Disturbances In Lipid Metabolism Research Articles

Therapeutic potential of AAV-FL-Klotho in obesity: Impact on weight loss and lipid metabolism in mice

Klotho, an anti-aging protein, has gained attention for its protective effects against various diseases, including metabolic disorders, through recombinant Klotho administration. However, the potential of Klotho as a target for gene therapy requires further exploration, as it remains relatively understudied in the context of metabolic disorders. In this study, we demonstrate that AAV-full length(FL)-Klotho administration induces weight loss in mice and provides protection against high-fat diet (HFD)-induced obesity and hepatic steatosis, concurrently reducing the weights of white adipose tissue and liver. AAV-FL-Klotho administration also enhanced thermogenic gene expression in brown adipose tissue (BAT) and improved the morphology of interscapular BAT. The weight loss effect of AAV-FL-Klotho was found to be, at least in part, mediated by UCP1-dependent thermogenesis in brown adipocytes, potentially influenced by hepatokines secreted from AAV-FL-Klotho-transduced hepatocytes. These findings suggest that AAV-FL-Klotho is an attractive candidate for gene therapy to combat obesity. Nevertheless, unbiased experiments have also revealed disturbances in lipid metabolism due to AAV-FL-Klotho, as evidenced by the emergence of lipomas and increased expression of hepatic lipogenic proteins.

Homomultivalent Polymeric Nanotraps Disturb Lipid Metabolism Homeostasis and Tune Pyroptosis in Cancer.

Genetic manipulations and pharmaceutical interventions to disturb lipid metabolism homeostasis have emerged as an attractive approach for the management of cancer. However, the research on the utilization of bioactive materials to modulate lipid metabolism homeostasis remains constrained. In this study, heptakis (2,3,6-tri-O-methyl)-β-cyclodextrin (TMCD) is utilized to fabricate homomultivalent polymeric nanotraps, and surprisingly, its unprecedented ability to perturb lipid metabolism homeostasis and induce pyroptosis in tumor cells is found. Through modulation of the density of TMCD arrayed on the polymers, one top-performing nanotrap, PTMCD4, exhibits the most powerful cholesterol-trapping and depletion capacity, thus achieving prominent cytotoxicity toward different types of tumor cells and encouraging antitumor effects in vivo. The interactions between PTMCD4 and biomembranes of tumor cells effectively enable the reduction of cellular phosphatidylcholine and cholesterol levels, thus provoking damage to the biomembrane integrity and perturbation of lipid metabolism homeostasis. Additionally, the interplays between PTMCD4 and lysosomes also induce lysosomal stress, activate the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasomes, and subsequently trigger tumor cell pyroptosis. To sum up, this study first introduces dendronized bioactive polymers to manipulate lipid metabolism and has shed light on another innovative insight for cancer therapy.

Yam Gruel alone and in combination with metformin regulates hepatic lipid metabolism disorders in a diabetic rat model by activating the AMPK/ACC/CPT-1 pathway

