Search Results (157)

Cerebral vasospasm (CVS) following a subarachnoid hemorrhage (SAH) is a critical complication driven by imbalances between vasodilators and vasoconstrictors. This review explores the bidirectional interplay between nitric oxide (NO) and endothelin-1 (ET-1) in CVS pathogenesis. NO, a potent vasodilator mainly produced by endothelial and neuronal nitric oxide synthase (eNOS/nNOS) under normal physiological conditions, is scavenged early after SAH by hemoglobin derivatives, leading to microcirculatory dysfunction, pericyte constriction, and impaired neurovascular coupling. Conversely, ET-1 exacerbates vasoconstriction by suppressing NO synthesis via ROS-dependent eNOS uncoupling and Rho-kinase activation. The NO/ET-1 axis further influences delayed cerebral ischemia (DCI) through mechanisms like 20-HETE-mediated cGMP suppression and oxidative stress. Emerging therapies—including NO donors, NOS gene therapy, and ET-1 receptor antagonists—aim to restore this balance. Understanding these pathways offers translational potential for mitigating CVS and improving outcomes post-SAH. Full article

Fluoride is a widespread environmental toxin that disrupts metabolic and endocrine functions, but its impact on pancreatic inflammation and hormone secretion remains unclear. This study examined how chronic fluoride exposure affects pancreatic inflammation and secretory function in rats. Pregnant Wistar rats received sodium fluoride (NaF) at 50 mg/L in drinking water during gestation and lactation. Male offspring continued exposure until 3 months old. Controls received fluoride-free water. Pancreatic tissue and serum were collected. Fluoride levels were measured potentiometrically. Eicosanoids were quantified by SPE and HPLC. Serum insulin, glucagon, and somatostatin were measured by ELISA. Histological and biochemical markers of inflammation and oxidative stress were assessed. Fluoride exposure did not lead to significant accumulation in the pancreas or serum. However, fluoride-exposed rats exhibited a significant decrease in serum insulin and somatostatin concentrations, while glucagon levels remained unchanged. Additionally, the pancreas of fluoride-treated animals showed markedly elevated levels of pro-inflammatory eicosanoids, including prostaglandin E2, leukotrienes A4 and B4, and HETE/HODE derivatives, indicating activation of cyclooxygenase and lipoxygenase pathways. Sustained low-dose fluoride exposure induced pancreatic inflammation and disrupted endocrine homeostasis in rats. These findings suggest that chronic fluoride intake may impair insulin secretion and promote pre-diabetic alterations, warranting further research. Full article

Background: Pathological pregnancy is associated with various complications that may affect the health of both the mother and her offspring. In recent years, lipid metabolites such as hydroxyeicosatetraenoic (HETE) fatty acids and hydroxyoctadecadienoic (HODE) fatty acids have gained increasing interest as potential biomarkers of pathological processes in pregnancy. The aims of the present study were to investigate changes in HETE and HODE levels during pathological pregnancy and to assess their potential role in the development and monitoring of pregnancy complications. Attempts were made to determine associations in cross-sectional studies and relationships in longitudinal ones. Methods: In this study, a liquid chromatograph (HPLC) was used to separate the eicosanoids. The study group consisted of 72 Caucasian women, divided into a control group (n = 51) and a group with non-physiological pregnancy (n = 21). Results: The study results show that the levels of the tested metabolites of the cyclooxygenase (COX) and lipoxygenase (LOX) pathways increased as pregnancy progressed. Women with non-physiological courses of pregnancy who developed gestational diabetes and/or preeclampsia were characterized by dysregulation of the inflammatory signaling processes involving eicosanoids. Conclusions: Carbohydrate abnormalities during pregnancy were mainly associated with increased synthesis of 5-oxoETE and the use of 5-HETE in the control group but were not visible in the diabetic group. HODE acids probably do not play a significant role in pathological pregnancy. The relatively small size of the pathological group and the wide range of gestational age mean that the tests should be standardized and carried out on a larger scale. Full article

