger receptors and lectin-like oxLDL scavenger receptor-1 (LOX-1). However, lipoprotein modifications can alter lipid turnover; for example, the modification of apo B through oxidation and glycation increases LDL uptake by CD36, scavenger receptors A (SRA)-I and SRA-II, and the lectin-like receptor family [86,96,97], which induces endothelial damage. ...
October 2023
Nature Reviews Cardiology
... Consistent with this, multiple studies have established that high levels of anti-PC antibodies are protective against many age-associated diseases. Indeed, high levels of anti-PC IgM antibodies (as well as the levels of anti IgM anti-OxLDL and anti-malondialdehyde-modified low-density lipoprotein, MDA LDL) are predictive of the decreased rate of progression of carotid intima-media thickness in patients with hypertension 54,55 , associated with lower risk of acute myocardial infarction 56 , and protective against thromboembolic disease 57 . The levels of anti-PC IgM are significantly higher in patients with SLE who have low disease activity, less organ damage, and no cardiovascular events 58,59 . ...
May 2023
Journal of Lipid Research
... In volanesorsen-treated patients, 3-month TG reductions reached −88%, while the 12-month reduction in the hepatic fat fraction was as high as −53%. Of note, individual analysis of the COMPASS, APPROACH, and BROADEN trials revealed that volanesorsen exerts a favorable effect on hepatic fat and might potentially prevent steatohepatitis in patients with HTG of different etiology [63]. ...
April 2023
Journal of Clinical Lipidology
... Five incidents of acute pancreatitis occurred, all in patients of the placebo group [39]. The long-term efficacy and sustainability of volanesorsen in reducing plasma TG levels was also supported by an open-label extension trial based on the previously mentioned trials [40]. ...
March 2023
Journal of Clinical Lipidology
... Negative associations between apoCIII and hsCRP were observed in MD and RA patients, even after adjusting for TG. Similarly, Hsu et al. (2023) reported that APOC3 loss-of-function variants were linked to modestly increased serum hsCRP levels, contrary to the expected reduction [39]. Mokkala et al. (2020) also observed that VLDL particles were positively associated with Glyc-A but inversely associated with hsCRP [20]. ...
February 2023
Nature Immunology