Phospholipid Metabolism Research Articles

Multi‐omics approach reveals disturbances in brain phosphatidylcholine metabolism in Alzheimer’s Disease

AbstractBackgroundLipid dysregulation is implicated in Alzheimer’s disease (AD) pathology, given its involvement in amyloid β processing, myelination, and cell membrane structure. Studies have demonstrated increased phosphatidylcholine (PC) hydrolysis in the brains of AD individuals, but the connections between AD and PC metabolism are not fully understood.MethodTo investigate the alterations in PC metabolism in AD, we analyzed publicly available transcriptomic, metabolomic, and lipidomic data from the ROSMAP study, which included dorsolateral prefrontal cortex (DLPFC) tissue and serum samples. DLPFC and serum samples were classified based on clinical consensus diagnosis of cognitive status at the time of death and the last valid clinical diagnosis, respectively. Concentration differences were determined with a linear model using the Limma R package.ResultAccording to the lipidomic results, the concentration of total PC‐containing glycerophospholipid was significantly decreased in AD DLPFC samples (P < 0.05). Specifically, diacyl‐PC and acyl‐alkyl‐PC, the two most abundant subclasses, were significantly decreased in the brains of AD patients (P < 0.05). The concentration of the PC breakdown product, glycerophosphocholine (GPC), was increased in AD patient brains (P‐value < 0.05). However, GPC phosphodiesterase 1 (GPCPD1), the enzyme that further hydrolyzes GPC to free choline, was downregulated and choline abundance was reduced in AD DLPFC samples (P < 0.05). The expression of phosphatidylethanolamine N‐methyltransferase (PEMT), which converts PE to PC, was reduced as was the abundance of PEMT products (PC 18:2/20:4 and PC 18:0/20:4, P < 0.05). These alterations in the brain were not observed in the serum.ConclusionThese results indicate that PC metabolism is disturbed in the DLPFC of AD patients, with evidence of increased PC breakdown and reduced GPC hydrolysis as well as reduced conversion of PE to PC in AD brains. However, these changes in the brain are not reflected in serum. Further studies are needed to better understand changes in phospholipid metabolism in the brains of AD patients.

Efektivitas Citicoline sebagai Agen Neuroprotektif dalam Tata Laksana Traumatic Brain Injury

Background: Traumatic brain injury (TBI) is a condition resulting from physical trauma to the head which can cause structural damage to the brain and interfere with cognitive, motor and emotional functions. Citicoline is a natural compound that plays an important role in phospholipid metabolism and neurotransmitter synthesis in the brain. This evidence-based case report (EBCR) study aims to provide scientific evidence of the potential benefits of citicoline in improving clinical outcomes in TBI patients. Method: Literature search using the PICO format. The formulation of clinical questions was arranged by case. Search for articles on March 6–7th 2023 using the Publish or Perish (PoP) software with the target of searching articles for the last 10 years (2013-2023) on the Scopus, Pubmed, Google Scholar databases, and manual searches on the Cochrane database, using the keyword 'traumatic brain' injury' AND 'therapy' AND 'citicoline' AND 'neuroprotective' AND 'treatment' AND 'outcome' along with synonyms and related terms. Results: Four studies were obtained, with the level of evidence 1a which resulted from a meta-analysis or systematic review of various randomized controlled trials, which were then critically reviewed. Two studies reported no significance of clinical assessment and the Glasgow Coma Scale (GCS); two other studies showed significant results at the level of independence. Conclusion: This study shows that citicoline is beneficial in the independence of TBI patients but does not produce a significant difference in the Glasgow Coma Scale assessment.

Metabolites and 12‐Year Cognitive Measures Among a Cohort of Boston Area Puerto Ricans

AbstractBackgroundRecent studies have identified plasma metabolites associated with cognitive decline and Alzheimer’s disease; however, little research on this topic has been conducted in Latinos, especially Puerto Ricans. This study aims to add to the growing body of metabolomics research in Latinos to better understand and improve the health of this population.MethodWe assessed the association between plasma metabolites and global cognition, as well as memory and executive function component scores, over 12 y of follow‐up in 736 participants of the Boston Puerto Rican Health Study (BPRHS). Metabolites were measured with untargeted metabolomic profiling (Metabolon, Inc) at baseline. We used covariable adjusted linear mixed models (LMM) with a metabolite*time interaction term to identify metabolites (of 621 measured) associated with ∼12y cognitive trajectory.ResultWe observed strong inverse associations between medium‐chain fatty acids, caproic acid, and the dicarboxylic acids, azelaic and sebacic acid, with global cognition and memory. Metabolites on the tyrosine and tryptophan pathways as well as several phospholipids, were associated with improvement in cognitive trajectory. We also observed an association between glucose and taurocholate, a primary bile acid, and worse executive function trajectory.ConclusionThe metabolites identified in this study are generally consistent with prior literature and highlight a role for tryptophan, bile acid, branched chain amino acid, phospholipid and glucose metabolism in cognitive decline.