Ischemic stroke is a leading cause of mortality and disability in adults. The inflammatory cascade is driven by various inflammatory molecules, such as interleukin-1β (IL-1β), and counteracted by its antagonist, interleukin-1 receptor antagonist (IL-1Ra). Eicosanoids are inflammatory derivatives of free fatty acids. Arachidonic acid (AA) derivatives exhibit pro-inflammatory activity, while eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derivatives, known as specialized pro-resolving mediators, have anti-inflammatory properties. This study aimed to analyze potential associations between eicosanoids and key inflammatory molecules, including IL-1β and its antagonist IL-1Ra. In this prospective study, we investigated inflammatory molecules in 73 ischemic stroke patients. We analyzed interactions between IL-1β, IL-1Ra, and eicosanoids as follows: resolvin E1, prostaglandin E2, resolvin D1, lipoxin A4 (5S, 6R, 15R), protectin DX, maresin 1, leukotriene B4, 18RS-HEPE, 13S-HODE, 9S-HODE, 15S-HETE, 17 HDHA, 12S-HETE, 5-oxo-ETE, and 5-HETE. In 73 ischemic stroke patients, mean IL-1β was 1.31 ± 1.54 pg/mL and IL-1Ra 810.8 ± 691.0 pg/mL. Spearman correlations showed positive associations between IL-1β and protectin DX (ρ = 0.56, p < 0.001), and 17 HDHA (ρ = 0.26, p < 0.05) and 5-oxo-ETE (ρ = 0.27, p < 0.05). IL-1Ra correlated negatively with protectin DX (ρ = −0.58, p < 0.001) and 17 HDHA (ρ = −0.29, p < 0.05), and positively with leukotriene B4 (ρ = 0.34, p < 0.005). After multivariable adjustment, associations with IL-1β lost statistical significance, whereas the inverse relationships between IL-1Ra and protectin DX/17 HDHA remained significant (p < 0.005). Despite the known anti-inflammatory roles of protectin DX and 17 HDHA, and the pro-inflammatory role of leukotriene B4, their activity in the early subacute phase of ischemic stroke appears to be influenced by complex interplays, possibly mediated by IL-1β and IL-1Ra. The activity of protectin DX, 17 HDHA, and leukotriene B4 is correlated with IL-1β and IL-1Ra levels in the early subacute phase of stroke. Full article

Background: Atherosclerosis is a chronic vascular disease triggered by lipid accumulation. Auricularia heimuer is rich in various bioactive compounds that have anti-inflammatory, antioxidant, and hypolipidemic properties. The specific beneficial effects of A. heimuer on atherosclerosis and its underlying mechanisms require further investigation. Methods: In this study, ApoE^−/− mice were utilized as models of atherosclerosis induced by a high-fat diet (HFD) to investigate the effects of A. heimuer. Analyses of gut microbiota and serum metabolomics were conducted to elucidate the potential mechanism. Results: In HFD-fed ApoE^−/− mice, A. heimuer significantly inhibited the increase in body weight, regulated lipid levels, and alleviated aortic lesions. A. heimuer also modulated the abundance of intestinal flora such as Akkermansia and Ruminococcus and altered the levels of serum metabolites, including 12(S)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HETE) and N-acetyl galactosamine 4-sulfate. Furthermore, A. heimuer alleviated oxidative stress and inflammatory responses, thereby mitigating atherosclerosis via the Nrf2/NF-κB signaling pathway. Conclusions: These findings suggest that A. heimuer may serve as a potential therapeutic strategy for atherosclerosis. Full article

Although significant advances in the treatment of breast cancer have been made over the last few decades, searching for more effective prophylaxis and therapy for this type of cancer is still topical. Orphan cytochromes (CYPs) P450 are enzymes whose functions and substrates are not fully known. The overexpression of some orphan CYPs in breast cancer tissue warrants attention as a possible breast cancer prophylaxis/treatment target or biomarker. Of particular interest is CYP4Z1, which seems to be specific for breast cancer, including triple-negative breast cancer (TNBC). The currently available data indicate that inhibition of CYP4Z1 breast-specific expression may reduce the growth, progression, angiogenesis, and invasiveness of breast cancer. Although less specific, the other orphan CYPs, such as CYP2W1, CYP2S1, CYP2U1, and CYP4X1, exhibit significantly higher expression in breast tumors compared to normal tissues. The available data indicate that these CYP isoforms catalyze the hydroxylation of fatty acids. Their products, such as epoxyeicosatrienoic acids (EETs) or hydroxyeicosatetraenoic acids (HETEs), are considered critical modulators of cancer progression. Therefore, inhibition of the expression and activity of these orphan CYPs might be more useful in cancer treatment than in prophylaxis. This review summarizes current knowledge of orphan CYPs in breast tissue and their possible application in drug targeting or prognosis assessment. Full article

