Search Results (197)

Elevated plasma lipoprotein(a) [Lp(a)] levels represent a predominantly genetically determined risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease (CAVD). Mechanistically, Lp(a) transports oxidized phospholipids, lysophosphatidylcholine, and autotaxin, components capable of promoting inflammation, oxidative stress, and valvular fibrocalcific remodeling. This review synthesizes the molecular, cellular, and clinical evidence linking Lp(a) to CAVD progression. Retention of Lp(a) and other apolipoprotein B-containing lipoproteins in the valvular matrix promotes endothelial activation, recruitment of cells of the monocytic lineage, and the release of proinflammatory mediators. Oxidized phospholipids and the autotaxin–lysophosphatidic acid axis activate redox-dependent pathways and promote the transition of valvular interstitial cells toward myofibroblastic and/or osteogenic phenotypes. These processes converge in alterations in cholesterol metabolism, the release of procalcifying extracellular vesicles, and hydroxyapatite nucleation. Genetic and imaging evidence supports an association between elevated Lp(a), microcalcifying activity, and accelerated hemodynamic progression. Although anti-Lp(a) therapies substantially reduce plasma Lp(a) concentrations, their effect on valvular outcomes has not yet been demonstrated. Full article

Major depressive disorder (MDD) is not reducible to a single neurotransmitter deficit. Current explanations commonly involve monoaminergic dysfunction, hypothalamic–pituitary–adrenal axis dysregulation, immune-inflammatory activation, impaired neuroplasticity and synaptic dysfunction, together with metabolic and neurovascular abnormalities. Lipidomic studies have repeatedly identified glycerophospholipid abnormalities in MDD, but their mechanistic meaning remains unresolved because changes in bulk lipid abundance do not explain how altered lipid metabolism becomes a receptor-level neural signal. This review develops a testable interpretation of the lysophosphatidylcholine (LPC)–autotaxin (ATX)–lysophosphatidic acid (LPA)–LPA receptor (LPAR) axis in which LPC species generated during phospholipid turnover provide ATX substrates, ATX activity determines local LPA generation, LPA production and inactivation shape ligand availability, and LPAR signaling links the lipid product to neural output. This structure shifts the focus from total lipid abundance to matched assessment of lipid species, enzyme activity, anatomical site and receptor subtype. Human studies report lower serum and cerebrospinal fluid (CSF) ATX in MDD, lower CSF LPA 22:6 in MDD and schizophrenia, and negative total LPA findings that caution against biomarker oversimplification. Depression-relevant and broader stress- or anxiety-related experimental studies show that ATX, LPA and LPAR perturbation can affect hippocampal function, synaptic physiology, emotional behavior and stress resilience. The key unresolved issue is whether brain-accessible LPC species, active ATX, locally generated LPA, LPA inactivation capacity and receptor-specific output can be demonstrated within the same MDD-relevant fluid, brain-interface site or neural circuit. Future work should therefore move from fluid-level association toward pathway closure through targeted and spatial lipidomics, anatomical ATX activity mapping, LPA inactivation assays, blood–brain barrier (BBB)/interface analysis, LPAR perturbation and matched circuit or behavioral readouts. Full article

Background/Objectives: Lysophosphatidic acid (LPA) is a bioactive lipid mediator implicated in neuropathic pain (NP). Depressive symptoms frequently accompany NP and adversely affect outcomes, yet objective biomarkers remain limited. This study aimed to identify cerebrospinal fluid (CSF) LPA molecular species associated with depressive symptoms in patients with NP. Methods: CSF samples were obtained from 48 patients, and LPA species, including positional isomers (sn-1 and sn-2), were quantified using liquid chromatography–tandem mass spectrometry. Depressive symptoms were assessed using the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). Statistical analyses were performed to evaluate associations among depressive symptoms, clinical variables, and LPA species. Results: CSF LPA18:0 was significantly associated with HADS-D scores (r = 0.380, p = 0.010), with the strongest association observed for the sn-1 isoform (r = 0.385, p = 0.009). In multivariable analysis, LPA18:0 sn-1 remained independently associated with depressive symptoms, alongside pain intensity and pain catastrophizing (R² = 0.386). Structural equation modeling supported an association between LPA18:0 sn-1 and depressive symptoms independent of pain-related factors. Conclusions: These findings suggest that CSF LPA18:0 sn-1 may be associated with a biological dimension of depressive distress and may represent a candidate biomarker of depressive distress in NP. However, these findings should be interpreted cautiously, as the analyses were exploratory, and further validation in independent and longitudinal cohorts is warranted. Full article

