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Communications Biology Sep 2023Ferroptosis is a recently recognized form of regulated cell death, characterized by iron-dependent accumulation of lipid peroxidation. Ample evidence has depicted that...
Ferroptosis is a recently recognized form of regulated cell death, characterized by iron-dependent accumulation of lipid peroxidation. Ample evidence has depicted that ferroptosis plays an essential role in the cause or consequence of human diseases, including cancer, neurodegenerative disease and acute kidney injury. However, the exact role and underlying mechanism of ferroptosis in fibrotic kidney remain unknown. Acyl-CoA synthetase long-chain family member 4 (ACSL4) has been demonstrated as an essential component in ferroptosis execution by shaping lipid composition. In this study, we aim to discuss the potential role and underlying mechanism of ACSL4-mediated ferroptosis of tubular epithelial cells (TECs) during renal fibrosis. The unbiased gene expression studies showed that ACSL4 expression was tightly associated with decreased renal function and the progression of renal fibrosis. To explore the role of ACSL4 in fibrotic kidney, ACSL4 specific inhibitor rosiglitazone (ROSI) was used to disturb the high expression of ACSL4 in TECs induced by TGF-β, unilateral ureteral obstruction (UUO) and fatty acid (FA)-modeled mice in vivo, and ACSL4 siRNA was used to knockdown ACSL4 in TGF-β-induced HK2 cells in vitro. The results demonstrated that inhibition and knockdown of ACSL4 effectively attenuated the occurrence of ferroptosis in TECs and alleviated the interstitial fibrotic response. In addition, the expression of various profibrotic cytokines all decreased after ROSI-treated in vivo and in vitro. Further investigation showed that inhibition of ACSL4 obviously attenuates the progression of renal fibrosis by reducing the proferroptotic precursors arachidonic acid- and adrenic acid- containing phosphatidylethanolamine (AA-PE and AdA-PE). In conclusion, these results suggest ACSL4 is essential for tubular ferroptotic death during kidney fibrosis development and ACSL4 inhibition is a viable therapeutic approach to preventing fibrotic kidney diseases.
Topics: Animals; Humans; Mice; Acute Kidney Injury; Cell Death; Epithelial Cells; Fibrosis; Neurodegenerative Diseases; Rosiglitazone
PubMed: 37670055
DOI: 10.1038/s42003-023-05272-5 -
Diabetes, Metabolic Syndrome and... 2023Among chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) is one of the commonest. Although empagliflozin has several therapeutic uses in treating...
PURPOSE
Among chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) is one of the commonest. Although empagliflozin has several therapeutic uses in treating cardiovascular and renal disorders, its impacts and mechanisms on NAFLD are poorly understood. This research aimed to examine the metabolic regulatory mechanism through which empagliflozin protects against NAFLD.
METHODS
Equal grouping of twenty-seven male C57BL/6J mice into those fed a normal diet (NCD), those fed a high-fat diet (HFD), and those fed an HFD with empagliflozin (Empa) was approached. HE, oil red O staining, and Masson staining were utilized for evaluating the pathological damage to the liver and the mice's liver and body weights. Lipids, blood glucose, and inflammation index were compared across the three groups. Liquid chromatography/mass spectrometry (LC-MS) has been employed for identifying liver metabolomics.
RESULTS
The findings suggested that empagliflozin mitigated the inflammatory and oxidative stress response associated with the buildup of lipids caused by HFD. Differentially expressed metabolites (DEMs) were identified by metabonomics analysis as present in both the HFD/NCD and Empa/HFD groups. These DEMs were primarily found in lipids and organic acids like lysophosphatidylcholine (lysoPC), lecithin (PC), triglyceride (TG), palmitic acid, and L-isoleucine. Among the enriched pathways that were shown to be important were those involved in the metabolism of histidine, arachidonic acid, the control of lipolysis in adipocytes, and insulin resistance. There was a strong correlation between inflammation and oxidative stress in most of the metabolites. The inflammation and oxidative stress unbalance were ameliorated by empagliflozin.
CONCLUSION
NAFLD mice model showed considerable improvement in metabolic abnormalities and liver protection after treatment with empagliflozin. The process may include the overexpression of L-isoleucine and the downregulation of lysoPC, PC, TG, and palmitic acid to reduce liver harm caused by lipotoxicity.