Background/Objectives: Lichen simplex chronicus (LSC) of the vulva is a chronic dermatologic disorder characterized by persistent pruritus, compulsive scratching, and progressive thickening of the vulvar skin. Currently, LSC diagnosis primarily relies on clinical presentation, with histopathological examination performed when the diagnosis is unclear. However, the precise pathogenic mechanisms driving the disease remain poorly understood. This study aimed to investigate the pathogenesis of LSC and evaluate the feasibility of tape stripping as a non-invasive diagnostic technique. Methods: Skin specimens were obtained using both traditional biopsy and tape stripping methods, and the metabolites and oxidized lipids in these samples were analyzed using advanced mass spectrometry techniques. Results: Our findings suggest that 20-hydroxyeicosatetraenoic acid (20-HETE), an oxidized derivative of arachidonic acid (AA), activates the TRPV1 receptor, thereby exacerbating the itch–scratch cycle. This activation upregulates energy metabolism and promotes epidermal hyperplasia, providing new insights into the disease’s pathophysiology. Conclusions: Our study suggests that tape stripping could serve as a viable non-invasive diagnostic tool for LSC, with linoleic acid (LA) and AA potentially acting as biomarkers for the disease. Full article

Chronic kidney disease (CKD) has now reached epidemic proportions in many parts of the world, primarily due to the high incidence of diabetes and hypertension. By 2040, CKD is predicted to be the fifth-leading cause of years of life lost. Developing strategies to prevent CKD and to reduce its progression to kidney failure is thus of great public health significance. Hypertension is known to be both a cause and a consequence of kidney damage and an eminently modifiable risk factor. An increased risk of hypertension, especially among women, has been linked to chronic exposure to the ubiquitous food contaminant cadmium (Cd). The mechanism is unclear but is likely to involve its action on the proximal tubular cells (PTCs) of the kidney, where Cd accumulates. Here, it leads to chronic tubular injury and a sustained drop in the estimated glomerular filtration rate (eGFR), a common sequela of ischemic acute tubular necrosis and acute and chronic tubulointerstitial inflammation, all of which hinder glomerular filtration. The present review discusses exposure levels of Cd that have been associated with an increased risk of hypertension, albuminuria, and eGFR ≤ 60 mL/min/1.73 m² (low eGFR) in environmentally exposed people. It highlights the potential role of 20-hydroxyeicosatetraenoic acid (20-HETE), the second messenger produced in the kidneys, as the contributing factor to gender-differentiated effects of Cd-induced hypertension. Use of GFR loss and albumin excretion in toxicological risk calculation, and derivation of Cd exposure limits, instead of β₂-microglobulin (β₂M) excretion at a rate of 300 µg/g creatinine, are recommended. Full article