(1) Different classes of antidepressant drugs have been shown to activate lysophosphatidic acid (LPA) receptors, but their effects on the receptor signaling stimulated by LPA have not been fully investigated. In the present study, we examined the effect of the tricyclic antidepressant amitriptyline on the LPA-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Rho signaling in C6 glioma cells and cultured rat astrocytes. (2) LPA receptor signaling was investigated by using Western blot and microscopic immunofluorescence assays. Rho activation was determined by a pull-down assay. (3) Amitriptyline potentiated the LPA-induced activation of ERK1/2 signaling, as indicated by the more than additive increases in the phosphorylation/activation of key components of this pathway including fibroblast growth factor 1 receptor, MEK1/2, ERK1/2, Elk-1, and cyclic AMP response element binding protein (CREB). Amitriptyline also enhanced the expression of brain-derived neurotrophic factor (BDNF) elicited by LPA. In contrast, the antidepressant failed to mimic the LPA-induced activation of Rho and Rho-dependent responses, such as the reversal of astrocyte stellation, accumulation of stress fibers, and the phosphorylation of focal adhesion kinase and myosin target subunit of myosin phosphatase isoform 1. Moreover, when combined with LPA, amitriptyline curtailed Rho activation and the Rho-mediated cellular responses. (4) These results demonstrate that in astroglial cells, amitriptyline exerts a balanced action on LPA-activated receptors by enhancing the neuroprotective ERK1/2-CREB-BDNF signaling and dampening the potentially detrimental Rho–ROCK pathway, and suggest that this unique property may contribute to the antidepressant activity of the drug. Full article

