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Communications Biology Jun 2024Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety...
Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Lecithin, sucrose fatty acid esters, carboxymethylcellulose (CMC), and mono- and diglycerides (MDG) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study demonstrates that sucrose fatty acid esters and carboxymethylcellulose induce hyperglycemia and hyperinsulinemia in a mouse model. Lecithin, sucrose fatty acid esters, and CMC disrupt glucose homeostasis in the in vitro insulin-resistance model. MDG impairs circulating lipid and glucose metabolism. All emulsifiers change the intestinal microbiota diversity and induce gut microbiota dysbiosis. Lecithin, sucrose fatty acid esters, and CMC do not impact mucus-bacterial interactions, whereas MDG tends to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrate the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes.
Topics: Animals; Emulsifying Agents; Dysbiosis; Gastrointestinal Microbiome; Mice; Male; Metabolic Diseases; Mice, Inbred C57BL; Carboxymethylcellulose Sodium; Sucrose; Insulin Resistance; Lecithins
PubMed: 38902371
DOI: 10.1038/s42003-024-06224-3 -
The Journal of Nutrition Jun 2024Healthy plant-based diets have been associated with lower risk of type 2 diabetes (T2D). Metabolomics can be leveraged to identify potential pathways through which diet...
BACKGROUND
Healthy plant-based diets have been associated with lower risk of type 2 diabetes (T2D). Metabolomics can be leveraged to identify potential pathways through which diet influences disease risk.
OBJECTIVE
To identify profiles of serum metabolites reflective of plant-based diets of varying quality and examine associations with cardiometabolic risk and T2D.
METHODS
We included data from 687 participants of the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort. An overall plant-based diet index (PDI), healthy PDI (hPDI), and unhealthful PDI (uPDI) were estimated from food frequency questionnaires. Serum metabolites were assayed using ultra-performance liquid chromatography mass spectrometry. Elastic net regression was used to identify sets of metabolites predictive of each diet index and metabolite profile scores were calculated as the weighted sum of the selected metabolites. Cross-sectional associations between metabolite profile scores and cardiometabolic measures and prospective associations with incident T2D were evaluated with multivariable adjusted linear and logistic regressions.
RESULTS
Metabolite profiles for PDI, hPDI, and uPDI consisted of n=51, 55, and 45 metabolites, respectively. Metabolites strongly positively correlated with diet indices included phosphatidylcholine (16:0/18:3) for PDI, phosphatidylethanolamine (20:1/20:4) and pantothenate for hPDI, and lysophosphatidylglycerol (18:2/0:0), proline, and lauric acid for uPDI. Higher metabolite profile scores for PDI and hPDI were associated with lower glycemia and lipids measures, whereas a higher uPDI metabolite score was associated with higher triglycerides and lower LDL-C and HDL-C. A higher metabolite score for hPDI was additionally associated with lower adiposity measures, higher liver fat attenuation, higher adiponectin), lower odds of overweight and obesity (OR 0.64 [95% CI: 0.51-0.81] and 0.59 [95% CI: 0.48-0.74], respectively) and lower odds of incident T2D (OR 0.66 [95% CI: 0.45-0.97]).
CONCLUSION
Metabolite profiles of different plant-based diets were identified. Metabolite profiles of overall and healthy plant-based diets were associated with favorable cardiometabolic risk profiles.
PubMed: 38901635
DOI: 10.1016/j.tjnut.2024.06.007 -
International Journal of Pharmaceutics Jun 2024Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By...
Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By encapsulating active pharmaceutical ingredients - ranging from small molecule drugs to proteins and nucleic acids - these nanocarriers enhance treatment efficacy and safety. However, their commercial success faces hurdles, such as the lack of a systematic design approach and the issues related to scalability and reproducibility. This work aims to provide insights into the drug-phospholipid interaction by combining molecular dynamic simulations and thermodynamic modelling techniques. In particular, we have made a connection between the structural properties of the drug-phospholipid system and the physicochemical performance of the drug-loaded liposomal nanoformulations. We have considered two prototypical drugs, felodipine (FEL) and naproxen (NPX), and one model hydrogenated soy phosphatidylcholine (HSPC) bilayer membrane. Molecular dynamic simulations revealed which regions within the phospholipid bilayers are most and least favoured by the drug molecules. NPX tends to reside at the water-phospholipid interface and is characterized by a lower free energy barrier for bilayer membrane permeation. Meanwhile, FEL prefers to sit within the hydrophobic tails of the phospholipids and is characterized by a higher free energy barrier for membrane permeation. Flory-Huggins thermodynamic modelling, small angle X-ray scattering, dynamic light scattering, TEM, and drug release studies of these liposomal nanoformulations confirmed this drug-phospholipid structural difference. The naproxen-phospholipid system has a lower free energy barrier for permeation, higher drug miscibility with the bilayer, larger liposomal nanoparticle size, and faster drug release in the aqueous medium than felodipine. We suggest that this combination of molecular dynamics and thermodynamics approach may offer a new tool for designing and developing lipid-based nanocarriers for unmet medical applications.