BackgroundAs independent and correctable risk factors, disturbances in lipid metabolism are significantly associated with type 2 diabetes mellitus (T2DM). This research investigated the mechanism underlying the lipid-regulating effects of Yam Gruel in diabetic rats.MethodsFirst, rats in the control group were given a normal diet, and a diabetic rat model was established via the consumption of a diet that was rich in both fat and sugar for six weeks followed by the intraperitoneal injection of streptozotocin (STZ). After the model was established, the rats were divided into five distinct groups: the control group, model group, Yam Gruel (SYZ) group, metformin (MET) group, and combined group; each treatment was administered for six weeks. The fasting blood glucose (FBG), body and liver weights as well as liver index of the rats were determined. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), aspartic acid transaminase (AST), alanine aminotransferase (ALT), and nonesterified fatty acid (NEFA) levels were measured. Oil Red O staining was used to assess hepatic steatosis. In addition, the levels of Phospho-acetyl-CoA carboxylase (p-ACC), acetyl coenzyme A carboxylase (ACC), AMP-activated protein kinase (AMPK), Phospho-AMPK (p-AMPK), carnitine palmitoyl transferase I (CPT-1), and Malonyl-CoA decarboxylase (MLYCD) in liver tissues were measured by real-time PCR (q-PCR) and western blotting.ResultsAfter 6 weeks of treatment, Yam Gruel alone or in combination with metformin significantly reduced FBG level, liver weight and index. The concentrations of lipid indices (TG, TC, NEFA, and LDL-C), the levels of liver function indices (ALT and AST) and the degree of hepatic steatosis was improved in diabetic rats that were treated with Yam Gruel with or without metformin. Furthermore, Yam Gruel increased the protein levels of p-ACC/ACC, p-AMPK/AMPK, MLYCD, and CPT-1, which was consistent with the observed changes in gene expression. Additionally, the combination of these two agents was significantly more effective in upregulating the expression of AMPK pathway-related genes and proteins.ConclusionsThese results demonstrated that Yam Gruel may be a potential diet therapy for improving lipid metabolism in T2DM patients and that it may exert its effects via AMPK/ACC/CPT-1 pathway activation. In some respects, the combination of Yam Gruel and metformin exerted more benefits effects than Yam Gruel alone.

Long-term polystyrene nanoplastic exposure disrupt hepatic lipid metabolism and cause atherosclerosis in ApoE-/- mice

Nanoplastics (NPs) exposure is usually linked with abnormal inflammation and oxidative stress, which are high-risk triggers of atherosclerosis; however, whether this exposure causes the development of atherosclerosis is vague. Here, we found that PS NPs co-exposure with ox-LDL induces significant accumulation of lipid, as well as oxidative stress and inflammation in RAW264.7 macrophages. Using an ultrasound biomicroscope (UBM), we observed the emergence of atherosclerotic plaques at the aortic arch of apolipoprotein knockout (ApoE-/-) mice after being exposed to PS NPs for three months. Oil-red O and hematoxylin-eosin (H&E) staining at the mice’s aortic root also observed the deposition of lipids with plaque formation. Moreover, the development of atherosclerotic disease is associated with disturbances in lipid metabolism and oxidative stress damage in the mice liver. In conclusion, this study provides additional evidence to further understand the possible cardiovascular damage caused by NPs exposure.

The role of the autonomic nervous system in polycystic ovary syndrome.

This article reviewed the relationship between the autonomic nervous system and the development of polycystic ovary syndrome (PCOS). PCOS is the most common reproductive endocrine disorder among women of reproductive age. Its primary characteristics include persistent anovulation, hyperandrogenism, and polycystic ovarian morphology, often accompanied by disturbances in glucose and lipid metabolism. The body's functions are regulated by the autonomic nervous system, which consists mainly of the sympathetic and parasympathetic nervous systems. The autonomic nervous system helps maintain homeostasis in the body. Research indicates that ovarian function in mammals is under autonomic neural control. The ovaries receive central nervous system information through the ovarian plexus nerves and the superior ovarian nerves. Neurotransmitters mediate neural function, with acetylcholine and norepinephrine being the predominant autonomic neurotransmitters. They influence the secretion of ovarian steroids and follicular development. In animal experiments, estrogen, androgens, and stress-induced rat models have been used to explore the relationship between PCOS and the autonomic nervous system. Results have shown that the activation of the autonomic nervous system contributes to the development of PCOS in rat. In clinical practice, assessments of autonomic nervous system function in PCOS patients have been gradually employed. These assessments include heart rate variability testing, measurement of muscle sympathetic nerve activity, skin sympathetic response testing, and post-exercise heart rate recovery evaluation. PCOS patients exhibit autonomic nervous system dysfunction, characterized by increased sympathetic nervous system activity and decreased vagal nerve activity. Abnormal metabolic indicators in PCOS women can also impact autonomic nervous system activity. Clinical studies have shown that various effective methods for managing PCOS regulate patients' autonomic nervous system activity during the treatment process. This suggests that improving autonomic nervous system activity may be an effective approach in treating PCOS.

