Search Results (53)

The Phosphoinositide Specific-Phospholipase C (PI-PLC) family of enzymes plays a crucial role in various cellular processes by catalyzing the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂] into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG), which are essential messengers mediating critical intracellular signaling pathways. Herein, we carry out a comprehensive analysis of the structure, function, regulation, and implications of the PI-PLC family enzymes in both physiological and pathological contexts. More specifically, we discuss the structural features of PI-PLCs, elucidating their conserved domains and catalytic mechanisms. Furthermore, we explore the multifaceted roles of PI-PLCs in signal transduction, cellular homeostasis, and membrane dynamics, whilst highlighting the intricate regulatory mechanisms governing their activity such as protein–protein interactions, post-translational modifications, and lipid modulation. Lastly, we assess the involvement of PI-PLCs in various diseases, such as cancer, neurological disorders, immune dysregulation, and male infertility, emphasizing their potential as therapeutic targets. Full article

Background/Objectives: Timely and effective clinical management of leishmaniasis depends on a deep understanding of parasite biology and drug resistance mechanisms. Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes are critical for parasite survival and immune evasion and possibly influence treatment outcomes. This study aimed to characterize the PI-PLC gene family in the Leishmania infantum and Leishmania major genomes, with a focus on their expression profiles in antimony-susceptible and -resistant strains to uncover their diagnostic and prognostic relevance. Methods: This study conducted a comprehensive genome-wide screening to identify PI-PLC genes in L. infantum and L. major, followed by detailed analyses of their gene structures, conserved motifs, chromosomal localization, and phylogenetic relationships. To explore potential roles in drug resistance and clinical prognosis, RNA-seq data from antimony-resistant and -susceptible L. infantum strains were analyzed for differential gene expression. Results: Twenty-two PI-PLC genes were identified in each species, displaying conserved catalytic domains and diverse biochemical characteristics. Phylogenetic and chromosomal analyses revealed gene clustering and distribution patterns. Importantly, expression profiling highlighted several PI-PLC genes with differential regulation in resistant strains, suggesting a role in treatment response and potential as molecular markers. Conclusions: Our findings suggest that PI-PLC genes may be associated with drug susceptibility in L. infantum, warranting further functional investigation to validate their role as potential molecular markers. Full article

Sea anemones (Actiniaria, Cnidaria) are promising targets for biomedical research, as they produce unique bioactive compounds, including toxins and antimicrobial peptides (AMPs). However, the diversity and mechanisms underlying their chemical defenses remain poorly understood. In this study, we investigate the proteomic profiles of the unexplored sea anemone Actinia fragacea by analyzing its venom nematocyst extract, tissues, and mucus secretion. A total of 4011 different proteins were identified, clustered into 3383 protein groups. Among the 83 putative toxins detected, actinoporins, neurotoxins, and phospholipase A2 were uncovered, as well as two novel zinc metalloproteinases with two specific domains (ShK) associated with potassium channel inhibition. Common Gene Ontology (GO) terms were related to immune responses, cell adhesion, protease inhibition, and tissue regeneration. Furthermore, 1406 of the 13,276 distinct peptides identified were predicted as potential AMPs, including a putative Aurelin-like AMP localized within the nematocysts. This discovery highlights and strengthens the evidence for a cnidarian-exclusive Aurelin peptide family. Several other bioactive compounds with distinctive defense functions were also detected, including enzymes, pattern recognition proteins (PRPs), and neuropeptides. This study provides the first proteome map of A. fragacea, offering a critical foundation for exploring novel bioactive compounds and valuable insights into its molecular complexity. Full article