PubMed: 37645238
DOI: 10.2147/DMSO.S422327 -
Nutrients Dec 2023Breastfeeding or standard infant formulas, alongside phenylalanine (Phe)-free protein substitutes, constitute the dietary management for infants with PKU to guarantee... (Review)
Review
Breastfeeding or standard infant formulas, alongside phenylalanine (Phe)-free protein substitutes, constitute the dietary management for infants with PKU to guarantee protein requirements are met in compliance with metabolic tolerance. This work aims to analyse the nutritional composition of Phe-free infant protein substitutes, in terms of macronutrients, micronutrients and functional components, available for PKU dietary management in Italy. A total of seven infant Phe-free protein substitutes were included in this review, six powder and one liquid. A second analysis was conducted to compare them to the composition of formulas intended for healthy infants, taking into consideration the Commission Delegated Regulation (EU) 2016/127 and Commission Delegated Regulation (EU) 2016/128 for micronutrients. The analysis revealed heterogeneity among protein substitutes suitable for infants with PKU. The energy and protein equivalents (P.Eq.) content are different; all of the substitutes contain docosahexaenoic acid (DHA) and arachidonic acid (ARA), while eicosapentaenoic acid (EPA), fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), human milk oligosaccharides (HMOs) and nucleotides are not present in all the substitutes. More attention should be paid to these infant products to ensure metabolic control of PKU, and also promote proper growth, cognitive neurodevelopment, favourable gut microbiota composition, and immune system health, while reducing the risk for non-communicable diseases (NCDs).
Topics: Infant; Humans; Phenylalanine; Italy; Nutrients; Micronutrients; Oligosaccharides
PubMed: 38201860
DOI: 10.3390/nu16010030 -
Scientific Reports Aug 2023Hashimoto thyroiditis is an autoimmune disease characterized by hypothyroidism and a high level of anti-thyroid autoantibodies. It has shown to negatively impact female...
Hashimoto thyroiditis is an autoimmune disease characterized by hypothyroidism and a high level of anti-thyroid autoantibodies. It has shown to negatively impact female fertility; however, the mechanisms are unclear. Ovarian follicular fluid appears to be the key to understanding how Hashimoto thyroiditis affecst fertility. Thus, we aimed to evaluated the metabolic profile of follicular fluid and antithyroid autoantibody levels in the context of Hashimoto thyroiditis. We collected follicular fluid from 61 patients, namely 38 women with thyroid autoantibody positivity and 23 women as negative controls, undergoing in vitro fertilization treatment. Follicular fluid samples were analyzed using metabolomics, and thyroid autoantibodies were measured. Fifteen metabolites with higher concentrations in the follicular fluid samples from Hashimoto thyroiditis were identified, comprising five possible affected pathways: the glycerophospholipid, arachidonic acid, linoleic acid, alpha-linolenic acid, and sphingolipid metabolism pathways. These pathways are known to regulate ovarian functions. In addition, antithyroglobulin antibody concentrations in both serum and follicular fluid were more than tenfold higher in women with Hashimoto thyroiditis than in controls. Our data showed that the metabolic profile of follicular fluid is altered in women with Hashimoto thyroiditis, suggesting a potential mechanistic explanation for the association of this disease with female infertility.
Topics: Humans; Female; Hashimoto Disease; Follicular Fluid; Autoantibodies; Autoimmune Diseases; Metabolomics
PubMed: 37532758
DOI: 10.1038/s41598-023-39514-7 -
Obesity exacerbates influenza-induced respiratory disease via the arachidonic acid-p38 MAPK pathway.Frontiers in Pharmacology 2023Obesity is a risk factor for severe influenza, and asthma exacerbations caused by respiratory viral infections. We investigated mechanisms that increase the severity of...
Obesity is a risk factor for severe influenza, and asthma exacerbations caused by respiratory viral infections. We investigated mechanisms that increase the severity of airway disease related to influenza in obesity using cells derived from obese and lean individuals, and and models. Primary human nasal epithelial cells (pHNECs) derived from obese compared with lean individuals developed increased inflammation and injury in response to influenza A virus (IAV). Obese mice infected with influenza developed increased airway inflammation, lung injury and elastance, but had a decreased interferon response, compared with lean mice. Lung arachidonic acid (AA) levels increased in obese mice infected with IAV; arachidonic acid increased inflammatory cytokines and injury markers in response to IAV in human bronchial epithelial (HBE) cells. Obesity in mice, and AA in HBE cells, increased activation of p38 MAPK signaling following IAV infection; inhibiting this pathway attenuated inflammation, injury and tissue elastance responses, and improved survival. In summary, obesity increases disease severity in response to influenza infection through activation of the p38 MAPK pathway in response to altered arachidonic acid signaling.
