Search Results (1,425)

The A3 adenosine receptor (A3AR) is a stress-inducible G-protein-coupled receptor that is selectively upregulated in inflamed, hypoxic, and fibrotic tissues as well as in many malignancies, while remaining weakly expressed in most normal organs. This distinctive expression pattern provides a strong biological basis for pathology-selective pharmacology. Activation of A3AR by highly selective agonists, including piclidenoson (IB-MECA) and namodenoson (Cl-IB-MECA), initiates signaling through Gi proteins and phospholipase C (PLC), which in turn regulate a coordinated network of downstream intracellular pathways, including PI3K/Akt, NF-κB, MAPKs, and Wnt/β-catenin, resulting in suppression of inflammation, inhibition of pathological cell survival, and protection of metabolically stressed tissues. Over the three decades, extensive preclinical studies have demonstrated that A3AR agonism exerts anti-cancer, anti-fibrotic, immunomodulatory, neuroprotective, and organ-protective effects across diverse disease models, including hepatocellular carcinoma, pancreatic cancer, psoriasis, osteoarthritis, metabolic dysfunction-associated steatohepatitis, ischemic stroke, neurodegeneration, ophthalmic disorders, and inherited metabolic syndromes. Importantly, these mechanistic insights have been translated into clinical programs, with piclidenoson and namodenoson demonstrating favorable safety profiles and disease-modifying activity in inflammatory, fibrotic, and oncologic indications. This review integrates molecular, cellular, and translational evidence to highlight A3AR activation as a unifying therapeutic principle for diseases driven by inflammation, oxidative stress, hypoxia, and dysregulated cell survival, positioning selective A3AR agonists as first-in-class agents targeting the A3AR, with broad clinical applicability across multiple disease domains. Full article

Functional changes in PNPLA6 (Patatin-like phospholipase domain-containing protein 6), caused by gene mutations or inhibition by organophosphates, affect the levels of various phospholipids. In humans, this leads to organophosphorus compound-induced delayed neurotoxicity syndrome (OPIDN) and a number of rare diseases. In this study, we analyze the role of the Swiss cheese gene (sws), an ortholog of PNPLA6, in spermatogenesis in Drosophila melanogaster. We report that the sws¹ mutation affects membrane remodeling during spermatid individualization, as well as spermatid coiling during the late stages of spermatogenesis. In addition, the sws¹ mutation leads to changes in the transcriptome in the testes of flies. We also demonstrate that sws is required for the proper functioning of important biological barriers in Drosophila. Full article

Mulberry (Morus spp.) is valued for sericulture, medicine, and ecological restoration of degraded lands. Phospholipase A (PLA) enzymes hydrolyze membrane lipids and play critical roles in plant growth and stress responses, yet the PLA family in mulberry remains uncharacterized. Here, we performed genome-wide identification of Morus notabilis PLA genes in order to systematically analyze their phylogenetic relationships and gene structures, and profile their expression across tissues and under drought and salt stress, thereby providing candidate genes for future functional studies on stress tolerance. Fifty non-redundant PLA genes were identified and classified into three subfamilies: pPLA (22), PLA2 (nine), and PLA1 (19). Most predicted PLA proteins are small (100–500 aa) with predicted instability. Gene structures varied from 1 to 21 exons, and subfamily specific conserved domains (patatin/C2, PLATZ, lipase_3) were detected. Promoters contained stress- and hormone-responsive elements. Expression patterns across five tissues revealed distinct preferential patterns: 56% of genes showed highest expression in roots, with one-fifth in leaves. Under stress, 10 and 12 MnPLA genes were increased >2-fold (log₂FC > 1.0) by drought and salt, respectively. Notably, XP_010108435.1 and XP_024022961.1 exhibited leaf-specific high expression and were salt-induced (log₂FC > 1.0); XP_010090405.1 (leaf-specific low) was drought-induced (log₂FC > 1.0); and XP_024023462.1 (root-specific high) was induced by both stresses. These results provide a basis for functional studies and genetic improvement of stress tolerance in mulberry. Full article

