Altered Lipid Metabolism Research Articles

Untargeted Lipidomic Profiling of Amniotic Fluid Reveals Dysregulated Lipid Metabolism in Healthy Normal-Weight Mothers with Fetal Macrosomia

Background: Alterations in maternal lipid metabolism have been elucidated by several studies in relation to macrosomia. However, the lipidome of the intrauterine compartment associated with macrosomia, particularly in early pregnancy, remains largely unknown. Objectives: (1) To compare the lipidomic profile of early 2nd trimester amniotic fluid (AF) of healthy mothers with normal body mass index who gave birth to large-for-gestational age (LGA) versus appropriate-for-gestational age (AGA) infants; and (2) to examine if insulin and glucose concentrations in AF were associated with the AF lipidomic profile. Methods: In this nested case–control study, bio-banked AF samples were collected from pregnant women undergoing routine amniocentesis at 12–22 weeks of gestation. A subsample of 15 LGA infants (cases) were contrasted with 15 AGA infants (controls). An untargeted lipidomics analysis using liquid chromatography quadrupole time-of-flight mass spectrometry was conducted. Univariate and multivariate statistical analyses (principal component analysis and partial least-squares discriminant analysis) were used to extract differentially abundant (DA) features with high variable importance in projection (VIP) scores. Results: LGA AF was characterized by elevations of 30 phosphatidic acid species. Among other DA features, sphingomyelin (SM 14:0;O2/20:1) had the highest VIP score and was markedly elevated in LGA AF. Neither insulin nor glucose was associated with 2nd trimester AF lipidomic profiles in these healthy, normal-weight mothers. Conclusion: These findings provide evidence of early dysregulated lipid metabolism in healthy, normal-weight mothers with LGA infants.

Metabolic abnormalities and reprogramming in cats with naturally occurring hypertrophic cardiomyopathy.

The heart is a metabolic organ rich in mitochondria. The failing heart reprograms to utilize different energy substrates, which increase its oxygen consumption. These adaptive changes contribute to increased oxidative stress. Hypertrophic cardiomyopathy (HCM) is a common heart condition, affecting approximately 15% of the general cat population. Feline HCM shares phenotypical and genotypical similarities with human HCM, but the disease mechanisms for both species are incompletely understood. Our goal was to characterize global changes in metabolome between healthy control cats and cats with different stages of HCM. Serum samples from 83 cats, the majority (70/83) of which were domestic shorthair and included 23 healthy control cats, 31 and 12 preclinical cats with American College of Veterinary Internal Medicine (ACVIM) stages B1 and B2, respectively, and 17 cats with history of clinical heart failure or arterial thromboembolism (ACVIM stage C), were collected for untargeted metabolomic analysis. Multiple linear regression adjusted for age, sex and body weight was applied to compare between control and across HCM groups. Our study identified 1253 metabolites, of which 983 metabolites had known identities. Statistical analysis identified 167 metabolites that were significantly different among groups (adjusted P<0.1). About half of the differentially identified metabolites were lipids, including glycerophospholipids, sphingolipids and cholesterol. Serum concentrations of free fatty acids, 3-hydroxy fatty acids and acylcarnitines were increased in HCM groups compared with control group. The levels of creatine phosphate and multiple Krebs cycle intermediates, including succinate, aconitate and α-ketoglutarate, also accumulated in the circulation of HCM cats. In addition, serum levels of nicotinamide and tryptophan, precursors for de novo NAD+ biosynthesis, were reduced in HCM groups versus control group. Glutathione metabolism was altered. Serum levels of cystine, the oxidized form of cysteine and cysteine-glutathione disulfide, were elevated in the HCM groups, indicative of heightened oxidative stress. Further, the level of ophthalmate, an endogenous glutathione analog and competitive inhibitor, was increased by more than twofold in HCM groups versus control group. Finally, several uremic toxins, including guanidino compounds and protein bound putrescine, accumulated in the circulation of HCM cats. Our study provided evidence of deranged energy metabolism, altered glutathione homeostasis and impaired renal uremic toxin excretion. Altered lipid metabolism suggested perturbed structure and function of cardiac sarcolemma membrane and lipid signalling.