Background: Renal cell carcinoma (RCC) represents the most common form of invasive kidney cancer in adults. Among the components critical to cellular regulation is Phospholipase C Beta 2 (PLCB2), a member of the phospholipase C enzyme family. This enzyme plays a vital role in managing key cellular functions such as growth, differentiation, migration, and survival. Despite its significant importance, the specific expression patterns and molecular mechanisms of PLCB2 in the progression of RCC are not well understood. Methods: This investigation employed a combination of bioinformatics analyses, scRNA-seq, functional assays, transcriptome sequencing, real-time quantitative PCR (RT-PCR), immunofluorescence, rescue experiments, and Western blotting to explore the regulatory function of PLCB2 in driving the epithelial-mesenchymal transition (EMT) in RCC through the PI3K/AKT signaling pathway. Results:PLCB2 expression is significantly elevated in RCC samples, and this increase is inversely correlated with patient prognosis. The knockdown of PLCB2 in RCC cell lines leads to a marked reduction in cell proliferation, invasion, migration, and EMT. Transcriptome sequencing further revealed that PLCB2 is significantly associated with the PI3K/AKT pathway. Notably, the PI3K activator 740Y-P was able to reverse the reductions in migration, invasion, and EMT caused by the PLCB2 knockdown. Conclusions: Our findings underscore the pivotal role of PLCB2 in regulating RCC invasion and metastasis by modulating the EMT via the PI3K/AKT signaling pathway. This highlights PLCB2 not only as a key prognostic biomarker, but also as a promising therapeutic target in the treatment of advanced-stage RCC, offering new avenues for more effective interventions. Full article

Background: Phospholipase A (PLA) enzymes catalyze the hydrolysis of glycerophospholipids, releasing free fatty acids and lysophospholipids that play vital roles in plant growth, development, and stress responses. Methods: This study identified and analyzed SlPLA genes through bioinformatics and further explored the function of PLA genes under cold stress through virus-induced gene silencing (VIGS) experiments. Results: This study systematically characterized the SlPLA gene family in tomato, identifying 80 genes distributed across 12 chromosomes. Phylogenetic analysis categorized these genes into three groups: pPLA, PLA1, and PLA2. Conserved motifs and gene structure analysis revealed distinct patterns, with some genes lacking untranslated regions (UTRs), which suggests functional diversification. Promoter analysis indicated that SlPLA genes are regulated by light, hormones, and stress-related elements, particularly cold stress. RNA-seq data and qRT-PCR results indicated the differential expression of SlPLA genes across various tissues in tomato cultivars (Heinz and Micro-Tom). Under cold stress, certain SlPLA genes, especially SlPLA1-2, were up-regulated, suggesting their involvement in cold tolerance. Silencing SlPLA1-2 resulted in increased membrane damage, elevated malondialdehyde (MDA) levels, higher electrolyte leakage, and a lower expression of cold-responsive genes within the ICE1-CBF-COR pathway and jasmonic acid (JA) biosynthesis. Conclusions: This study discovered 80 SlPLA genes in tomato across 12 chromosomes, categorizing them into pPLA, PLA1, and PLA2 via phylogenetic analysis. The qRT-PCR analysis identified that SlPLA1-2 was strongly induced by cold stress, and further experiments regarding genetics and physiology revealed that SlPLA1-2 boosts the cold tolerance of tomato by affecting the CBF signaling pathway and JA biosynthesis, offering insights for future stress-resilience breeding. Full article

The tyrosine protein kinase (TXK) gene, as a member of the non-receptor tyrosine kinase Tec family, plays a vital role in signal transduction mediation. Phospholipase C epsilon 1 (PLCE1), a membrane-associated enzyme, is of paramount importance for the differentiation of myoblasts and the normal functioning of muscle tissue. In recent years, both of these genes have been reported to be associated with the economic traits of animals. This study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) in the TXK and PLCE1 genes and growth traits in Ashidan yaks and to search for potential molecular marker loci that can influence Ashidan yak breeding. A cGPS liquid microarray was utilized to genotype 232 Ashidan yaks and to analyze correlations between two SNP loci in the TXK and PLCE1 genes and yak body weight, body height, body length, and chest circumference at different periods. The results indicated that the g.55,999,531C>T locus of the TXK gene and the g.342,350T>G locus of the PLCE1 gene were significantly correlated with the growth traits of Ashidan yaks. Among these, individuals with the CC genotype at the g.55,999,531C>T locus showed a significantly higher body length at 6 months old compared to TT individuals, and those with the CT genotype at 12 months old had a significantly higher chest circumference than TT individuals. At the g.342,350T>G locus, the body height of GG genotype individuals at 18 months of age was significantly higher than that of TT genotype individuals and TG genotype individuals. The above findings can be used as theoretical support for the subsequent improvement of Ashidan yak breeding. Full article