The incidence of Hashimoto’s disease (HD) increases with age and in people who have other autoimmune diseases. It is characterized by lymphocytic infiltration, fibrosis, and atrophy of the thyroid parenchyma with the simultaneous presence of thyroid peroxidase antibodies (ATPO) and/or thyroglobulin antibodies (ATG). Eicosanoids are formed via the cyclooxygenase (COX), lipoxygenase (LOX), and monooxygenase (CYP450) pathways with arachidonic acid (ARA), resulting in the production of epoxyeicosatrienoic acids (EETs) or hydroxyeicosatetraenoic acids (HETEs). These eicosanoids can act in an autocrine or paracrine manner on target cells. This study aimed to examine whether a gluten-free diet (GFD) can modulate the enzymatic pathways of the pro-inflammatory ARA cascade. The study material consisted of serum samples from Caucasian female patients with HD aged 18–55 years. Participants were enrolled in the study based on the presence of an ultrasound characteristic of HD, and elevated serum levels of anti-thyroid peroxidase antibodies and anti-thyroglobulin antibodies. Patients with confirmed celiac disease did not participate in the study. A total of 78 samples were analyzed, with 39 collected after 3 months of following a GFD. Eicosanoids (thromboxane B2, prostaglandin E2, leukotriene B4, and 16R-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid (16-RS HETE)) were extracted using high-performance liquid chromatography. The contribution of leukotriene (LTB) was analyzed in the LOX pathway, prostaglandins (PGE2) and thromboxane (TXB2) were selected for the involvement of the COX pathway, and 16RS HETE was used for the CYP450 pathway. All parameters were analyzed before and after a 3-month dietary intervention that included a gluten-free diet. In the obtained results, only one mediator, leukotriene B4, was significant (p < 0.05). The mean level on the initial visit was 0.202 ± 0.11 (SD), while it was 0.421 ± 0.27 (SD) on the subsequent visit, indicating a significant increase in its level after implementing a GFD. Although there was a trend in the CYP 450 pathway of decreased 16-RS HETE, the presented correlations show that thromboxane B4 and 16RS-HETE were positively correlated with the body mass and body fat mass of the examined patients. There was a trend in the CYP 450 pathway of decreased 16-RS HETE after GFD. Thromboxane B4 and 16RS-HETE levels before GFD were positively correlated with the body mass and body fat mass of the examined patients. A gluten-free diet in HD does not suppress the synthetic pathways of LOX, COX, or cytochrome P450 (CYP450). The level of adipose tissue has a greater impact on the inflammatory processes in HD than a gluten-free diet. This study does not confirm the suppressive effect of a gluten-free diet on the pro-inflammatory arachidonic acid cascade in any of the three analyzed mediator synthesis LOX, COX, CYP450 pathways. Full article

This study aims to explore the pathogenic mechanism of H-type hypertension. A rat model of H-type hypertension was established through high-methionine dietary intervention, with subsequent folic acid administration. Untargeted serum metabolomic profiling identified a significant reduction in arachidonic acid (AA) levels in the methionine-enriched group, which were effectively normalized following folic acid supplementation. Transcriptomic analysis revealed methionine-induced upregulation of AA pathway-associated genes Cyp1a1 and Gpr75. In contrast, after the intervention with folic acid, a downregulation of these genes was observed. These findings were corroborated through Western blotting and RT-qPCR validation. In vitro studies using EA.hy926 endothelial cells demonstrated that methionine exposure significantly elevated CYP1A1 expression. Furthermore, methionine stimulation induced marked upregulation of GPR75 and its downstream signaling components (NRAS, MEK1, and ERK1). Population-level evidence from the U.S. NHANES database substantiated significant correlations between essential fatty acids (AA, LA, and GLA) and H-type hypertension prevalence. Our research findings suggest that the CYP1A1/20-HETE/GPR75 axis-mediated dysregulation of AA metabolism may be one of the key pathological mechanisms of H-type hypertension. The research results provide clues for the discovery of new therapeutic targets for H-type hypertension. Full article

G protein-coupled receptor 75 (GPR75), a novel member of the rhodopsin-like G protein-coupled receptor (GPCR) family, has been identified across various tissues and organs, where it contributes to biological regulation and disease progression. Recent studies suggest potential interactions between GPR75 and ligands such as 20-hydroxyeicosatetraenoic acid (20-HETE) and C-C motif chemokine ligand 5 (CCL5/RANTES); however, its definitive endogenous ligand remains unidentified, and GPR75 is currently classified as an orphan receptor by International Union of Basic and Clinical Pharmacology (IUPHAR). Research on GPR75 deorphanization has underscored its critical roles in disease models, particularly in metabolic health, glucose regulation, and stability of the nervous and cardiovascular systems. However, the signaling pathways of GPR75 across different pathological conditions require further investigation. Importantly, ongoing studies are targeting GPR75 for drug development, exploring small molecule inhibitors, antibodies, and gene silencing techniques, positioning GPR75 as a promising GPCR target for treating related diseases. This review summarizes the recent advancements in GPR75 deorphanization research, examines its functions across tissues and systems, and highlights its links to metabolic, cardiovascular, and neurological disorders, thereby providing a resource for researchers to better understand the biological functions of this receptor. Full article