Utility of the triglycerides/HDL cholesterol ratio in older adult patients in Colombia

Abstract Introduction Alterations in lipid metabolism are responsible for atherogenesis and an increased risk of atherosclerotic cardiovascular disease. The triglycerides to high-density lipoprotein cholesterol ratio (TG/HDL-C) is used to assess the risk of cardiovascular diseases; however, it has not been evaluated in older adults. The aim of the present study is to evaluate the TG/HDL-C ratio in elderly patients and analyze its correlation and discriminatory capacity with cardiovascular risk factors according to data from the SABE Colombia survey. Purpose Describe the sociodemographic characteristics, cardiovascular history, lifestyle, and cardiovascular risk score in the older adult population included in the SABE Colombia Study.Describes the distribution of triglyceride levels, cholesterol, and the TAG-HDL ratio in the older adult population included in the SABE Colombia Study. Evaluate the relationship between the TAG/HDL Cholesterol Index and cardiovascular risk factors such as hypertension, prediabetes, type 2 diabetes mellitus, cardiovascular disease, cerebrovascular disease Determine if there is a correlation and the degree of correlation between the TAG/HDL Cholesterol ratio and variables related to higher cardiovascular risk and stablish cutoff points of the triglyceride to HDL cholesterol ratio as indicators of the onset of risk factors Materials and Methods Cross-sectional study in adults aged 60 years and older included in the national SABE Colombia survey (National Survey of Health, Well-being, and Ageing conducted in Colombia in 2015), which included 244 municipalities from all departments of the country. A correlation test was performed to assess the presence and degree of correlation between the TAG/HDL index and cardiovascular risk factors, and ROC curve analysis was conducted to evaluate the performance of the TAG/HDL index in identifying risk factors. Results A total of 23,694 patients with the necessary information for the study were included. The median age was 69 years, 57.3% were women, and 34.3% were of white race. 23.5% had hypertension, and 16.4% had diabetes mellitus. 13.4% had a history of cardiovascular disease, and 2.5% had cerebrovascular disease. While the specific correlation between the index and different cardiovascular risk factors is generally low to moderate, good discriminatory capacity was found for diabetes and metabolic syndrome with the following values: diabetes, with an area under the curve (AUC) of 0.871 and a cut-off point of 9.17; and for metabolic syndrome, the AUC was 0.840, with a cut-off point of 8.81. Conclusions Our findings show that the TG/HDL ratio has intermediate correlation for different cardiovascular risk factors; however, it has excellent predictive ability for the presence of diabetes and metabolic syndrome. These findings are very useful in the clinical evaluation, screening, and detection of cardiovascular risk factors in the population aged 60 years and older in Colombia.Scatter plots of TAG/HDL ratio comparedROC curves for diabetes and metabolic s

Leveraging ML for profiling lipidomic alterations in breast cancer tissues: a methodological perspective

In this study, a comprehensive methodology combining machine learning and statistical analysis was employed to investigate alterations in the metabolite profiles, including lipids, of breast cancer tissues and their subtypes. By integrating biological and machine learning feature selection techniques, along with univariate and multivariate analyses, a notable lipid signature was identified in breast cancer tissues. The results revealed elevated levels of saturated and monounsaturated phospholipids in breast cancer tissues, consistent with external validation findings. Additionally, lipidomics analysis in both the original and validation datasets indicated lower levels of most triacylglycerols compared to non-cancerous tissues, suggesting potential alterations in lipid storage and metabolism within cancer cells. Analysis of cancer subtypes revealed that levels of PC 30:0 were relatively reduced in HER2(−) samples that were ER(+) and PR(+) compared to those that were ER(−) and PR(−). Conversely, HER2(+) tumors, which were ER(−) and PR(−), exhibited increased concentrations of PC 30:0. This increase could potentially be linked to the role of Stearoyl-CoA-Desaturase 1 in breast cancer. Comprehensive metabolomic analyses of breast cancer can offer crucial insights into cancer development, aiding in early detection and treatment evaluation of this devastating disease.

