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•This randomized, double-blind trial compared 2 AYP-101 concentrations (25 mg/mL and 50 mg/mL) with placebo for submental fat reduction.•The 25 mg/mL group significantly improve subjective outcomes compared to placebo, while no significant differences were observed in objective volume reduction.•Both concentrations were well-tolerated, although the 25 mg/mL group exhibited fewer adverse effects. Submental fat (SMF) accumulation can affect self-image and psychological well-being, leading to a demand for nonsurgical treatment. AYP-101, which contains soybean phosphatidylcholine (SPC), is under investigation for SMF reduction. This study aimed to compare 2 concentrations of AYP-101 to placebo injections to determine the optimal concentration and evaluate safety and efficacy in reducing moderate to severe SMF in an Asian population. This single-center, randomized, double-blind, placebo-controlled phase II trial enrolled 96 participants with moderate to severe SMF. Participants were randomly assigned to receive either a placebo or AYP-101 at either a low concentration (25 mg/mL) or a high concentration (50 mg/mL), administered every 2 weeks for up to 6 sessions. The primary endpoint was the proportion of participants achieving at least a 1-grade improvement in both the Evaluator-Reported Submental Fat Rating Scale (ER-SMFRS) and the Subject-Reported Submental Fat Rating Scale (SR-SMFRS) at 4 and 12 weeks after the final injection. At 4 weeks post-treatment, 69.70% of the low-concentration group and 48.39% of the high-concentration group exhibited improvement in the ER-SMFRS, compared to 22.58% in the placebo group. Significant differences were noted between the low-concentration and placebo groups (P = 0.0002), with similar results at 12 weeks. AYP-101, administered biweekly at a concentration of 25 mg/mL, appears to be a safe and effective nonsurgical option for reducing SMF in Asians.

Key Points The association of low plasma high-density lipoprotein cholesterol (HDL-C) concentration with elevated cardiovascular disease risk is firmly established in men and women over a wide age range, across several cardiometabolic disease states, including type 2 diabetes, and in many populations and ethnic groups. These associations underpinned the HDL hypothesis coined 40 years ago, stating that “a reduction of plasma HDL concentration may accelerate the development of atherosclerosis, and hence ischaemic heart disease, by impairing the clearance of cholesterol from the arterial wall”. Although the hypothesis was about HDL particle concentration, the evidence for the idea was based on HDL-C concentration data, as there was no method of measuring the former at the time. Genetic studies, including Mendelian randomization analysis, have shown that plasma HDL-C itself is not anti-atherogenic. However, genetic epidemiology has not yet been used to test the causality of low HDL particle number and coronary heart disease. Two short-term clinical trials of the effects of intravenous reconstituted HDLs on coronary lesions in patients with acute coronary syndrome gave encouraging results, but failed to provide unequivocal evidence of benefit. The small molecules tested to date in Phase III outcome trials do not specifically target HDL, and more specifically HDL particle number, and therefore the HDL hypothesis is yet to be tested. Three classes of agents that raise HDL-C in addition to lowering low-density lipoprotein (LDL) and/or plasma triglycerides have been tested. Although trial results with fibrates and niacin produced variable outcomes, meta-analyses supported the beneficial effects of both, although it was not possible to attribute them to HDL. Two trials of cholesteryl ester transfer protein (CETP) inhibitors have failed to show benefit, in one case possibly owing to an increase in blood pressure. The interrelationships between HDL-C concentration, HDL particle number and HDL particle subpopulations of defined composition are complex, as are their relationships to reverse cholesterol transport and other anti-atherogenic properties. Nevertheless, an understanding of these relationships will be essential for the rational development of new HDL therapies. Several novel approaches are under clinical development, including second-generation CETP inhibitors, new HDL infusion therapies, recombinant lecithin–cholesterol acyltransferase (LCAT) infusion therapy, and apolipoprotein A1 (APOA1) transcriptional upregulators. Additional strategies to target HDL metabolism that are emerging include APOA1-mimetic peptides, liver X receptor agonists, farnesoid X receptor agonists, endothelial lipase inhibitors, antagonists of microRNAs and antisense oligonucleotides targeted at the genes that are implicated in HDL metabolism. Evidence supporting the hypothesis that raising plasma levels of high-density lipoprotein (HDL) cholesterol could be cardioprotective has fuelled intense efforts to develop HDL-targeted therapies, but several recent clinical trial failures have introduced controversy. Kingwell and colleagues discuss the current understanding of the HDL hypothesis, considering what has been learned, what remains to be tested and how this knowledge could be used in the development of novel therapies. Since the discovery in the 1970s that plasma levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with cardiovascular outcome, it has been postulated that HDL is anti-atherogenic and that increasing HDL-C levels is a promising therapeutic strategy. However, the recent failure of three orally active, HDL-C-raising agents has introduced considerable controversy, prompting the question of whether increasing the cholesterol cargo of HDL in a non-selective manner is an effective pharmacological approach for the translation of its atheroprotective and vasculoprotective activities. The interrelationships between HDL-C concentration, HDL particle number and levels of diverse HDL particle subpopulations of defined composition are complex, as are their relationships with reverse cholesterol transport and other anti-atherogenic functions. Such complexity highlights the incompleteness of our understanding of the biology of HDL particles. This article examines the HDL hypothesis in molecular and mechanistic terms, focusing on features that have been addressed, those that remain to be tested, and potential new targets for future pharmacological interventions.

