Colorectal carcinogenesis involves coordinated reorganization of epithelial architecture, metabolism, and microenvironmental interactions. Among lipid signaling pathways, the sphingolipid rheostat has traditionally been described as a balance between ceramides and sphingosine-1-phosphate (S1P), with opposite effects on cell death and survival. However, current evidence suggests that this model is too simplified for colorectal cancer. Here, we discuss the sphingolipid rheostat as a spatially organized and stage-dependent signaling network shaped by enzymatic control, lipid transport, extracellular carrier association, and receptor context. During adenoma formation, ceramide-related metabolic programs may support progenitor cell function, while luminal ceramide generation by alkaline sphingomyelinase provides a surface-associated checkpoint linked to epithelial turnover. In carcinomas, coordinated rewiring of multiple regulatory nodes, including increased S1P synthesis, reduced degradation, altered export, and diversion of ceramide into complex sphingolipids, appears to favor persistent pro-survival signaling. These changes are associated with apoptosis resistance, angiogenesis, invasion, and immune modulation. We further emphasize that sphingolipid signaling depends on exposure biology, including cellular source, transporter usage, and carrier distribution in the circulation. This framework may help explain why blood-based sphingolipid measurements do not always reflect tumor-local sphingolipid organization. A compartment-aware view of sphingolipid biology may therefore improve interpretation of lipid biomarkers and identify stage-specific therapeutic vulnerabilities.
Antibiotics remain the cornerstone of treatment for infectious disease, yet a growing body of evidence shows that these drugs also disrupt host inflammatory and metabolic pathways well beyond their intended antimicrobial target. One consequence that has received comparatively little attention is their effect on lipid mediator signaling. Polyunsaturated fatty acids serve as precursors to lipid mediators that keep the vasculature in balance by governing both inflammatory and resolving pathways. Antibiotic exposure disturbs this balance in two connected ways, by driving gut microbiota dysbiosis and by directly impairing mitochondrial function and raising oxidative stress. Together these changes tilt lipid mediator profiles toward pro-inflammatory eicosanoids at the expense of pro-resolving mediators, promoting endothelial dysfunction, atherosclerosis progression, and myocardial injury. This review brings together the laboratory and clinical evidence linking antibiotic use to lipid mediator disturbances and cardiovascular risk, and considers strategies that may help preserve lipid mediator balance during antibiotic therapy.
BACKGROUND:Acute inflammation after myocardial infarction (MI) is required for healing, but inadequate resolution may contribute to adverse remodeling and heart failure. Specialized pro-resolving mediators (SPMs) and eicosanoids derived from polyunsaturated fatty acids regulate the intensity and duration of inflammation. OBJECTIVE:To assess whether circulating fatty acid metabolites measured early after MI are associated with post-infarction left ventricular ejection fraction (LVEF). METHODS:This study included 164 patients with MI (STEMI and NSTEMI) treated with primary percutaneous coronary intervention (PCI). Blood samples were collected 24-48 h after PCI. Fatty acid metabolites were isolated by solid-phase extraction and quantified using HPLC with diode-array detection. Transthoracic echocardiography was performed before discharge; patients were categorized as low-EF (LVEF <40%, n = 31) or preserved-EF (LVEF ≥40%, n = 133). Group differences were tested using t-tests; Pearson correlations were calculated for selected metabolites. RESULTS:Low-EF patients had higher hs-troponin and white blood cell count than preserved-EF patients (p = 0.035 and p = 0.040). Concentrations of leukotriene B4 and 12(S)-HETE were higher in the low-EF group (p = 0.040 and p = 0.020), whereas resolvin E1, maresin 1, and lipoxin A4 were lower (p = 0.0001, p = 0.040, and p = 0.010). No significant differences were observed for resolvin D1, thromboxane B2, or prostaglandin E2. CONCLUSIONS:Early after MI, reduced LVEF is associated with higher pro-inflammatory lipid mediators and lower pro-resolving mediators, suggesting an imbalance between inflammatory activation and resolution in patients with early systolic dysfunction.
PURPOSE:To compare diazoxide (DZ), an ATP-sensitive potassium channel opener and latanoprost free acid (LFA), the active metabolite of the prostaglandin analogue latanoprost, a first-line agent for intraocular pressure (IOP) reduction in patients with glaucoma, on IOP, retinal ganglion cell (RGC) density, retinal morphology, and glial cell activation in the DBA/2J mouse model of pigment dispersion glaucoma. METHODS:DBA/2J mice age 4 months received daily topical applications of DZ (5 mM) or LFA (0.1 mM) in one eye, while the fellow eye received vehicle. IOP was measured prior to treatment and twice weekly throughout the 23-week treatment period. Immunofluorescence staining was used to quantify RGC density with RNA binding protein with multiple splicing (RBPMS) and glial cell activation as a measure of neuroinflammation with glial fibrillary acidic protein (GFAP). Hematoxylin and eosin staining was used to evaluate retinal morphology. RESULTS:IOP was reduced by both DZ (30%) and LFA (24%) for a portion of the experimental period. DZ did not alter RGC survival, reactive gliosis, or RGC morphology. Conversely, LFA treatment was associated with a significant reduction in RGCs, an increase in reactive gliosis, and altered RGC morphology characteristic of cell death. CONCLUSIONS:DZ lowered IOP without notable retinal side effects. In contrast, LFA reduced IOP but was associated with enhanced RGC neurodegeneration and increased neuroinflammation. Further studies are needed to determine whether LFA-mediated changes are specific to the DBA/2J mouse or if other models with underlying pro-inflammatory microenvironments may be susceptible to RGC loss with prostaglandin analog therapy.