PubMed: 38901537
DOI: 10.1016/j.ijpharm.2024.124367 -
Journal of Chromatography. B,... Jun 2024Lipidomics is focusing on the screening of lipid species in complex mixtures using mass spectrometry-based approaches. In this work, we aim to enhance the intestinal...
Lipidomics is focusing on the screening of lipid species in complex mixtures using mass spectrometry-based approaches. In this work, we aim to enhance the intestinal lipidome coverage within the Oligo-Mouse-Microbiota (OMM) colonized mouse model by testing eight mobile phase conditions on five reversed-phase columns. Our selected mobile phase modifiers included two ammonium salts, two concentrations, and the addition of respective acids at 0.1 %. We compared two columns with hybrid surface technology, two with ethylene bridged hybrid technology and one with core-shell particles. Best performance was attained for standards and intestinal lipidome, using either ammonium formate or acetate in ESI(+) or ammonium acetate in ESI(-) for all column technologies. Notably, a concentration of 5 mM ammonium salt showed optimal results for both modes, while the addition of acids had a negligible effect on lipid ionization efficiency. The HST BEH C18 column improved peak width and tailing factor parameters compared to other technologies. We achieved the highest lipid count in colon and ileum content, including ceramides, phosphatidylethanolamines and phosphatidylcholines, when using 5 mM ammonium acetate in ESI(-). Conversely, in ESI(+) 5 mM ammonium formate demonstrated superior coverage for diacylglycerols and triacylglycerols.
PubMed: 38901159
DOI: 10.1016/j.jchromb.2024.124188 -
Cell Reports Jun 2024Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and...
Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways, including TGF-β signaling expressed by CD68 monocytes, and the metabolites phosphatidylcholine (PC) and phosphatidylethanolamine (PE) positively correlate with broadly neutralizing antibody responses against DENV. In contrast, expression of pro-inflammatory pathways and cytokines (IFN and IL-1) in CD68 monocytes and primary and secondary bile acids negatively correlates with broad DENV-specific antibody responses. Induction of TGF-β and IFNs is done respectively by PC/PE and bile acids in CD68 and CD68 monocytes. The inhibition of viral sensing by PC/PE-induced TGF-β is confirmed in vitro. Our studies show that the balance between metabolites and the pro- or anti-inflammatory state of innate immune cells drives broad and protective B cell response to a live attenuated dengue vaccine.
PubMed: 38900640
DOI: 10.1016/j.celrep.2024.114370 -
Hepatology (Baltimore, Md.) Jun 2024Liver hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of...
BACKGROUND AND AIMS
Liver hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature.
APPROACH AND RESULTS
Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine (PC), and sphingolipid (SL) derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids (SFA-PC) and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) and Ceramide Synthase 5 (CERS5) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy.
CONCLUSION
In conclusion, our study elucidates the metabolic reprogramming gnature of lipid metabolism in HCC, identifies prognostic markers, and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.
PubMed: 38899975
DOI: 10.1097/HEP.0000000000000962 -
ACS Pharmacology & Translational Science Jun 2024Dexamethasone (DEX) was applied in neonatal respiratory distress syndrome treatment of pregnant women. We established a pharmacokinetics (PK)/pharmacodynamics(PD)/end...
Dexamethasone (DEX) was applied in neonatal respiratory distress syndrome treatment of pregnant women. We established a pharmacokinetics (PK)/pharmacodynamics(PD)/end point model of pregnant animals based on published data and then extrapolated to simulate fetal exposure and lung maturation in pregnant women. We first established the PK/PD/end point model for DEX in pregnant sheep. We considered the competitive effect of cortisol (Cort) and DEX binding with glucocorticoid receptor and then used the indirect response model to describe disaturated-phosphatidylcholine (DSPC) dynamics. Based on that, we established a regression relationship between DSPC and fetal lung volume (V40). We then extrapolated the PD/end point model of pregnant sheep to pregnant monkeys by corrected stages of morphologic lung maturation in two species. Finally, we utilized the interspecies extrapolation strategy to simulate fetal exposure (AUC) and V40 relationship in pregnant women. The current model could well describe the maternal-fetal PK of DEX in pregnant animals. Simulated DEX AUC values of the umbilical venous to maternal plasma ratio in pregnant sheep and monkeys were 0.31 and 0.27, respectively. The simulated Cort curve and V40 in pregnant sheep closely matched the observed data within a 2-fold range. For pregnant monkeys, model-simulated V40 were well fitted with external verification data, which showed good interspecies extrapolation performance. Finally, we simulated fetal exposure-response relationship in pregnant women, which indicated that the fetal AUC of DEX should not be less than 300 and 100 ng/mL·hr at GW28 and GW34 to ensure fetal lung maturity. The current model preliminarily provided support for clinical DEX dose optimization.