This study evaluated how a lemon essential oil–rutin–chitosan coating (CS-LEO/NE-R), prepared from a 5:95 (v/v) lemon essential oil/rutin-containing nanoemulsion and a chitosan solution containing 1.5% chitosan, 1% acetic acid, and 5% glycerol, combined with controlled freezing-point storage preserves seasoned white snakehead fillets. Compared with controlled freezing-point storage alone, the combined treatment significantly inhibited oxidation, volatile nitrogen accumulation, texture softening, and microbial growth. On Day 10, the coating group recorded a total viable count of 4.98 log CFU/g, which was below the national limit (5 log CFU/g), whereas the control group went beyond this limit by Day 7. This extended the microbiological and physicochemical acceptability period by approximately 3 days under the present experimental conditions. Untargeted metabolomics revealed 2267 metabolites, and the differentially abundant ones mainly comprised amino acids, heterocyclic compounds, aldehydes, ketones, and esters. KEGG enrichment suggested that changes in linoleic acid metabolism, terpenoid related annotations, the actin cytoskeleton, and the phospholipase D signaling pathway were associated with delayed quality deterioration. This work provides a theoretical basis for the composite biopreservation of aquatic products. Full article

Serum and plasma are the most widely used matrices in metabolomics and human biomonitoring studies; however, the optimal matrix for integrated non-targeted analysis (NTA) workflows combining metabolomics and exposomics has not been systematically evaluated. This pilot study applied parallel NTA workflows to paired serum and plasma samples from five individuals to characterize matrix-dependent differences and provide an empirical basis for matrix selection in integrated studies. Three analytical methods were employed: one metabolomic method (Method 1) using Hydrophilic Interaction Liquid Chromatography (HILIC) and Reversed-Phase Liquid Chromatography (RPLC) columns and one exposomics (Method 2) method using an RPLC column, each analyzed in both electrospray ionization (ESI) positive and negative modes. Overall, serum and plasma showed broad similarity, with substantial overlap in detected features and strong linear correlations between paired samples (R² = 0.70–0.87). However, PCA revealed systematic differences between the two matrices along PC1 and PC2, likely attributable to matrix effects arising from coagulation-related compositional changes in serum. For metabolomics, glycerophospholipids, sphingolipids, and acylcarnitines were consistently enriched in serum, attributable to platelet activation and phospholipase release during blood coagulation, consistent with prior reports. In contrast, oxidized fatty acid species were predominantly elevated in plasma, warranting caution in oxylipin-focused studies using serum. For exogenous chemical profiling, the two matrices performed comparably, with 32 out of 36 annotated features showing no significant matrix-dependent differences (p > 0.05), including PFAS, pharmaceuticals, and diverse xenobiotics. These findings support the interchangeability of serum and plasma for broad exposomics studies. Overall, while both matrices provided broadly comparable global coverage, plasma may represent a more appropriate matrix for integrated NTA workflows, as it better preserves in vivo metabolite composition and minimizes coagulation-induced confounding, though validation in larger cohorts is needed. Full article

Despite the vast biodiversity of Mexican vipers, venom of endemic species has been barely studied. Here we analyzed the venom composition of three endemic species of rattlesnakes: Crotalus aquilus, C. triseriatus, and C. ravus. We used quantitative chromato-mass-spectrometry and compared venoms with C. molossus, a species commonly found in North America, in a comparative and phylogenetic framework. In total, we identified 165 proteins grouped in 19 main protein families, consistent with previous reports for viperid venoms. In C. aquilus and C. triseriatus, the most predominant protein-family type was Serine Proteases, and in C. triseriatus and C. molossus it was Snake Venom Metalloproteases. The Label-free quantification revealed a high proportion of Snake Venom Metalloproteases in C. aquilus, C. triseriatus, and C. molossus, reaching 28–47% of the total venom. In contrast, in C. ravus 47% of the venom was composed of Phospholipases A₂. Among the four species analyzed, C. triseriatus and C. aquilus were most similar in compositional profiles and their profiles are highly correlated. Venom composition in terminal clades and taxa were better explained by protein losses than evolution of new proteins. The triseriatus group share seven proteins, while the clade C. aquilus + C. triseriatus share seven derived protein features, of which six are protein losses. Full article

