Pub Date : 2025-12-21DOI: 10.1016/j.prostaglandins.2025.107055
Nila Ganamurali , Sarvesh Sabarathinam
Digoxin, a cardiac glycoside with established roles in heart failure and arrhythmia, increasingly exemplifies drug–microbiome–host interactions. Its bioavailability and efficacy are profoundly influenced by Eggerthella lenta–mediated reduction, producing inactive metabolites that reshape systemic physiology. Emerging evidence demonstrates that digoxin-induced gut dysbiosis perturbs arachidonic acid metabolism, altering cyclooxygenase-driven prostaglandin production and disrupting vascular tone and inflammatory homeostasis. These changes extend to lipid regulation, where reduced short-chain fatty acid production and bile acid derangements impair hepatic lipid utilization, promoting steatosis and metabolic dysfunction. This review integrates mechanistic insights into digoxin–microbiota interactions, prostaglandin pathway perturbation, and lipid imbalance, emphasizing their clinical significance and therapeutic implications for precision medicine in cardiovascular care.
{"title":"Digoxin-induced gut dysbiosis: Mechanistic links to prostaglandin dysregulation and lipid metabolic imbalance","authors":"Nila Ganamurali , Sarvesh Sabarathinam","doi":"10.1016/j.prostaglandins.2025.107055","DOIUrl":"10.1016/j.prostaglandins.2025.107055","url":null,"abstract":"<div><div>Digoxin, a cardiac glycoside with established roles in heart failure and arrhythmia, increasingly exemplifies drug–microbiome–host interactions. Its bioavailability and efficacy are profoundly influenced by <em>Eggerthella lenta</em>–mediated reduction, producing inactive metabolites that reshape systemic physiology. Emerging evidence demonstrates that digoxin-induced gut dysbiosis perturbs arachidonic acid metabolism, altering cyclooxygenase-driven prostaglandin production and disrupting vascular tone and inflammatory homeostasis. These changes extend to lipid regulation, where reduced short-chain fatty acid production and bile acid derangements impair hepatic lipid utilization, promoting steatosis and metabolic dysfunction. This review integrates mechanistic insights into digoxin–microbiota interactions, prostaglandin pathway perturbation, and lipid imbalance, emphasizing their clinical significance and therapeutic implications for precision medicine in cardiovascular care.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"182 ","pages":"Article 107055"},"PeriodicalIF":2.5,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-16DOI: 10.1016/j.prostaglandins.2025.107054
Xiaoying Chen , Huiling Jin , Guanyi Zheng
Background
Atherosclerosis is a complex chronic inflammatory disease. Although SREBF1 has been implicated in the regulation of atherosclerotic progression, its precise mechanisms remain incompletely understood.
Methods
The study constructed an in vitro model of atherosclerosis by exposing vascular smooth muscle cells (VSMCs) to oxidized low-density lipoprotein. The model was validated through inverted microscopy, quantitative polymerase chain reaction, and western blotting. The effects of SREBF1 on VSMC’s functions, including proliferation, migration, and clonogenic capacity, were assessed using Cell Counting Kit-8 assays, scratch wound healing assays, and colony formation assays, and western blotting following SREBF1 knockdown or overexpression. The PPARγ signalling pathway was further examined by western blotting and dual-luciferase reporter gene assay.
Results
The experimental results demonstrated that knockdown of SREBF1 significantly enhanced VSMC proliferation and migration while suppressing the expression of the two contractile markers SM22α and α-SMA. Mechanistic studies revealed that SREBF1 directly upregulated PPARγ transcriptional activity, activated PPARγ expression, and inhibited phosphorylated PPARγ expression. Notably, the addition of GW9662, a specific PPARγ signalling inhibitor, partially reversed the regulatory effects of SREBF1 overexpression on VSMC proliferation, migration, and phenotype.
Conclusion
This research found that SREBF1 maintains the contractile phenotype of VSMCs by activating PPARγ signalling, suggesting that SREBF1 may serve as a key molecule in ameliorating atherosclerosis.