Protective effect of steroidal saponins on heat stress in the liver of largemouth bass (Micropterus salmoides) revealed by metabolomic analysis

With global warming, high water temperature events are becoming more frequent in summer. The liver of the largemouth bass (Micropterus salmoides) is particularly sensitive to heat stress, especially in the rapid growth period with high nutrient concentration. In this experiment, a metabolomic analysis was conducted to reveal how steroidal saponins alleviated high temperature stress in largemouth bass. Fish were divided into three groups, two groups fed the basic diet, the third group fed the experimental diet contained steroidal saponins. After the fish ingested the diets for four weeks, the heat temperature stress test began. The first group fed basic diet without the heat stress (C), and the second group fed basic diet with the heat stress (H), and the third group fed experimental diet containing steroidal saponins with heat stress (HS). After 1-week of heat stress, metabolic analysis showed that high temperature stress mainly affected phospholipid metabolism, fatty acid metabolism, glutathione metabolism and bile metabolism in the fish livers of H group. The expression of genes glutathione peroxidase and heme oxygenase-1 were decreased and the nuclear factor kappa-B activated inflammation in fish feeding in group H. The adenosine 5′-monophosphate-activated protein kinase pathway was activated in the HS group. Compare to the fish in H group, those metabolism observed in fish in HS group were greatly improved, similar to the C group. Thus, steroidal saponins could help relieve the liver burden when largemouth bass facing heat stress in summer.

Microbial phosphorus recycling in soil by intra- and extracellular mechanisms

Rising global stoichiometric imbalance between increasing nitrogen (N) availability and depleting phosphorus (P) resources increases the importance of soil microbial P recycling. The contribution of extra- versus intracellular P (re-)cycling depending on ecosystem nutrient status is vastly unclear, making soil microorganisms a blind spot in our understanding of ecosystem responses to increasing P deficiency. We quantified P incorporation into microbial DNA and phospholipids by 33P labeling under contrasting conditions: low/high P soil × low/high carbon (C)NP application. By combining 33P and 14C labeling with tracing of microbial community biomarkers and functional genes, we disengaged the role of DNA and phospholipids in soil P cycling. Microorganisms in low P soil preferentially allocated P to phospholipids with an acceleration of phospholipids metabolism driven by C addition, which was strongly related to high abundances of microbial community members (e.g. some G-) with a fast phospholipids turnover. In high P soil, however, more P was allocated to DNA with a microbial functional shift towards DNA synthesis to support a replicative growth when sufficient C was supplied, which was coupled with a strong enrichment of fungal copiotrophs and microbial genes coding DNA primase. Consequently, adaptation to low P availability accelerated microbial intracellular P recycling through reutilization of the P stored in phospholipids. However, microorganisms under high P availability commonly adopted extracellular P recycling with release and reuse of DNA P by microbial death-growth dynamics. These results advance our understanding on microbial adaptation to P deficiency in soil by regulating component-specific P pathways and reflect the specific functions of phospholipids and DNA for P recycling.

Key regulator PNPLA8 drives phospholipid reprogramming induced proliferation and migration in triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and leads to the poorest patient outcomes despite surgery and chemotherapy treatment. Exploring new molecular mechanisms of TNBC that could lead to the development of novel molecular targets are critically important for improving therapeutic options for treating TNBC.MethodsWe sought to identify novel therapeutic targets in TNBC by combining genomic and functional studies with lipidomic analysis, which included mechanistic studies to elucidate the pathways that tie lipid profile to critical cancer cell properties. Our studies were performed in a large panel of human breast cancer cell lines and patient samples.ResultsComprehensive lipid profiling revealed that phospholipid metabolism is reprogrammed in TNBC cells. We discovered that patatin-like phospholipase domain-containing lipase 8 (PNPLA8) is overexpressed in TNBC cell lines and tissues from breast cancer patients. Silencing of PNPLA8 disrupted phospholipid metabolic reprogramming in TNBC, particularly affecting the levels of phosphatidylglycerol (PG), phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and glycerophosphocholine (GPC). We showed that PNPLA8 is essential in regulating cell viability, migration and antioxidation in TNBC cells and promoted arachidonic acid and eicosanoid production, which in turn activated PI3K/Akt/Gsk3β and MAPK signaling.ConclusionsOur study highlights PNPLA8 as key regulator of phospholipid metabolic reprogramming and malignant phenotypes in TNBC, which could be further developed as a novel molecular treatment target.