Exploring the mechanism and phytochemicals in Psoraleae Fructus-induced hepatotoxicity based on RNA-seq, in vitro screening and molecular docking

Psoraleae Fructus (PF) is a widely-used herb with diverse pharmacological activities, while its related hepatic injuries have aroused public concerns. In this work, a systematic approach based on RNA sequencing (RNA-seq), high-content screening (HCS) and molecular docking was developed to investigate the potential mechanism and identify major phytochemicals contributed to PF-induced hepatotoxicity. Animal experiments proved oral administration of PF water extracts disturbed lipid metabolism and promoted hepatic injuries by suppressing fatty acid and cholesterol catabolism. RNA-seq combined with KEGG enrichment analysis identified mitochondrial oxidative phosphorylation (OXPHOS) as the potential key pathway. Further experiments validated PF caused mitochondrial structure damage, mtDNA depletion and inhibited expressions of genes engaged in OXPHOS. By detecting mitochondrial membrane potential and mitochondrial superoxide, HCS identified bavachin, isobavachalcone, bakuchiol and psoralidin as most potent mitotoxic compounds in PF. Moreover, molecular docking confirmed the potential binding patterns and strong binding affinity of the critical compounds with mitochondrial respiratory complex. This study unveiled the underlying mechanism and phytochemicals in PF-induced liver injuries from the view of mitochondrial dysfunction.

Antipyretic effects of Xiangqin Jiere granules on febrile young rats revealed by combining pharmacodynamics, metabolomics, network pharmacology, molecular biology experiments and molecular docking strategies

Xiangqin Jiere granules (XQJRG) is a proprietary Chinese medicine treating children’s colds and fevers, but its mechanism of action is unclear. The aim of this study was to explore the antipyretic mechanisms of XQJRG based on pharmacodynamics, non-targeted metabolomics, network pharmacology, molecular biology experiments, molecular docking, and molecular dynamics (MD) simulation. Firstly, the yeast-induced fever model was constructed in young rats to study antipyretic effect of XQJRG. Metabolomics and network pharmacology studies were performed to identify the key compounds, targets and pathways involved in the antipyretic of XQJRG. Subsequently, MetScape was used to jointly analyze targets from network pharmacology and metabolites from metabolomics. Finally, the key targets were validated by enzyme-linked immunosorbent assay (ELISA), and the affinity and stability of key ingredient and targets were evaluated by molecular docking and MD simulation. The animal experimental results showed that after XQJRG treatment, body temperature of febrile rats was significantly reduced, 13 metabolites were significantly modulated, and pathways of differential metabolite enrichment were mainly related to amino acid and lipid metabolism. Network pharmacology results indicated that quercetin and kaempferol were the key active components of XQJRG, TNF, AKT1, IL6, IL1B and PTGS2 were core targets. ELISA confirmed that XQJRG significantly reduced the plasma concentrations of IL-1β, IL-6, and TNF-α, and the hypothalamic concentrations of COX-2 and PGE2. Molecular docking demonstrated that the binding energies of kaempferol to the core targets were all below −5.0 kcal/mol. MD simulation results showed that the binding free energies of TNF-kaempferol, IL6-kaempferol, IL1B-kaempferol and PTGS2-kaempferol were −87.86 kcal/mol, −70.41 kcal/mol, −69.95 kcal/mol and −106.67 kcal/mol, respectively. In conclusion, XQJRG has antipyretic effects on yeast-induced fever in young rats, and its antipyretic mechanisms may be related to the inhibition of peripheral pyrogenic cytokines release by constituents such as kaempferol, the reduction of hypothalamic fever mediator production, and the amelioration of disturbances in amino acid and lipid metabolism. Communicated by Ramaswamy H. Sarma

