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Genes Jun 2024Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid...
Multifactor Analyses of Frontal Cortex Lipids in the APP/PS1 Model of Familial Alzheimer's Disease Reveal Anomalies in Responses to Dietary n-3 PUFA and Estrogenic Treatments.
Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid alterations are linked to neurodegenerative diseases, especially Alzheimer's disease (AD). The complexity of the brain lipidome and its metabolic regulation has hampered the identification of critical processes associated with the onset and progression of AD. While most experimental studies have focused on the effects of known factors on the development of pathological hallmarks in AD, e.g., amyloid deposition, tau protein and neurofibrillary tangles, neuroinflammation, etc., studies addressing the causative effects of lipid alterations remain largely unexplored. In the present study, we have used a multifactor approach combining diets containing different amounts of polyunsaturated fatty acids (PUFAs), estrogen availabilities, and genetic backgrounds, i.e., wild type (WT) and APP/PS1 (FAD), to analyze the lipid phenotype of the frontal cortex in middle-aged female mice. First, we observed that severe n-3 PUFA deficiency impacts the brain n-3 long-chain PUFA (LCPUFA) composition, yet it was notably mitigated by hepatic de novo synthesis. n-6 LCPUFAs, ether-linked fatty acids, and saturates were also changed by the dietary condition, but the extent of changes was dependent on the genetic background and hormonal condition. Likewise, brain cortex phospholipids were mostly modified by the genotype (FAD>WT) with nuanced effects from dietary treatment. Cholesterol (but not sterol esters) was modified by the genotype (WT>FAD) and dietary condition (higher in DHA-free conditions, especially in WT mice). However, the effects of estrogen treatment were mostly observed in relation to phospholipid remodeling in a genotype-dependent manner. Analyses of lipid-derived variables indicate that nerve cell membrane biophysics were significantly affected by the three factors, with lower membrane microviscosity (higher fluidity) values obtained for FAD animals. In conclusion, our multifactor analyses revealed that the genotype, diet, and estrogen status modulate the lipid phenotype of the frontal cortex, both as independent factors and through their interactions. Altogether, the outcomes point to potential strategies based on dietary and hormonal interventions aimed at stabilizing the brain cortex lipid composition in Alzheimer's disease neuropathology.
Topics: Alzheimer Disease; Animals; Fatty Acids, Omega-3; Mice; Frontal Lobe; Female; Disease Models, Animal; Amyloid beta-Protein Precursor; Estrogens; Mice, Transgenic; Presenilin-1; Lipid Metabolism; Humans
PubMed: 38927745
DOI: 10.3390/genes15060810 -
Biomedicines Jun 2024Perfluorinated alkyl acids (PFAAs) are persistent organic pollutants affected by BMI and ethnicity, with contradictory reports of association with vitamin D deficiency.
BACKGROUND
Perfluorinated alkyl acids (PFAAs) are persistent organic pollutants affected by BMI and ethnicity, with contradictory reports of association with vitamin D deficiency.
METHODS
Twenty-nine Caucasian women with non-obese polycystic ovary syndrome (PCOS) and age- and BMI-matched Caucasian control women ( = 30) were recruited. Paired serum samples were analyzed for PFAAs ( = 13) using high-performance liquid chromatography-tandem mass spectrometry. Tandem mass spectrometry determined levels of 25(OH)D and the active 1,25(OH)D.
RESULTS
Women with and without PCOS did not differ in age, weight, insulin resistance, or systemic inflammation (C-reactive protein did not differ), but the free androgen index was increased. Four PFAAs were detected in all serum samples: perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS). Serum PFOS was higher in PCOS versus controls (geometric mean [GM] 3.9 vs. 3.1 ng/mL, < 0.05). Linear regression modeling showed that elevated PFHxS had higher odds of a lower 25(OH)D (OR: 2.919, 95% CI 0.82-5.75, = 0.04). Vitamin D did not differ between cohorts and did not correlate with any PFAAs, either alone or when the groups were combined. When vitamin D was stratified into sufficiency (>20 ng/mL) and deficiency (<20 ng/mL), no correlation with any PFAAs was seen.
CONCLUSIONS
While the analyses and findings here are exploratory in light of relatively small recruitment numbers, when age, BMI, and insulin resistance are accounted for, the PFAAs do not appear to be related to 25(OH)D or the active 1,25(OH)D in this Caucasian population, nor do they appear to be associated with vitamin D deficiency, suggesting that future studies must account for these factors in the analysis.
