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Frontiers in Neuroscience 2023Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons. Despite extensive research, the...
BACKGROUND
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons. Despite extensive research, the exact etiology of ALS remains elusive. Emerging evidence highlights the critical role of the immune system in ALS pathogenesis and progression. Damage-Associated Molecular Patterns (DAMPs) are endogenous molecules released by stressed or damaged cells, acting as danger signals and activating immune responses. However, their specific involvement in ALS remains unclear.
METHODS
We obtained single-cell RNA sequencing (scRNA-seq) data of ALS from the primary motor cortex in the Gene Expression Omnibus (GEO) database. To better understand genes associated with DAMPs, we performed analyses on cell-cell communication and trajectory. The abundance of immune-infiltrating cells was assessed using the single-sample Gene Set Enrichment Analysis (ssGSEA) method. We performed univariate Cox analysis to construct the risk model and utilized the least absolute shrinkage and selection operator (LASSO) analysis. Finally, we identified potential small molecule drugs targeting ALS by screening the Connectivity Map database (CMap) and confirmed their potential through molecular docking analysis.
RESULTS
Our study annotated 10 cell types, with the expression of genes related to DAMPs predominantly observed in microglia. Analysis of intercellular communication revealed 12 ligand-receptor pairs in the pathways associated with DAMPs, where microglial cells acted as ligands. Among these pairs, the SPP1-CD44 pair demonstrated the greatest contribution. Furthermore, trajectory analysis demonstrated distinct differentiation fates of different microglial states. Additionally, we constructed a risk model incorporating four genes (TRPM2, ROCK1, HSP90AA1, and HSPA4). The validity of the risk model was supported by multivariate analysis. Moreover, external validation from dataset GSE112681 confirmed the predictive power of the model, which yielded consistent results with datasets GSE112676 and GSE112680. Lastly, the molecular docking analysis suggested that five compounds, namely mead-acid, nifedipine, nifekalant, androstenol, and hydrastine, hold promise as potential candidates for the treatment of ALS.
CONCLUSION
Taken together, our study demonstrated that DAMP entities were predominantly observed in microglial cells within the context of ALS. The utilization of a prognostic risk model can accurately predict ALS patient survival. Additionally, genes related to DAMPs may present viable drug targets for ALS therapy.
PubMed: 37942135
DOI: 10.3389/fnins.2023.1259742 -
Frontiers in Nutrition 2023The development of inflammatory lung disorders in children may be related to maternal fatty acid intake during pregnancy. We therefore examined maternal fatty acid (FA)...
The development of inflammatory lung disorders in children may be related to maternal fatty acid intake during pregnancy. We therefore examined maternal fatty acid (FA) status during pregnancy and its associations with inflammatory markers and lung conditions in the child by analyzing data from the MEFAB cohort using multivariate canonical correlation analysis (CCA). In the MEFAB cohort, 39 different phospholipid FAs were measured in maternal plasma at 16, 22 and 32 weeks of pregnancy, and at day of birth. Child inflammatory markers and self-reported doctor diagnosis of inflammatory lung disorders were assessed at 7 years of age. Using CCA, we found that maternal FA levels during pregnancy were significantly associated with child inflammatory markers at 7 years of age and that Mead acid (20:3n-9) was the most important FA for this correlation. To further verify the importance of Mead acid, we examined the relation between maternal Mead acid levels at the day of birth with the development of inflammatory lung disorders in children at age 7. After stratification for the child's sex, maternal Mead acid levels at day of birth were significantly related with self-reported doctor diagnosis of asthma and lung infections in boys, and bronchitis and total number of lung disorders in girls. Future studies should investigate whether the importance of Mead acid in the relation between maternal FA status and inflammation and lung disorders in the child is due to its role as biomarker for essential fatty acid deficiency or due to its own biological function as pro-inflammatory mediator.
PubMed: 37927506
DOI: 10.3389/fnut.2023.1264278 -
Lipids in Health and Disease Oct 2023Mead acid (MA, 5,8,11-eicosatrienoic acid) is an n-9 polyunsaturated fatty acid (PUFA) and a marker of essential fatty acid deficiency, but nonetheless generally draws... (Review)
Review
Mead acid (MA, 5,8,11-eicosatrienoic acid) is an n-9 polyunsaturated fatty acid (PUFA) and a marker of essential fatty acid deficiency, but nonetheless generally draws little attention. MA is distributed in various normal tissues and can be converted to several specific lipid mediators by lipoxygenase and cyclooxygenase. Recent pathological and epidemiological studies on MA raise the possibility of its effects on inflammation, cancer, dermatitis and cystic fibrosis, suggesting it is an endogenous multifunctional PUFA. This review summarizes the biosynthesis, presence, metabolism and physiological roles of MA and its relation to various diseases, as well as the significance of MA in PUFA metabolism.