Hepatic effects of acetochlor chiral isomers in zebrafish and L02 cells

The pesticide acetochlor (ACT) is a chiral isomer commonly detected in the global environment, yet its specific impacts on liver function remain poorly understood. We utilized zebrafish and L02 cells as research models to comprehensively investigate how ACT and its chiral isomers affect the liver. Our investigations unveiled that the R, Rac, and S isomers of ACT disrupt hepatic lipid transport, catabolism, and synthesis, leading to delayed yolk sac absorption and the accumulation of lipids in zebrafish embryos. These isomers induce oxidative stress in the liver of zebrafish embryos, reducing antioxidant levels and enzyme activity. The accumulated lipids in the liver render it susceptible to oxidative stress, further exacerbating hepatocyte damage. Hepatocyte damage manifests as extensive vacuolization of liver cells and alterations in liver morphology, which are induced by R, Rac, and S. Furthermore, we elucidated the molecular mechanisms underpinning the disturbance of hepatic lipid metabolism by R, Rac, and S in L02 cells. These compounds stimulate lipid synthesis through the upregulation of the AMPK/SREBP-1c/FAS pathway while inhibiting lipolysis via downregulation of the PPAR-α/CPT-1a pathway. Remarkably, our results highlight that S exhibits significantly higher hepatotoxicity in comparison to R. This study provides valuable insights into the hepatic effects of ACT chiral isomers.

Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics

AimSjögren-Larsson syndrome (SLS) is a rare neurometabolic disorder that mainly affects brain, eye and skin and is caused by deficiency of fatty aldehyde dehydrogenase. Our recent finding of a profoundly disturbed brain tissue lipidome in SLS prompted us to search for similar biomarkers in plasma as no functional test in blood is available for SLS. Methods and resultsWe performed plasma lipidomics and used a newly developed bioinformatics tool to mine the untargeted part of the SLS plasma and brain lipidome to search for SLS biomarkers. Plasma lipidomics showed disturbed ether lipid metabolism in known lipid classes. Untargeted lipidomics of both plasma and brain (white and grey matter) uncovered two new endogenous lipid classes highly elevated in SLS. The first biomarker group were alkylphosphocholines/ethanolamines containing different lengths of alkyl-chains where some alkylphosphocholines were > 600-fold elevated in SLS plasma. The second group of biomarkers were a set of 5 features of unknown structure. Fragmentation studies suggested that they contain ubiquinol and phosphocholine and one feature was also found as a glucuronide conjugate in plasma. The plasma features were highly distinctive for SLS with levels >100–1000-fold the level in controls, if present at all. We speculate on the origin of the alkylphosphocholines/ethanolamines and the nature of the ubiquinol-containing metabolites. ConclusionsThe metabolites identified in this study represent novel endogenous lipid classes thus far unknown in humans. They represent the first plasma metabolite SLS-biomarkers and may also yield more insight into SLS pathophysiology.

Hiperhomocisteinemija kao faktor rizika za razvoj patoloških promena u kardiovaskularnom sistemu - mehanizmi i posledice