PubMed: 37680710
DOI: 10.3389/fphar.2023.1248873 -
Lipids in Health and Disease Nov 2023Intervertebral disc degeneration (IVDD) is widely recognized as the primary etiological factor underlying low back pain, often necessitating surgical intervention as the...
Role of arachidonic acid metabolism in intervertebral disc degeneration: identification of potential biomarkers and therapeutic targets via multi-omics analysis and artificial intelligence strategies.
BACKGROUND
Intervertebral disc degeneration (IVDD) is widely recognized as the primary etiological factor underlying low back pain, often necessitating surgical intervention as the sole recourse in severe cases. The metabolic pathway of arachidonic acid (AA), a pivotal regulator of inflammatory responses, influences the development and progression of IVDD.
METHODS
Initially, a comparative analysis was conducted to investigate the relationship between AA expression patterns and different stages of IVDD using single-cell sequencing (scRNA-seq) data. Additionally, three machine learning methods (LASSO, random forest, and support vector machine recursive feature elimination) were employed to identify hub genes associated with IVDD. Subsequently, a novel artificial intelligence prediction model was developed for IVDD based on an artificial neural network algorithm and validated using an independent dataset. The identified hub genes were further subjected to functional enrichment, immune infiltration, and Connectivity Map analysis. Moreover, external validation was performed using flow cytometry and real-time reverse transcription polymerase chain reaction analysis.
RESULTS
Both scRNA-seq and bulk RNA-seq data revealed a positive correlation between the severity of IVDD and the AA metabolic pathway. They also revealed increased AA metabolic activity in macrophages and neutrophils, as well as enhanced intercellular communication with nucleus pulposus cells. Utilizing advanced machine learning algorithms, five hub genes (AKR1C3, ALOX5, CYP2B6, EPHX2, and PLB1) were identified, and an incipient diagnostic model was developed with an AUC of 0.961 in the training cohort and 0.72 in the validation cohort. An in-depth exploration of the functionality of these hub genes revealed their notable association with inflammatory responses and immune cell infiltration. Lastly, AH6809 was found to delay IVDD by inhibiting AKR1C3.
CONCLUSIONS
This study offers comprehensive insights into potential biomarkers and small molecules associated with the early pathogenesis of IVDD. The identified biomarkers and the developed integrated diagnostic model hold great promise in predicting the onset of early IVDD. AH6809 was established as a therapeutic target for AKR1C3 in the treatment of IVDD, as evidenced by computer simulations and biological experiments.
Topics: Humans; Artificial Intelligence; Arachidonic Acid; Intervertebral Disc Degeneration; Multiomics; Biomarkers
PubMed: 38007425
DOI: 10.1186/s12944-023-01962-5 -
International Journal of Molecular... Sep 2023Polyunsaturated fatty acids (PUFAs) undergo lipid peroxidation and conversion into malondialdehyde (MDA). MDA reacts with acetaldehyde to form malondialdehyde-modified...
Lipid Peroxidation of the Docosahexaenoic Acid/Arachidonic Acid Ratio Relating to the Social Behaviors of Individuals with Autism Spectrum Disorder: The Relationship with Ferroptosis.
Polyunsaturated fatty acids (PUFAs) undergo lipid peroxidation and conversion into malondialdehyde (MDA). MDA reacts with acetaldehyde to form malondialdehyde-modified low-density lipoprotein (MDA-LDL). We studied unsettled issues in the association between MDA-LDL and the pathophysiology of ASD in 18 individuals with autism spectrum disorders (ASD) and eight age-matched controls. Social behaviors were assessed using the social responsiveness scale (SRS). To overcome the problem of using small samples, adaptive Lasso was used to enhance the interpretability accuracy, and a coefficient of variation was used for variable selections. Plasma levels of the MDA-LDL levels (91.00 ± 16.70 vs. 74.50 ± 18.88) and the DHA/arachidonic acid (ARA) ratio (0.57 ± 0.16 vs. 0.37 ± 0.07) were significantly higher and the superoxide dismutase levels were significantly lower in the ASD group than those in the control group. Total SRS scores in the ASD group were significantly higher than those in the control group. The unbeneficial DHA/ARA ratio induced ferroptosis via lipid peroxidation. Multiple linear regression analysis and adaptive Lasso revealed an association of the DHA/ARA ratio with total SRS scores and increased MDA-LDL levels in plasma, resulting in neuronal deficiencies. This unbeneficial DHA/ARA-ratio-induced ferroptosis contributes to autistic social behaviors and is available for therapy.