Topics: Humans; Fatty Acids, Unsaturated; 8,11,14-Eicosatrienoic Acid; Inflammation
PubMed: 37838679
DOI: 10.1186/s12944-023-01937-6 -
Clinical Nutrition (Edinburgh, Scotland) Sep 2023Severe acute malnutrition (SAM) is a global concern. Studies on the impact of ready-to-use therapeutic foods (RUTFs) on polyunsaturated fatty acids (PUFA) are almost... (Randomized Controlled Trial)
Randomized Controlled Trial
Changes in polyunsaturated fatty acids during treatment of malnourished children may be insufficient to reach required essential fatty acid levels - A randomised controlled trial.
BACKGROUND & AIMS
Severe acute malnutrition (SAM) is a global concern. Studies on the impact of ready-to-use therapeutic foods (RUTFs) on polyunsaturated fatty acids (PUFA) are almost non-existent. The aim was to investigate the change in whole-blood PUFA and nutrition and health markers among Cambodian children with SAM after treatment with RUTFs.
METHODS
The trial was an 8-week randomised clinical trial of the effectiveness of locally produced fish-based RUTF (L-RUTF) vs standard milk-based RUFT (S-RUTF). Whole-blood fatty acids were analysed using dried blood spots. Nutrition and health markers were assessed using anthropometric assessment and blood samples for markers of inflammation. The trial was conducted at the National Pediatric Hospital, Phnom Penh, Cambodia, with one hundred and twenty-one 6-59-month-old children in treatment for SAM.
RESULTS
L-RUTF had a higher content of n-3 PUFA and a higher content of arachidonic acid (AA) and docosahexaenoic acid (DHA), while S-RUTF had the highest content of n-6 PUFA. At baseline, the children presented with a Mead acid level in whole-blood of around 0.08% of total fatty acids (FA%) and an omega-3 index of ∼0.91 ± 0.44. After eight weeks of S-RUTF treatment, linoleic acid (LA), AA, n-6/n-3 PUFA ratio, and Mead acid levels were increased. The L-RUTF intervention did not change the whole-blood PUFAs from baseline. At discharge, the children in the L-RUTF group had a lower n-6/n-3 PUFA ratio than the children in the S-RUTF group, driven by a lower alpha-linolenic acid (ALA) (0.20 vs 0.27 FA%, p = 0.004) and lower LA (15.77 vs 14.21 FA%, p = 0.018) with no significant differences in AA or DHA levels. Weight-for-height z-score at discharge was negatively associated with total PUFA (β -1.4 FA%, 95%CI. -2.7; -0.1), n-6 LCPUFA (β -1.3 FA%, 95%CI. -1.3; -0.3), and AA (β -0.6 FA%, 95%CI. -1.0; -0.2). Age-adjusted height was negatively associated with the Mead acid:AA ratio (β -1.2 FA%, 95%CI. -2.2; -0.2). No significant change was seen in inflammation markers within groups or between groups during treatment, and n-3 and n-6 PUFAs were not associated with markers of inflammation or haemoglobin status at discharge.
CONCLUSION
The trial found that whole-blood markers of PUFA status were low in children at admission and discharge from SAM treatment, indicating that the currently recommended composition of RUTFs are not able to correct their compromised essential fatty acid status. The higher content of DHA and AA in L-RUTF did not give rise to any improvement in PUFA status. No changes in health markers or associations between PUFA and health markers were found.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT02907424.
Topics: Animals; Fatty Acids, Unsaturated; Fatty Acids, Omega-3; Fatty Acids, Essential; Severe Acute Malnutrition; Docosahexaenoic Acids; Linoleic Acid; Arachidonic Acid; Inflammation; Fatty Acids
PubMed: 37572581
DOI: 10.1016/j.clnu.2023.08.003 -
IScience Jun 2023The retina is a notable tissue with high metabolic needs which relies on specialized vascular networks to protect the neural retina while maintaining constant supplies...