{"title":"SREBF1 maintains the contractile phenotype of vascular smooth muscle cells via PPARγ signalling","authors":"Xiaoying Chen , Huiling Jin , Guanyi Zheng","doi":"10.1016/j.prostaglandins.2025.107054","DOIUrl":"10.1016/j.prostaglandins.2025.107054","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis is a complex chronic inflammatory disease. Although SREBF1 has been implicated in the regulation of atherosclerotic progression, its precise mechanisms remain incompletely understood.</div></div><div><h3>Methods</h3><div>The study constructed an <em>in vitro</em> model of atherosclerosis by exposing vascular smooth muscle cells (VSMCs) to oxidized low-density lipoprotein. The model was validated through inverted microscopy, quantitative polymerase chain reaction, and western blotting. The effects of SREBF1 on VSMC’s functions, including proliferation, migration, and clonogenic capacity, were assessed using Cell Counting Kit-8 assays, scratch wound healing assays, and colony formation assays, and western blotting following SREBF1 knockdown or overexpression. The PPARγ signalling pathway was further examined by western blotting and dual-luciferase reporter gene assay.</div></div><div><h3>Results</h3><div>The experimental results demonstrated that knockdown of SREBF1 significantly enhanced VSMC proliferation and migration while suppressing the expression of the two contractile markers SM22α and α-SMA. Mechanistic studies revealed that SREBF1 directly upregulated PPARγ transcriptional activity, activated PPARγ expression, and inhibited phosphorylated PPARγ expression. Notably, the addition of GW9662, a specific PPARγ signalling inhibitor, partially reversed the regulatory effects of SREBF1 overexpression on VSMC proliferation, migration, and phenotype.</div></div><div><h3>Conclusion</h3><div>This research found that SREBF1 maintains the contractile phenotype of VSMCs by activating PPARγ signalling, suggesting that SREBF1 may serve as a key molecule in ameliorating atherosclerosis.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"182 ","pages":"Article 107054"},"PeriodicalIF":2.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1016/j.prostaglandins.2025.107053
Ehsan Pashay Ahi , Andrew H. House
Lipidomics, the comprehensive study of cellular lipids and their roles in biological systems, has become a transformative tool across diverse fields of biology and medicine. Beyond its applications in studying metabolic disorders and cancer, lipidomics is gaining importance in areas such as developmental biology, ecology, and evolution, revealing critical insights into cellular processes and organismal adaptations. However, interpreting lipidomics data at the molecular level, particularly through the lens of signaling pathways, remains a challenge. Despite the central role of signaling pathways in regulating lipid metabolism and signaling, no comprehensive review has systematically compiled these pathways or explored their significance in lipidomics research. This review addresses this gap by providing a structured, catalogue-like overview of signaling pathways that regulate or are influenced by lipid signals. It includes pathways fundamental to lipid metabolism and related lipid-based biological processes, as well as emerging lipid-dependent mechanisms underlying energy balance, environmental adaptation, and developmental processes. Each pathway is briefly discussed in the context of its molecular roles in lipidomics and its potential impact on diverse research fields. By compiling this knowledge, the review serves as a guide for interpreting lipidomics data, identifying key pathways for targeted research, and bridging connections with other scientific disciplines. This structured approach promotes the integration of lipidomics into broader biological contexts, advancing our understanding of lipid-mediated processes and fostering innovation across multiple fields of study.
{"title":"Signaling pathways shaping the field of lipidomics","authors":"Ehsan Pashay Ahi , Andrew H. House","doi":"10.1016/j.prostaglandins.2025.107053","DOIUrl":"10.1016/j.prostaglandins.2025.107053","url":null,"abstract":"<div><div>Lipidomics, the comprehensive study of cellular lipids and their roles in biological systems, has become a transformative tool across diverse fields of biology and medicine. Beyond its applications in studying metabolic disorders and cancer, lipidomics is gaining importance in areas such as developmental biology, ecology, and evolution, revealing critical insights into cellular processes and organismal adaptations. However, interpreting lipidomics data at the molecular level, particularly through the lens of signaling pathways, remains a challenge. Despite the central role of signaling pathways in regulating lipid metabolism and signaling, no comprehensive review has systematically compiled these pathways or explored their significance in lipidomics research. This review addresses this gap by providing a structured, catalogue-like overview of signaling pathways that regulate or are influenced by lipid signals. It includes pathways fundamental to lipid metabolism and related lipid-based biological processes, as well as emerging lipid-dependent mechanisms underlying energy balance, environmental adaptation, and developmental processes. Each pathway is briefly discussed in the context of its molecular roles in lipidomics and its potential impact on diverse research fields. By compiling this knowledge, the review serves as a guide for interpreting lipidomics data, identifying key pathways for targeted research, and bridging connections with other scientific disciplines. This structured approach promotes the integration of lipidomics into broader biological contexts, advancing our understanding of lipid-mediated processes and fostering innovation across multiple fields of study.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"182 ","pages":"Article 107053"},"PeriodicalIF":2.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1016/j.prostaglandins.2025.107052