For decades, the pharmacological identity of Panax ginseng has been primarily attributed to triterpenoid saponins known as ginsenosides. However, accumulating evidence indicates that ginseng also contains a structurally distinct lipid–protein complex, termed gintonin, enriched in lysophosphatidic acid (LPA) species. Unlike ginsenosides, which predominantly exert modulatory effects on membrane dynamics and intracellular kinase pathways, gintonin directly activates LPA G protein-coupled receptors (GPCRs), thereby inducing rapid phospholipase C (PLC) activation and intracellular Ca²⁺ mobilization. Biochemical analyses have identified major LPA species within the gintonin fraction, including C16:0, C18:1, and other unsaturated LPA species such as C18:2 stabilized within a proteinaceous matrix that may influence receptor engagement kinetics. Pharmacological studies demonstrate that gintonin preferentially activates LPA₁ and LPA₃ receptor subtypes, triggering downstream signaling cascades involving MAPK, PI3K/Akt, and Rho pathways. These receptor-mediated effects occur on a rapid temporal scale, distinguishing gintonin from the slower transcriptional and kinase-modulating actions of ginsenosides. In this review, we synthesize current evidence regarding the chemical architecture, receptor pharmacology, and signaling dynamics of gintonin and propose a dual signaling framework in which steroid-like saponins and lipid GPCR ligands represent complementary molecular axes within P. ginseng. Recognition of this layered signaling organization refines the molecular understanding of ginseng biology and highlights gintonin as a unique plant-derived GPCR ligand system.
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Kidney transplantation (KTx) corrects many uremia-related metabolic disturbances; however, dyslipidemia remains common in kidney transplant recipients and contributes to persistent cardiovascular risk. Lipoprotein(a) [Lp(a)] is a largely genetically determined proatherogenic lipoprotein that increases in advanced chronic kidney disease (CKD) and may decrease after restoration of renal function. Autotaxin (ATX), an enzyme involved in proinflammatory lipid signaling through the ATX–lysophosphatidic acid axis, has also been implicated in cardiovascular pathology, but its early post-transplant dynamics remain poorly characterized. In addition to quantitative lipid abnormalities, CKD is associated with high-density lipoprotein (HDL) dysfunction and reduced paraoxonase-1 (PON-1) activity; however, data on early post-transplant changes in PON-1 activity are limited. In this prospective observational study, lipid profile parameters, Lp(a) concentration, ATX activity, and PON-1 activity were assessed in 55 Caucasian patients with CKD stage 5, most of whom were dialysis-dependent, before and 2–3 weeks after KTx. All recipients received tacrolimus-based maintenance immunosuppression with corticosteroids and mycophenolate mofetil. After KTx, Lp(a) levels decreased by a median of 21% and ATX activity by 28% (both p < 0.001). Lp(a) and ATX showed no cross-sectional or longitudinal association either before or after transplantation, and their percentage changes were not correlated. In contrast, conventional lipid fractions increased significantly, including total cholesterol (+22%), LDL cholesterol (+27%), HDL cholesterol (+24%), and triglycerides (+55%) (all p < 0.001). PON-1 activity increased by approximately 13% after KTx (p < 0.001), and its percentage change correlated positively with the increase in HDL cholesterol. In exploratory analyses, the magnitude of Lp(a) reduction was associated with early graft function: patients with eGFR <45 mL/min/1.73 m² exhibited a significantly smaller decline in Lp(a) than those with better graft function (−4.8% vs. −26.7%, p = 0.009). Multivariable analysis showed that demographic characteristics, body mass index, tacrolimus exposure, and post-transplant eGFR did not independently predict the magnitude of Lp(a) reduction. Tacrolimus trough concentrations and cumulative corticosteroid exposure were not associated with lipid parameters or their changes, except for a single subgroup difference in PON-1 activity of uncertain clinical significance. In summary, in the early period after KTx under tacrolimus-based immunosuppression, Lp(a) concentration and ATX activity decrease, whereas conventional lipid fractions increase and PON-1 activity improves. These changes were not associated with tacrolimus exposure or cumulative corticosteroid dose. The reduction in Lp(a) was associated with early graft function in exploratory analyses, suggesting that recovery of renal function may contribute to early post-transplant Lp(a) dynamics; however, no independent causal relationship was established, and the findings should be interpreted cautiously given the limited sample size and exploratory design. The clinical significance of these changes for long-term cardiovascular and graft outcomes requires further investigation. Full article

Scientific evidence supports the role of the autotaxin-lysophosphatidic acid (ATX-LPA) pathway in obesity and liver damage. The present study aim is to investigate variations in serum ATX and LPA levels across different BMI categories in a subcohort of subjects with MASLD. The study sample comprises 199 patients with liver steatosis from the most recent follow-up of the MICOL study, a prospective cohort study established in 1985, based on a random sample of the population of Castellana Grotte. In adjusted model, a positive association of BMI with ATX was observed when modeled as both a continuous (β = 0.018, p < 0.001, 0.012 to 0.024 95% C.I.) and categorical variable β = 0.170, p < 0.001, 0.111 to 0.228 95% C.I.). Conversely, a negative association was observed for LPA alone (β = −0.083, p = 0.020, −0.152 to −0.013 95% C.I.) and for the BMI and LPA interaction term (β = −0.109, p = 0.002, −0.176 to −0.042 95% C.I.). A positive association between ATX levels and BMI was found, whereas LPA levels tended to decrease with increasing BMI. Within the obese subgroup, ATX concentrations were notably higher in female compared to male participants. These findings suggest that elevated ATX in MASLD may reflect obesity-related metabolic and inflammatory alterations rather than adiposity alone, possibly involving altered LPA feedback and metabolism. Full article

