A hallmark of cystic fibrosis (CF) is dysregulated lipid metabolism marked by an imbalance of pro-inflammatory to pro-resolving metabolites. Despite the breadth of evidence associating mutation of the cystic fibrosis conductance regulator (CFTR) with dysregulation of the production of oxylipins, oxidized lipid mediators with specialized functions generated during inflammation, few studies have directly measured whether overexpression of wild-type (WT) CFTR is sufficient to equilibrate oxylipin levels in CF models. In this study, targeted lipidomics was used to compare the oxylipin profiles of the parental CFBE41o- immortalized bronchial epithelial cell line homozygous for F508del CFTR, the most common CFTR mutation in people with CF, with the same cell line overexpressing WT CFTR (CFBE41o- o/e WT CFTR). Overexpression of WT CFTR in the CFBE41o- background resulted in decreased production of prostaglandins and increased production of precursors of specialized pro-resolving mediators, including 14,15-epoxyeicosatrienoic acid (14(15)-EET) compared to the parent CFBE41o- cell line, likely due to a decrease in production of inducible COX-2 associated with inflammation and an increase in COX-1 and PPARγ associated with resolution of inflammation. Additionally, highly effective modulator therapy (HEMT) improves pulmonary health for people with CF (PwCF) by targeting the underlying biochemical dysfunction of mutant CFTR. However, its impact on dysregulated lipid metabolism remains under-investigated. Despite inducing production and trafficking of F508del CFTR, treatment of the CFBE41o- parental cell line monolayers with the HEMT elexacaftor-tezacaftor-ivacaftor (ETI) increased levels of the prostaglandin E2 (PGE). This disparity in cellular response by CFBE41o- cells to overexpression of WT CFTR and exposure to ETI was due to differences in production of prostaglandin biosynthetic and regulatory proteins upstream of oxylipin biosynthesis.

Murine bone marrow-derived macrophages (BMDMs) are widely used to study macrophage functions in vitro. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are routinely used to differentiate monocytes into M1- and M2-like macrophages, respectively. Although macrophage-derived eicosanoids regulate both inflammation and its resolution, the impact of these differentiation factors on eicosanoid production remains poorly understood. Additionally, eicosanoid secretion and transportation has never been characterised in these macrophage populations. In the present study, we show that BMDMs differentiated in the presence of GM-CSF (hereafter referred to as GM-BMDMs) produce markedly lower levels of arachidonic acid (AA)-derived prostanoids following lipopolysaccharide (LPS) activation than macrophages differentiated with M-CSF (hereafter referred to as M-BMDMs). Moreover, we found that GM-BMDMs failed to rapidly release LPS-induced prostanoids. Mechanistically, this delayed release of prostanoids likely arises from reduced expression of the prostaglandin efflux transporter multidrug resistance protein-4 (MRP4) alongside a concomitant upregulation of the influx prostaglandin transporter (PGT). Our results also highlight that analyses of both cell pellets and supernatants are essential when comparing oxylipin profiles between M1- and M2-like macrophages. We next studied the phagocytic capacity of GM-BMDMs and found that GM-BMDMs display a blunted increase in phagocytosis of fluorescent E. coli bioparticles after LPS stimulation compared to M-BMDMs. Pharmacological inhibition of microsomal prostaglandin E synthase-1 (mPGES-1), but not cyclooxygenase-2 (COX-2), promotes phagocytic capacity, suggesting that mPGES-1 inhibitors may be superior to COX-2 inhibitors for suppressing inflammation. Collectively, our findings reveal that GM-CSF not only modulates the production and trafficking of prostanoids but also constrains phagocytic activity in response to LPS, which can be enhanced by mPGES-1 inhibition.

Essential hypertension (EH) contributes to death and morbidity. CYP4 genes influence EH via 20-hydroxyeicosatetraenoic acid production. Identifying genetic risk factors may reveal biomarkers for EH among Jordanian patients.