Co-exposure to polystyrene microplastics and cypermethrin enhanced the effects on hepatic phospholipid metabolism and gut microbes in adult zebrafish

Microplastics (MPs) can absorb environmental pollutants from the aquatic environment to cause mixed toxicity, which has received widespread attention. However, studies on the joint effects of MPs and insecticides are limited. As one of the most widely used pyrethroids, there was a large amount of residual cypermethrin (CYP) in water due to insufficient decomposition. Here, adult female zebrafish were exposed to MPs, CYP, and their mixtures for 21 days, respectively. After exposures, the MPs and CYP caused tissue damage to the liver. Hepatic triglyceride (TG) level increased significantly after MPs + CYP exposure, and the expression of genes about glycolipids metabolism was significantly altered. Furthermore, metabolome results suggested that MPs + CYP exposure resulted in increased content of some glycerophospholipid, affecting phospholipid metabolism-related pathways. In addition, through 16 s rDNA sequencing, it was found that MPs + CYP led to significant changes in the proportion of dominant phyla. Interestingly, Cetobacterium which increased in CYP and the co-exposure group was positively correlated with most lipid metabolites. Our results suggested that co-exposure to MPs and CYP enhanced the disturbances in hepatic phospholipid metabolism by affecting the gut microbial composition, while these changes were not observed in separate treatment groups. These results emphasized the importance of studying the joint toxicity of MPs and insecticides.

Genome-wide association study exploring the genetic architecture of eggshell speckles in laying hens

BackgroundEggshell speckle phenotype is an important trait in poultry production because they affect eggshell quality. However, the genetic architecture of speckled eggshells remains unclear. In this study, we determined the heritability of eggshell speckles and conducted a genome-wide association study (GWAS) on purebred Rhode Island Red (RIR) hens at 28 weeks to detect potential genomic loci and candidate genes associated with eggshell speckles.ResultsThe heritability of eggshell speckles was 0.35 at 28 weeks, and the speckle level is not related to other eggshell quality traits in terms of phenotypic correlation. We detected 311 SNPs (6 significantly, and 305 suggestively associated) and 39 candidate genes associated with eggshell speckles. Based on the pathway analysis, the 39 candidate genes were mainly involved in alpha-linolenic acid metabolism, linoleic acid metabolism, ether lipid metabolism, GnRH signaling pathway, vascular smooth muscle contraction, and MAPK signaling pathway. Ultimately, ten genes, LOC423226, SPTBN5, EHD4, LOC77155, TYRO3, ITPKA, DLL4, PLA2G4B, PLA2G4EL5, and PLA2G4EL6 were considered the most promising genes associated with eggshell speckles that were implicated in immunoregulation, calcium transport, and phospholipid metabolism, while its function in laying hens requires further studies.ConclusionsThis study provides new insights into understanding the genetic basis of eggshell speckles and has practical application value for the genetic improvement of eggshell quality.

The divergent ER-mitochondria encounter structures (ERMES) are conserved in parabasalids but lost in several anaerobic lineages with hydrogenosomes

BackgroundThe endoplasmic reticulum (ER)-mitochondria membrane contact sites (MCS) are extensively studied in aerobic eukaryotes; however, little is known about MCS in anaerobes with reduced forms of mitochondria named hydrogenosomes. In several eukaryotic lineages, the direct physical tether between ER and the outer mitochondrial membrane is formed by ER-mitochondria encounter structure (ERMES). The complex consists of four core proteins (Mmm1, Mmm2, Mdm12, and Mdm10) which are involved in phospholipid trafficking. Here we investigated ERMES distribution in organisms bearing hydrogenosomes and employed Trichomonas vaginalis as a model to estimate ERMES cellular localization, structure, and function.ResultsHomology searches revealed that Parabasalia-Anaeramoebae, anaerobic jakobids, and anaerobic fungi are lineages with hydrogenosomes that retain ERMES, while ERMES components were gradually lost in Fornicata, and are absent in Preaxostyla and Archamoebae. In T. vaginalis and other parabasalids, three ERMES components were found with the expansion of Mmm1. Immunofluorescence microscopy confirmed that Mmm1 localized in ER, while Mdm12 and Mmm2 were partially localized in hydrogenosomes. Pull-down assays and mass spectrometry of the ERMES components identified a parabasalid-specific Porin2 as a substitute for the Mdm10. ERMES modeling predicted a formation of a continuous hydrophobic tunnel of TvMmm1-TvMdm12-TvMmm2 that is anchored via Porin2 to the hydrogenosomal outer membrane. Phospholipid-ERMES docking and Mdm12-phospholipid dot-blot indicated that ERMES is involved in the transport of phosphatidylinositol phosphates. The absence of enzymes involved in hydrogenosomal phospholipid metabolism implies that ERMES is not involved in the exchange of substrates between ER and hydrogenosomes but in the unidirectional import of phospholipids into hydrogenosomal membranes.ConclusionsOur investigation demonstrated that ERMES mediates ER-hydrogenosome interactions in parabasalid T. vaginalis, while the complex was lost in several other lineages with hydrogenosomes.