Phosphatidic acid (PA) is increasingly recognized as an important endogenous regulator of cell proliferation and migration, playing relevant roles in physiology and pathology. However, the potential and prominence of extracellular PA in controlling cell functions are not so well established. The present review article has been undertaken to update and discuss the latest findings on extracellular PA as regulator of cell homeostasis, with special attention being paid to its role in the regulation of cell growth and migration. Specifically, exogenous PA potently stimulates myoblast proliferation and lung cancer cell migration, pointing to a critical role of this glycerophospholipid in the regulation of muscle cell regeneration and lung cancer dissemination. Interestingly, both of these actions are mediated through interaction of PA with lysophosphatidic acid (LPA) receptors and the subsequent activation of different signal transduction pathways. In particular, PA induces mitogen-activated protein kinase kinase (MEK)/extracellularly regulated kinases (ERK) 1 and 2, phosphatidylinositol 3-kinase (PI3K)/Akt, focal adhesion kinase (FAK)/Rac1, and Janus kinase-2 (JAK2)/signal transducer and activator of transcription 3 (STAT3). These findings may contribute to a better understanding of muscle cell biology and may help to develop new therapeutic strategies to treat lung cancer dissemination. Full article

Ovarian cancer remains a major cause of mortality in women aged 74 years and under. Dysregulation of the PI3K/AKT/mTOR and NFκB signaling pathways has been associated with poor outcomes and treatment resistance. This study evaluated three potential anticancer agents targeting these pathways: buparlisib (a pan-PI3K/mTORC1 inhibitor), SN32976 (a PI3K p110α inhibitor), and pterostilbene (a resveratrol analogue that downregulates PI3K/AKT and NFκB signaling). Their efficacy was tested in 3D collagen models of ovarian cancer, using SKOV3 and OVCAR8 cell lines, activated by tumor necrosis factor-alpha (TNFα) and lysophosphatidic acid (LPA). Using concentrations derived from 2D assays, viability, collagen gel sizes, secretion of interleukin 6/8 (IL-6/8) and signal pathway proteins were analyzed. All compounds were less effective in 3D models than in 2D cultures, with high cell viability maintained. TNFα and LPA did not significantly alter drug sensitivity, and collagen gel contraction was largely unaffected. While the compounds did not consistently change signaling protein levels, they generally reduced secretion of pro-inflammatory cytokines IL-6 and IL-8. Growth in 3D collagen gels conferred drug resistance on OVCAR8 but not SKOV3 models. Overall, these findings provide preclinical support for further investigation of SN32976 and pterostilbene in ovarian cancer models. Full article

Hot air drying is widely used in edible mushroom processing, but often leads to quality changes, including browning and flavor changes. This study focused on Phallus impudicus (P. impudicus), combining dynamic monitoring of browning-related indicators with lipidomics technology to systematically investigate the mechanism by which lipid changes influence quality during hot air drying. The results showed that drying significantly altered lipid metabolism. Encompassing 28 subclasses, five major lipid categories were identified: glycerophospholipids (GP), glycolipids (GL), sphingolipids (SP), isoprenylglycolipids (PR), and fatty acids (FA). From among these, the total content of GP remained the highest and increased significantly after drying, whereas the contents of GL and FA decreased markedly. Hydrolysis of structural lipids led to the collapse of cellular structure, and the levels of hydrolyzed lipids phosphatidic acid (PA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and lysophosphatidic acid (LPA) increased significantly after drying, which may adversely affect long-term storage. Furthermore, increased lipid unsaturation intensified browning, and lipid oxidation also promoted the formation of volatile flavor compounds. Overall, this lipidomic research demonstrated that hot air drying determines the final quality and flavor profile of dried P. impudicus through coordinated mechanisms involving membrane lipid oxidation, structural membrane damage, browning, and flavor generation. These findings provided a new insight into the mechanism of quality changes and a theoretical basis for quality improvement and process regulation for dried edible mushroom products. Full article