The use of metabolomics and machine learning algorithms to predict post-transplant diabetes mellitus in renal transplant patients on Tacrolimus therapy.

Tacrolimus (TAC) has significantly improved kidney graft survival following transplantation, though it is associated with adverse side effects. The most prevalent complication resulting from excessive TAC exposure is the onset of de novo diabetes mellitus (DM), a condition that can negatively impact both renal graft function and patient outcomes. De novo DM is linked to an increased risk of chronic transplant dysfunction, as well as cardiovascular morbidity and mortality. Although the underlying mechanisms remain unclear, emerging research in the field of omics shows promise. The aim of this study was to investigate the metabolomic profile of kidney transplant patients who developed de novo DM, in comparison to those who did not, following TAC exposure, using untargeted metabolomic analysis through ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) and machine learning algorithms. A cohort of 34 kidney transplant patients on a Tacrolimus regimen for at least 6 months was enrolled in the study, with serum samples collected from each patient. Comprehensive profiling of serum metabolites was performed, enabling the classification of patients into de novo diabetes mellitus and non diabetes groups. The metabolomic analysis of serum was conducted using UHPLC-MS. Of the 34 patients, 16 were diagnosed with TAC-induced diabetes. A total of 334 metabolites were identified in the serum samples, of which 10 demonstrated a significant correlation with the de novo diabetes mellitus group. Most of these metabolites were linked to alterations in lipid metabolism. The application of metabolomics in kidney transplant patients undergoing a Tacrolimus regimen is both feasible and effective in identifying metabolites associated with de novo diabetes mellitus. This approach may provide valuable insights into the metabolic alterations underlying TAC-induced diabetes.

Spiroplasma endosymbiont reduction of host lipid synthesis and Stomoxyn-like peptide contribute to trypanosome resistance in the tsetse fly Glossina fuscipes.

The tsetse fly, Glossina fuscipes fuscipes ( Gff ) is of high public health relevance. Gff exhibits strong innate resistance to trypanosomes, especially when infected with the endosymbiotic bacterium Spiroplasma . This study investigated how the bacterium Spiroplasma inside Gff enables them to be resistant to trypanosome infection. Our results indicate alterations in host lipid metabolism with reduction in levels of triglycerides, suggesting a potential metabolic barrier that limits the viability to parasite. In addition, we discovered a small peptide, stomoxyn, exclusively in Gff and related Palpalis tsetse species. We have shown that Gff synthetic Stomoxyn has antibacterial and antitrypanosomal properties and lowering Stomoxyn levels in Gff correlates with increased parasite prevalence. We suggest that strategies to increase Spiroplasma prevalence or enhance stomoxyn expression through paratransgenic approaches could be promising avenues for reducing trypanosomiasis transmission.

Alteration of Lipid Metabolism in Hypoxic Cancer Cells

Alteration of Lipid Metabolism in Hypoxic Cancer Cells

FADS1 Genetic Variant and Omega-3 Supplementation Are Associated with Changes in Fatty Acid Composition in Red Blood Cells of Subjects with Obesity.