Secreted phospholipase 2 (sPLA2) is the largest family of phospholipase A2 (PLA2) enzymes with 11 mammalian isoforms. Each sPLA2 exhibits different localizations and specific properties, being involved in a very wide spectrum of biological processes. The enzymatic activity of sPLA2 has been well described; however, recent findings have shown that they could regulate different signaling pathways by acting directly as ligands. Arachidonic acid (AA) and its derivatives are produced by sPLA2 in collaboration with other molecules in the extracellular space, making important impacts on the cellular environment, being especially relevant in the contexts of immunity and cancer. For these reasons, this review focuses on sPLA2 functions in processes such as the promotion of EMT, angiogenesis, and immunomodulation in the context of tumor initiation and progression. Finally, we will also describe how this knowledge has been applied in the search for new sPLA2 inhibitory compounds that can be used for cancer treatment. Full article

Kraits are venomous snakes of the genus Bungarus from the family Elapidae. Their venom typically demonstrates neurotoxicity; however, the toxicity is significantly influenced by the snake’s species and geographical origin. Among the Bungarus species, Bungarus suzhenae and B. bungaroides have been poorly studied, with little to no information available regarding their venom composition. In this study, a proteomic approach was employed using LC-MS/MS to identify proteins from trypsin-digested peptides. The analysis revealed 102 venom-related proteins from 18 distinct functional protein families in the venom of B. suzhenae, with the primary components being three-finger toxins (3-FTx, 25.84%), phospholipase A₂ (PLA₂, 40.29%), L-amino acid oxidase (LAAO, 10.33%), Kunitz-type serine protease inhibitors (KUN, 9.48%), and snake venom metalloproteinases (SVMPs, 6.13%). In the venom of B. bungaroides, 99 proteins from 17 families were identified, with primary components being 3-FTx (33.87%), PLA₂ (37.91%), LAAO (4.21%), and KUN (16.60%). Enzymatic activity assays confirmed the presence of key venom enzymes. Additionally, the LD50 values for B. suzhenae and B. bungaroides were 0.0133 μg/g and 0.752 μg/g, respectively, providing a reference for toxicity studies of these two species. This research elucidates the proteomic differences in the venoms of these two species, offering a foundation for developing antivenoms and clinical treatments for envenomation. Full article

Peroxiredoxin 6 (Prdx6), a unique 1-Cys member of the peroxiredoxin family, exhibits peroxidase activity, phospholipase activity, and lysophosphatidylcholine acyltransferase (LPCAT) activity. Prdx6 has been known to be an important enzyme for the maintenance of lipid peroxidation repair, cellular metabolism, inflammatory signaling, and antioxidant damage. Growing research has demonstrated that the altered activity of this enzyme is linked with various pathological processes including central nervous system (CNS) disorders. This review discusses the distinctive structure, enzyme activity, and function of Prdx6 in different CNS disorders, as well as emphasizing the significance of Prdx6 in neurological disorders. Full article

Little is known of the biochemical composition and functional features of the venoms of poorly known Colombian coral snakes. Here, we provide a preliminary characterization of the venom of two Colombian endemic coral snake species, Micrurus medemi and M. sangilensis, as well as Colombian populations of M. helleri. Electrophoresis and RP-HPLC techniques were used to identify venom components, and assays were conducted to detect enzyme activities, including phospholipase A₂, hyaluronidase, and protease activities. The median lethal dose was determined using murine models. Cytotoxic activities in primary cultures from hippocampal neurons and cancer cell lines were evaluated. The venom profiles revealed similarities in electrophoretic separation among proteins under 20 kDa. The differences in chromatographic profiles were significant, mainly between the fractions containing medium-/large-sized and hydrophobic proteins; this was corroborated by a proteomic analysis which showed the expected composition of neurotoxins from the PLA₂ (~38%) and 3FTx (~17%) families; however, a considerable quantity of metalloproteinases (~12%) was detected. PLA₂ activity and protease activity were higher in M. helleri venom according to qualitative and quantitative assays. M. medemi venom had the highest lethality. All venoms decreased cell viability when tested on tumoral cell cultures, and M. helleri venom had the highest activity in neuronal primary culture. These preliminary studies shed light on the venoms of understudied coral snakes and broaden the range of sources that could be used for subsequent investigations of components with applications to specific diseases. Our findings also have implications for the clinical manifestations of snake envenoming and improvements in its medical management. Full article