PubMed: 38927462
DOI: 10.3390/biomedicines12061255 -
Biomedicines May 2024The enzyme 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) is involved in the catabolism of the amino acid tyrosine in organisms such as bacteria, plants, and animals. It...
The enzyme 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) is involved in the catabolism of the amino acid tyrosine in organisms such as bacteria, plants, and animals. It catalyzes the conversion of 4-hydroxyphenylpyruvate to a homogenisate in the presence of molecular oxygen and Fe(II) as a cofactor. This enzyme represents a key step in the biosynthesis of important compounds, and its activity deficiency leads to severe, rare autosomal recessive disorders, like tyrosinemia type III and hawkinsinuria, for which no cure is currently available. The 4-HPPD C-terminal tail plays a crucial role in the enzyme catalysis/gating mechanism, ensuring the integrity of the active site for catalysis through fine regulation of the C-terminal tail conformation. However, despite growing interest in the 4-HPPD catalytic mechanism and structure, the gating mechanism remains unclear. Furthermore, the absence of the whole 3D structure makes the bioinformatic approach the only possible study to define the enzyme structure/molecular mechanism. Here, wild-type 4-HPPD and its mutants were deeply dissected by applying a comprehensive bioinformatics/evolution study, and we showed for the first time the entire molecular mechanism and regulation of the enzyme gating process, proposing the full-length 3D structure of human 4-HPPD and two novel key residues involved in the 4-HPPD C-terminal tail conformational change.
PubMed: 38927403
DOI: 10.3390/biomedicines12061196 -
Biomolecules Jun 2024Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of...
Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous angiotensin II infusion (1000 ng/kg body weight/min), with daily administration of necrosulfonamide (5 mg/kg body weight) or vehicle starting 3 days prior to angiotensin II infusion for 30 days. Necrosulfonamide treatment remarkably suppressed AAA enlargement, as indicated by reduced suprarenal maximal external diameter and surface area, and lowered the incidence and reduced the severity of experimental AAAs. Histologically, necrosulfonamide treatment attenuated medial elastin breaks, smooth muscle cell depletion, and aortic wall collagen deposition. Macrophages, CD4 T cells, CD8 T cells, and neovessels were reduced in the aneurysmal aortas of necrosulfonamide- as compared to vehicle-treated angiotensin II-infused mice. Atherosclerosis and intimal macrophages were also substantially reduced in suprarenal aortas from angiotensin II-infused mice following necrosulfonamide treatment. Additionally, the levels of serum interleukin-1β and interleukin-18 were significantly lower in necrosulfonamide- than in vehicle-treated mice without affecting body weight gain, lipid levels, or blood pressure. Our findings indicate that necrosulfonamide reduced experimental AAAs by preserving aortic structural integrity as well as reducing mural leukocyte accumulation, neovessel formation, and systemic levels of interleukin-1β and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease.
Topics: Animals; Angiotensin II; Aortic Aneurysm, Abdominal; Mice; Male; Sulfonamides; Apolipoproteins E; Phosphate-Binding Proteins; Disease Models, Animal; Mice, Inbred C57BL; Macrophages; Indoles; Mice, Knockout, ApoE; Gasdermins
PubMed: 38927129
DOI: 10.3390/biom14060726 -
Biomolecules May 2024Acute pancreatitis (AP) is a complex inflammatory condition that can lead to systemic inflammatory responses and multiple organ dysfunction. This study investigates the...
Acute pancreatitis (AP) is a complex inflammatory condition that can lead to systemic inflammatory responses and multiple organ dysfunction. This study investigates the role of Galectin-3 (Gal-3), a β-galactoside-binding lectin, in modulating acquired immune responses in AP. Acute pancreatitis was induced by ligation of the bile-pancreatic duct in wild-type and Galectin-3-deficient C57BL/6 mice. We determined the phenotypic and molecular features of inflammatory cells, serum concentrations of amylase, pancreatic trypsin activity, and pancreatic and lung pathology. Galectin-3 deficiency decreased the total number of CD3CD49 T cells and CD4 T helper cells, downregulated the production of inflammatory cytokine and IFN-γ, and increased the accumulation of IL-10-producing Foxp3 T regulatory cells and regulatory CD4 T cells in the pancreata of diseased animals. The deletion of Galectin-3 ameliorates acute pancreatitis characterized by lowering serum amylase concentration and pancreatic trypsin activity, and attenuating of the histopathology of the lung. These findings shed light on the role of Galectin-3 in acquired immune response in acute pancreatitis and identify Galectin-3 as an attractive target for investigation of the immunopathogenesis of disease and for consideration as a potential therapeutic target for patients with acute inflammatory disease of the pancreas.