Endocrine hormones ghrelin and leptin play opposing roles in regulating appetite, energy homeostasis and body weight. Dysregulation of these hormones contributes significantly to the development of obesity and associated metabolic disorders. This narrative review examines the mechanisms underlying leptin and ghrelin signaling in the central nervous system, explores the molecular causes of leptin resistance and altered ghrelin secretion, and evaluates current and novel therapeutic approaches that target these hormones to treat obesity and related comorbidities. Relevant experimental, clinical, and translational studies were reviewed to provide an overview of the molecular mechanisms, physiological interactions and therapeutic potential of the leptin-ghrelin axis. The available evidence indicates that leptin promotes satiety and energy expenditure, whereas ghrelin stimulates appetite and adipogenesis. Obesity is characterized by elevated leptin levels associated with leptin resistance and reduced ghrelin levels with altered secretion patterns. Extrinsic factors, including inflammation, psychological stress and sleep deprivation, further disrupt the leptin-ghrelin axis. Promising therapeutic approaches, including leptin sensitizers, ghrelin antagonists, and combination hormone therapies, require further clinical validation. Understanding the complex interplay between leptin and ghrelin is crucial to the advancement of hormone-based obesity therapy. Future research should focus on restoring leptin sensitivity, modulating ghrelin signaling and implementing customized, multi-hormonal therapeutic techniques for long-term metabolic health.
Fucoidan, a marine polysaccharide, has demonstrated potential in treating cardiovascular diseases, including coronary artery disease (CAD). CAD treatment includes lowering blood coagulation, blood fat levels, and having heart-protective activity. This study aimed to evaluate the potential of fucoidan compounds isolated from brown algae (Sargassum polycystum C. Agardh) on anticoagulant effects through measurements of PT, APTT, and TT, as well as lipid profile, body weight, heart and aortic mass index, LDH, and CK-MB, as well as in Wistar rats (Rattus norvegicus). A total of 36 animals were divided into six groups. Group I received a standard diet without treatment; Group II received 0.5% CMC; Group III was treated with simvastatin at 20mg/kg BW; and Groups IV, V, and VI received fucoidan at doses of 30mg/200g BW, 40mg/200g BW, and 50mg/200g BW, respectively. Statistical analysis of the lipid profile showed that all fucoidan doses significantly reduced total cholesterol and triglyceride levels, although HDL levels were not increased. Organ weight analysis revealed a significant reduction (p < 0.05) in aortic weight in all treated groups, while no significant changes were observed in body or heart weight. Seven days of fucoidan administration also significantly reduced CK-MB and LDH serum levels (p < 0.05). In conclusion, fucoidan compounds Sargassum polycystum C. Agardh at all tested doses show potential in the treatment of CAD by lowering total cholesterol and triglyceride levels, reducing aortic weight, prolonging coagulation times (PT, APTT, and TT), and decreasing CK-MB and LDH levels.
BACKGROUND:The Cytochrome 4F2 (CYP4F2) rs2108622 genetic variant influences the production of 20-Hydroxyeicosatetraenoic acid (20-HETE), which affects the blood pressure. Previous findings from our group indicate that CYP4F2 rs2108622 genotype is associated with essential hypertension. AIMS:This study aims to find out the association of CYP4F2 rs2108622 genotype with the response of valsartan and amlodipine among hypertensive patients. METHODS:56 hypertensive patients on 80 mg valsartan and 34 on 5 mg amlodipine were genotyped for CYP4F2 rs2108622 genetic variant using PCR-RFLP method. The systolic (SBP) and diastolic (DBP) blood pressures data before and after one month antihypertensive treatment were collected from the computer record of the hospital. The patients were unrelated Arabs attending the University of Jordan Hospital. RESULTS:We found that carriers of CYP4F2 rs2108622 CC genotype have greater reduction in SBP (mean difference -28.5 ± 15.2 for valsartan and vs. -32.3 ± 5.5 mmHg for amlodipine) in comparison with CT and TT genotypes, this difference did not reach the statistical significance (P value> 0.05). Furthermore, the CYP4F2 rs2108622 genotype was not associated significantly (P value> 0.05) with valsartan and amlodipine responses after adjustment the responses with sex, BMI, age, and smoking status of the patients. DISCUSSION:While there is a trend suggesting CYP4F2 rs2108622 CC genotype may respond better to valsartan and amlodipine responses, the absence of statistical significance supports the need for larger pharmacogenetic studies. CONCLUSIONS:It can be concluded from the findings of this study that there is a lack of association between the CYP4F2 rs2108622 genotype and valsartan and amlodipine responses among a sample of Jordanians with essential hypertension.