Background/Objectives: Neuroinflammation, a hallmark of Alzheimer’s disease (AD), is characterized by elevated levels of inflammatory signaling molecules, including cytokines and eicosanoids, as well as increased microglial reactivity, and is augmented by gut microbiota dysbiosis via the gut–brain axis. We conducted a pilot experiment to elucidate the anti-inflammatory effects of dietary omega-3 polyunsaturated fatty acid (ω-3 PUFA) eicosapentaenoic acid (EPA) on the gut microbiota and neuroinflammation. Methods: Female APP/PS1 mice (TG) and non-transgenic littermates (WT), 13–14 months old, were fed a diet supplemented with 0.3% EPA or control chow for 3 weeks. The gut microbiota composition, hippocampal and plasma eicosanoids levels, platelet activation, and microglial phagocytosis, as well as the brain and retinal genes and protein expression, were analyzed. Results: EPA supplementation decreased the percentage of Bacteroidetes and increased bacteria of the phylum Firmicutes in APP/PS1 and WT mice. Inflammatory lipid mediators were elevated in the hippocampus of the TG mice, accompanied by a reduction in the endocannabinoid docosahexaenoyl ethanolamide (DHEA). Dietary EPA did not affect hippocampal lipid mediators, but reduced the levels of arachidonic-derived 5-HETE and N-arachidonoylethanolamine (AEA) in WT plasma. Moreover, EPA supplementation decreased major histocompatibility complex class II (MHCII) gene expression in the retina in both genotypes, and MHCII+ cells in the hippocampus of TG mice. Conclusions: This pilot study showed that short-term EPA supplementation shaped the gut microbiota by increasing butyrate-producing bacteria of the Firmicutes phylum and decreasing Gram-negative LPS-producing bacteria of the Bacteroidetes phylum, and downregulated the inflammatory microglial marker MHCII in two distinct regions of the central nervous system (CNS). Further investigation is needed to determine whether EPA-mediated effects on the microbiome and microglial MHCII have beneficial long-term effects on AD pathology and cognition. Full article

Soil salinization threatens global agriculture, reducing crop productivity and food security. Developing strategies to improve salt tolerance is crucial for sustainable agriculture. This study examines the role of organic fertilizer in mitigating salt stress in rice (Oryza sativa L.) by integrating NDVI and metabolomics. Using salt-sensitive (19X) and salt-tolerant (HHZ) cultivars, we aimed to (1) evaluate changes in NDVI and metabolite content under salt stress, (2) assess the regulatory effects of organic fertilizer, and (3) identify key metabolites involved in stress response and fertilizer-induced regulation. Under salt stress, survival rate of the 19X plants dropped to 6%, while HHZ maintained 38%, with organic fertilizer increasing survival rate to 25% in 19X and 66% in HHZ. NDVI values declined sharply in 19X (from 0.56 to <0.25) but remained stable in HHZ (~0.56), showing a strong correlation with survival rate (R² = 0.87, p < 0.01). NDVI provided a dynamic, non-destructive assessment of rice health, offering a faster and more precise evaluation of salt tolerance than survival rate analysis. Metabolomic analysis identified 12 key salt-tolerant metabolites, including citric acid, which is well recognized for regulating salt tolerance. HTPA, pipecolic acid, maleamic acid, and myristoleic acid have previously been reported but require further study. Additionally, seven novel salt-tolerant metabolites—tridecylic acid, propentofylline, octadeca penten-3-one, 14,16-dihydroxy-benzoxacyclotetradecine-dione, cyclopentadecanolide, HpODE, and (±)8,9-DiHETE—were discovered, warranting further investigation. Organic fertilizer alleviated salt stress through distinct metabolic mechanisms in each cultivar. In 19X, it enhanced antioxidant defenses and energy metabolism, mitigating oxidative damage and improving fatty acid metabolism. In contrast, HHZ primarily benefitted from improved membrane stability and ion homeostasis, reducing lipid peroxidation and oxidative stress. These findings primarily support the identification and screening of salt-tolerant rice cultivars while also highlighting the need for cultivar-specific fertilization strategies to optimize stress resilience and crop performance. Based on the correlation analysis, 26 out of 53 differential metabolites were significantly correlated with NDVI, confirming a strong association between NDVI shifts and key metabolic changes in response to salt stress and organic fertilizer application. By integrating NDVI and metabolomics, this study provides a refined method for evaluating salt stress responses, capturing early NDVI changes and key salinity stress biomarkers. This approach may prove valuable for application in salt-tolerant variety screening, precision agriculture, and sustainable farming, contributing to scientific strategies for future crop improvement and agricultural resilience. Full article