Efficient recycling of red blood cells (RBCs) requires not only heme cleavage but also stabilization of reactive intermediates generated during iron liberation. Lipocalin Prostaglandin D₂ Synthase (L-PGDS, β-trace protein), best known for prostaglandin synthesis, possesses structural and biochemical features consistent with a buffering role in heme catabolism. Here, we show that L-PGDS knockout mice exhibit elevated plasma, increased total splenic iron, reduced total hepatic iron, decreased plasma free heme/hemin, and modest RBC enlargement, consistent with disrupted iron release. Transcript-protein mismatches in key iron regulators, including NRF2 and FPN, further suggest redox imbalance and impaired iron sensing. Despite normal Hmox1 expression, these mice display widespread evidence of inefficient porphyrin clearance. Combined with prior findings that L-PGDS binds ferric biliverdin and is upregulated during heme overload, our results support a model in which L-PGDS buffers porphyrin intermediates to facilitate their safe processing and clearance. This study identifies L-PGDS as a putative auxiliary factor in heme catabolism, with implications for iron recycling, erythropoiesis, and systemic iron homeostasis. All data in this report are from male mice.

Estradiol is a critical hormone that regulates morphological and functional changes in the bovine endometrium throughout the estrous cycle. Prostaglandin E (PGE), a well-established inflammatory mediator, also plays an essential role in endometrial physiology. Whether PGE acts as an intermediary in estradiol-related activities within the bovine endometrium remains unclear. The results revealed that 17β-estradiol at 10M and 10M induced PGE secretion in endometrial explants, whereas a higher concentration (10M) downregulated PGE₂ secretion. In endometrial epithelial cells, 17β-estradiol at concentrations ranging from 10 to 10M stimulated PGE secretion. In endometrial stromal cells, 17β-estradiol at 10 to 10M concentrations promoted PGE production. PGE synthesis was inhibited by the mPGES-1 inhibitor MF63 [2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl) isophthalonitrile] in the presence of 17β-estradiol (10M), highlighting mPGES-1 as a key enzyme in 17β-estradiol-induced PGE production in the bovine endometrium. Furthermore, both the mRNA and protein levels of endometrial growth factors, including fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor A (VEGFA), matrix metalloproteinase-2 (MMP-2), and MMP-9, were increased by 17β-estradiol (10M). This effect was reversed by pretreatment with the mPGES-1 inhibitor MF63 in endometrial cells and explants. Notably, supplementation with exogenous PGE restored the expression of these growth factors in the presence of both 17β-estradiol (10M) and MF63. In conclusion, mPGES-1-derived PGE serves as a crucial mediator of the 17β-estradiol-induced expression of FGF-2, VEGFA, MMP-2, and MMP-9 in the bovine endometrium, underscoring its significant role in regulating endometrial function.

Multidrug resistance (MDR) is a major dilemma in the effective chemotherapy treatment of breast cancer. Potential strategies to combat MDR include inhibiting efflux pumps such as ATP-binding cassette (ABC) transporters and calcium channel pumps like transient receptor potential (TRP) channels and blocking the metastatic pathway by inhibiting the antiapoptotic proteins like Bcl-2, while enhancing the apoptotic proteins like caspase-3.

Acute lung injury (ALI) is a common disorder of the respiratory system with high mortality. Inducing mitophagy is generally considered to be an effective target for alleviating ALI. We aimed to elucidate the role of immunity related GTPase M (IRGM) in ALI by using a lipopolysaccharide (LPS)-induced alveolar epithelial cell model. Firstly, IRGM expression in A549 cells under LPS conditions was evaluated. Then, IRGM was upregulated and oxidative stress was evaluated by measuring intracellular reactive oxygen species (ROS) using 2', 7'-Dichlorofluorescin diacetate (DCFH-DA) staining. The permeability of A549 cells was determined by detecting transepithelial electrical resistance (TEER) value and fluorescein isothiocyanate-dextran 4 (FITC-FD4) fluorescence. Proteins related to epithelial barrier, mitophagy and mitochondrial function were assessed. Further Mdivi-1 (an inhibitor of mitophagy) addition or cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) signaling overexpression was conducted to investigate the potential mechanism. Results suggested that IRGM was downregulated in LPS-treated A549 cells and IRGM upregulation alleviated LPS-induced oxidative stress, inflammation and barrier dysfunction in A549 cells. IRGM upregulation induced mitophagy and maintains mitochondrial function in LPS-treated A549 cells. Particularly, Mdivi-1 treatment or cGAS overexpression abrogated the impacts of IRGM upregulation on oxidative stress, inflammation and barrier dysfunction in LPS-treated A549 cells. Collectively, IRGM attenuates LPS-triggered alveolar epithelial cell damage by enhancing mitophagy to inactivate cGAS/STING signaling.

