BACKGROUND:Cyclooxygenase-2 (COX-2) and its product prostaglandin E₂ (PGE₂) are key mediators of parafollicular cell proliferation and calcitonin secretion in medullary thyroid carcinoma (MTC). Although COX-2 inhibitors exhibit anti-proliferative effects, the molecular mechanisms underlying their influence on cell-cycle regulation remain unclear. OBJECTIVE:This study explored the effects of the selective COX-2 inhibitor DuP-697 on proteins associated with G₂/M regulatory signaling in human medullary thyroid carcinoma TT cells. METHODS:TT cells were treated with DuP-697 (40-160 nM) for 3-72 h. Immunofluorescence analyses were performed to quantify cyclin B1, phosphorylated Cdc2 (Tyr15), Myt1, phosphorylated Wee1, p21, and phosphorylated histone H3. RESULTS:DuP-697 induced time-dependent alterations in multiple proteins associated with G₂/M regulation. Early exposure (3-24 h) was associated with increased cyclin B1 and phosphorylated Cdc2, accompanied by transient elevation of phosphorylated histone H3. With prolonged treatment (48-72 h), phosphorylated histone H3 levels declined, while Myt1 expression remained persistently elevated and phosphorylation of Wee1 displayed dynamic modulation. In parallel, p21 expression was selectively reduced at intermediate and late time points. These coordinated changes suggest a shift in the balance of G₂/M-associated regulatory signals over time. CONCLUSION:Taken together, these findings indicate that DuP-697 is associated with time-dependent modulation of proteins involved in G₂/M regulatory signaling in TT cells. Rather than providing direct evidence of cell-cycle arrest, the results support an exploratory model in which COX-2 inhibitor exposure is accompanied by dynamic reorganization of mitotic and checkpoint-related regulatory components. Further functional studies, including direct assessment of cell-cycle distribution and mitotic progression, are required to clarify the biological consequences of these regulatory changes.
Hepatic inflammaging is a prominent feature of aging, yet the timing and pathway architecture of hepatic oxylipin remodeling remain unclear. Here, we integrated liver histopathology with targeted LC-MS/MS profiling of oxylipins across 2, 12, 18, and 24 months in male Sprague-Dawley rats, and related mediator shifts to age-associated regulation of key metabolic enzymes, supported by human patterns. Aging was accompanied by progressive inflammatory infiltration and steatotic remodeling, alongside clear separation of hepatic oxylipin landscapes. By midlife (12-18 months), ω-6 outputs were enriched for arachidonic acid (AA)-linked mediators, including 8-iso-PGF₂α, tetranor-12(S)-HETE, and the CYP4A-associated ω-hydroxylation product 20-HETE, whereas selected linoleic acid (LA) epoxide/diol derivatives declined. In late aging (24 months), hepatic resolvin E1 (RvE1) decreased markedly despite preserved or increased ω-3 substrates/intermediates, coinciding with accumulation of DHA-derived oxidation products. These changes paralleled induction of Cyp4a8 and suppression of Alox15, and human data revealed partially aligned age-associated patterns in selected pathway-related markers in hepatic CYP4A11/ALOX15 expression and circulating mediators. Collectively, we define a staged hepatic oxylipin imbalance during aging, characterized by heightened CYP4A/20-HETE tone and attenuated ALOX15/RvE1-associated resolution.
Guggulsterone (GSS), a plant-derived steroid from Commiphora mukul, exhibits complex pharmacological behavior through modulation of nuclear receptors and detoxification enzymes. Acting as an antagonist of the Farnesoid X receptor (FXR) and an agonist of the Pregnane X receptor (PXR), guggulsterone influences the transcription of cytochrome P450 enzymes (notably CYP3A4 and CYP2C9) and transporters such as MDR1 and OAT2. This review synthesizes current mechanistic insights from molecular, pharmacokinetic, and in silico analyses, highlighting its dual regulatory effects on metabolism and drug resistance. Despite therapeutic promise in metabolic disorders, poor bioavailability and bile acid dysregulation pose translational challenges. Future work should emphasize isomer-specific activity, delivery optimization, and human-relevant models to clarify its pharmacological and toxicological potential.