Drought stress seriously threatens human food security, and enhancing crops’ drought tolerance is an urgent problem to be solved in breeding. Quinoa is known for its high nutritional value and strong drought tolerance, but its molecular mechanism in response to drought stress is still unclear. In this study, we used drought-tolerant (D2) and drought-sensitive (ZK1) quinoa varieties, and PEG-6000 was used to simulate drought stress in quinoa seedlings. Phenotypic and physiological biochemical indicators were measured during the seedling stage, and LC-MS was used for a metabolite analysis of drought stress to explore the drought tolerance mechanism of quinoa under drought stress. With the intensification of drought stress, chlorophyll content gradually increased, and D2 reached its maximum at W4, an increase of 49.85% compared with W1. The total chlorophyll content, photosynthesis rate, and stomatal conductance of ZK1 were significantly lower than D2 under moderate and severe drought stress. Metabolomic results showed that a total of 1295 positive ion mode (pos) metabolites and 914 negative ion mode (neg) metabolites were identified. Of these, 12(R)-HETE, phosphatidylcholine, monogalactose diester (MGDG), and stachyose up-regulated expression under drought stress. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that unsaturated fatty acid biosynthesis and glycerophospholipid metabolism pathways were significantly enriched. In summary, our results elucidate that quinoa responds to drought stress by accumulating chlorophyll and sugars, activating unsaturated fatty acid metabolism, and protecting the photosynthetic system. These findings provide new insights for the breeding of drought-tolerant quinoa varieties and the study of drought tolerance mechanisms. Full article

Background: Astrocytes play a key role in the inflammatory process accompanying various neurological diseases. Extracellular ATP accompanies inflammatory processes in the brain, but its effect on lipid mediators (oxylipins) in astrocytes remains elusive. Metformin is a hypoglycemic drug with an anti-inflammatory effect that has been actively investigated in the context of therapy for neuroinflammation, but its mechanisms of action are not fully elucidated. Therefore, we aimed to characterize the effects of ATP on inflammatory markers and oxylipin profiles; determine the dependence of these effects on the adaptation of astrocytes to high glucose levels; and evaluate the possibility of modulating ATP effects using metformin. Methods: We estimated the ATP-mediated response of primary rat astrocytes cultured at normal (NG, 5 mM) and high (HG, 22.5 mM) glucose concentrations for 48 h before stimulation. Cell responses were assessed by monitoring changes in the expression of inflammatory markers (TNFα, IL-6, IL-10, IL-1β, iNOS, and COX-2) and the synthesis of oxylipins (41 compounds), assayed with ultra-high-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). Intracellular pathways were assessed by analyzing the phosphorylation of p38; ERK MAPK; transcription factors STAT3 and NF-κB; and the enzymes mediating oxylipin synthesis, COX-1 and cPLA2. Results: The stimulation of cells with ATP does not affect the expression of pro-inflammatory markers, increases the activities of p38 and ERK MAPKs, and activates oxylipin synthesis, shifting the profiles toward an increase in anti-inflammatory compounds (PGD2, PGA2, 12-HHT, and 18-HEPE). The ATP effects are reduced in HG astrocytes. Metformin potentiated ATP-induced oxylipin synthesis (11-HETE, PGD2, 12-HHT, 15-HETE, 13-HDoHE, and 15-HETrE), which was predominantly evident in NG cells. Conclusions: Our data provide new evidence showing that ATP induces the release of anti-inflammatory oxylipins, and metformin enhances these effects. These results should be considered in the development of anti-inflammatory therapeutic approaches aimed at modulating astrocyte function in various pathologies. Full article