Rhema Khairnar, Md Asrarul Islam, Kuljeet Singh, Divya K. Shetty, Anjali Yadav, Vikas V. Dukhande, Sunil Kumar
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, and its prevalence poses a serious health threat globally. MASLD is a multifactorial hepatic disorder, but insulin resistance is a key player. Our prior in vivo studies revealed that the absence of lipocalin prostaglandin D2 synthase (L-PGDS) leads to the development of MASLD, often coexisting with insulin resistance. Briefly, L-PGDS belongs to the arachidonic acid pathway and enzymatically catalyzes the conversion of prostaglandin H2 to prostaglandin D2, which imparts physiological effects via DP1 and DP2 receptors. L-PGDS plays a crucial role in MASLD; however, its mechanistic regulation remains unexplored. Therefore, we aimed to study the biochemical regulation of L-PGDS using a cellular model of MASLD. We successfully recapitulated the MASLD phenotype in HepG2 cells by co-treating with palmitate and insulin. Our results showed significant downregulation of L-PGDS and decreased PGD2 levels in an insulin-resistant state. To study this L-PGDS downregulation, we employed MG132, chloroquine, cycloheximide, and immunoprecipitation to assess proteasomal degradation, autophagy, translational activity, and ubiquitination, respectively. However, the above pathways were not involved. Interestingly, gene and protein expression results revealed the clues for L-PGDS downregulation, showing significantly decreased transcription and subsequently protein levels. Additionally, subcellular localization results showed that insulin resistance induced the trafficking of L-PGDS from the cytoplasm to the nucleus. In summary, L-PGDS downregulation possibly involves transcription-translation and/or subcellular localization pathways. However, further studies are required to delineate the molecular mechanism of L-PGDS downregulation and apply this knowledge to MASLD pathogenesis and treatment.
{"title":"Revealing the biochemical regulations of L-PGDS in hepatic insulin-resistance using HepG2 cells","authors":"Rhema Khairnar, Md Asrarul Islam, Kuljeet Singh, Divya K. Shetty, Anjali Yadav, Vikas V. Dukhande, Sunil Kumar","doi":"10.1016/j.prostaglandins.2025.107052","DOIUrl":"10.1016/j.prostaglandins.2025.107052","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, and its prevalence poses a serious health threat globally. MASLD is a multifactorial hepatic disorder, but insulin resistance is a key player. Our prior <em>in vivo</em> studies revealed that the absence of lipocalin prostaglandin D<sub>2</sub> synthase (<span>L</span>-PGDS) leads to the development of MASLD, often coexisting with insulin resistance. Briefly, <span>L</span>-PGDS belongs to the arachidonic acid pathway and enzymatically catalyzes the conversion of prostaglandin H<sub>2</sub> to prostaglandin D<sub>2,</sub> which imparts physiological effects via DP1 and DP2 receptors. <span>L</span>-PGDS plays a crucial role in MASLD; however, its mechanistic regulation remains unexplored. Therefore, we aimed to study the biochemical regulation of <span>L</span>-PGDS using a cellular model of MASLD. We successfully recapitulated the MASLD phenotype in HepG2 cells by co-treating with palmitate and insulin. Our results showed significant downregulation of <span>L</span>-PGDS and decreased PGD<sub>2</sub> levels in an insulin-resistant state. To study this <span>L</span>-PGDS downregulation, we employed MG132, chloroquine, cycloheximide, and immunoprecipitation to assess proteasomal degradation, autophagy, translational activity, and ubiquitination, respectively. However, the above pathways were not involved. Interestingly, gene and protein expression results revealed the clues for <span>L</span>-PGDS downregulation, showing significantly decreased transcription and subsequently protein levels. Additionally, subcellular localization results showed that insulin resistance induced the trafficking of <span>L</span>-PGDS from the cytoplasm to the nucleus. In summary, <span>L</span>-PGDS downregulation possibly involves transcription-translation and/or subcellular localization pathways. However, further studies are required to delineate the molecular mechanism of <span>L</span>-PGDS downregulation and apply this knowledge to MASLD pathogenesis and treatment.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"182 ","pages":"Article 107052"},"PeriodicalIF":2.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
Aim
To determine the prevalence of CYP4F2 rs2108622 genetic variants, determine their influence on the systolic (SBP) and diastolic blood pressure (DBP), and their association with the risk of EH disease among Jordanian patients.