The type VI secretion system (T6SS) is a contact-dependent, contractile multiprotein complex widely distributed among Gram-negative bacteria. It mediates the translocation of effector proteins into bacterial competitors and eukaryotic host cells, promoting environmental fitness and contributing to virulence. In Salmonella, five pathogenicity islands encoding T6SSs (SPI-6, SPI-19, SPI-20, SPI-21, and SPI-22) have been described, along with an expanding repertoire of associated effector proteins. However, their global diversity and distribution remain incompletely resolved due to limited genomic sampling. To address this, we analyzed a curated dataset of 490 Salmonella genomes representing 45 serotypes. T6SS regions were identified using SecreT6, revealing that SPI-6 is widely distributed, whereas SPI-19, SPI-20, and SPI-21 are restricted to a subset of serotypes. SPI-20 and SPI-21 were exclusively found in S. enterica subsp. arizonae and diarizonae, while SPI-22 was absent from all analyzed genomes. All open reading frames within T6SS clusters were then analyzed for effector prediction and functional annotation. This approach recovered 32 out of 45 previously described T6SS effectors and identified several novel candidates. These included a cytidine deaminase with predicted DNase activity in SPI-6: two candidate nuclease effectors in SPI-19 with DNase and RNase activities, and four putative effectors in SPI-21, including enzymes with predicted peptidoglycan hydrolase activity, a potential inhibitor of eukaryotic ATPases, and a membrane pore-forming toxin. Additionally, a putative phospholipase effector was identified within a VgrG-associated genomic island in a subset of S. enterica subsp. diarizonae isolates. Collectively, these findings expand the known repertoire of Salmonella T6SS effector proteins and highlight their functional diversity. Full article

Despite the critical role of lipid-mediated signaling in regulating host immunity, endorsed by growing evidence, the interaction between lipid metabolism and immune response remains largely unknown. This review aims to elucidate the immunomodulatory role of a lung-enriched lipid metabolic pathway mediated by the phospholipase A2 (PLA₂) family, which comprises a diverse range of lipid-hydrolyzing enzymes. Based on their location, structure, substrate specificity and physiological roles, PLA₂s can be classified into secreted PLA₂s (sPLA₂s), cytosolic PLA₂s (cPLA₂s), calcium-independent PLA₂s (iPLA₂s), and lysosomal-associated PLA₂s (lPLA₂s). These PLA₂ isoforms are similar in that they can all cleave cellular membrane-associated phospholipids, releasing free lysophospholipids and fatty acids such as arachidonic acid, which subsequently serve as precursors for a wide range of bioactive mediators responsible for physiological functions and pathological changes. Respiratory infections, especially those caused by bacteria and viruses, represent a substantial threat to the health of the population worldwide and cause billions of disease cases and millions of deaths annually. Respiratory infections provoke airway inflammation, characterized by increased vascular permeability and the influx of immune cells, resulting in tissue damage, impaired gas exchange, acute respiratory distress syndrome (ARDS) and even death. During infections and inflammatory milieu, airway-expressed PLA₂ can further increase and exhibit protection by restricting pathogens and inflammation or, in contrast, exacerbate the pathogenesis. In this manuscript, we will provide an overview of the current knowledge on the biological functions of PLA₂ isoforms, especially concerning membrane-associated isoforms in respiratory infections, and offer insight into the spatial and temporal regulation of immune responses mediated by PLA₂ and the subsequent modulation of host–pathogen interactions and the balance between protective effects and pathological outcomes. Full article