Obesity is characterized by low-grade chronic inflammation, which can be modulated by lipid mediators derived from omega-3 (n-3) polyunsaturated fatty acids (PUFA). Obesity is a multifactorial disease, where genetic and environmental factors strongly interact to increase its development. In this context, the FADS1 gene encodes the delta-5 desaturase protein, which catalyzes the desaturation of PUFA. The rs174547 genetic variant of FADS1 has been associated with alterations in lipid metabolism, particularly with decreases in eicosapentaenoic acid (EPA) and arachidonic acid (AA) concentrations. To analyze the effect of an n-3-supplemented diet on the fatty acid profile and composition in red blood cells (RBCs) of obese subjects carrying the rs174547 variant of the FADS1 gene. Seventy-six subjects with obesity were divided into two groups: omega-3 (1.5 g of n-3/day) and placebo (1.5 g of sunflower oil/day). The dietary intervention consisted of a four-month follow-up. Anthropometric, biochemical, and dietary variables were evaluated monthly. The total fatty acid profile in RBC was determined using gas chromatography. The rs174547 variant was analyzed through allelic discrimination. The n-3 index (O3I) increased at the end of the intervention in both groups. Subjects carrying the CC genotype showed significant differences (minor increase) in n-6, n-3, total PUFA, EPA, DHA, and the O3I in RBCs compared to TT genotype carriers in the n-3 group. The diet supplemented with EPA and DHA is ideal for providing the direct products that bypass the synthesis step affected by the FADS1 rs174547 variant in subjects carrying the CC genotype. The O3I confirmed an increase in n-3 fatty acids in RBCs at the end of the intervention.

Serum lipidome reveals lipid metabolic dysregulation in severe fever with thrombocytopenia syndrome

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is a rapidly progressing infectious disease with a high fatality rate caused by a novel bunyavirus (SFTSV). The role of lipids in viral infections is well-documented; however, the specific alterations in lipid metabolism during SFTSV infection remain elusive. This study aims to elucidate the lipid metabolic dysregulations in the early stages of SFTS patients.MethodsThis study prospectively collected peripheral blood sera from 11 critical SFTS patients, 37 mild SFTS patients, and 23 healthy controls during the early stages of infection for lipidomics analysis. A systematic bioinformatics analysis was conducted from three aspects integrating lipid differential expressions, lipid differential correlations, and lipid-clinical indices correlations to reveal the serum lipid metabolic dysregulation in SFTSV-infected individuals.ResultsOur findings reveal significant lipid metabolic dysregulation in SFTS patients. Specifically, compared to healthy controls, SFTS patients exhibited three distinct modes of lipid differential expression: increased levels of lipids including phosphatidylserine (PS), hexosylceramide (HexCer), and triglycerides (TG); decreased levels of lipids including lysophosphatidylcholine (LPC), acylcarnitine (AcCa), and cholesterol esters (ChE); and lipids showing “dual changes” including phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Finally, based on lipid metabolic pathways and literature analysis, we systematically elucidated the potential mechanisms underlying lipid metabolic dysregulation in the early stage of SFTSV infection.ConclusionsOur study presents the first global serum lipidome profile and reveals the lipid metabolic dysregulation patterns in the early stage of SFTSV infection. These findings provide a new basis for the diagnosis, treatment, and further investigation of the disease.

Effects of Perfluorinated Alkyl Substances (PFAS) on Amphibian Body and Liver Conditions: Is Lipid Metabolism Being Perturbed throughout Metamorphosis?