Cancer of neural cell origin are one of the most difficult to treat given their high resistance to chemotherapeutic drugs and high rate of recurrence. Furthermore, chemotherapy and radiotherapy interfere with the proliferation and survival of normal cells and thus, cause serious side effects. Essential fatty acids (EFAs) and their metabolites have been shown to induce apoptosis of tumor cells with no effect on normal cells. In the present study, we evaluated the effect of EFAs and their metabolites in combination of with anticancer drug doxorubicin on the proliferation, survival and potential mechanisms(s) of EFAs and their metabolites on three different tumor cells: human neuroblastoma cells (IMR-32) and human glioma cells (HNGC2 and LN229) in vitro. Of all the lipids tested, AA (arachidonic acid) and EPA (eicosapentaenoic acid) were found to be the most potent in their anti-tumor activity on both neuroblastoma and glioma cells in vitro. Both AA and EPA augmented the anti-tumor action of doxorubicin (IMR-32 > HNGC2 + LN229). Oxidative stress seems to have a major role in the induction of apoptosis of neuroblastoma cells (IMR-32) whereas, glioma cells (HNGC2 and LN229) showed activation of intrinsic apoptotic pathway leading to their death.
Activation of host inflammatory signaling pathways represents a critical determinant of tissue responses during Leishmania infection. Prostaglandin E₂ (PGE₂), synthesized by cyclooxygenase-2 (COX-2), has been implicated in the modulation of macrophage activation and disease pathology; however, the intracellular mechanisms regulating its production in specific host cell contexts remain incompletely defined. In the present study, we investigated the contribution of mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways to the regulation of the COX-2/PGE₂ axis during infection of J774A.1 macrophages with Leishmania mexicana promastigotes. Infection induced rapid and sustained ERK1/2 activation together with increased COX-2 expression and PGE₂ synthesis. In contrast, p38 MAPK activation was delayed and transient, declining rapidly compared with the sustained ERK1/2 response, while JNK phosphorylation remained minimal under the experimental conditions evaluated. Pharmacological inhibition of NF-κB signaling significantly reduced inflammatory mediator production without affecting early parasite internalization. In a BALB/c model of cutaneous leishmaniasis, local administration of the NF-κB inhibitor BAY11-7082 was associated with decreased lesion progression, suggesting that modulation of host inflammatory signaling may influence tissue pathology during infection. In axenic cultures, the compound produced a delayed reduction in parasite proliferation, indicating that potential direct antiparasitic effects may be limited under the experimental conditions evaluated. Overall, these findings support a role for coordinated MAPK and NF-κB activation in the regulation of COX-2-dependent lipid mediator production during L. mexicana infection and highlight the relevance of context-dependent host inflammatory signaling as a complementary factor influencing disease progression.
Background Meningiomas, among the most common primary intracranial tumors, present significant clinical challenges, particularly due to the propensity for recurrence in higher-grade variants and the paucity of effective non-surgical therapies.Lipid metabolism plays a critical role in tumor progression; however, the specific lipid dysregulation underlying meningioma biology remains incompletely understood. Methods In this study, meningioma tissues and patient-matched arachnoid membrane tissues were collected from 12 patients undergoing meningioma resection surgery. A comprehensive lipidomic analysis was performed on these tissues, and lipid metabolic differences between meningioma and arachnoid tissues were evaluated using multiple t-tests with appropriate correction for multiple comparisons. Results Our analyses revealed pronounced lipidomic remodeling in meningiomas, characterized by an overall increase in total lipid abundance compared with arachnoid tissues. Specifically, phospholipids such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) were significantly elevated, whereas phosphatidylinositol (PI) levels were reduced. Fatty acid composition also displayed distinct alterations, with decreased saturated fatty acids (SFAs) and increased polyunsaturated fatty acids (PUFAs). In addition, glycerophospholipids and sphingolipids, including sphingomyelin (SM) and ceramide (Cer), exhibited significant remodeling, reflecting profound metabolic reprogramming in meningiomas. Correlation analyses further suggested associations between specific lipid species (e.g., MePC and SM) and clinicopathological features such as tumor size and patient age. Conclusion These findings highlight the pivotal role of lipid metabolic reprogramming in meningioma pathogenesis and underscore the potential of lipidomic profiling to identify biologically relevant biomarkers and therapeutic targets through comparison with arachnoid tissue.