Differences in the metabolites of brown and milled rice grains of semiwaxy and conventional japonica varieties.

In this study, we analyzed the differences in metabolites between semiwaxy japonica rice (Yangnongxiang 28 [YNX28]) and conventional japonica rice (Hongyang 5 [HY5]) before and after brown rice milling. The metabolites of brown and milled rice grains from the two rice varieties were analyzed by LC-MS-based nontargeted metabolomics. A total of 266 differentially abundant metabolites (DMs) were tentatively identified in brown rice grains of YNX28 (YNX28B) compared with milled rice grains of YNX28 (YNX28H), and these included 248 upregulated and 12 downregulated DMs. A total of 273 (234 upregulated and 39 downregulated) DMs were tentatively identified in brown rice grains of HY5 (HY5B) compared with milled rice grains of this variety (HY5H). Kyoto Encyclopedia of Genes and Genomes pathway involved and enrichment analyses revealed that 53 and 7 metabolite pathways were enriched and significantly enriched (p<0.05), respectively, in the DMs identified in YNX28B compared with YNX28H, and the main enriched pathways were related to starch and sucrose metabolism, glycerol phospholipid metabolism, arginine and proline metabolism, and glycine, serine and threonine metabolism. Forty-six metabolite pathways were enriched in DMs identified in HY5B compared with HY5H, and these included 16 pathways that were significantly enriched (p<0.05); in addition, the main enriched pathways were related to starch and sucrose metabolism, glycerol phospholipid metabolism, arginine and proline metabolism, and glycine, serine and threonine metabolism. This study provides a theoretical reference for further on the changes in metabolites during rice processing and provides a basis for improving the nutritional quality in rice. PRACTICAL APPLICATION: Original data were obtained regarding the changes of different metabolites in semiwaxy japonica rice and conventional japonica rice before and after processing. The purpose of this study was to investigate the difference of metabolite loss in two rice varieties before and after processing. This paper reports on the differences of metabolites between the two types of japonica rice before and after processing, as well as the changes of key metabolites before and after processing, it also provides important theoretical basis for developing new rice varieties with good nutritional quality.

PacC mediates spatial regulation of the phospholipid metabolism in the apple fruit-Penicillium expansum interaction

As a core component of the Pal/Rim-pH signaling pathway in pathogenic fungi, the transcription factor PacC induces the partial acidification of host tissues and modulates the activity of extracellular fungal enzymes. However, the spatial regulation of PacC on phospholipase activity in fruit has not been reported. In this study, the role of the PePacC in Penicillium expansum was investigated by analyzing pH, phospholipid metabolism, cell membrane permeability, and malondialdehyde (MDA) levels in different tissues of apple fruit inoculated with a PePacC-deficient strain of P. expansum (ΔPePacC). The results showed that the pathogenicity and acidification ability were impaired when PePacC was deleted in P. expansum. Compared to the WT inoculation, deletion of PePacC spatially and dynamically regulated the activities of phospholipase A1 (PLA1), PLA2, PLC, and PLD, and the levels of phosphatidylcholine (PC), inositol 1, 4, 5-trisphosphate (IP3), phosphatidylinositol 4, 5-bisphosphate (PIP2), phosphatidylinositol (PI), and phosphatidic acid (PA), and altered the extent of damage to the cell membrane integrity at and outside of the junction of the leading edge of decay in apple fruit during P. expansum infection. Taken together, the present study showed that PacC could mediate the acidifying ability of P. expansum to colonize host fruit, and dynamically regulate the spatial changes of phospholipid metabolism in different apple tissues. Furthermore, both host defense responses and pathogen virulence mechanisms are involved in the apples-P. expansum interaction.