Type 2 diabetes mellitus (T2DM) is a multidimensional metabolic disorder characterized by hyperglycemia, insulin insensitivity, and dysfunction and degeneration of β-cells. Increase in the levels of free fatty acids (FFAs) in blood plasma is a typical symptom of obesity and metabolic syndrome, which influences the mechanisms of insulin resistance and β-cell impairment. Acute increase in FFA levels blocks glucose uptake by insulin-sensitive skeletal muscles while chronic increase in FFA levels results in hepatic insulin resistance which causes gluconeogenic flux and lipotoxicity in pancreatic βcells. FFA-induced insulin resistance involves various molecular pathways and generation of lipid intermediates (diacylglycerol and ceramides), activation of serine/threonine kinases (PKC), induction of oxidative and endoplasmic reticulum stresses, and inflammatory signaling via nuclear factor-κB (NF-κB) and toll-like receptor (TLR) signaling pathways. Recent studies have indicated that the fetuin-A-FFA complex is an important endogenous ligand of TLR4 that causes inflammation and metabolic dysregulation. In addition, certain FFAs, especially ω-6 polyunsaturated fatty acids, can elicit ferroptosis which is a new form of lipid peroxidation-mediated cell death in β-cells, thereby expanding the extent of FFA-mediated lipotoxicity. This review covers recent information on the mechanisms and clinical factors related to the role of FFAs in insulin resistance and T2DM pathogenesis, and the contribution of experimental research towards developing therapeutic strategies in normalizing the levels of FFA and inhibiting downstream lipotoxicity-related pathways.
BACKGROUND AND AIMS:Polycystic ovary syndrome (PCOS) is a metabolic disorder that significantly impacts female fertility. Lipids and inflammation are key factors in the pathogenesis and progression of PCOS. This study aims to elucidate the complex causal relationships involving 179 lipids, 91 inflammatory markers, and PCOS using robust Mendelian Randomization (MR) methods based on Genome-Wide Association Studies (GWAS). Additionally, we seek to quantify the mediating effects of inflammation markers on lipid in PCOS. METHODS AND RESULTS:After rigorous screening of eligible SNPs, IVW was employed, supplemented by Simple mode, Weighted median, Weighted mode, and Bayesian Weighted Mendelian Randomization analyses. Sensitivity analyses were performed to ensure result accuracy. Mediation analysis was conducted to identify inflammation factors mediating the lipid-PCOS pathway. We identified 11 lipids causally associated with PCOS, including sterol esters, phosphatidylcholine, sphingomyelin, and triacylglycerol. MR Analysis linked these lipids to 58 inflammatory factors, of which only two were associated with PCOS, with β-NGF increasing the risk of PCOS by 6.50% and uPA reducing it by 4.60%. Mediator analysis showed the effect of uPA-mediated phosphatidylcholine (18:2_20:4) on PCOS. CONCLUSION:This study is the first to use MR to explore causal links between lipids, inflammatory factors, and PCOS. We identified uPA as a key mediator and uncovered 11 lipids significantly associated with PCOS, highlighting the phosphatidylcholine (18:2_20:4)-uPA-PCOS pathway. Our findings suggest targeting lipid metabolism and using phosphatidylcholine (18:2_20:4) and uPA as biomarkers and tools for evaluating therapeutic efficacy in PCOS.
BACKGROUND:Osteoporosis is a major global health issue characterized by imbalanced bone remodeling. Neuropeptide Y (NPY) is a key regulator of energy metabolism and bone homeostasis, but its role in osteoporosis progression remains poorly defined. METHODS:This study enrolled 74 participants, including 38 osteoporosis patients and 36 controls, and evaluated the relationship of NPY levels with other clinical indicators. NPY knockout and wild-type mice with or without ovariectomy were used to investigate the role of NPY in bone loss and changes in the bone lipid profile. Bone loss was assessed by micro-computed tomography. Tissue lipidomic analysis was performed by liquid chromatography mass spectrometry. RESULTS:The serum NPY levels of female patients with osteoporosis were significantly elevated compared with the corresponding control group. In female patients, lumbar spine T-score, spin T-score and vitamin D level showed significant negative correlation with NPY level. NPY knockdown protected against ovariectomy-induced bone loss, and their lipids in bone were profiled. As many as 18 lipids classes were quantified, and overall levels of phosphatidylinositol and lysophosphatidyl choline were greatly changed with NPY silence. In detail, 49 lipids were significantly altered due to NPY in OVX mice, 12 of which were related to osteoporosis. Interestingly, TAG was the main component among them, and it indicated some specific TAG could be connected with NPY on osteoporosis. CONCLUSIONS:NPY ablation protects against osteoporosis by altering bone lipid metabolism. Therefore, NPY could be a potential target for osteoporosis treatment.
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.