Methods
This case-control study consisted of 200 Jordanian individuals recruited from Jordan University Hospital, divided into two groups: 100 hypertensive patients (cases) and 100 non-hypertensive individuals (controls). The data for demographic, anthropometric, blood pressure measurements, glycaemic, and lipid profile measurements were collected from participants during their hospital visits and from the hospital’s computer’s record. The genotyping of CYP4F2 rs2108622 genetic variant was done using PCR-RFLP.
Results
EH patients had a significantly higher mean age (45.82 ± 10.6 years, P < 0.001) and BMI (30.84 ± 5.27 kg/m², P = 0.001) compared to controls. Obesity was significantly associated with EH (OR = 3.18, P = 0.01). The CT genotype of CYP4F2 rs2108622 was more frequent among EH patients (79 %) than controls (66 %) (P < 0.001) and was associated with increased EH risk (CT vs TT: OR = 3.02, P = 0.01; CT vs CC: OR = 2.71, P = 0.025). Genotype variations also showed significant associations with SBP (P = 0.019) and DBP (P = 0.017).
Conclusion
It can be concluded from this study that age, BMI and heterozygous CYP4F2 rs2108622 genotype are significantly associated with the occurrence of EH among Jordanians. The CYP4F2 rs2108622 genotype can be considered as a potential candidate biomarker of the development of EH. However, more studies with larger sample size are needed to validate the finding of this study.
{"title":"The association of Cytochrome 4F2 rs2108622 genetic variant and non-genetic factors with essential hypertension among Jordanian patients attending the University of Jordan Hospital","authors":"Enas Yousef Alkasasbeh , Yazun Bashir Jarrar , Wiam Khalil , Hussein Alhawari , Malek Zihlif","doi":"10.1016/j.prostaglandins.2025.107045","DOIUrl":"10.1016/j.prostaglandins.2025.107045","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Aim</h3><div>To determine the prevalence of <em>CYP4F2 rs2108622</em> genetic variants, determine their influence on the systolic (SBP) and diastolic blood pressure (DBP), and their association with the risk of EH disease among Jordanian patients.</div></div><div><h3>Methods</h3><div>This case-control study consisted of 200 Jordanian individuals recruited from Jordan University Hospital, divided into two groups: 100 hypertensive patients (cases) and 100 non-hypertensive individuals (controls). The data for demographic, anthropometric, blood pressure measurements, glycaemic, and lipid profile measurements were collected from participants during their hospital visits and from the hospital’s computer’s record. The genotyping of <em>CYP4F2 rs2108622</em> genetic variant was done using PCR-RFLP.</div></div><div><h3>Results</h3><div>EH patients had a significantly higher mean age (45.82 ± 10.6 years, <em>P</em> < 0.001) and BMI (30.84 ± 5.27 kg/m², <em>P</em> = 0.001) compared to controls. Obesity was significantly associated with EH (OR = 3.18, <em>P</em> = 0.01). The CT genotype of <em>CYP4F2 rs2108622</em> was more frequent among EH patients (79 %) than controls (66 %) (<em>P</em> < 0.001) and was associated with increased EH risk (CT vs TT: OR = 3.02, <em>P</em> = 0.01; CT vs CC: OR = 2.71, <em>P</em> = 0.025). Genotype variations also showed significant associations with SBP (<em>P</em> = 0.019) and DBP (<em>P</em> = 0.017).</div></div><div><h3>Conclusion</h3><div>It can be concluded from this study that age, BMI and heterozygous <em>CYP4F2 rs2108622</em> genotype are significantly associated with the occurrence of EH among Jordanians. The <em>CYP4F2 rs2108622</em> genotype can be considered as a potential candidate biomarker of the development of EH. However, more studies with larger sample size are needed to validate the finding of this study.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"181 ","pages":"Article 107045"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1016/j.prostaglandins.2025.107046
Matthew Stevenson, Bryan Chen, Ankita Srivastava, Christopher E. Hall, Louis Ragolia
Efficient recycling of red blood cells (RBCs) requires not only heme cleavage but also stabilization of reactive intermediates generated during iron liberation. Lipocalin-type 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.