PubMed: 38898943
DOI: 10.1021/acsptsci.3c00391 -
Food Chemistry May 2024The study investigated the lipid oxidation of pumpkin seed kernels (PSK) under different storage conditions (room temperature, vacuum-room temperature, refrigeration,...
The study investigated the lipid oxidation of pumpkin seed kernels (PSK) under different storage conditions (room temperature, vacuum-room temperature, refrigeration, and vacuum-refrigeration) using HPLC-MS and GC-MS. Experimental results found the vacuum-refrigeration group showed the lowest PV (0.24 g/100 g), diene (8.68), hexanal (356.64 ± 16.06 ng/g), and nonanal (132.05 ± 8.38 ng/g) after a 9-month storage. A total of 586 lipids, including 6 classes and 27 subclasses, were detected, 46 of which showed significant differences. Refrigeration samples had the highest diacylglycerol content, while room temperature samples demonstrated the highest triacylglycerol and phosphatidylcholine content. Differential lipid metabolite analyses indicated that storage conditions mainly affected glycerolipid metabolism, glycerophospholipid metabolism, and sphingolipid metabolism pathways in PSK, while glycerolipid and glycerophospholipid metabolism were still dominant. It revealed that refrigeration was more effective than vacuum in inhibiting the oxidation of PSK. These findings could offer valuable references for the storage, transportation, preservation, and the development and utilization of PSK.
PubMed: 38897071
DOI: 10.1016/j.foodchem.2024.139808 -
Advanced Science (Weinheim,... Jun 2024Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of various chronic metabolic hepatic diseases with limited therapeutics. Rubicon, an essential regulator...
Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of various chronic metabolic hepatic diseases with limited therapeutics. Rubicon, an essential regulator in lysosomal degradation, is reported to exacerbate hepatic steatosis in NAFLD mice and patients, indicating its probability of being a therapeutic target for NAFLD treatment. In this study, the therapeutic potential of Rubicon blockage is investigated. Lipid nanoparticles carrying Rubicon-specific CRISPR-Cas9 components exhibited liver accumulation, cell internalization, and Rubicon knockdown. A single administration of the nanoparticles results in attenuated lipid deposition and hepatic steatosis, with lower circulating lipid levels and decreased adipocyte size in NAFLD mice. Furthermore, the increase of phosphatidylcholine and phosphatidylethanolamine levels can be observed in the NAFLD mice livers after Rubicon silencing, along with regulatory effects on metabolism-related genes such as CD36, Gpcpd1, Chka, and Lpin2. The results indicate that knockdown of Rubicon improves glycerophospholipid metabolism and thereby ameliorates the NAFLD progression, which provides a potential strategy for NAFLD therapy via the restoration of Rubicon.
PubMed: 38894572
DOI: 10.1002/advs.202400493 -
Molecules (Basel, Switzerland) May 2024The 5-heterocyclic 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles were obtained as potential biologically active compounds. Lipophilicity is one of the most important... (Comparative Study)
Comparative Study
The 5-heterocyclic 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles were obtained as potential biologically active compounds. Lipophilicity is one of the most important physicochemical properties of compounds and was already taken into account during the drug candidates design and development. The lipophilicity of compounds was determined using the computational (log P) and chromatography (log k, R) methods. The experimental ones included the reverse-phase column high performance liquid chromatography RP (HPLC) with C8, C18, phosphatidylcholine (IAM), and cholesterol stationary phases and the thin layer chromatography (RP-HPTLC) with C8 and C18 stationary phases and various organic modifiers under the isocratic conditions. Descriptive statistics, correlation, and PCA analyses were used to compare the obtained results. For lipophilicity estimation of the tested compounds by HPTLC, dioxane and MeOH seem to be particularly beneficial as organic modifiers. The chromatographic lipophilicity parameters log k (R) were well correlated and highly redundant (85%) compared with those calculated. Most compounds possess lipophilicity parameters within the recommended range for drug candidates.
Topics: Thiadiazoles; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Hydrophobic and Hydrophilic Interactions; Computer Simulation; Chromatography, Reverse-Phase
PubMed: 38893351
DOI: 10.3390/molecules29112478