The protein corona formed on nanoparticles (NPs) has potential as a valuable diagnostic tool for improving plasma proteome coverage. Here, we show that spiking small molecules, including metabolites, lipids, vitamins, and nutrients into plasma can induce diverse protein corona patterns on otherwise identical NPs, significantly enhancing the depth of plasma proteome profiling. The protein coronas on polystyrene NPs when exposed to plasma treated with an array of small molecules allows for the detection of 1793 proteins marking an 8.25-fold increase in the number of quantified proteins compared to plasma alone (218 proteins) and a 2.63-fold increase relative to the untreated protein corona (681 proteins). Furthermore, we discovered that adding 1000 µg/ml phosphatidylcholine could singularly enable the detection of 897 proteins. At this specific concentration, phosphatidylcholine selectively depletes the four most abundant plasma proteins, including albumin, thus reducing the dynamic range of plasma proteome and enabling the detection of proteins with lower abundance. Employing an optimized data-independent acquisition approach, the inclusion of phosphatidylcholine leads to the detection of 1436 proteins in a single plasma sample. Our molecular dynamics results reveal that phosphatidylcholine interacts with albumin via hydrophobic interactions, H-bonds, and water bridges. The addition of phosphatidylcholine also enables the detection of 337 additional proteoforms compared to untreated protein corona using a top-down proteomics approach. Given the critical role of plasma proteomics in biomarker discovery and disease monitoring, we anticipate the widespread adoption of this methodology for the identification and clinical translation of biomarkers. The protein corona on nanoparticles has potential for application in protein diagnostics. Here, the authors report on the use of small molecules to change the protein and proteoform patterns of protein corona on otherwise identical nanoparticles, which can be leveraged to significantly enhance the depth of plasma proteome profiling.