Thromboxane A2 (TxA2) is an inflammatory lipid mediator released by blood platelets and monocytes/macrophages. TxA2 is unstable (half-life ∼1 min), but it induces platelet aggregation and vasoconstriction of arteries contributing to cardiovascular disease. Therefore, inhibiting thromboxane biosynthesis with pharmacological inhibitors may help to limit ischemic events. Carboxylesterase 1 (CES1) is a serine hydrolase with roles in xenobiotic and lipid metabolism. CES1 activity can be perturbed in biological systems with small-molecule inhibitors that covalently modify its active site serine residue. We surprisingly discovered that a CES1 inhibitor, WWL113, could also inhibit the activity of thromboxane A2 synthase (TBXAS1), which is responsible for converting prostaglandin H2 (PGH2) to TxA2. TxA2 is non-enzymatically converted to a stable inactive metabolite, TxB2, which can be measured by LC-MS/MS. Human monocytic cells (THP-1 cell line), which naturally express TBXAS1 and CES1, were pretreated for 30 min with increasing concentrations of either WWL113 or WWL229 (another CES1 inhibitor), followed by addition of exogenous PGH2 and the levels of TxB2 and PGE2 determined. WWL113 significantly decreased TxB2 levels, whereas prostaglandin E2 (PGE2) levels were increased. The concentration of WWL113 that inhibited TxB2 production by 50% (IC50) in THP-1 monocyte lysates and intact living macrophages was ∼0.1-0.2 µM. In contrast, WWL229 had no effect on the amounts of either lipid mediator in living cells and lysates. Recombinant human TBXAS1 protein was overexpressed in COS-7 cells and WWL113 was verified to be a bona fide TBXAS1 inhibitor (IC50=226 nM). These findings indicate that WWL113, which inhibits CES1 activity and exerts anti-inflammatory effects in vitro and in vivo, can also target TBXAS1. Thus, the beneficial effects of WWL113 observed in diet-induced obese mice may in part be related to its ability to block proinflammatory TxA2 production. It is, therefore, recommended that WWL229 be used instead of WWL113 to perturb CES1 activity in living cells and animal models.
BACKGROUND:Asthmatic cough is a common cause of chronic cough, and cough-variant asthma (CVA) and typical bronchial asthma (BA) display distinct pathophysiological characteristics. Eosinophilic airway inflammation is believed to contribute to the persistence and treatment resistance of chronic cough, although the underlying mechanisms remain unclear. This study aimed to elucidate the changes in lipid mediators and cough responses induced by eosinophilic airway inflammation. METHODS:We employed an ovalbumin (OVA)-sensitized guinea pig model to investigate the role of eosinophilic airway inflammation and prostaglandinI₂ (PGI₂) in bronchoconstriction-induced cough. Male Hartley guinea pigs were sensitized with OVA and aluminum hydroxide, followed by antigen challenge and methacholine (Mch)-induced bronchoconstriction. Cough responses were recorded, and bronchoalveolar lavage fluid (BALF) was analyzed for inflammatory cell counts and lipid mediator levels. RESULTS:OVA challenge alone increased eosinophil counts without affecting PGI₂, PGE₂, or cysteinyl leukotriene (Cys-LTs) levels. In contrast, Mch inhalation following OVA sensitization and antigen exposure significantly elevated both eosinophils and PGI₂, while cough responses tended to decrease. Cough frequency was negatively correlated with BALF eosinophil counts and positively correlated with the PGE₂/PGI₂ ratio. Administration of a PGI₂ receptor antagonist enhanced cough, whereas a PGI₂ analog suppressed it. CONCLUSIONS:Combined antigen exposure and bronchoconstriction induce PGI₂, which appears to suppress Aδ fiber-mediated cough. These findings underscore the importance of lipid mediator balance in cough regulation and suggest potential therapeutic strategies for asthmatic cough.