Apitherapy is a complementary therapeutic approach based on the use of bee-derived products, particularly bee venom (BV), also known as apitoxin. Bee venom is a complex mixture of biologically active compounds, including peptides, enzymes, and biogenic amines, that exhibit diverse pharmacological activities. Major bioactive constituents such as melittin, apamin, adolapin, and phospholipase A2 have attracted increasing scientific interest due to their anti-inflammatory, antioxidant, antimicrobial, analgesic, and immunomodulatory properties. This review provides a comprehensive overview of the biological effects and therapeutic potential of bee venom in the management of chronic diseases, particularly diabetes, cancer, and neurological disorders. Evidence from experimental and clinical studies suggests that BV and its components can modulate multiple molecular pathways associated with oxidative stress, inflammation, apoptosis, and immune responses. These mechanisms contribute to potential benefits in glycemic control, tumor suppression, neuroprotection, and pain management. Additionally, bee venom has been investigated for its capacity to influence signaling pathways involved in cellular proliferation and survival, highlighting its potential as a complementary strategy in the treatment of complex diseases such as neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases. Despite these promising therapeutic effects, the clinical use of BV remains limited due to safety concerns, particularly the risk of allergic reactions, systemic toxicity, and anaphylaxis. Recent advances in drug delivery systems and nanotechnology may help improve the safety and efficacy of BV-based therapies by enabling targeted delivery and controlled dosing. Overall, bee venom represents a promising source of bioactive compounds with potential applications in translational and integrative medicine; however, further well-designed clinical trials and mechanistic studies are necessary to establish its safety, efficacy, and long-term therapeutic value. Full article

Heat stress (HS), increasingly intensified by climate change, severely restricts tomato growth and productivity. Although core heat shock factor-mediated transcriptional networks have been extensively characterized, how lipid metabolic reprogramming is transcriptionally coordinated during thermotolerance remains unclear. Using SlHDZ19 overexpression and mutant lines together with transcriptomic, biochemical, promoter-binding, and gene-silencing analyses, we show that the homeobox-leucine zipper transcription factor SlHDZ19 promotes tomato (Solanum lycopersicum) thermotolerance by activating a PLA2-dependent lipid-metabolic transcriptional program in leaves. SlHDZ19 overexpression generally improved heat-stress performance, while SlHDZ19 mutant lines exhibited heightened sensitivity, including more severe wilting, higher electrolyte leakage, and reduced proline accumulation and CAT activity under heat stress. Transcriptomic analysis revealed that SlHDZ19 is required for the full induction of canonical heat-responsive genes and that the linoleic acid metabolism pathway was repeatedly implicated in SlHDZ19-dependent transcriptional changes. SlHDZ19 binds to and activates the promoters of SlPLA_2α, which encodes a phospholipase A2 involved in releasing linoleic acid from membrane lipids, and three lipoxygenase genes (SlLox7, SlLox8, and SlLoxC), accompanied by elevated overall PLA2 and LOX activities in SlHDZ19-overexpressing plants. Moreover, genetic silencing of SlPLA_2α in both wild-type and SlHDZ19-overexpressing backgrounds supported its functional requirement downstream of SlHDZ19 in thermotolerance. Collectively, our findings support a thermotolerance module in which SlHDZ19 transcriptionally regulates PLA2- and LOX-associated steps of linoleic acid metabolism, potentially linking lipid-associated signaling and membrane remodeling with heat stress adaptation in tomato. Full article