Phosphatidylcholine is a key component of the mucosal barrier. Treatment with modified release phosphatidylcholine aims to improve the impaired barrier function. The primary objective is to evaluate the efficacy of LT-02, a newly designed modified release phosphatidylcholine formula, in a multicenter setting. This is a double-blinded, randomized, placebo-controlled, superiority study conducted in 24 ambulatory referral centers in Germany, Lithuania, and Romania. A total of 156 patients with an inadequate response to mesalazine, a disease activity score (Simple Clinical Colitis Activity Index (SCCAI)) of ≥ 5, and bloody diarrhea underwent treatment with 0, 0.8, 1.6, or 3.2 g LT-02. The primary end point was defined a priori as changes in SCCAI from baseline to the end of treatment. The primary statistical model was a general linear least-squares model. The study was funded by the sponsor Lipid Therapeutics, Heidelberg, Germany, and registered at http://clinicaltrials.gov/show/NCT01011322. Baseline characteristics and dropouts were well balanced between all groups. The primary analyses revealed an SCCAI drop of 33.3% in the placebo group (from 9.0 to 6.0 points) compared with 44.3% in the 0.8 g LT-02 (from 8.8 to 4.9, P>0.05) and 40.7% in the 1.6 g groups (from 8.6 to 5.1, P>0.05). The 3.2 g group improved 51.7% from 8.5 to 4.1 (P=0.030 in comparison with placebo). The remission rate was 15% (6/40) in the placebo group compared with 31.4% (11/35) in the highest LT-02 dose group (P=0.089). Mucosal healing was achieved in 32.5% of placebo patients compared with 47.4% of LT-02 patients (P=0.098); the rates for histologic remission were 20% compared with 40.5%, respectively (P=0.016). There were 17 (48.6%) treatment-emergent adverse events in the highest dose group (and 0 serious adverse events (SAEs)) compared with 22 (55%) in the placebo group (4 SAEs). The primary end point analysis showed a statistically significant improvement in disease activity during LT-02 treatment in comparison with placebo. The drug was found to be very safe.

Topical ophthalmic antibiotics show low efficacy due to the well-known physiological defense mechanisms of the eye, which prevents the penetration of exogenous substances. Here, we aimed to incorporate besifloxacin into liposomes containing amines as positively charged additives and to evaluate the influence of this charge on drug delivery in two situations: (i) iontophoretic and (ii) passive treatments. Hypothesis are (i) charge might enhance the electromigration component upon current application improving penetration efficiency for a burst drug delivery, and (ii) positive charge might prolong formulation residence time, hence drug penetration. Liposomes elaborated with phosphatidylcholine (LP PC) or phosphatidylcholine and spermine (LP PC: SPM) were stable under storage at 6 ºC for 30 days, showed mucoadhesive characteristics, and were non-irritant, according to HET-CAM tests. Electron paramagnetic resonance spectroscopy measurements showed that neither the drug nor spermine incorporations produced evident alterations in the fluidity of the liposome's membranes, which retained their structural stability even under iontophoretic conditions. Mean diameter and zeta potential were 177.2 ± 2.7 nm and − 5.7 ± 0.3 mV, respectively, for LP PC; and 175.4 ± 1.9 nm and + 19.5 ± 1.0 mV, respectively, for LP PC:SPM. The minimal inhibitory concentration (MIC) and the minimal bactericide concentration (MBC) of the liposomes for P. aeruginosa showed values lower than the commercial formulation (Besivance). Nevertheless, both formulations presented a similar increase in permeability upon the electric current application. Hence, liposome charge incorporation did not prove to be additionally advantageous for iontophoretic therapy. Passive drug penetration was evaluated through a novel in vitro ocular model that simulates the lacrimal flow and challenges the formulation resistance in the passive delivery situation. As expected, LP PC: SPM showed higher permeation than the control (Besivance). In conclusion, besifloxacin incorporation into positively charged liposomes improved passive topical delivery and can be a good strategy to improve topical ophthalmic treatments.

Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine—choline, trimethylamine N -oxide (TMAO) and betaine—were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease. Heart disease is a gut issue Stanley Hazen and colleagues show that gut flora can influence cardiovascular disease by metabolizing a dietary phospholipid. A targeted metabolomics approach was used to identify plasma metabolites whose levels predict future risk for experiencing a non-fatal heart attack, stroke or death in subjects undergoing cardiac evaluation. Plasma levels of three metabolites of dietary phosphatidylcholine — choline, betaine and trimethylamine N -oxide (TMAO) — are associated with increased risk of cardiovascular disease. The gut flora is known to have a role in TMAO formation from choline. In addition, experiments in atherosclerosis-prone mice show that dietary choline enhances macrophage foam-cell formation and lesion formation — but not if the gut flora is depleted with antibiotics. This work suggests new diagnostic and therapeutic approaches for atherosclerotic heart disease. This paper shows that gut flora can influence cardiovascular disease, by metabolizing a dietary phospholipid. Using a metabolomics approach it is found that plasma levels of three metabolites of dietary phosphatidylcholine—choline, betaine and TMAO—are associated with increased risk of cardiovascular disease in humans. The gut flora is known to have a role in TMAO formation from choline, and this paper shows that dietary choline supplementation enhances macrophage foam cell formation and lesion formation in atherosclerosis-prone mice, but not if the gut flora are depleted with antibiotics.