Per- and polyfluoroalkyl substances (PFAS) may interact with peroxisome proliferator activated receptors (PPARs) and alter lipid homeostasis. Using Xenopus laevis, we investigated the effect of PFAS on (a) lipid homeostasis and whether this correlated to changes in body and hepatic condition; (b) the expression of hepatic genes regulated by PPAR; and (c) the hepatic lipidome. We chronically exposed tadpoles to 0.5 µg/L of either PFOS, PFHxS, PFOA, PFHxA, a binary mixture of PFOS and PFHxS (0.5 µg/L of each), or a control, from NF stage 52 through metamorphic climax. Growth, development, and survival were not affected, but we detected a sex-specific decrease in body condition at NF 66 (6.8%) and in hepatic condition (16.6%) across metamorphic climax for male tadpoles exposed to PFOS. We observed weak evidence for the transient downregulation of apolipoprotein-V (apoa5) at NF 62 in tadpoles exposed to PFHxA. Acyl-CoA oxidase 1 (acox1) was downregulated only in males exposed to PFHxS (Ln(Fold Change) = -0.54). We detected PFAS-specific downregulation of structural glycerophospholipids, while semi-quantitative profiling detected the upregulation in numerous glycerophospholipids, sphingomyelins, and diglycerides. Overall, our findings indicate that PFAS can induce sex-specific effects that change across larval development and metamorphosis. We demonstrate that PFAS alter lipid metabolism at environmentally relevant concentrations through divergent mechanisms that may not be related to PPARs, with an absence of effects on body condition, demonstrating the need for more molecular studies to elucidate mechanisms of PFAS-induced lipid dysregulation in amphibians and in other taxa.

Knock-Out of IKKepsilon Ameliorates Atherosclerosis and Fatty Liver Disease by Alterations of Lipid Metabolism in the PCSK9 Model in Mice.

The inhibitor-kappaB kinase epsilon (IKKε) represents a non-canonical IκB kinase that modulates NF-κB activity and interferon I responses. Inhibition of this pathway has been linked with atherosclerosis and metabolic dysfunction-associated steatotic liver disease (MASLD), yet the results are contradictory. In this study, we employed a combined model of hepatic PCSK9D377Y overexpression and a high-fat diet for 16 weeks to induce atherosclerosis and liver steatosis. The development of atherosclerotic plaques, serum lipid concentrations, and lipid metabolism in the liver and adipose tissue were compared between wild-type and IKKε knock-out mice. The formation and progression of plaques were markedly reduced in IKKε knockout mice, accompanied by reduced serum cholesterol levels, fat deposition, and macrophage infiltration within the plaque. Additionally, the development of a fatty liver was diminished in these mice, which may be attributed to decreased levels of multiple lipid species, particularly monounsaturated fatty acids, triglycerides, and ceramides in the serum. The modulation of several proteins within the liver and adipose tissue suggests that de novo lipogenesis and the inflammatory response are suppressed as a consequence of IKKε inhibition. In conclusion, our data suggest that the knockout of IKKε is involved in mechanisms of both atherosclerosis and MASLD. Inhibition of this pathway may therefore represent a novel approach to the treatment of cardiovascular and metabolic diseases.

Dyslipidemia in Pregnancy: A Systematic Review of Molecular Alterations and Clinical Implications.

Dyslipidemia in pregnancy presents unique clinical challenges due to its effects on maternal and fetal health. This systematic review hypothesizes that molecular alterations in lipid metabolism during pregnancy contribute to adverse pregnancy outcomes and seeks to identify the clinical implications of these changes. The rationale behind this review stems from the increased risk of complications such as preeclampsia, intrauterine growth restriction, and acute pancreatitis associated with dyslipidemia in pregnancy. The primary objective is to examine the interplay between lipid metabolism and pregnancy outcomes. To achieve this, a systematic review following PRISMA guidelines was conducted, with a comprehensive search of the PubMed database covering articles from January 2014 to June 2024. Inclusion criteria focused on studies assessing molecular alterations and clinical outcomes of dyslipidemia in pregnancy, while case reports and relevant clinical trials were analyzed to evaluate both maternal and fetal outcomes. A total of 12 studies were included in the final analysis. This study provided evidence of the need for early detection and management strategies to reduce risks. The outcomes revealed significant associations between dyslipidemia and adverse maternal outcomes such as preeclampsia, gestational diabetes, and pancreatitis, as well as fetal outcomes like preterm birth and fetal distress. Early lipid monitoring and intervention are crucial in mitigating these risks and suggests that a multidisciplinary approach is necessary to improve maternal and fetal health in pregnancies complicated by dyslipidemia.