Lysophosphatidic acid (LPA), a small bioactive glycerophospholipid, has been reported to play an indispensable role in the regulation of a wide range of cellular processes, including cell proliferation, morphology, differentiation, invasion, migration, and apoptosis. Besides, it has a diverse role in the development, differentiation, migration, and trafficking of immune cells. The role of LPA in the functioning of immune cells, such as macrophages, natural killer cells, T cells, and B cells has been poorly understood and is still a major thrust area for immunological research. Further, accumulating experimental evidence indicates the pro-tumoral action of LPA in various cancers, including hematological malignancies. Hematological malignancies or blood cancers are a group of neoplastic conditions derived from the cells of hematopoietic tissues. LPA is reported to promote the development and progression of cancers of hematological origin through altering apoptosis, invasion and migration, metabolism, and anti-tumor immune response. But still, the mechanistic pathways by which LPA supports the development and progression of hematological malignancies are not well explored. The present review aims to provide an elaborate survey on the role of LPA in the functioning of immune cells and its implication in hematological malignancies.

This study aimed to investigate brain signaling mechanisms affected by estradiol deficiency during menopause and how these pathways are modified with 17β-estradiol replacement to mitigate menopause-related changes, particularly in cognitive function and neuroinflammation, which are linked to the risk of dementia. Forty female white albino rats were divided into four groups: control, sham, ovariectomized (OVX), and OVX rats treated with 17β-estradiol. Cognitive tests using the Morris Water Maze assessed spatial learning and memory, while neurotransmitter levels were analyzed via HPLC. Serum levels of estrogen, Nerve Growth Factor (NGF), amyloid precursor protein(Aβ), and Postsynaptic Density Protein 95 (PSD-95) were measured using ELISA. Additionally, RT-PCR was used to evaluate the expression of gap junction protein connexin-43 (Cx43), Lipoprotein receptor-related protein (LRP1), and receptor for advanced glycation end products (RAGE), and aromatase expression was assessed via immunohistochemistry. Results showed that estrogen deficiency in OVX rats led to significant impairments in cognition, neurotransmitter signaling, and neurotrophic factors. Reduced NGF and altered PSD-95 levels indicated compromised neuronal health and synaptic plasticity. Increased aromatase expression reflected reduced local estrogen synthesis, potentially contributing to cognitive deficits. Upregulated RAGE and altered LRP1 expression suggested inflammatory and neurodegenerative processes, while decreased Cx43 expression and modified Aβ processing indicated impaired intercellular communication. Overall, the findings highlight the detrimental effects of estrogen deficiency on brain function and suggest that 17β-estradiol replacement may mitigate menopause-related cognitive decline and neuroinflammation.

Atherosclerosis is an inflammatory condition that contributes to myocardial infarction, cardiac arrest and stroke. Current knowledge of mushroom metabolomics in the context of atherosclerosis remains inadequate. Hence, further investigation into the underlying pathways and characterization of metabolites is necessary to establish a significant network for early-stage diagnosis of atherosclerosis. Therefore, the standard phytopreparation of Schizophyllum commune (SPPSC) was administered in hypercholesterolemic-induced rats. Sera were evaluated for lipid profile parameters; hepatic marker enzymes and the metabolic profile characterization was determined via liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). SPPSC suppressed the elevation of cholesterol, LDL, triglyceride and atherogenic coefficient levels while increased HDL concentration and restored the function of hepatic antioxidant enzymes. The predictive accuracies and partial least square discriminant analysis (PLS-DA) revealed clear separation in metabolic features between normal, untreated, olive oil and SPPSC treated groups. Pathway analysis of the most significant metabolites targeted towards anti-atherosclerotic and cardio-protective activities were tryptophan metabolism, sphingolipid metabolism, β-alanine metabolism, taurine and hypotaurine metabolism, glutathione metabolism, phenylalanine metabolism, primary bile acid biosynthesis, histidine metabolism, pantothenate and CoA biosynthesis and cysteine and methionine metabolism. Identified metabolites indicate that S. commune is novel in preventing atherosclerosis and enhancing endogenous antioxidant system, protecting the cardiovascular system, minimalizing inflammation and regulating endothelial dysfunction.