Biallelic PI4KA mutations Disrupt B Cell Mitochondrial Metabolism and Cause Hypogammaglobulinemia

Introduction Biallelic mutations in the PI4KA gene cause PI4KA-related disorder, a novel condition with neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal (GI; inflammatory bowel disease [IBD] and multiple intestinal atresia [MIA]) and immunological manifestations. PI4KA encodes phosphatidylinositol (PI) 4-kinase alpha, which catalyzes the first step of phosphoinositide metabolism, phosphorylating PI to PI4P (phosphatidylinositol 4-phosphate). Phosphoinositides collectively have fundamental signalling roles in the plasma membrane and other organelles. We collected comprehensive clinical and laboratory data on 13 patients and performed a multiomic strategy, combining transcriptome, proteome, lipidome and metabolome analyses of three patients' EBV-transformed cell lines to unravel the burden of B cell deficiency in PI4KA-related disorder and define the role of PI4KA in B cells. Results Recurrent or severe infections (8/13) and GI (either gastroesophageal reflux disease, MIA or IBD; 6/13) manifestations were frequent. Thyroid disease (either hypo- or hyperthyroidism; 2/13), juvenile idiopathic arthritis (JIA; 1/13) and non-Hodgkin lymphoma (1/13) were reported. At last follow up 11 patients were alive. Ten had either hypogammaglobulinemia, decreased absolute numbers of B cells or decreased B cell subsets. B cell subsets showed increased transitional (4/7), decreased naive (2/7) and decreased switched memory (4/7) B cells. B cell proliferation to T independent mitogens, specifically IgM + CpG or pokeweed, was impaired in 2/2. T-cell (either CD3+, CD4+ or CD8+) lymphopenia was detected in 4/13. T-cell proliferation was maintained in 5/5. NK cells were decreased in 6/13. Ig replacement therapy (4/13) and immunosuppressive treatment (due to JIA [1/13] or IBD [2/13]) were given. Lipidome analysis showed that different glycerophospholipids profile (i.e., phosphatidylcholine [PC], phosphatidylethanolamines [PE] and phosphatidylserine [PS]) was altered. Metabolome analysis and pathway enrichment analysis confirmed impaired phosphatidylethanolamine biosynthesis and additionally showed altered PIP metabolism and mitochondrial dysfunction (i.e., beta-oxidation of short and long fatty acids). Although the total number of mitochondria was not affected, the mitochondrial activity was significantly reduced. Integration analyses of proteomics, metabolomic and lipidomic data reveals biochemical mechanisms underlying biallelic PI4KA mutation. In particular, dysregulation of metabolic enzymes and pathways involved in glutathione metabolism and tricarboxylic acid cycle was found (Fig. 1). These metabolic impairments ultimately impacted on oxidative phosphorylation, thus disrupting mitochondrial integrity. Gene set enrichment analysis of differentially expressed genes suggested a skewing towards naive B cell gene sets. Pathways enrichment analysis of transcriptome and proteome showed enrichment in B cell receptor (BCR) pathway and complex, PI3K/mTOR pathway and phospholipids metabolism. PI4P and its metabolite PI(4,5)P2 are determinants of PM identity, specifically controlling cytoskeletal dynamics. Deranged basal actin organization was reverted after anti-IgM stimulation. Hyperactivation of PI3K targets (pAKT473, p4EBP1 and pS6) was observed. Dysregulation of RABGAP1, RAB8B and LAMP3 mRNA prompted us to investigate autophagy. Indeed, LC3 was increased either in the presence or absence of chloroquine, showing that PI4KA mutations enhanced autophagosome formation and inhibited its degradation. Conclusion Overall, by altering the production of several key lipids, biallelic PI4KA mutations disrupt B cell metabolism causing mitochondrial dysfunction, mTOR hyperactivation, increased autophagy and deranged cytoskeleton organization. PI4KA-related disorder is a novel syndromic inborn error of immunity causing B cell deficiency and hypogammaglobulinemia. Figure 1. Integration of proteomics, metabolomics and lipidomics reveals biochemical mechanisms underlying biallelic PI4KA mutations.