Topics: Animals; Pancreatitis; Galectin 3; Mice; T-Lymphocytes, Regulatory; Mice, Inbred C57BL; Mice, Knockout; Acute Disease; Male; Amylases
PubMed: 38927046
DOI: 10.3390/biom14060642 -
Respiratory Research Jun 2024The PI*S variant is one of the most prevalent mutations within alpha-1 antitrypsin deficiency (AATD). The risk of developing AATD-related lung disease in individuals...
BACKGROUND
The PI*S variant is one of the most prevalent mutations within alpha-1 antitrypsin deficiency (AATD). The risk of developing AATD-related lung disease in individuals with the PI*SS genotype is poorly defined despite its substantial prevalence. Our study aimed to characterize this genotype and its risk for lung disease and compare it with the PI*ZZ and PI*SZ genotypes using data from the European Alpha-1 antitrypsin Deficiency Research Collaboration international registry.
METHOD
Demographic, clinical, functional, and quality of life (QoL) parameters were assessed to compare the PI*SS characteristics with the PI*SZ and PI*ZZ controls. A propensity score with 1:3 nearest-neighbour matching was performed for the most important confounding variables.
RESULTS
The study included 1007 individuals, with PI*SS (n = 56; 5.6%), PI*ZZ (n = 578; 57.4%) and PI*SZ (n = 373; 37.0%). The PI*SS population consisted of 58.9% men, with a mean age of 59.2 years and a mean FEV1(% predicted) of 83.4%. Compared to PI*ZZ individuals they had less frequent lung disease (71.4% vs. 82.2%, p = 0.037), COPD (41.4% vs. 60%, p = 0.002), and emphysema (23.2% vs. 51.9%, p < 0.001) and better preserved lung function, fewer exacerbations, lower level of dyspnoea, and better QoL. In contrast, no significant differences were found in the prevalence of lung diseases between PI*SS and PI*SZ, or lung function parameters, exacerbations, dyspnoea, or QoL.
CONCLUSIONS
We found that, as expected, the risk of lung disease associated with the PI*SS genotype is significantly lower compared with PI*ZZ, but does not differ from that observed in PI*SZ individuals, despite having higher serum AAT levels.
TRIAL REGISTRATION
www.
CLINICALTRIALS
gov (ID: NCT04180319).
Topics: Humans; Male; Female; Middle Aged; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Genotype; Aged; Lung Diseases; Risk Factors; Registries; Quality of Life
PubMed: 38926693
DOI: 10.1186/s12931-024-02879-y -
Cell Death & Disease Jun 2024Liver regeneration is a complex process involving the crosstalk between parenchymal and non-parenchymal cells, especially macrophages. However, the underlying mechanisms...
Liver regeneration is a complex process involving the crosstalk between parenchymal and non-parenchymal cells, especially macrophages. However, the underlying mechanisms remain incompletely understood. Here, we identify the E3 ubiquitin ligase TRIM26 as a crucial regulator of liver regeneration. Following partial hepatectomy or acute liver injury induced by carbon tetrachloride, Trim26 knockout mice exhibit enhanced hepatocyte proliferation compared to wild-type controls, while adeno-associated virus (AAV)-mediated overexpression of Trim26 reverses the promotional effects. Mechanistically, Trim26 deficiency promotes the recruitment of macrophages to the liver and their polarization towards pro-inflammatory M1 phenotype. These M1 macrophages secrete Wnts, including Wnt2, which subsequently stimulate hepatocyte proliferation through the activation of Wnt/β-catenin signaling. In hepatocytes, Trim26 knockdown reduces the ubiquitination and degradation of β-catenin, thereby further enhancing Wnt/β-catenin signaling. Pharmacological inhibition of Wnt/β-catenin pathway by ICG-001 or depletion of macrophages by clodronate liposomes diminishes the pro-regenerative effects of Trim26 deficiency. Moreover, bone marrow transplantation experiments provide evidence that Trim26 knockout in myeloid cells alone can also promote liver regeneration, highlighting the critical role of macrophage Trim26 in this process. Taken together, our study uncovers TRIM26 as a negative regulator of liver regeneration by modulating macrophage polarization and Wnt/β-catenin signaling in hepatocytes, providing a potential therapeutic target for promoting liver regeneration in clinical settings.