The retina is a notable tissue with high metabolic needs which relies on specialized vascular networks to protect the neural retina while maintaining constant supplies of oxygen, nutrients, and dietary essential fatty acids. Here we analyzed the lipidome of the mouse retina under healthy and pathological angiogenesis using the oxygen-induced retinopathy model. By matching lipid profiles to changes in mRNA transcriptome, we identified a lipid signature showing that pathological angiogenesis leads to intense lipid remodeling favoring pathways for neutral lipid synthesis, cholesterol import/export, and lipid droplet formation. Noteworthy, it also shows profound changes in pathways for long-chain fatty acid production, vital for retina homeostasis. The net result is accumulation of large quantities of mead acid, a marker of essential fatty acid deficiency, and a potential marker for retinopathy severity. Thus, our lipid signature might contribute to better understand diseases of the retina that lead to vision impairment or blindness.
PubMed: 37213234
DOI: 10.1016/j.isci.2023.106777 -
Nutrients Apr 2023Malnutrition is prevalent in low-middle-income countries (LMICs), but it is usually clinically diagnosed through abnormal anthropometric parameters characteristic of... (Review)
Review
Malnutrition is prevalent in low-middle-income countries (LMICs), but it is usually clinically diagnosed through abnormal anthropometric parameters characteristic of protein energy malnutrition (PEM). In doing so, other contributors or byproducts of malnutrition, notably essential fatty acid deficiency (EFAD), are overlooked. Previous research performed mainly in high-income countries (HICs) shows that deficiencies in essential fatty acids (EFAs) and their -3 and -6 polyunsaturated fatty acid (PUFA) byproducts (also known as highly unsaturated fatty acids or HUFAs) lead to both abnormal linear growth and impaired cognitive development. These adverse developmental outcomes remain an important public health issue in LMICs. To identify EFAD before severe malnutrition develops, clinicians should perform blood fatty acid panels to measure levels of fatty acids associated with EFAD, notably Mead acid and HUFAs. This review demonstrates the importance of measuring endogenous fatty acid levels for measuring fatty acid intake in various child populations in LMICs. Featured topics include a comparison of fatty acid levels between global child populations, the relationships between growth and cognition and PUFAs and the possible mechanisms driving these relationships, and the potential importance of EFAD and HUFA scores as biomarkers of overall health and normal development.
Topics: Humans; Child; Fatty Acids; Fatty Acids, Essential; Fatty Acids, Unsaturated; alpha-Linolenic Acid; Malnutrition; Cognition; Fatty Acids, Omega-3
PubMed: 37111152
DOI: 10.3390/nu15081933 -
Frontiers in Molecular Biosciences 2023Retinol is widely used in topical skincare products to ameliorate skin aging and treat acne and wrinkles; however, retinol and its derivatives occasionally have adverse...
Retinol is widely used in topical skincare products to ameliorate skin aging and treat acne and wrinkles; however, retinol and its derivatives occasionally have adverse side effects, including the induction of irritant contact dermatitis. Previously, we reported that mead acid (5,8,11-eicosatrienoic acid), an oleic acid metabolite, ameliorated skin inflammation in dinitrofluorobenzene-induced allergic contact hypersensitivity by inhibiting neutrophil infiltration and leukotriene B production by neutrophils. Here, we showed that mead acid also suppresses retinol-induced irritant contact dermatitis. In a murine model, we revealed that mead acid inhibited keratinocyte abnormalities such as keratinocyte hyperproliferation. Consistently, mead acid inhibited p38 MAPK (mitogen-activated protein kinase) phosphorylation, which is an essential signaling pathway in the keratinocyte hyperplasia induced by retinol. These inhibitory effects of mead acid were associated with the prevention of both keratinocyte hyperproliferation and the gene expression of neutrophil chemoattractants, including Cxcl1 and Cxcl2, and they were mediated by a PPAR (peroxisome proliferator-activated receptor)-α pathway. Our findings identified the anti-inflammatory effects of mead acid, the use of which can be expected to minimize the risk of adverse side effects associated with topical retinoid application.
PubMed: 36825199
DOI: 10.3389/fmolb.2023.1097955 -
Clinical Science (London, England :... Dec 2022Persons with cystic fibrosis (CF) exhibit a unique alteration of fatty acid composition, marked especially among polyunsaturates by relative deficiency of linoleic acid...
Persons with cystic fibrosis (CF) exhibit a unique alteration of fatty acid composition, marked especially among polyunsaturates by relative deficiency of linoleic acid and excess of Mead acid. Relative deficiency of docosahexaenoic acid is variably found. However, the initial development of these abnormalities is not understood. We examined fatty acid composition in young CF ferrets and pigs, finding abnormalities from the day of birth onward including relative deficiency of linoleic acid in both species. Fatty acid composition abnormalities were present in both liver and serum phospholipids of newborn CF piglets even prior to feeding, including reduced linoleic acid and increased Mead acid. Serum fatty acid composition evolved over the first weeks of life in both non-CF and CF ferrets, though differences between CF and non-CF persisted. Although red blood cell phospholipid fatty acid composition was normal in newborn animals, it became perturbed in juvenile CF ferrets including relative deficiencies of linoleic and docosahexaenoic acids and excess of Mead acid. In summary, fatty acid composition abnormalities in CF pigs and ferrets exist from a young age including at birth independent of feeding and overlap extensively with the abnormalities found in humans with CF. That the abnormalities exist prior to feeding implies that dietary measures alone will not address the mechanisms of imbalance.