P-coumaric acid ameliorates Aβ25–35-induced brain damage in mice by modulating gut microbiota and serum metabolites

Alzheimer's disease (AD) is a progressive neurodegenerative disease for which there is a lack of effective therapeutic drugs. There is great potential for natural products to be used in the development of anti-AD drugs. P-coumaric acid (PCA), a small molecule phenolic acid widely distributed in the plant kingdom, has pharmacological effects such as neuroprotection, but its anti-AD mechanism has not been fully elucidated. In the current study, we investigated the mechanism of PCA intervention in the Aβ25–35-induced AD model using gut microbiomics and serum metabolomics combined with in vitro and in vivo pharmacological experiments. PCA was found to ameliorate cognitive dysfunction and neuronal cell damage in Aβ25–35-injected mice as measured by behavioral, pathological and biochemical indicators. 16S rDNA sequencing and serum metabolomics showed that PCA reduced the abundance of pro-inflammatory-associated microbiota (morganella, holdemanella, fusicatenibacter and serratia) in the gut, which were closely associated with metabolites of the glucose metabolism, arachidonic acid metabolism, tyrosine metabolism and phospholipid metabolism pathways in serum. Next, in vivo and in vitro pharmacological investigations revealed that PCA regulated Aβ25–35-induced disruption of glucose metabolism through activation of PI3K/AKT/Glut1 signaling. Additionally, PCA ameliorated Aβ25–35-induced neuroinflammation by inhibiting nuclear translocation of NF-κB and by modulating upstream MAPK signaling. In conclusion, PCA ameliorated cognitive deficits in Aβ25–35-induced AD mice by regulating glucose metabolism and neuroinflammation, and the mechanism is related not only to restoring homeostasis of gut microbiota and serum metabolites, but also to PI3K/AKT/Glut1 and MAPK/NF-κB signaling.

18 Regional patterns of mitochondrial function using phosphorus magnetic resonance spectroscopy in older adults at-risk for Alzheimer’s disease.

Objective:The brain is reliant on mitochondria to carry out a host of vital cellular functions (e.g., energy metabolism, respiration, apoptosis) to maintain neuronal integrity. Clinically relevant, dysfunctional mitochondria have been implicated as central to the pathogenesis of Alzheimer’s disease (AD). Phosphorous magnetic resonance spectroscopy (31p MRS) is a non-invasive and powerful method for examining in vivo mitochondrial function via high energy phosphates and phospholipid metabolism ratios. At least one prior 31p MRS study found temporal-frontal differences for high energy phosphates in persons with mild AD. The goal of the current study was to examine regional (i.e., frontal, temporal) 31p MRS ratios of mitochondrial function in a sample of older adults at-risk for AD. Given the high energy consumption in temporal lobes (i.e., hippocampus) and preferential age-related changes in frontal structure-function, we predicted 31p MRS ratios of mitochondrial function would be greater in temporal as compared to frontal regions.Participants and Methods:The current study leveraged baseline neuroimaging data from an ongoing multisite study at the University of Florida and University of Arizona. Participants were older adults with memory complaints and a first-degree family history of AD [N = 70; mean [M] age [years] = 70.9, standard deviation [SD] =5.1; M education [years] = 16.2, SD = 2.2; M MoCA = 26.5, SD = 2.4; 61.4% female; 91.5% non-latinx white]. To achieve optimal sensitivity, we used a single voxel method to examine 31p MRS ratios (bilateral prefrontal and left temporal). Mitochondrial function was estimated by computing 5 ratios for each voxel: summed adenosine triphosphate to total pooled phosphorous (ATP/TP; momentary energy), ATP to inorganic phosphate (ATP/Pi; energy consumption), phosphocreatine to ATP (PCr/ATP; energy reserve), phosphocreatine to inorganic phosphate (PCr/Pi; oxidative phosphorylation), and phosphomonoesters to phosphodiesters (PME/PDE; cellular membrane turnover rate). All ratios were corrected for voxel size and cerebrospinal fluid fraction. Separate repeated measures analyses of variance controlling for scanner site differences (RM ANCOVAs) were performed.Results:31p MRS ratios were unrelated to demographic characteristics and were not included as additional covariates in analyses. Results of separate RM ANCOVAs revealed all 31p MRS ratios of mitochondrial function were greater in left temporal relative to bilateral prefrontal voxel: ATP/TP (p &lt; .001), ATP/Pi (p = .001), PCr/ATP (p = .004), PCr/Pi (p = .004), and PME/PDE (p = .017). Effect sizes (partial eta squared) ranged from 0.6-.20.Conclusions:Consistent and extending one prior study, all 31p MRS ratios of mitochondrial function were greater in temporal as compared to frontal regions in older adults at-risk for AD. This may in part be related to the intrinsically high metabolic rate of the temporal region and preferential age-related changes in frontal structure-function. Alternatively, findings may reflect the influence of unaccounted factors (e.g., hemodynamics, auditory stimulation). Longitudinal study designs may inform whether patterns of mitochondrial function across different brain regions are present early in development, occur across the lifespan, or some combination. In turn, this may inform future studies examining differences in mitochondrial function (as measured using 31p MRS) in AD.