Cardiac hypertrophy represents a primary adaptive response of the heart to both mechanical stress and neurohormonal stimuli. However, beneficial hypertrophic adaptation eventually gives rise to maladaptive structural changes in the heart, ultimately leading to heart failure. Cyclooxygenase-2 (COX-2), a stress-inducible enzyme participating in the metabolism of arachidonic acid-derived eicosanoids, has been recognized as a central modulator of the adaptive changes of the hypertrophic heart through the production of bioactive prostaglandins. However, a growing number of studies have demonstrated the dual roles of COX-2-derived prostaglandins in the context of cardiac hypertrophy. Prostaglandin E₂ (PGE₂) and Prostaglandin I₂ (PGI₂), in addition to Prostaglandin D₂ (PGD₂), have been demonstrated as the major bioactive molecules primarily involved in this biological process. These prostaglandins exert their biological effects through the interaction of G-protein-coupled receptors. While the upregulation of COX-2 in the early injury phase enhances the inflammatory response as well as the release of the mentioned prostaglandins, which in turn primarily contributes to the aggravation of the injury of the heart muscle in the early phase of injury. On the contrary, the re-expression of COX-2 in the later phases primarily contributes to the cardioprotective response of the heart. The dual temporal nature of this process makes it complex. The purpose of this review is to compile the evolving data regarding the emerging dual roles of COX-2-derived prostaglandins in the context of cardiac hypertrophy.
BACKGROUND:Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) is closely linked to gut microbiota disorders and bile acid imbalance. Wulingsan (WLS) have shown promise in regulating these pathways, but its mechanism of action unclear. This study aimed to evaluate the therapeutic effect of WLS on the rat MASLD model from the perspectives of intestinal microbiota composition and bile acid homeostasis. METHODS:The MASLD model was induced by a high-fat diet (HFD) and treated with different doses of WLS. Body weight and serum lipid profiles were monitored, inflammation were assessed to ELISA and RT-qPCR. H&E staining to evaluate histopathological changes. The 16S rRNA sequencing and LC-MS/MS analysis of gut microbiota composition and bile acid profiles. The fecal microbiota transplantation (FMT) experiment verified the effect of WLS on the gut microbiota. RESULTS:WLS treatment reduces the body weight of MASLD rats, improves lipid indicators, and inhibits inflammation and liver damage. The results of the FMT experiment indicated that transplantation of fecal microbiota from WLS-treated donors regulated the gut microbial composition and restored bile acid metabolic homeostasis in recipient rats. DISCUSSION:This study demonstrates that WLS treats MASLD by modulating multiple pathological pathways. Its effects in improving lipid metabolism and reducing hepatic inflammation align with the pathophysiological mechanisms of MASLD, indicating direct hepatoprotective actions. WLS intervention significantly restored gut microbiota diversity, increased the proportion of beneficial bacteria, suppressed potentially harmful bacterial genera, and corrected dysbiosis. FMT experiments further confirmed that gut microbes play a crucial role in mediating the therapeutic benefits of WLS. When microbiota from WLS-treated donors were transplanted into recipient rats, significant improvements were observed in metabolic markers, hepatic histopathology, and bile acid homeostasis. Collectively, the data support that WLS improves MASLD through a multi-targeted strategy centered on the gut-liver axis. CONCLUSION:WLS has an effective therapeutic effect on MASLD by improving lipid metabolism, reducing liver inflammation, reshaping the intestinal microbiota and normalizing bile acid homeostasis.