Background/Objectives: Circulating platelets mediate physiological hemostasis and are implicated in pathological thrombosis, which can cause vascular occlusion, leading to heart attacks or strokes. Costunolide is a sesquiterpene lactone extracted from Saussurea lappa. Although this lactone has multiple biological effects, including anti-inflammatory and antioxidant effects, that help slow the progression of atherosclerosis, its influence on platelet activation remains unclear. In this study, we examined the potential antiplatelet and antithrombotic effects of costunolide. Methods: We used platelet aggregation, flow cytometry, and Western blot analysis to examine its in vitro antiplatelet effects. Results: Our results indicated that costunolide inhibited platelet aggregation induced by collagen, but not by thrombin or the thromboxane A₂ analog U46619, suggesting that costunolide selectively inhibits collagen-induced platelet activation. Additionally, costunolide blocked collagen-mediated granule release, calcium mobilization, and glycoprotein IIb/IIIa (GPIIb/IIIa) activation. Costunolide also inhibited phospholipase Cγ2 (PLCγ2), pleckstrin (a downstream target of protein kinase C), Akt, and mitogen-activated protein kinase. Moreover, it prevented collagen/epinephrine-induced pulmonary thrombosis and increased the survival rate of mice. Furthermore, costunolide delayed thrombus formation in the mesenteric vessels while it did not significantly affect hemostasis, suggesting it exhibits antithrombotic activity without bleeding tendency. These findings indicate that costunolide can block PLCγ2-PKC, Akt, and MAPK signaling pathways and subsequent granule release, calcium mobilization, and GPIIb/IIIa activation, eventually impeding platelet activation, platelet aggregation, and thrombus formation. Conclusions: In conclusion, besides its multiple biological activities that are beneficial for slowing the progression of atherosclerosis, we also demonstrated the antiplatelet and antithrombotic activities of costunolide. These effects highlight the therapeutic potential of costunolide in the treatment of patients with cardiovascular disease, particularly stroke and heart attack. Full article

Low levels of high-density lipoprotein cholesterol (HDL-C) are strongly associated with increased cardiovascular risk. However, under various pathological conditions, high-density lipoprotein (HDL) particles may undergo structural and functional modifications, leading to a progressive loss of antioxidant capacity and a shift from a cardioprotective to a proatherogenic phenotype. In this cross-sectional study, we investigated differences in HDL particle distribution and antioxidant function between individuals with elevated lipoprotein(a) [Lp(a)] levels (≥30 mg/dL) and those with low Lp(a) levels (<10 mg/dL). Serum low-density lipoprotein (LDL) and HDL subfractions were analyzed in twenty subjects with high Lp(a) and ten low-Lp(a) controls using non-denaturing polyacrylamide gel electrophoresis (PAGE, Lipoprint system). Enzymatic activities of paraoxonase-1 (PON1) and HDL-associated lipoprotein-associated phospholipase A₂ (HDL-Lp-PLA₂) were measured. Electrophoretic analysis revealed a significant increase in small HDL (S-HDL) in the high-Lp(a) group compared to the controls (34.1 ± 13.2% vs. 21.5 ± 2.7%, p = 0.01), alongside a reduction in large HDL (L-HDL) (19.6 ± 9.9% vs. 33.4 ± 3.8%, p < 0.001). Furthermore, the high Lp(a) group exhibited significantly lower HDL-PON1 activity (55 ± 12 vs. 67 ± 7 U/mL, p < 0.001) and HDL-Lp-PLA₂ activity (2.6 ± 1.0 vs. 3.6 ± 1.2 nmol/min/mL, p < 0.02) compared with the controls. These findings suggest that markedly elevated Lp(a) levels are associated with a shift toward a more proatherogenic HDL subfraction profile and impaired antioxidant functionality, which may reflect mechanisms linked to increased atherosclerotic cardiovascular disease (ASCVD) risk. Full article