Effects of soda water on blood lipid and metabolic profiling of urine in hyperlipidemia rats using UPLC/Triple-TOF MS

The effects of a natural soda water (Shi Han Quan, SHQ) on hyperlipidemia and the changes of urine metabolic profiling by metabolomics techniques were investigate. Thirty six Wistar rats weighing 160–200 g were divided into control group, hyperlipidemia (HL) group, and hyperlipidemia + SHQ water (SHQ) group. The metabolites in urine were determined using ultra high performance liquid chromatography-triple-time of flight-mass spectrometry (UPLC/Triple-TOF MS). At the end of 1 month and 3 months, the total glyceride (TG) level was significantly lower in SHQ group compared to HL group. There was no significantly difference in total cholesterol (TC) levels in HL group compared with SHQ group. The results showed that dinking SHQ water can improve the TG, but with no effects on TC. After drinking SHQ water for 3 months, the rats in different groups could be classified into different clusters according to the metabolites in urine. Total 15 important metabolites were found and correlated with disturbance of amino acid, phospholipid, fatty acid and vitamin metabolism, which suggested the changes of metabolism in the body and possible mechanism by which SHQ improved the TG. These findings provide a new insight for the prevention and control of hyperlipidemia.

Phycobiliprotein Peptide Extracts from Arthrospira platensis Ameliorate Nonalcoholic Fatty Liver Disease by Modulating Hepatic Lipid Profile and Strengthening Fat Mobilization.

Arthrospira platensis phycobiliprotein peptide extracts (PPEs) exhibit potential mitigative effects on hepatic steatosis. However, the precise role of PPEs in addressing high-fat-induced nonalcoholic fatty liver disease (NAFLD), as well as the underlying mechanism, remains to be elucidated. In this study, NAFLD was induced in rats through a high-fat diet (HFD), and the rats were subsequently treated with PPEs for a duration of 10 weeks. The outcomes of this investigation demonstrate that PPE supplementation leads to a reduction in body weight gain, a decrease in the accumulation of lipid droplets within the liver tissues, alterations in hepatic lipid profile, regulation of lipolysis-related gene expression within white adipose tissues and modulation of intestinal metabolites. Notably, PPE supplementation exhibits a potential to alleviate liver damage by manipulating neutral lipid metabolism and phospholipid metabolism. Additionally, PPEs appear to enhance fat mobilization by up-regulating the gene expression levels of key factors such as HSL, TGL, UCP1 and UCP2. Furthermore, PPEs impact intestinal metabolites by reducing the levels of long-chain fatty acids while concurrently increasing the levels of short-chain fatty acids. The findings from this study unveil the potential of PPE intervention in ameliorating NAFLD through the modulation of hepatic lipid profile and the reinforcement of the fat mobilization of intestinal metabolites. Thus, PPEs exhibit noteworthy therapeutic effects in the context of NAFLD.

Salvianolic acid B and tanshinone IIA synergistically improve early diabetic nephropathy through regulating PI3K/Akt/NF-κB signaling pathway

Ethnopharmacological relevanceDiabetic nephropathy (DN) is one of the most common and serious complications of diabetes, which lacks effective treatment. Salviae Miltiorrhizae Radix Et Rhizoma is one of the key compatible traditional Chinese medicine in the prescription for the treatment of DN. Salvianolic acid B and tanshinone IIA are two monomer active components with high content and clear structure in Salvia miltiorrhiza, which can effectively improve early (DN), respectively. Aim of the studyTo evaluate the compatible effect of salvianolic acid B and tanshinone IIA on early DN rats and elucidate the mechanism. MethodsEarly DN rats were induced by streptozotocin combined with high glucose and high fat diet, and intervened by salvianolic acid B, tanshinone IIA and their combinations. The pathological sections of kidney, liver and biochemical indexes were analyzed. Network pharmacology method was used to predict the possible mechanism. The mechanisms were elucidated by metabolomics, Elisa, and Western blot. ResultsGiven our analysis, salvianolic acid B and tanshinone IIA can synergistically regulate 24 h UTP, Urea and Scr and improve kidney damage in early DN rats. The metabolic abnormalities of early DN rats were improved by regulating the biosynthesis of saturated fatty acids, glycerol phospholipid metabolism, steroid biosynthesis, alanine, and arachidonic acid. Salvianolic acid B combined with tanshinone IIA at a mass ratio of 13.4:1 can significantly reduce kidney inflammation, up-regulate p-PI3K/PI3K and p-Akt/Akt and down-regulate p-NF-κB/NF-κB, which better than the single-used group and can be reversed by PI3K inhibitor LY294002. ConclusionSalvianolic acid B and tanshinone IIA can synergistically improve glucose and lipid disorders, liver and kidney damage, and resist kidney inflammation in early DN rats, and the mechanism may be related to regulating PI3K/Akt/NF-κB signaling pathway.