Cancer-associated foam cells hamper protective T cell immunity and favor tumor progression in human colon carcinogenesis

BackgroundColorectal cancer (CRC) remains a significant healthcare burden worldwide, characterized by a complex interplay between obesity and chronic inflammation. While the relationship between CRC, obesity and altered lipid metabolism is...

Butyl benzyl phthalate induces neurotoxicity in Eisenia fetida: Mechanisms revealed by biochemical and metabolomic analyses

Phthalates, particularly butyl benzyl phthalate (BBP), are ubiquitous environmental contaminants with potential neurotoxic effects. However, their impact on soil organisms, especially earthworms (Eisenia fetida), remains poorly understood. The current study investigated the neurotoxic effects of BBP on Eisenia fetida in artificial and red soils using an integrated approach combining biochemical assays, metabolomics, and molecular docking. Earthworms were exposed to 0, 1, and 10 mg kg−1 BBP for 14 and 28 days. Biochemical assays revealed significant increases in oxidative stress markers and disruptions in neurotransmission-related enzyme activities. Metabolomic analysis of the cerebral ganglia identified alterations in energy metabolism, lipid metabolism, and neuroactive ligand-receptor interaction signaling pathways. Molecular docking studies corroborated these findings, showing strong interactions between BBP and essential neuronal proteins, particularly the sodium pump. The integration of these data suggests that BBP-induced neurotoxicity in Eisenia fetida is primarily mediated by calcium signaling pathway dysfunction and calcium homeostasis imbalance. Notably, neurotoxic effects were more pronounced in red soil than in artificial soil, highlighting the importance of considering soil type in ecotoxicological assessments. The current study provides novel insights into the mechanisms of BBP-induced neurotoxicity in soil invertebrates and underscores the potential ecological risks associated with phthalate contamination in agricultural environments.

Physical inactivity and breakfast skipping caused visceral fat accumulation in rats.

Physical inactivity as well as breakfast skipping is known as risk factor for various metabolic diseases, such as obesity and type 2 diabetes. We have previously reported that a breakfast skipping model, in which the timing of feeding is delayed, induces abnormal lipid metabolism by altering the circadian rhythm of lipid metabolism-related genes in rats. The purpose of this study was to elucidate the synergistic effect of physical inactivity and breakfast skipping on lipid metabolism. We adopted sciatic neurectomized rats as physically inactive models, because we confirmed that the rats mildly decreased their spontaneous locomotor activity compared to sham-operated rats. And then the physically inactive model rats were fed a mild high-fat diet during zeitgeber time (ZT) 12-0 in the control group and ZT16-0 in the breakfast skipping group for 11days. Body weight gain and total food intake were similar in both groups. Breakfast skipping induced a significant visceral fat accumulation, which was not observed in our previous breakfast skipping or physically inactive studies. The mRNA levels of clock and lipogenesis-related genes were altered by breakfast skipping in the liver and epididymal adipose tissue, and serum insulin level was altered by breakfast skipping. These results suggest that physical inactivity and breakfast skipping synergistically induces drastic visceral fat accumulation due to the alteration of circadian clock and lipid metabolism in the liver and adipose tissue. Therefore, regular feeding timing plays an important role in the health of a sedentary modern society.

Glycosphingolipids Associated Metabolic Disorders

Lipids play diverse roles in sustaining life, including energy storage, hormonal balance, and cellular communication. Alterations in lipid metabolism can lead to various disorders, including diabetes, atherosclerosis, cancer, and neurodegenerative diseases. Among these disorders, lysosomal storage disorders (LSDs) related to glycosphingolipids metabolism present significant challenges. This review systematically analyzes the current literature on LSDs, focusing on classification, clinical presentations, diagnostic advancements, available treatments, and emerging therapeutic strategies. Glycosphingolipids biosynthesis, particularly its role in viral dissemination and melanin synthesis, underscores its significance in health and disease. Additionally, the review delves into specific LSDs, such as Fabry disease, Gaucher disease, Sandhoff disease, Tay-Sachs disease, and Krabbe disease, highlighting their pathophysiology, prevalence, and treatment options. Enzyme replacement therapy and hematopoietic stem cell transplantation are mainstays in LSD treatment, but gene therapy shows promise. Furthermore, the review explores the role of glycosphingolipids in non-communicable diseases like diabetes, cancer, atherosclerosis, lupus, Alzheimer's, Parkinson's disease, and influenza. Understanding glycosphingolipid metabolism offers insights into disease mechanisms and therapeutic targets, paving the way for improved treatments and ultimately enhancing patient outcomes.