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of cirrhosis and a major risk factor for hepatocellular carcinoma and liver-related death. Diabetes medications have been studied as potential treatments for NAFLD. Glucagon-like peptide-1 agonists (GLP-1RAs) have been rarely reported in the treatment of NAFLD alone as an anti-diabetic drug, and its specific mechanism of action is unknown. We investigated whether the therapeutic effect of liraglutide (LRG, a representative drug of GLP-1RAs) on hepatic steatosis is related to regulating lipid metabolism and enhancing autophagy in the hepatocytes.

Oxidative stress is caused by an imbalance between accumulation and production of oxygen reactive species (ROS) in tissues and cells and play a key role in many diseases. This systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to analyze the effects of walnut consumption on biomarkers of oxidative stress. Databases including PubMed, Scopus, Embase and Web of science were searched until November 30th, 2024. Data were subjected to meta-analysis using a random effects model to examine the effect sizes of the pooled results. Four studies were identified eligible to be included in current meta-analysis. Walnut consumption resulted in a significant increase in catalase activity (CAT) (WMD: 42.20; 95 % CI: 34.28, 50.11). Walnut consumption did not affect other biomarkers of oxidative stress such as lipid peroxidation (LPO), reduced glutathione (GSH), oxidized glutathione (GSSG) and oxygen radical absorbance capacity (ORAC). Overall, this meta-analysis demonstrated walnut consumption increase CAT, but did not affect other biomarkers of oxidative stress. This suggests that walnut may have played an indirect and mild role in health. However, due to the limited number of studies, further investigations is suggested in this regard.

Pomegranate, rich in bioactive compounds such as polyphenols and flavonoids, has been studied for its potential lipid-modulating effects, yet evidence remains inconsistent. This systematic review and meta-analysis aimed to evaluate the impact of pomegranate consumption on plasma lipid profiles by synthesizing data from randomized controlled trials (RCTs). Following PRISMA guidelines, 37 RCTs (n = 2695 participants) were included after searching Scopus and MEDLINE databases. Studies assessed pomegranate products (juice, extract, seed oil) administered orally for ≥ 7 days, with lipid parameters, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) as outcomes. Data were pooled using RevMan 5.3 with random-effects models. Results indicated that pomegranate intake significantly increased HDL-C levels (mean difference: 2.50 mg/dL, 95 % CI: 1.00-4.00, p < 0.05), while no significant changes were observed in TC, LDL-C, or TG. Subgroup analyses revealed pronounced HDL-C elevation in non-alcoholic fatty liver disease (NAFLD) patients, health participants and interventions lasting ≥ 8 weeks. Heterogeneity across studies was attributed to variations in intervention duration, dosage forms, and participant characteristics. Publication bias was nonsignificant (Egger's test, p > 0.05). These findings suggest that pomegranate supplementation may improve HDL-C, potentially through modulation of HDL-associated enzymes like paraoxonase. However, further large-scale, long-term RCTs are warranted to confirm these effects and explore synergistic benefits with standard lipid-lowering therapies.

Age-related diseases are often associated with a disruption of RedOx balance that can lead to lipid peroxidation with the formation of oxysterols, especially those oxidized on carbon-7: 7-ketocholesterol (also known as 7-oxo-cholesterol) and 7β-hydroxycholesterol. Like cholesterol, these oxysterols have 27 carbons, they are composed of a sterane nucleus and have a hydroxyl function in position 3. The oxysterols 7-ketocholesterol and 7β-hydroxycholesterol are mainly formed by cholesterol autoxidation and are biomarkers of oxidative stress. These two oxysterols are frequently found at increased levels in the biological fluids (plasma, cerebrospinal fluid), tissues and/or organs (arterial wall, retina, brain) of patients with age-related diseases, especially cardiovascular diseases, neurodegenerative diseases (mainly Alzheimer's disease), ocular diseases (cataract, age-related macular degeneration), and sarcopenia. Depending on the cell type considered, 7-ketocholesterol and 7β-hydroxycholesterol induce either caspase- dependent or -independent types of cell death associated with mitochondrial and peroxisomal dysfunctions, autophagy and oxidative stress. The caspase dependent type of cell death associated with oxidative stress and autophagy is defined as oxiapoptophagy. These two oxysterols are also inducers of inflammation. These biological features associated with the toxicity of 7-ketocholesterol, and 7β-hydroxycholesterol are often observed in patients with age-related diseases, suggesting an involvement of these oxysterols in the pathophysiology of these disorders. The cytotoxic effects of 7-ketocholesterol and 7β-hydroxycholesterol are counteracted on different cell models by representative nutrients of the Mediterranean diet: ω3 and ω9 fatty acids, polyphenols, and tocopherols. There are also evidences, mainly in cardiovascular diseases, of the benefits of α-tocopherol and phenolic compounds. These in vitro and in vivo observations on 7-ketocholesterol and 7β-hydroxycholesterol, which are frequently increased in age-related diseases, reinforce the interest of nutritherapeutic treatments to prevent and/or cure age-related diseases currently without effective therapies.