Hyperhomocysteinemia represents a pathological condition characterized by an increased concentration of homocysteine in the blood, exceeding the threshold of 15 µmol/L. Hyperhomocysteinemia can be caused by genetic defects in enzymes involved in the metabolism of homocysteine and inadequate intake of vitamin B6, folic acid, and/or vitamin B12, disturbances in kidney and thyroid function, malignant diseases, psoriasis, and diabetes, as well as the use of certain medications, alcohol, tobacco, and caffeine. Hyperhomocysteinemia leads to damage to blood vessels through the induction of the proliferation of vascular smooth muscle cells, disruption of physiological endothelial functions, accumulation of reactive oxygen and nitrogen species, i.e., induction of oxidative and nitrosative stress, increased production of collagen, and degradation of the elastic fibers of the arterial wall, disturbance in the production of nitric oxide, dysfunction in the H2S signaling pathway, cellular hypomethylation, homocysteinylation of proteins, and disturbances in lipid metabolism. These pathophysiological mechanisms lead to accelerated atherosclerosis, which ultimately results in diseases such as acute myocardial infarction, heart failure, stroke, and peripheral vascular disease. In patients with the aforementioned diseases, or with associated risk factors such as hypertension, diabetes, obesity, smoking, or a positive family history of coronary heart disease, it is of great importance to determine and monitor the concentration of homocysteine in the blood and to take measures in the form of lifestyle changes aimed at secondary prevention of the consequences that hyperhomocysteinemia brings with it.

Lipid metabolic profiling and diagnostic model development for hyperlipidemic acute pancreatitis.

Hyperlipidemic acute pancreatitis (HLAP) is a form of pancreatitis induced by hyperlipidemia, posing significant diagnostic challenges due to its complex lipid metabolism disturbances. This study compared the serum lipid profiles of HLAP patients with those of a healthy cohort using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Orthogonal partial least squares discriminant analysis (OPLS-DA) was applied to identify distinct lipid metabolites. Logistic regression and LASSO regression were used to develop a diagnostic model based on the lipid molecules identified. A total of 393 distinct lipid metabolites were detected, impacting critical pathways such as fatty acid, sphingolipid, and glycerophospholipid metabolism. Five specific lipid molecules were selected to construct a diagnostic model, which achieved an area under the curve (AUC) of 1 in the receiver operating characteristic (ROC) analysis, indicating outstanding diagnostic accuracy. These findings highlight the importance of lipid metabolism disturbances in HLAP. The identified lipid molecules could serve as valuable biomarkers for HLAP diagnosis, offering potential for more accurate and early detection.

Protocatechuic acid alleviates TMAO-aggravated atherosclerosis via mitigating inflammation, regulating lipid metabolism, and reshaping gut microbiota.

Trimethylamine-N-oxide (TMAO) is a risk factor for atherosclerosis. As a natural phenolic acid, protocatechuic acid (PCA) is abundant in various plant foods. The present study investigated the effect of PCA on TMAO-aggravated atherosclerosis in ApoE-/- mice. The mice were randomly divided into five groups and fed one of the following five diets for 12 weeks: namely a low-fat diet (LFD), a western diet (WD), a WD + 0.2% TMAO diet (WDT), a WDT + 0.5% PCA diet (WDT + LPCA), and a WDT + 1.0% PCA diet (WDT + HPCA). Results demonstrated that dietary TMAO exacerbated the development of atherosclerosis by eliciting inflammation and disturbing lipid metabolism. The diet with PCA at 1% reduced TMAO-induced aortic plaque by 30% and decreased the levels of plasma pro-inflammatory cytokines. PCA also improved lipid metabolism by up-regulating the hepatic gene expression of peroxisome proliferator-activated receptor alpha (PPARα). In addition, PCA supplementation enhanced fecal excretion of fatty acids and decreased hepatic fat accumulation. PCA supplementation favorably modulated gut microbiota by increasing the α-diversity with an increase in the abundance of beneficial genera (Rikenella, Turicibacter, Clostridium_sensu_stricto and Bifidobacterium) and a decrease in the abundance of the harmful Helicobacter genus. In summary, PCA could alleviate the TMAO-exacerbated atherosclerosis and inflammation, improve the lipid metabolism, and modulate gut microbiota.

Targeting transcription factor pu.1 for improving neurologic outcomes after spinal cord injury.