Topics: Animals; Liver Regeneration; Macrophages; Ubiquitin-Protein Ligases; Mice; Mice, Knockout; beta Catenin; Wnt Signaling Pathway; Hepatocytes; Mice, Inbred C57BL; Tripartite Motif Proteins; Cell Proliferation; Liver; Cell Polarity; Male; Ubiquitination
PubMed: 38926362
DOI: 10.1038/s41419-024-06798-0 -
Science Advances Jun 2024Once considered as a "metabolic waste," lactate is now recognized as a major fuel for tricarboxylic acid (TCA) cycle. Our metabolic flux analysis reveals that skeletal...
Once considered as a "metabolic waste," lactate is now recognized as a major fuel for tricarboxylic acid (TCA) cycle. Our metabolic flux analysis reveals that skeletal muscle mainly uses lactate to fuel TCA cycle. Lactate is transported through the cell membrane via monocarboxylate transporters (MCTs) in which MCT1 is highly expressed in the muscle. We analyzed how MCT1 affects muscle functions using mice with specific deletion of MCT1 in skeletal muscle. MCT1 deletion enhances running performance, increases oxidative fibers while decreasing glycolytic fibers, and enhances flux of glucose to TCA cycle. MCT1 deficiency increases the expression of mitochondrial proteins, augments cell respiration rate, and elevates mitochondrial activity in the muscle. Mechanistically, the protein level of PGC-1α, a master regulator of mitochondrial biogenesis, is elevated upon loss of MCT1 via increases in cellular NAD level and SIRT1 activity. Collectively, these results demonstrate that MCT1-mediated lactate shuttle plays a key role in regulating muscle functions by modulating mitochondrial biogenesis and TCA flux.
Topics: Animals; Monocarboxylic Acid Transporters; Muscle, Skeletal; Symporters; Lactic Acid; Organelle Biogenesis; Mice; Citric Acid Cycle; Mitochondria; Sirtuin 1; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Mice, Knockout; Glycolysis
PubMed: 38924407
DOI: 10.1126/sciadv.adn4508 -
Proceedings of the National Academy of... Jul 2024The non-neural cholinergic system plays a critical role in regulating immune equilibrium and tissue homeostasis. While the expression of choline acetyltransferase...
The non-neural cholinergic system plays a critical role in regulating immune equilibrium and tissue homeostasis. While the expression of choline acetyltransferase (ChAT), the enzyme catalyzing acetylcholine biosynthesis, has been well documented in lymphocytes, its role in the myeloid compartment is less understood. Here, we identify a significant population of macrophages (Mϕs) expressing ChAT and synthesizing acetylcholine in the resolution phase of acute peritonitis. Using -GFP reporter mice, we observed marked upregulation of ChAT in monocyte-derived small peritoneal Mϕs (SmPMs) in response to Toll-like receptor agonists and bacterial infections. These SmPMs, phenotypically and transcriptionally distinct from tissue-resident large peritoneal macrophages, up-regulated ChAT expression through a MyD88-dependent pathway involving MAPK signaling. Notably, this process was attenuated by the TRIF-dependent TLR signaling pathway, and our tests with a range of neurotransmitters and cytokines failed to induce a similar response. Functionally, deficiency in Mϕs led to significantly decreased peritoneal acetylcholine levels, reduced efferocytosis of apoptotic neutrophils, and a delayed resolution of peritonitis, which were reversible with exogenous ACh supplementation. Intriguingly, despite B lymphocytes being a notable ChAT-expressing population within the peritoneal cavity, deletion in B cells did not significantly alter the resolution process. Collectively, these findings underscore the crucial role of Mϕ-derived acetylcholine in the resolution of inflammation and highlight the importance of the non-neuronal cholinergic system in immune regulation.
Topics: Animals; Choline O-Acetyltransferase; Peritonitis; Mice; Macrophages, Peritoneal; Acetylcholine; Myeloid Differentiation Factor 88; Mice, Inbred C57BL; Signal Transduction; Inflammation; B-Lymphocytes; Toll-Like Receptors; Phagocytosis; Macrophages; Mice, Knockout
PubMed: 38923993
DOI: 10.1073/pnas.2402143121