Topics: Humans; Animals; Swine; Cystic Fibrosis; Fatty Acids; Ferrets; Phospholipids; Docosahexaenoic Acids; Linoleic Acids
PubMed: 36416119
DOI: 10.1042/CS20220450 -
Biomedicines Oct 2022The relationship between advanced nonalcoholic steatohepatitis (NASH) and plasma fatty acid composition remains unknown. We aimed to examine the plasma fatty acid...
The relationship between advanced nonalcoholic steatohepatitis (NASH) and plasma fatty acid composition remains unknown. We aimed to examine the plasma fatty acid composition in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) and evaluate the relationship between histological findings and fatty acid composition. Overall, 235 patients (134 women) with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. Multivariate analyses adjusted for age, sex, body mass index, alanine aminotransferase, hemoglobin A1c, creatinine, total cholesterol, triglyceride, and NAFLD Activity Score values showed that lower levels of arachidic, behenic, α-linolenic, eicosatetraenoic, docosapentaenoic, and docosahexaenoic acids and higher levels of mead acid were associated with fibrosis stage 3-4. Furthermore, higher lauric acid, myristic acid, and palmitic acid levels and monounsaturated fatty acids such as palmitoleic acid and oleic acid were significantly associated with high NAS in analyses adjusted for the same factors and fibrosis stage. The plasma fatty acid composition was associated with the histological evidence of NASH. Increased synthesis of fatty acids is associated with NASH; insufficient intake of n-3 essential fatty acids and reduced elongation of fatty acids are associated with fibrosis in NASH. These features may help clinicians to understand and treat advanced NASH cases.
PubMed: 36289802
DOI: 10.3390/biomedicines10102540 -
Journal of Dairy Science Oct 2022The objective of this study was to determine the effect of early lactation body condition (BC) loss in multiparous dairy cows on serum lipids and the effect of these...
The objective of this study was to determine the effect of early lactation body condition (BC) loss in multiparous dairy cows on serum lipids and the effect of these changes on oocyte and cumulus cell transcriptomes. Body condition loss in dairy cattle after parturition is associated with reduced fertility and increased pregnancy loss. The complex interplay between BC, nutrition, dry matter intake, milk production, and time of calving has presented a barrier to understanding mechanisms leading to reduced fertility. We identified cows that lost BC (L group; n = 10) or maintained or gained BC (M/G group; n = 8) during the first 27 to 33 d in milk and investigated changes in serum fatty acids and oocyte and cumulus cell transcriptomes at 75 to 81 d in milk. The L group had increased serum levels of nonesterified fatty acids and mead acid, and reduced serum levels of petroselaidic acid and behenic acid. Transcriptome analyses revealed 38 differentially expressed genes (DEG) in oocytes and 71 DEG in cumulus cells of L (n = 3) compared with M/G group (n = 3). Network analysis connected serum fatty acid changes to downstream effects including reduced inflammatory response and mitochondrial membrane depolarization, increased production of reactive oxygen species, and functions related to fatty acid metabolism and cytoplasmic organization in oocytes. These effects were associated with predicted effects on signaling in oocytes through calcium, insulin, O-GlcNAcase (OGA), fibroblast growth factor receptor 4 (FGF4R), peroxisome proliferator activated receptor gamma coactivator 1 α (PPARGC1A), and phospholipase D2 (PLD2) pathways, with a connection to the cumulus cell via calcium signaling. These results connect BC loss following parturition to changes in serum lipid levels, and changes potentially affecting oocyte quality; thus, these results provide new insight into mechanism of reduced fertility.
Topics: 3-Hydroxybutyric Acid; Animals; Calcium; Cattle; Cumulus Cells; Diet; Fatty Acids; Fatty Acids, Nonesterified; Female; Insulins; Lactation; Milk; Oocytes; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Postpartum Period; Pregnancy; Reactive Oxygen Species; Receptor, Fibroblast Growth Factor, Type 4; Transcriptome
PubMed: 35940920
DOI: 10.3168/jds.2022-21919