Curcumin is a bioactive compound derived from the rhizome of Curcuma longa (turmeric) that has garnered increasing attention for its potential health benefits. However, its use in clinical practice is limited due to its generally poor bioavailability. This issue can be overcome using novel delivery systems that enhance curcumin's solubility, extend its residence time in plasma, improve its pharmacokinetic profile, and increase its cellular uptake. Novel curcumin formulations with improved bioavailability have been suggested to elevate plasma concentrations of lipoprotein(a) (Lp(a)), but there is no definitive evidence of a causal relationship. To address this, a systematic literature search was conducted in multiple electronic databases to identify relevant randomized placebo-controlled clinical studies published without a time limit. A meta-analysis of data suggested that dietary supplementation with highly bioavailable forms of curcumin significantly reduces Lp(a) levels [Standardized Mean Difference (SMD)= -0.96 (95 % Confidence Interval (CI): -1.82, -0.11)]. The effect size was robust in the leave-one-out sensitivity analysis and was not primarily driven by any single study. Of course, the clinical significance of this observation should be more thoroughly evaluated in longer-term trials, where the combined metabolic and anti-inflammatory effects of curcumin have vascular protective effects.

A major challenge in cancer treatment is the detrimental effects of anticancer drugs on healthy organs and tissues. This study aims to investigate the protective effects of Lutein (LU) against Cisplatin (CT)-induced toxicity in rat liver, utilizing biochemical and histopathological assessments.

Lipid droplets (LDs) are essential intracellular organelles involved in lipid storage and metabolism, playing critical roles in various cellular processes and diseases. Researchers require efficiently isolate and analyze LDs to understand lipid metabolism and related pathologies. This review summarizes recent advances in LD isolation methods, including traditional techniques such as centrifugation and density gradient centrifugation, as well as emerging technologies like automated and high-throughput approaches. We explore the applications of these methods in lipid metabolism research and discuss the challenges faced by current isolation techniques. Future directions, including automation, single-cell analysis, and integration with advanced analytical tools, are also highlighted to provide insights for the next generation of LD research.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver condition associated with metabolic syndrome, often aggravated by inflammation and mitochondrial dysfunction. This study aims to explore the therapeutic potential of magnoflorine, an alkaloid with known anti-inflammatory properties, in ameliorating NAFLD by modulating mitochondrial autophagy and inhibiting the NLRP3 inflammasome.

Phagocytosis is a key process in human innate immune response. Human macrophages are important phagocytes engulfing and neutralizing pathogens and cell debris. In addition, they modulate the inflammatory process by releasing cytokines and lipid mediators. However, the link between oxylipins and phagocytosis in different macrophage phenotypes remains poorly understood. In order to better understand the link between phagocytosis and the arachidonic acid (ARA) cascade, we established a phagocytosis assay in primary human 'inflammatory' M1- and 'anti-inflammatory' M2-like macrophages from peripheral blood mononuclear cells (PBMC), representing extremes of macrophage phenotypes. The branches of the ARA cascade were investigated by quantitative targeted proteomics and metabolomics. M1-like macrophages show a higher abundance of cyclooxygenase (COX)-2 and its products particularly after LPS stimulus compared to M2-like macrophages. LPS increased phagocytosis in M2-like, but not in M1-like macrophages. We demonstrate that the COX product prostaglandin E2 (PGE) modulates the differential effects of LPS on phagocytosis: Via the EP4 receptor PGE signaling suppresses phagocytosis in primary human macrophages. Thus, blockage of COX, e.g. by non-steroidal anti-inflammatory drugs (NSAID), leads to an increase of phagocytosis also in 'inflammatory' M1-like macrophages. This supports the well-described anti-inflammatory effects of these drugs and underscores the importance of the link between the COX branch of the ARA cascade and the regulation of phagocytosis in human macrophages.