An economically viable stable isotope-enhanced multiple reaction monitoring method for total fatty acid analysis in a mouse model of non-alcoholic fatty liver disease

The complex pathological mechanisms of non-alcoholic fatty liver disease (NAFLD) are closely related to dysregulated lipid metabolism, and the therapeutic effects of the traditional Chinese medicine Zexie-Baizhu Decoction (AA) on NAFLD have been gaining increasing attention. However, research into altered lipid metabolism, especially fatty acids, in NAFLD and the intervention of AA faces technical challenges, especially in the precise quantitative analysis of fatty acids in biological samples. The high complexity of biological matrices, particularly after drug intervention, greatly increases the difficulty of detection. Therefore, this study innovatively developed a simple and economical stable isotope derivatization technique by synthesizing d6N,N-dimethylethylenediamine (d6-DMED) in the laboratory, establishing a simple and economical method for fatty acid quantification. This method employs a chemical reaction under low-temperature conditions to ensure the efficient synthesis of d6-DMED. Using ultra-high performance liquid chromatography-triple quadrupole mass spectrometry technique (UHPLC-MS/MS), combined with optimized chromatographic separation conditions and dynamic multiple reaction monitoring mode, the study established a highly sensitive detection method for 35 fatty acid derivatives. Methodological evaluation showed that the limits of quantification ranged from 0.002 to 0.060 μM, with high linearity of R² > 0.995. Additionally, the relative recovery rates were between 93.14% and 106.63%. To further demonstrate the feasibility of this method for fatty acid quantification, it was applied to measure fatty acids in multiple tissues in a mouse NAFLD model, as well as the effects of AA intervention on fatty acid metabolism. This rapid, simple, and cost-effective detection method not only enhances the understanding of NAFLD mechanisms but also provides a new strategy for evaluating the biological complex system after drug intervention.

Surfactant Phospholipid Kinetics in Ventilated Children after Therapeutic Surfactant Supplementation

Acute lung Injury leads to alterations in surfactant lipid composition and metabolism. Although several mechanisms contribute to dysregulated surfactant metabolism, studies investigating in vivo surfactant metabolism are limited. The aim of this study is to characterise surfactant phospholipid composition and flux utilising a stable isotope labelling technique in mechanically ventilated paediatric patients. Paediatric patients (&lt;16 years of age) received 3.6 mg/kg intravenous methyl-D9-choline chloride followed by the endotracheal instillation of 100 mg/kg of exogenous surfactant after 24 h. Bronchioalveolar fluid samples were taken at baseline and 12, 24, 36, 48, 72 and 96 h after methyl-D9-choline infusion. Nine participants (median age of 48 days) were recruited. The primary phosphatidylcholine (PC) composition consisted of PC16:0/16:0 or DPPC (32.0 ± 4.5%). Surfactant supplementation resulted in a 30% increase in DPPC. Methyl-D9 PC enrichment was detected after 12 h and differed significantly between patients, suggesting variability in surfactant synthesis/secretion by the CDP-choline pathway. Peak enrichment was achieved (0.94 ± 0.15% of total PC) at 24 h after methyl-D9-choline infusion. There was a trend towards reduced enrichment with the duration of mechanical ventilation prior to study recruitment; however, this was not statistically significant (p = 0.19). In this study, we demonstrated the fractional molecular composition and turnover of surfactant phospholipids, which was highly variable between patients.