Lipidomics based on liquid chromatography-high resolution mass spectrometry reveals the protective role of peroxisome proliferator-activated receptor alpha on kidney stone formation in mice treated with glyoxylate.

Few studies have examined the relationship between lipid metabolism and kidney stone formation, particularly the role of key lipid regulatory factors in kidney stone formation. We evaluated the effect of the lipid regulatory factor-peroxisome proliferator-activated receptor alpha on the formation of renal stones in mice by injecting them with glyoxylate followed by treatment with either a peroxisome proliferator-activated receptor alpha agonist fenofibrate or an antagonist GW6471 (GW). Liquid chromatography coupled with trapped ion mobility spectrometry-quadrupole-time-of-flight mass spectrometry-based lipidomics was used to determine the lipid profile in the mouse kidneys. Histological and biochemical analyses showed that the mice injected with glyoxylate exhibited crystal precipitation and renal dysfunction. Crystallization decreased significantly in the fenofibrate group, whereas it increased significantly in the GW group. A total of 184 lipids, including fatty acyls, glycerolipids, glycerophospholipids, and sphingolipids differed significantly between the mice in the model and control groups. Peroxisome proliferator-activated receptor alpha activity negatively correlated with glyoxylate-induced kidney stone formation in mice, which may be related to improved fatty acid oxidation, maintenance of ceramide/complex sphingolipids cycle balance, and alleviation of disorder in phospholipid metabolism.

Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice

Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted thermogenesis and energy balance in obesity and aging. Phospholipid cardiolipin (CL) and phosphatidic acid (PA) jointly regulate mitochondrial membrane architecture and dynamics, with mitochondria-associated endoplasmic reticulum membranes (MAMs) serving as the platform for phospholipid biosynthesis and metabolism. However, little is known about the regulators of MAM phospholipid metabolism and their connection to mitochondrial function. We discover that LCN2 is a PA binding protein recruited to the MAM during inflammation and metabolic stimulation. Lcn2 deficiency disrupts mitochondrial fusion-fission balance and alters the acyl-chain composition of mitochondrial phospholipids in brown adipose tissue (BAT) of male mice. Lcn2 KO male mice exhibit an increase in the levels of CLs containing long-chain polyunsaturated fatty acids (LC-PUFA), a decrease in CLs containing monounsaturated fatty acids, resulting in mitochondrial dysfunction. This dysfunction triggers compensatory activation of peroxisomal function and the biosynthesis of LC-PUFA-containing plasmalogens in BAT. Additionally, Lcn2 deficiency alters PA production, correlating with changes in PA-regulated phospholipid-metabolizing enzymes and the mTOR signaling pathway. In conclusion, LCN2 plays a critical role in the acyl-chain remodeling of phospholipids and mitochondrial bioenergetics by regulating PA production and its function in activating signaling pathways.

A Sedentary Lifestyle Changes the Composition and Predicted Functions of the Gut Bacterial and Fungal Microbiota of Subjects from the Same Company

A sedentary lifestyle affects the diversity and composition of the gut microbiota, but previous studies have mainly focused on bacteria instead of fungi. Here, we compared both the fecal bacterial and fungal microbiota compositions and functions in sedentary persons and controls. Subjects from the China Railway Corporation, including 99 inspectors and 88 officials, were enrolled in our study. Fecal microbiota communities were analyzed using 16S rRNA gene sequencing for bacteria and ITS sequencing for fungi. We found that the diversity of the gut microbiota of the sedentary group was significantly lower than that of the control group (P < 0.05). The sedentary group had a higher abundance of Firmicutes, a lower abundance of Actinobacteria and Proteobacteria and a higher abundance of Ascomycota, and a lower abundance of Basidiomycota. Furthermore, functional prediction analysis of the fungal microbiota revealed more L-tryptophan degradation to 2-amino-3-carboxymuconate semialdehyde, more phospholipid remodeling (phosphatidylethanolamine, yeast), and more L-tyrosine degradation I, as well as less pentose phosphate pathway (non-oxidative branch), less adenosine nucleotide biosynthesis and less L-valine biosynthesis in the sedentary group (P < 0.05). Thus, a sedentary lifestyle changes the composition and function of the gut microbiota. It may change the pentose phosphate pathway (non-oxidative branch), nucleic acid and amino acid biosynthesis and phospholipid metabolism in fungi.