Phospholipase A2 group VI (PLA2G6) regulates phospholipid remodeling and cellular homeostasis, and its mutations cause neurodegenerative disorders, including neurodegeneration with brain iron accumulation and PLA2G6-associated parkinsonism (PARK14). Although many cases present in adulthood, a substantial subset shows early onset, indicating that PLA2G6 dysfunction can affect neuronal systems during developmental stages. However, whether PLA2G6 directly regulates early neurogenesis remains undefined. Here, using zebrafish embryos, we investigated the role of Pla2g6 during neural development through loss- and gain-of-function approaches. pla2g6 is dynamically expressed during embryogenesis, with enrichment in the developing central nervous system during neurogenesis. CRISPR/Cas9-mediated Pla2g6 deficiency did not alter neural progenitor formation but significantly reduced neuronal precursors. Expression of the disease-associated PLA2G6 D331Y variant phenocopied this effect, confirming that the observed phenotype results from loss of Pla2g6 function. The reduction in neuronal precursors occurred without changes in proliferation but was accompanied by a marked increase in apoptosis, identifying neuronal precursor cell death as the primary mechanism. Under oxidative stress conditions, Pla2g6 overexpression reduced neuronal apoptosis, whereas Pla2g6 deficiency markedly enhanced reactive oxygen species -induced apoptosis. These findings establish Pla2g6 as a regulator of oxidative stress-associated apoptotic signaling during neurogenesis. Together, these results define Pla2g6 as a stage-specific determinant of neuronal precursor survival, linking lipid homeostasis and oxidative stress control to early neural development. This study establishes a developmental framework for PLA2G6-associated disorders and positions impaired neuronal precursor survival as a contributing mechanism underlying disease onset. Full article

Snakebite envenoming is a major yet neglected tropical disease in sub-Saharan Africa, where antivenom efficacy is critically limited by intraspecific venom variation shaped by local ecological pressures. Nigeria’s sharply contrasting Sudan Savanna (North) and Lowland Rainforest (South) provide an ideal natural system to investigate this variation, yet a comparative analysis of its medically important snakes has been lacking. We conducted an integrated proteomic and functional characterization of venoms from the puff adder (Bitis arietans) and black-necked spitting cobra (Naja nigricollis) collected in Kaduna (North) and Ibadan (South). Using high-resolution LC-MS/MS, SDS-PAGE, and biochemical assays (phospholipase A₂, protease, fibrinogenolytic, hemolytic, and coagulation activities), we mapped region-specific venom compositions and characterized their functional activities. Bitis arietans displayed region-associated divergence: southern venom was enriched in serine proteases, whereas northern venom was dominated by lectins and distinct snake venom metalloproteinase isoforms. Naja nigricollis showed a conserved phospholipase A₂/three-finger toxins backbone, yet southern venoms exhibited elevated snake venom metalloproteinase III and L-amino acid oxidase. These molecular differences manifested functionally, with southern B. arietans venom showing higher protease activity than northern B. arietans, whereas southern and northern N. nigricollis venom exhibited similar protease activity but enhanced phospholipase A₂ activity in southern N. nigricollis. This work provides the first integrated proteomic and functional comparison of venoms from northern and southern Nigerian venom sample of B. arietans and N. nigricollis. While based on a limited number of individuals, the observed differences should be considered preliminary and indicative of potential regional trends rather than population-level characteristics. Full article

Animal venoms induce systemic inflammatory response syndrome through their interaction, inter alia, with pattern recognition receptors (PRRs) of the innate immune system. CD5 and CD6 are lymphoid members of the scavenger receptor cysteine-rich superfamily, endowed with PRR activity against microbial-associated molecular patterns (MAMPs) derived from bacteria, fungi, viruses and/or parasites. In this study, we aimed to investigate CD5 and CD6 interaction with cobra (Naja haje), scorpion (Androctonus australis) and honeybee (Apis mellifera) venoms. Binding assays revealed direct, dose-dependent and specific interaction of soluble human CD5 and CD6 receptors with protein nature components from the three venoms. Proteomic analysis identified venom nerve growth factor, basic phospholipase A2 (PLA2) and cobra venom factor, in cobra venom, and scorpion venom toxins targeting potassium (α-KTx 8.1) and sodium channels (Neurotoxin-1″ and G-TI) as potentially interacting components with CD5 and CD6. Further studies confirmed direct binding of bee venom main components, phospholipase A2 and melittin, to both soluble CD5 and CD6 receptors. Interestingly, in vitro PLA2 activity from cobra and bee venom was significantly reduced by both soluble CD5 and CD6 receptors. These findings broaden the PRR properties of CD5 and CD6 and support their potential involvement in envenomation pathophysiology. Full article