New Application of an Old Drug: Anti-Diabetic Properties of Phloroglucinol.

Phloroglucinol (PHG), an analgesic and spasmolytic drug, shows promise in preventing high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and insulin resistance. In Wistar rats, 10 weeks of PHG treatment did not prevent HFD-induced weight gain but significantly mitigated fasting hyperglycemia, impaired insulin responses, and liver steatosis. This protective effect was not linked to hepatic lipogenesis or AMP-activated protein kinase (AMPK) activation. Instead, PHG improved mitochondrial function by reducing oxidative stress, enhancing ATP production, and increasing anti-oxidant enzyme activity. PHG also relaxed gastric smooth muscles via potassium channel activation and nitric oxide (NO) signaling, potentially delaying gastric emptying. A pilot intervention in pre-diabetic men confirmed PHG's efficacy in improving postprandial glycemic control and altering lipid metabolism. These findings suggest PHG as a potential therapeutic for NAFLD and insulin resistance, acting through mechanisms involving mitochondrial protection, anti-oxidant activity, and gastric motility modulation. Further clinical evaluation is warranted to explore PHG's full therapeutic potential.

DNA Methylation Age Mediates Effect of Metabolic Profile on Cardiovascular and General Aging.

Alterations in lipid metabolism and DNA methylation are 2 hallmarks of aging. Connecting metabolomic, epigenomic, and aging outcomes help unravel the complex mechanisms underlying aging. We aimed to assess whether DNA methylation clocks mediate the association of circulating metabolites with incident atherosclerotic cardiovascular disease (ASCVD) and frailty. The China Kadoorie Biobank is a prospective cohort study with a baseline survey from 2004 to 2008 and a follow-up period until December 31, 2018. We used the Infinium Methylation EPIC BeadChip to measure the methylation levels of 988 participants' baseline blood leukocyte DNA. Metabolite profiles, including lipoprotein particles, lipid constituents, and various circulating metabolites, were measured using quantitative nuclear magnetic resonance. The pace of DNA methylation age acceleration (AA) was calculated using 5 widely used epigenetic clocks (the first generation: Horvath, Hannum, and Li; the second generation: Grim and Pheno). Incident ASCVD was ascertained through linkage with local death and disease registries and national health insurance databases, supplemented by active follow-up. The frailty index was constructed using medical conditions, symptoms, signs, and physical measurements collected at baseline. A total of 508 incident cases of ASCVD were documented during a median follow-up of 9.5 years. The first generation of epigenetic clocks was associated with the risk of ASCVD (P<0.05). For each SD increment in LiAA, HorvathAA, and HannumAA, the corresponding hazard ratios for ASCVD risk were 1.16 (1.05-1.28), 1.10 (1.00-1.22), and 1.17 (1.04-1.31), respectively. Only LiAA mediated the association of various metabolites (lipids, fatty acids, histidine, and inflammatory biomarkers) with ASCVD, with the mediating proportion reaching up to 15% for the diameter of low-density lipoprotein (P=1.2×10-2). Regarding general aging, a 1-SD increase in GrimAA was associated with an average increase of 0.10 in the frailty index (P=2.0×10-3), and a 33% and 63% increased risk of prefrailty and frailty at baseline (P=1.5×10-2 and 5.8×10-2), respectively; this association was not observed with other clocks. GrimAA mediated the effect of various lipids, fatty acids, glucose, lactate, and inflammatory biomarkers on the frailty index, with the mediating proportion reaching up to 22% for triglycerides in very small-sized very low-density lipoprotein (P=6.0×10-3). These findings suggest that epigenomic mechanisms may play a role in the associations between circulating metabolites and the aging process. Different mechanisms underlie the first and second generations of DNA methylation age in cardiovascular and general aging.