After spinal cord injury (SCI), lipid metabolism dysregulation at the lesion site exacerbates secondary damage. The transcription factor pu.1 has been implicated as a negative regulator of multiple lipid metabolism-related genes and pathways. However, its role in post-SCI lipid metabolism remains unclear. We employed a mouse model of complete T10 crush SCI. Non-targeted metabolomics and bioinformatics analysis were utilized to investigate lipid metabolism at the lesion site after SCI. Polarized light imaging was used to evaluate the presence of cholesterol crystals. DB1976, a specific inhibitor of pu.1, was administered to examine its impact on local lipid metabolism after SCI. Immunofluorescence staining was performed to assess pu.1 expression and distribution, and to evaluate lipid droplet formation, astrocytic/fibrotic scar development, inflammatory cell infiltration, and tight junctions within the vasculature. Non-targeted metabolomics and bioinformatics analyses revealed significant alterations in lipid metabolism components after SCI. Moreover, immunofluorescence staining and polarized light imaging demonstrated substantial BODIPY+ lipid droplet accumulation and persistent cholesterol crystal formation at the lesion site after SCI. Increased pu.1 expression was predominantly observed within macrophages/microglia at the lesion site after SCI. DB1976 treatment significantly mitigated lipid droplet accumulation and cholesterol crystal formation, reduced CD68+ macrophage/microglial infiltration, and attenuated fibrotic scar formation. Moreover, DB1976 treatment promoted the expression of claudin-5 and zonula occludens-1 between vascular endothelial cells and enhanced GFAP+ glial connectivity after SCI. Our study reveals a significant correlation between lipid metabolism disturbance post-SCI and transcription factor pu.1 upregulation, specifically in macrophages/microglia at the lesion site. Thus, targeted pu.1 modulation has the potential to yield promising results by substantially diminishing the deposition of lipid metabolism byproducts at the lesion site and fostering a milieu conducive to SCI repair.

The Regulatory Mechanism of Smilax China L. Saponins against Nonalcoholic Fatty Liver Is Revealed by Metabolomics and Transcriptomics.

This study was to investigate the effects of Smilax China L. saponins (SCS) on non-alcoholic fatty liver disease (NAFLD). Rats were fed a high-fat diet (HFD) for 8 weeks to induce NAFLD, followed by SCS treatment for 8 weeks. The effect of SCS on liver injury was observed by H&E staining and the regulative mechanism of SCS on lipid formation was exposed by detecting Oil red O, insulin resistance (IR), and fatty acids synthesis (FAS). Furthermore, transcriptomics and metabolomics were performed to analyze the potential targets. The experimental results indicated that SCS exerted a positive curative effect in alleviating HFD-induced overweight, hepatic injury, steatosis, and lipid formation and accumulation in rats, and the preliminary mechanism studies showed that SCS could alleviate IR, inhibit FAS expression, and reduce Acetyl-CoA levels. Besides, the integrative analysis of transcriptomics and metabolomics exposed the targets of SCS to regulate lipid production likely being the sphingolipid metabolism and glycerophospholipid metabolism pathways. This study demonstrates that SCS significantly ameliorates lipid metabolic disturbance in rats with NAFLD by relieving insulin resistance, inhibiting the FAS enzymes, and regulating the sphingolipid and glycerophospholipid metabolism pathways.

Targeting Mitochondrial Dysfunction for the Prevention and Treatment of Metabolic Disease by Bioactive Food Components.

Dysfunctional mitochondria have been linked to the pathogenesis of obesity-associated metabolic diseases. Excessive energy intake impairs mitochondrial biogenesis and function, decreasing adenosine-5'-triphosphate production and negatively impacting metabolically active tissues such as adipose tissue, skeletal muscle, and the liver. Compromised mitochondrial function disturbs lipid metabolism and increases reactive oxygen species production in these tissues, contributing to the development of insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease. Recent studies have demonstrated the therapeutic potential of bioactive food components, such as resveratrol, quercetin, coenzyme Q10, curcumin, and astaxanthin, by enhancing mitochondrial function. This review provides an overview of the current understanding of how these bioactive compounds ameliorate mitochondrial dysfunction to mitigate obesity-associated metabolic diseases.