Topics: Humans; Docosahexaenoic Acids; Arachidonic Acid; Autism Spectrum Disorder; Lipid Peroxidation; Ferroptosis; Lipoproteins, LDL; Malondialdehyde
PubMed: 37834244
DOI: 10.3390/ijms241914796 -
Prostaglandins & Other Lipid Mediators Aug 2024Menopause is a normal stage in the human female aging process characterized by the cessation of menstruation and the ovarian production of estrogen and progesterone... (Review)
Review
Menopause is a normal stage in the human female aging process characterized by the cessation of menstruation and the ovarian production of estrogen and progesterone hormones. Menopause is associated with an increased risk of several different diseases. Cardiovascular diseases are generally less common in females than in age-matched males. However, this female advantage is lost after menopause. Cardiac hypertrophy is a disease characterized by increased cardiac size that develops as a response to chronic overload or stress. Similar to other cardiovascular diseases, the risk of cardiac hypertrophy significantly increases after menopause. However, the exact underlying mechanisms are not yet fully elucidated. Several studies have shown that surgical or chemical induction of menopause in experimental animals is associated with cardiac hypertrophy, or aggravates cardiac hypertrophy induced by other stressors. Arachidonic acid (AA) released from the myocardial phospholipids is metabolized by cardiac cytochrome P450 (CYP), cyclooxygenase (COX), and lipoxygenase (LOX) enzymes to produce several eicosanoids. AA-metabolizing enzymes and their respective metabolites play an important role in the pathogenesis of cardiac hypertrophy. Menopause is associated with changes in the cardiovascular levels of CYP, COX, and LOX enzymes and the levels of their metabolites. It is possible that these changes might play a role in the increased risk of cardiac hypertrophy after menopause.
Topics: Cardiomegaly; Arachidonic Acid; Humans; Animals; Female; Menopause; Postmenopause; Cytochrome P-450 Enzyme System; Prostaglandin-Endoperoxide Synthases; Lipoxygenase; Disease Models, Animal
PubMed: 38740361
DOI: 10.1016/j.prostaglandins.2024.106851 -
Cells Sep 2023Lysophosphatidic acid (LPA) signalling is essential for maintaining germ cell viability during mouse spermatogenesis; however, its role in human spermatozoa is unknown....
Lysophosphatidic acid (LPA) signalling is essential for maintaining germ cell viability during mouse spermatogenesis; however, its role in human spermatozoa is unknown. We previously demonstrated that peroxiredoxin 6 (PRDX6) calcium-independent phospholipase A (iPLA) releases lysophospholipids such as LPA or arachidonic acid (AA) and that inhibiting PRDX6 iPLA activity impairs sperm cell viability. The exogenous addition of LPA bypassed the inhibition of PRDX6 iPLA activity and maintained the active phosphoinositide 3-kinase (PI3K)/AKT pathway. Here, we aimed to study PI3K/AKT pathway regulation via LPA signalling and protein kinases in maintaining sperm viability. The localization of LPARs in human spermatozoa was determined using immunocytochemistry, and P-PI3K and P-AKT substrate phosphorylations via immunoblotting. Sperm viability was determined using the hypo-osmotic swelling test. LPAR1, 3, 5 and 6 were located on the sperm plasma membrane. The inhibition of LPAR1-3 with Ki16425 promoted the impairment of sperm viability and decreased the phosphorylation of PI3K AKT substrates. Inhibitors of PKC, receptor-type PTK and PLC impaired sperm viability and the PI3K/AKT pathway. Adding 1-oleoyl-2-acetyl-snglycerol (OAG), a cell-permeable analog of diacylglycerol (DAG), prevented the loss of sperm viability and maintained the phosphorylation of PI3K. In conclusion, human sperm viability is supported by LPAR signalling and regulated by PLC, PKC and RT-PTK by maintaining phosphorylation levels of PI3K and AKT substrates.
Topics: Humans; Male; Lysophospholipids; Peroxiredoxin VI; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Semen
PubMed: 37681929
DOI: 10.3390/cells12172196