Lysophosphatidic acid (LPA) is a cell-signaling lipid that has been proposed as an early-stage biomarker for ovarian cancer (OC). Diagnosing OC in Stage I is critical to improving patient outcomes, increasing the survival rate from 30% (when diagnosed in late stages of the disease) to over 90%. This significant improvement is due to the success of early interventions; however, current diagnostic methods are not as effective at early-stage detection, with only 15% of cases diagnosed in Stage I and over 70% diagnosed in Stage III or IV. There is a strong need for LPA detection that is sensitive, specific, rapid, low-cost, and automated to truly validate its effectiveness as a diagnostic characteristic for OC. We report the preliminary development and characterization of one such biosensor, which makes use of the advantages of magnetic particles and chemiluminescence for quick, sensitive detection of LPA. The sensor has proven to be viable, with a positive response to LPA concentration, a measurement time of 5 s after incubation, and an LOD of 3.5 nM. Full article

Dysregulated extracellular matrix (ECM) deposition and epithelial–mesenchymal transition (EMT) in the trabecular meshwork (TM) contribute to glaucoma-associated fibrotic remodeling, and lysophosphatidic acid (LPA) potently induces these profibrotic responses in human trabecular meshwork (HTM) cells. We investigated whether an ethanolic extract of Diospyros kaki leaves (EEDK) attenuates LPA-induced fibrosis and explored the underlying mechanisms. HTM cells were stimulated with LPA and treated with ethanol-based EEDK extracts. Expression of ECM/fibrosis-related genes (FN1, ACTA2, COL1A1, COL3A1, COL4A1, COL6A2, CCN2) and EMT markers (CDH2, VIM, SNAI1) was assessed, along with cell migration using a wound-healing assay. Upstream regulatory pathways were examined via transcription factor prediction, AP-1 reporter assays, and analyses of MAPK/AP-1 signaling. Among the extracts tested, the 70% ethanol EEDK extract showed the strongest antifibrotic activity, significantly reducing LPA-induced ECM gene/protein expression and inhibiting HTM cell migration in a dose-dependent manner, whereas the 90% ethanol extract showed minimal effects. LPA robustly activated MAPK-dependent AP-1 signaling, and either pharmacologic inhibition of MAPK pathways or treatment with 70% ethanol EEDK comparably suppressed AP-1 activity and decreased downstream ECM/EMT gene expression. Thus, 70% ethanol EEDK mitigates LPA-induced TM fibrosis by inhibiting MAPK/AP-1-mediated transcription, supporting its potential as an antifibrotic strategy for glaucoma. Full article