Role of carotid-femoral (aortic) pulse wave velocity measurement in the evaluation of cardiovascular risk in children with idiopathic nephrotic syndrome

Introduction and objective: The study was aimed to evaluate carotid-femoral (aortic) pulse wave velocity (cfPWV) in children with idiopathic nephrotic syndrome. Materials and methods: A total of 48 children with idiopathic nephrotic syndrome were enrolled in the study, including 35 patients in acute phase and 32 in remission. In 19 patients, measurements were performed twice: in relapse and in remission. The control group consisted of 22 healthy children. In all children, cfPWV measurements were performed. Selected clinical, biochemical parameters and fetuin-A concentrations were determined. Results: The patients with idiopathic nephrotic syndrome had significantly higher cfPWV both in relapse and in remission, as compared to the control group. Fetuin-A levels were significantly lower in both phases of the disease than in the healthy controls. cfPWV in relapse positively correlated with body weight, body mass index, systolic, diastolic, mean and pulse pressure. cfPWV in remission positively correlated with body weight, residual proteinuria, and total and low-density lipoproteins cholesterol. Systolic blood pressure in relapse, body weight, and total cholesterol in remission were found to be independent risk factors for increased cfPWV. Total cholesterol in remission was an independent risk factor for an increase of cfPWV to height rate. Conclusions: Increased cfPWV in children with idiopathic nephrotic syndrome indicates the possibility of premature cardiovascular complications. Significant effects of the modifiable risk factors, such as arterial pressure, body weight and disturbances of lipid metabolism, on arterial stiffness may contribute to early diagnostic and therapeutic interventions to improve the prognosis in patients with idiopathic nephrotic syndrome. Measurements of cfPWV may be useful in the assessment of cardiovascular risk in children with idiopathic nephrotic syndrome.

Increased fatty acid synthesis and disturbed lipid metabolism in Neuro2a cells after repeated cocaine exposure: A preliminary study

Chronic use of cocaine prompts neurodegeneration and neuroinflammation. Lipids play pivotal roles in neuronal function and pathology. Although evidence correlates cocaine use with the alteration of lipid metabolism in blood and brain, the precise mechanism remains to be elucidated. In this study, we explore the effect of cocaine on neuronal fatty acid profiles in vitro. Neuro2a cells following seven days of repeated exposure to cocaine (0, 600, 800, 1000 μM) showed apoptosis-irrelevant cell death, dysregulated autophagy, activation of atypical endoplasmic reticulum stress response, increased saturated and unsaturated fatty acid synthesis, and disrupted lipid metabolism. These preliminary findings indicated the association between lipid metabolism and cocaine-induced neurotoxicity, which should be beneficial for understanding the neurotoxicity of cocaine.

Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson’s disease

BackgroundUntargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways.ObjectiveIdentify metabolic disturbances associated with Parkinson’s disease (PD) in two population-based studies using untargeted metabolomics.MethodsWe performed a metabolome-wide association study (MWAS) of PD using serum-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS) using two distinct population-based case-control populations. We also combined our results with a previous publication of 34 metabolites linked to PD in a large-scale, untargeted MWAS to assess external validation.ResultsLC-HRMS detected 4,762 metabolites for analysis (HILIC: 2716 metabolites; C18: 2046 metabolites). We identified 296 features associated with PD at FDR<0.05, 134 having a log2 fold change (FC) beyond ±0.5 (228 beyond ±0.25). Of these, 104 were independently associated with PD in both discovery and replication studies at p<0.05 (170 at p<0.10), while 27 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, among the externally validated features were the microbial-related metabolites, p-cresol glucuronide (FC=2.52, 95% CI=1.67, 3.81, FDR=7.8e-04) and p-cresol sulfate. P-cresol glucuronide was also associated with motor symptoms among patients. Additional externally validated metabolites associated with PD include phenylacetyl-L-glutamine, trigonelline, kynurenine, biliverdin, and pantothenic acid. Novel associations include the anti-inflammatory metabolite itaconate (FC=0.79, 95% CI=0.73, 0.86; FDR=2.17E-06) and cysteine-S-sulfate (FC=1.56, 95% CI=1.39, 1.75; FDR=3.43E-11). Seventeen pathways were enriched, including several related to amino acid and lipid metabolism.ConclusionsOur results revealed PD-associated metabolites, confirming several previous observations, including for p-cresol glucuronide, and newly implicating interesting metabolites, such as itaconate. Our data also suggests metabolic disturbances in amino acid and lipid metabolism and inflammatory processes in PD.