{"title":"Lipocalin-type prostaglandin D₂ synthase (L-PGDS) deficiency disrupts heme catabolism and iron homeostasis in mice","authors":"Matthew Stevenson, Bryan Chen, Ankita Srivastava, Christopher E. Hall, Louis Ragolia","doi":"10.1016/j.prostaglandins.2025.107046","DOIUrl":"10.1016/j.prostaglandins.2025.107046","url":null,"abstract":"<div><div>Efficient recycling of red blood cells (RBCs) requires not only heme cleavage but also stabilization of reactive intermediates generated during iron liberation. Lipocalin-type Prostaglandin D₂ Synthase (<span>L</span>-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 <span>L</span>-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 <span>L</span>-PGDS binds ferric biliverdin and is upregulated during heme overload, our results support a model in which <span>L</span>-PGDS buffers porphyrin intermediates to facilitate their safe processing and clearance. This study identifies <span>L</span>-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.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"181 ","pages":"Article 107046"},"PeriodicalIF":2.5,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.prostaglandins.2025.107044
Jianyang Liu , Helena Idborg , Marina Korotkova , Per-Johan Jakobsson
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.
{"title":"Pro-inflammatory differentiation by GM-CSF reduces prostanoid release and phagocytic activity in murine bone marrow-derived macrophages","authors":"Jianyang Liu , Helena Idborg , Marina Korotkova , Per-Johan Jakobsson","doi":"10.1016/j.prostaglandins.2025.107044","DOIUrl":"10.1016/j.prostaglandins.2025.107044","url":null,"abstract":"<div><div>Murine bone marrow-derived macrophages (BMDMs) are widely used to study macrophage functions <em>in vitro</em>. 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 <em>E. coli</em> 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.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"181 ","pages":"Article 107044"},"PeriodicalIF":2.5,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145565057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-08DOI: 10.1016/j.prostaglandins.2025.107043
Dustin G. Brown , Jonathan Manke , Michael Armstrong , Sangya Yadav , John O. Marentette , James R. Roede , Eszter K. Vladar , Nichole Reisdorph , Vanessa V. Phelan
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 (PGE2). 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.
{"title":"Impact of overexpression of wild-type CFTR and elexacaftor-tezacaftor-ivacaftor on oxylipin production by the CFBE41o- bronchial epithelial cell line","authors":"Dustin G. Brown , Jonathan Manke , Michael Armstrong , Sangya Yadav , John O. Marentette , James R. Roede , Eszter K. Vladar , Nichole Reisdorph , Vanessa V. Phelan","doi":"10.1016/j.prostaglandins.2025.107043","DOIUrl":"10.1016/j.prostaglandins.2025.107043","url":null,"abstract":"<div><div>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<sub>2</sub>). 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.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"181 ","pages":"Article 107043"},"PeriodicalIF":2.5,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145490048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-22DOI: 10.1016/j.prostaglandins.2025.107042
Fatma F. Elsayed , Dina M. Abo-elmatty , Zakaria El -khayat , Emad Tolba , Alaa S. Wahba , Jihan Hussien
Background
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.
Results
The results demonstrated that treatment with either EPA or EPA/PCL led to a marked suppression of doxorubicin resistance, as evidenced by a significant reduction in tumor size, measured by caliper, in the treated groups over the course of the experiment. Furthermore, the combination of EPA or EPA-loaded PCL with DOX modulated the expression of drug resistance genes and apoptotic pathways by targeting transient receptor potential canonical 5 (TRPC5), P-glycoprotein (P-gp), and Bcl-2, while simultaneously enhancing the expression of caspase-3. Additionally, nano-characterization of the PCL particles using transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential analysis demonstrated their favorable stability and physicochemical properties.
Conclusion
The present study investigated the effect of eicosapentaenoic acid (EPA)-loaded polycaprolactone (PCL) in overcoming drug resistance when used in combination with doxorubicin (DOX), as compared to DOX alone and EPA in its original form. Interestingly, it reveals a promising approach to ameliorate the resistance of Doxorubicin in breast cancer.