Background: Korean red ginseng marc (KRGM), a by-product of Korean red ginseng (KRG) processing, retains numerous bioactive compounds with potential health benefits. Among them, KRGM-derived gintonin (KRGM-gintonin) is particularly rich in lysophosphatidic acid (LPA) and phospholipids, which have been linked to favorable metabolic effects. This study investigated the anti-obesity potential of KRGM-gintonin in high-fat diet (HFD)–induced obese mice, focusing on its impact on weight regulation, liver health, and energy metabolism. Methods: Obese mice (C57BL/6N, 4 weeks, male) were administered KRGM-gintonin either orally for 25 weeks or through intracerebroventricular (ICV) injection for 14 weeks. Throughout the study, body weight, food intake, metabolic parameters, liver tissue morphology, behavioral performance, and thermogenic gene expression were carefully monitored to evaluate treatment effects. Results: Both oral and ICV administration of KRGM-gintonin significantly reduced body weight gain in HFD-fed obese mice without altering food intake, suggesting enhanced energy expenditure. Treatment through both routes improved physical performance and increased metabolic rate. Oral KRGM-gintonin also alleviated fatty liver, reduced plasma triacylglycerol and cholesterol levels, and promoted the expression of thermogenesis-related genes, including uncoupling protein-1 (UCP1) and hormone-sensitive lipase (HSL), specifically in brown adipose tissue. Additionally, oral administration lowered tumor necrosis factor-α (TNF-α) expression, indicating anti-inflammatory activity and further supporting metabolic health. Conclusions: KRGM-gintonin exerts strong anti-obesity effects, primarily through oral administration, with supportive evidence from central ICV action. These findings highlight its potential as a functional therapeutic agent for obesity prevention and management, offering dual benefits in metabolic regulation and inflammation control. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a frequent manifestation of obesity and other metabolic diseases. Autotaxin (ATX), an enzyme involved in the generation of lysophosphatidic acid (LPA), has recently emerged as a potential biomarker of metabolic inflammation and liver disease progression. Vegetable-based dietary interventions have been shown to reduce liver steatosis, but evidence of the impact of this dietary approach on ATX levels remains limited. Objectives: To evaluate the short-term effects of a bioactive vegetable-enriched diet from the Brassicaceae and Asteraceae families on serum ATX levels and liver-related parameters in individuals with obesity and MASLD, with a specific focus on sex differences. Methods: In this two-month pilot study, 44 obese adults (BMI > 30 kg/m²) underwent clinical and instrumental assessments at baseline (T0) and after the dietary intervention (T1). Results: After the intervention, serum ATX levels significantly decreased (from 206.3 ± 52.8 to 191.7 ± 45.7 ng/mL, p < 0.001), and there were improvements in metabolic parameters (BMI, waist circumference, blood pressure, fat mass, insulin, HOMA-IR, triglycerides, total and LDL cholesterol) and liver indices (CAP, ALT, AST, γGT). The multivariate GEE model confirmed a significant reduction in ATX, independent of age, sex, FFM, LPA, LSM, Hemoglobin A1c, and PAI-1 (β = −9.87, p < 0.001). When stratified by sex, women exhibited a more pronounced reduction in ATX levels (β = −12.24; p = 0.005) compared to men (β = −9.43; p = 0.014). Conclusions: A short-term, vegetable-enriched dietary intervention can significantly reduce serum ATX levels and improve metabolic and liver-related parameters in individuals with MASLD. Sex-specific analysis reveals a greater ATX-lowering effect in women, suggesting potential sex-based differences in ATX metabolism or dietary responsiveness. These findings suggest that ATX may serve as a modifiable biomarker responsive to nutritional intervention and a potential therapeutic target in metabolic liver disease. Full article

Bone marrow-derived mononuclear cells (BMMCs) have shown beneficial effects on tissue repair, largely attributed to the paracrine action of bioactive mediators such as lysophosphatidic acid (LPA). This study aimed to evaluate the effects of BMMC treatment in a rat model of renal ischemia/reperfusion (I/R) injury, focusing on LPA-related molecular pathways. Male Wistar rats were divided into three groups: control; I/R, subjected to bilateral renal artery clamping for 30 min followed by 24 h of reperfusion; and I/R + BMMC, which received 1 × 10⁶ BMMCs per kidney directly into the renal capsule post-ischemia. During reperfusion, the rats were placed in metabolic cages for urine collection, renal function and protein expression. BMMC treatment did not reverse the I/R-induced increase in urine volume or decrease in glomerular filtration rate, serum potassium, or filtered sodium load. However, it prevented proteinuria, increased blood urea nitrogen, and enhanced urinary potassium excretion. Mechanistically, BMMC treatment prevented I/R-induced upregulation of LPAR1, downregulated LPAR2 and LPAR3, restored plasma LPA levels, and reduced renal autotaxin content. These results suggest that BMMCs modulate harmful LPA-related signaling and may contribute to renal protection through paracrine mechanisms in the setting of acute I/R injury. Full article