Multiomics was used to clarify the mechanism by which air pollutants affect chronic obstructive pulmonary disease: A human cohort study

Exposure to air pollutants has been associated with various adverse health outcomes, including chronic obstructive pulmonary disease (COPD). However, the precise underlying mechanism by which air pollution impacts COPD through remains insufficiently understood. To elucidated the molecular mechanism by which air pollutant exposure contributes to alterations in the gut microbiome and metabolism in AECOPD patients, we employed metagenomics and untargeted metabolomics to analyse the gut microbial, faecal, and serum metabolites. The correlations among air pollutants, gut microbes, serum metabolites, and blood biochemical markers were assessed using generalised additive mixed models and Spearman correlation analysis. The findings revealed that for every 10 μg/m3 increase in PM2.5 concentration, the α-diversity of the gut flora decreased by 2.16% (95% CI: 1.80%−2.53%). We found seven microorganisms that were significantly associated with air pollutants, of which Enterococcus faecium, Bacteroides fragilis, Ruthenibacterium lactatiformans, and Subdoligranulum sp.4_3_54A2FAA were primarily associated with glycolysis. We identified 13 serum metabolites and 17 faecal metabolites significantly linked to air pollutants. Seven of these metabolites, which were strongly associated with air pollutants and blood biochemical indices, were found in both serum and faecal samples. Some of these metabolites, such as 2,5-furandicarboxylic acid, C-8C1P and melatonin, were closely associated with disturbances in lipid and fatty acid metabolism in AECOPD patients. These findings underscore the impact of air pollutants on overall metabolism based on influencing gut microbes and metabolites in AECOPD patients. Moreover, these altered biomarkers establish the biologic connection between air pollutant exposure and AECOPD outcomes.The identification of pertinent biomarkers provides valuable insights for the development of precision COPD prevention strategies.

Childhood overweight and obesity: age stratification contributes to the differences in metabolic characteristics.

The aim of this study was to identify the differential metabolic characteristics of children with overweight and obesity and understand their potential mechanism in different age stratifications. Four hundred seventy-three children were recruited and divided into two age stratifications: >4 years (older children) and ≤4 years (younger children), and overweight and obesity were defined according to their BMI percentile. A one dimensional proton nuclear magnetic resonance(1 H-NMR)-based metabolomics strategy combined with pattern recognition methods was used to identify the metabolic characteristics of childhood overweight and obesity. Four and sixteenpotential biomarkers related to overweight and two and twentypotential biomarkers related to obesity were identified from younger and older children, respectively. Fluctuations in phenylalanine, tyrosine, glutamine, leucine, histidine, and ascorbate co-occurred in children with obesity at two age stratifications. The disturbances in biosynthesis and metabolism of amino acids, lipid metabolism, and galactose metabolism disturbance were mainly involved in children with overweight and obesity. The metabolic disturbances show a significant progression from overweight to obesity in children, and different metabolic characteristics were demonstrated in age stratifications. The changes in the levels of phenylalanine, tyrosine, glutamine, leucine, histidine, and ascorbate were tracked with the persistence of childhood obesity. These findings will promote the mechanistic understanding of childhood overweight and obesity.