Inflammation initiates and progresses due to overexpression of the arachidonic acid cascade mediators. Cyclooxygenase (COX) and lipoxygenase (LOX) are considered to be the primary targets, and the aim of this study was to assess the anti- inflammatory activity of several herbal compounds as dual COX-LOX inhibitors on prostatic diseases. Compounds Timosaponin AⅡ, timosaponin AⅢ, berberine and demethyleneberberine were selected according to our previous studies. Human prostate cancer cells (PC-3) were cultured and the cell viability was detected by CCK-8 method at different concentrations. Ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was applied to monitor the changes of AA metabolites after treatment. Western blot and qPCR were used to detect COX-2 and LOX-5 at protein and mRNA levels, respectively. Additionally, the levels of inflammatory factors (IL-6, IL-1β, TNF-α) in each group were detected by ELISA. After drug interference, 13 altered metabolites associated with the COX/LOX pathway, including PGE2, 5-HETE, LTB4, etc. were identified in cell medium. Quantitative metabolomics analysis showed that the candidate compounds could significantly decreased the concentrations of dual target related metabolites to varying degrees (P < 0.01). These compounds could also suppressed COX-2 and LOX-5 expression at the protein and mRNA levels simultaneously. Moreover, the levels of cytokine IL-6, IL-1β and TNF-α were also significantly reduced in the treated group compared to controls (P < 0.05 or P < 0.01). Our findings revealed the four active compounds were potential COX/LOX dual-target inhibitors, which inhibited a range of inflammatory responses by interfering with AA metabolism and down-regulating the levels of COX and LOX metabolites.
BACKGROUND:Atherosclerosis is a chronic inflammatory pathology driven by lipid accumulation and immune activation. 25-Hydroxycholesterol (25-HC), an oxysterol synthesized by cholesterol 25-hydroxylase (CH25H) in response to inflammatory stimuli, has emerged as a potent bioactive lipid mediator at the nexus of cholesterol homeostasis and innate immunity. OBJECTIVE:Unlike broader reviews on oxysterols, this article synthesizes the multifaceted and context-dependent roles of 25-HC in atherogenesis. We aim to elucidate its specific mechanistic actions across endothelial cells, macrophages, and vascular smooth muscle cells (VSMCs), emphasizing its dual nature and potential as a therapeutic target. METHODS:We conducted a comprehensive review of the literature to integrate mechanistic insights into 25-HC signaling pathways, their regulation by specific transcription factors, and their impact on vascular pathology. RESULTS:25-HC exhibits a distinct biphasic dose-response. At physiological concentrations, it maintains lipid homeostasis through suppression of SREBP processing and activation of LXR signaling. However, supraphysiological accumulation induces oxidative stress, mitochondrial dysfunction, and a coordinated activation of apoptosis and autophagy, ultimately precipitating cytotoxicity. Mechanistically, 25-HC disrupts membrane lipid rafts and activates the RIG-I/MAVS axis to drive pro-inflammatory cytokine secretion (e.g., IL-8). Within the plaque microenvironment, it impairs macrophage efferocytosis by downregulating MerTK and promotes VSMC proliferation and migration via PI3K/AKT pathways. Conversely, the transcription factor KLF4 and enzymatic sulfation by SULT2B1b act as critical protective checkpoints against 25-HC-mediated toxicity. CONCLUSION:25-HC is not merely a biochemical byproduct but a functional determinant of plaque instability. Its impact is strictly governed by local concentration gradients and metabolic regulation. Future therapeutic strategies should focus on modulating the CH25H/KLF4 axis and promoting oxysterol sulfation to mitigate vascular inflammation and prevent atherosclerosis progression.