{"title":"The role of eicosapentaenoic acid-loaded nanoparticles on alleviating drug resistance in xenograft breast cancer model","authors":"Fatma F. Elsayed , Dina M. Abo-elmatty , Zakaria El -khayat , Emad Tolba , Alaa S. Wahba , Jihan Hussien","doi":"10.1016/j.prostaglandins.2025.107042","DOIUrl":"10.1016/j.prostaglandins.2025.107042","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Results</h3><div>The results demonstrated that treatment with either EPA or EPA/PCL led to a marked suppression of doxorubicin resistance, as evidenced by a significant reduction in tumor size, measured by caliper, in the treated groups over the course of the experiment. Furthermore, the combination of EPA or EPA-loaded PCL with DOX modulated the expression of drug resistance genes and apoptotic pathways by targeting transient receptor potential canonical 5 (TRPC5), P-glycoprotein (P-gp), and Bcl-2, while simultaneously enhancing the expression of caspase-3. Additionally, nano-characterization of the PCL particles using transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential analysis demonstrated their favorable stability and physicochemical properties.</div></div><div><h3>Conclusion</h3><div>The present study investigated the effect of eicosapentaenoic acid (EPA)-loaded polycaprolactone (PCL) in overcoming drug resistance when used in combination with doxorubicin (DOX), as compared to DOX alone and EPA in its original form. Interestingly, it reveals a promising approach to ameliorate the resistance of Doxorubicin in breast cancer.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"181 ","pages":"Article 107042"},"PeriodicalIF":2.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-02DOI: 10.1016/j.prostaglandins.2025.107041
Wenhui Bao , Shuangyi Zhang , Jiamin Zhao , Zhiguo Gong , Yunjie Bai , Yanqin Dong , Wei Mao , Bo Liu
Estradiol is a critical hormone that regulates morphological and functional changes in the bovine endometrium throughout the estrous cycle. Prostaglandin E2 (PGE2), a well-established inflammatory mediator, also plays an essential role in endometrial physiology. Whether PGE2 acts as an intermediary in estradiol-related activities within the bovine endometrium remains unclear. The results revealed that 17β-estradiol at 10−10 M and 10−9 M induced PGE2 secretion in endometrial explants, whereas a higher concentration (10−7 M) downregulated PGE₂ secretion. In endometrial epithelial cells, 17β-estradiol at concentrations ranging from 10−10 to 10−8 M stimulated PGE2 secretion. In endometrial stromal cells, 17β-estradiol at 10−10 to 10−7 M concentrations promoted PGE2 production. PGE2 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 (10−9 M), highlighting mPGES-1 as a key enzyme in 17β-estradiol-induced PGE2 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 (10−9 M). This effect was reversed by pretreatment with the mPGES-1 inhibitor MF63 in endometrial cells and explants. Notably, supplementation with exogenous PGE2 restored the expression of these growth factors in the presence of both 17β-estradiol (10−9 M) and MF63. In conclusion, mPGES-1-derived PGE2 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.
{"title":"Prostaglandin E2 is a crucial intermediator of 17β-estradiol-induced growth factor expression in bovine endometrial cells and explants","authors":"Wenhui Bao , Shuangyi Zhang , Jiamin Zhao , Zhiguo Gong , Yunjie Bai , Yanqin Dong , Wei Mao , Bo Liu","doi":"10.1016/j.prostaglandins.2025.107041","DOIUrl":"10.1016/j.prostaglandins.2025.107041","url":null,"abstract":"<div><div>Estradiol is a critical hormone that regulates morphological and functional changes in the bovine endometrium throughout the estrous cycle. Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), a well-established inflammatory mediator, also plays an essential role in endometrial physiology. Whether PGE<sub>2</sub> acts as an intermediary in estradiol-related activities within the bovine endometrium remains unclear. The results revealed that 17β-estradiol at 10<sup>−10</sup> M and 10<sup>−9</sup> M induced PGE<sub>2</sub> secretion in endometrial explants, whereas a higher concentration (10<sup>−7</sup> M) downregulated PGE₂ secretion. In endometrial epithelial cells, 17β-estradiol at concentrations ranging from 10<sup>−10</sup> to 10<sup>−8</sup> M stimulated PGE<sub>2</sub> secretion. In endometrial stromal cells, 17β-estradiol at 10<sup>−10</sup> to 10<sup>−7</sup> M concentrations promoted PGE<sub>2</sub> production. PGE<sub>2</sub> synthesis was inhibited by the mPGES-1 inhibitor MF63 [2-(6-chloro-1H-phenanthro[9,10-<em>d</em>]imidazol-2-yl) isophthalonitrile] in the presence of 17β-estradiol (10<sup>−9</sup> M), highlighting mPGES-1 as a key enzyme in 17β-estradiol-induced PGE<sub>2</sub> 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 (10<sup>−9</sup> M). This effect was reversed by pretreatment with the mPGES-1 inhibitor MF63 in endometrial cells and explants. Notably, supplementation with exogenous PGE<sub>2</sub> restored the expression of these growth factors in the presence of both 17β-estradiol (10<sup>−9</sup> M) and MF63. In conclusion, mPGES-1-derived PGE<sub>2</sub> 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.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"181 ","pages":"Article 107041"},"PeriodicalIF":2.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号