Liver triacylglycerol (TAG) synthesis and secretion are closely linked to nutrient availability. After a meal, hepatic TAG formation from fatty acids is decreased, largely due to a reduction in circulating free fatty acids (FFA). Despite the postprandial decrease in FFA-driven esterification and oxidation, VLDL-TAG secretion is maintained to support peripheral lipid delivery and metabolism. The regulatory mechanisms underlying the postprandial control of VLDL-TAG secretion remain unclear. Here, we demonstrated that the mTOR complex 1 (mTORC1) is essential for this sustained VLDL-TAG secretion and lipid homeostasis. In murine models, the absence of hepatic mTORC1 reduced circulating TAG, despite hepatosteatosis, while activation of mTORC1 depleted liver TAG stores. Additionally, mTORC1 promoted TAG secretion by regulating phosphocholine cytidylyltransferase α (CCTα), the rate-limiting enzyme involved in the synthesis of phosphatidylcholine (PC). Increasing PC synthesis in mice lacking mTORC1 rescued hepatosteatosis and restored TAG secretion. These data identify mTORC1 as a major regulator of phospholipid biosynthesis and subsequent VLDL-TAG secretion, leading to increased postprandial TAG secretion.

Enhanced de novo lipogenesis mediated by sterol regulatory element-binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage-activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.

Neurodegeneration occurring in multiple sclerosis (MS) contributes to the progression of disability. It is therefore important to identify and neutralize the mechanisms that promote neurodegeneration in MS. Here, we report that oxidized phosphatidylcholines (OxPCs) found in MS lesions, previously identified as end-product markers of oxidative stress, are potent drivers of neurodegeneration. Cultured neurons and oligodendrocytes were killed by OxPCs, and this was ameliorated by microglia. After OxPC injection, mouse spinal cords developed focal demyelinating lesions with prominent axonal loss. The depletion of microglia that accumulated in OxPC lesions exacerbated neurodegeneration. Single-cell RNA sequencing of lesioned spinal cords identified unique subsets of TREM2 high mouse microglia responding to OxPC deposition. TREM2 was detected in human MS lesions, and TREM2 −/− mice exhibited worsened OxPC lesions. These results identify OxPCs as potent neurotoxins and suggest that enhancing microglia-mediated OxPC clearance via TREM2 could help prevent neurodegeneration in MS. Oxidized phosphatidylcholines found in MS lesions are not just markers of oxidative stress but are also promoters of demyelination and axon injury. Microglia suppress oxidized-phosphatidylcholine-mediated neurodegeneration by phagocytosis through TREM2.

The production of trimethylamine-N-oxide (TMAO) from dietary phosphatidylcholine was found to be dependent on metabolism by the intestinal microbiota. Increased TMAO levels were associated with an increased risk of incident major adverse cardiac events. The phospholipid phosphatidylcholine (lecithin) is the major dietary source of choline, a semiessential nutrient that is part of the B-complex vitamin family. 1 , 2 Choline has various metabolic roles, ranging from its essential involvement in lipid metabolism and cell-membrane structure to its role as a precursor for the synthesis of the neurotransmitter acetylcholine. Choline and some of its metabolites, such as betaine, can also serve as a source of methyl groups that are required for proper metabolism of certain amino acids, such as homocysteine and methionine. 3 There is a growing awareness that intestinal microbial organisms, collectively termed microbiota, participate in the . . .