BACKGROUND:Intracerebral hemorrhage (ICH) is a destructive cerebrovascular disease, whose secondary injury can trigger severe neuroinflammatory responses. Resolvin D1 (RvD1), as an endogenous specific pro-resolving mediator, has been demonstrated to possess significant anti-inflammatory effects. However, how brain networks relate to RvD1 biosynthesis and the therapeutic potential of RvD1 in post-hemorrhagic repair processes within the brain remain unclear. METHODS:Serum RvD1 levels were measured at admission and discharge in 40 ICH patients, and their correlation with neurological functional outcomes was analyzed. Combining neuroimaging and Mendelian randomization, we investigated the association between brain network integrity and genetically predicted plasma RvD1 levels. Network pharmacology identified key targets, and an oxyhemoglobin-induced BV2 microglial model validated RvD1's BDNF-dependent anti-inflammatory and anti-apoptotic effects. RESULTS:Serum RvD1 levels decreased from admission to discharge during recovery, with significant correlation between its changes and neurological improvement. Neuroimaging and MR analysis revealed that brain network integrity is significantly associated with genetically predicted plasma RvD1 levels, partially explaining interindividual prognostic variation. Mechanistically, RvD1 modulates microglial metabolism, alleviates oxidative stress, and promotes anti-inflammatory polarization involving the BDNF/AKT signaling network. CONCLUSION:Genetically predicted plasma RvD1 levels correlate with macro-level brain network integrity while simultaneously promoting micro-level neural repair. This approach overcomes limitations of previous single-pathway or static indicator studies, offering novel biomarkers and intervention strategies with predictive and therapeutic potential for ICH.
Inflammatory responses comprise a crucial defense mechanism against infection and injury. Prostanoids, including prostaglandin E2 (PGE2), are well-known to play important roles in the generation of inflammatory responses. However, their excessive or prolonged activation can cause tissue damage and drive the development of diseases. Resolvin E-series (RvEs), including RvE1, RvE2, and RvE3, are specialized pro-resolving mediators that actively promote the resolution of inflammation. Here, using human macrophage-like U937 cells, we show that RvE1 and RvE2, but not RvE3, suppressed protein expression of cyclooxygenase (COX)-2, an essential and inducible enzyme involved in prostanoid synthesis during the onset of inflammatory responses. Furthermore, the suppression of COX-2 protein expression by RvE1 and RvE2 was suggested to involve enhanced ubiquitin-proteasome-dependent degradation, resulting in the rapid reduction of PGE2 production by decreasing functional COX-2. This is the first reported evidence that RvEs exert pro-resolving effects on macrophage-associated COX-2/PGE2 signaling. Importantly, RvEs reduced COX-2 expression at the low concentration of 10 nM without affecting COX-1 expression. Thus, they may represent promising candidates for novel anti-inflammatory drugs with potentially fewer gastrointestinal side effects than exhibited by many nonsteroidal anti-inflammatory drugs.
Lipid deposition plays a key role in the progression of diabetic kidney disease. We previously demonstrated that resveratrol modulates the junctional adhesion molecule-like protein (JAML)/Sirtuin 1 (Sirt1) pathway involved in lipid synthesis in the kidneys of mice under high-fat diet conditions, reducing lipid deposition. However, the specific mechanisms by which resveratrol affects palmitic acid (PA)-induced lipid accumulation and metabolism in podocytes remain unclear. In this study, we used mouse podocyte cell line 5 (MPC-5) to investigate the role of the JAML/Sirt1 pathway in de novo lipid synthesis. Resveratrol attenuated the abnormal expression of key components in the JAML/Sirt1 lipid synthesis pathway induced by PA in MPC-5 podocytes. Specifically, siRNA-mediated silencing of JAML increased Sirt1 expression in PA-treated MPC-5 podocytes, downregulating sterol regulatory element-binding protein-1, carbohydrate response element-binding protein, and adipose differentiation-related protein. In contrast, JAML overexpression reversed these effects. Resveratrol attenuated the metabolic abnormalities caused by JAML overexpression, suggesting that it inhibits intracellular lipid deposition in MPC-5 podocytes by regulating the JAML/Sirt1 pathway. Our findings provide new evidence that resveratrol improves lipid deposition in the kidneys and a new treatment strategy for renal diseases associated with lipid deposition in the kidneys.
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.
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.
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.
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.
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.