Host molecules with antimicrobial properties belong to a large family of mediators including type-IIA secreted phospholipase A2 (sPLA2-IIA). The latter is a potent bactericidal agent with high selectivity against Gram-positive bacteria, but it may also play a role in modulating the host inflammatory response. However, several pathogen-associated molecular patterns (PAMPs) or toxins produced by pathogenic bacteria can modulate the levels of sPLA2-IIA by either inducing or inhibiting its expression in host cells. Thus, the final sPLA2-IIA concentration during the infection process is determined by the orchestration between the levels of toxins that stimulate and those that downregulate the expression of this enzyme. The stimulation of sPLA2-IIA expression is a process that participates in the clearance of invading bacteria, while inhibition of this expression highlights a mechanism by which certain bacteria can subvert the immune response and invade the host. Here, we will review the major functions of sPLA2-IIA in the airways and the role of bacterial toxins in modulating the expression of this enzyme. We will also summarize the major mechanisms involved in this modulation and the potential consequences for the pulmonary host response to bacterial infection. Full article

Through a process termed clot retraction, platelets cause thrombi to shrink and become more stable. After platelets are activated via inside-out signaling, glycoprotein αIIbβIII binds to fibrinogen and initiates a cascade of intracellular signaling that ends in actin remodeling, which causes the platelet to change its shape. Clot retraction is also important for wound healing. Although the detailed molecular biology of clot retraction is only partially understood, various substances and physiological conditions modulate clot retraction. In this review, we describe some of the current literature pertaining to clot retraction modulators. In addition, we discuss compounds from Cudrania trucuspidata, Arctium lappa, and Panax ginseng that diminish clot retraction and have numerous other health benefits. Caffeic acid and diindolylmethane, both common in plants and vegetables, likewise reduce clot retraction, as do all-trans retinoic acid (a vitamin A derivative), two MAP4K inhibitors, and the chemotherapeutic drug Dasatinib. Conversely, the endogenous anticoagulant Protein S (PS) and the matricellular protein secreted modular calcium-binding protein 1 (SMOC1) both enhance clot retraction. Most studies aiming to identify mechanisms of clot retraction modulators have focused on the increased phosphorylation of vasodilator-stimulated phosphoprotein and inositol 1,4,5-triphosphate receptor I and the decreased phosphorylation of various phospholipases (e.g., phospholipase A2 (PLA₂) and phosphatidylinositol-specific phospholipase Cγ2 (PLCγ₂), c-Jun N-terminal kinase, and (PI3Ks). One study focused on the decreased phosphorylation of Sarcoma Family Kinases (SFK), and others have focused on increased cAMP levels and the downregulation of inflammatory markers such as thromboxanes, including thromboxane A2 (TXA₂) and thromboxane B2 (TXB₂); prostaglandin A2 (PGE2); reactive oxygen species (ROS); and cyclooxygenase (COX) enzyme activity. Additionally, pregnancy, fibrinolysis, and the autoimmune condition systemic lupus erythematosus all seem to affect, or at least have some relation with, clot retraction. All the clot retraction modulators need in-depth study to explain these effects. Full article

Lung cancer (LC) is the second most common neoplasm in men and the third most common in women. In the last decade, LC therapies have undergone significant improvements with the advent of immunotherapy. However, the effectiveness of the available treatments remains insufficient due to the presence of therapy-resistant cancer cells. For decades, chemotherapy and radiotherapy have dominated the treatment strategy for LC; however, relapses occur rapidly and result in poor survival. Malignant lung tumors are classified as either small- or non-small-cell lung carcinoma (SCLC and NSCLC). Despite improvements in the treatment of LC in recent decades, the benefits of surgery, radiotherapy, and chemotherapy are limited, although they have improved the prognosis of LC despite the persistent low survival rate due to distant metastasis in the late stage. The identification of novel prognostic molecular markers is crucial to understand the underlying mechanisms of LC initiation and progression. The potential role of phosphatidylinositol in tumor growth and the metastatic process has recently been suggested by some researchers. Phosphatidylinositols are lipid molecules and key players in the inositol signaling pathway that have a pivotal role in cell cycle regulation, proliferation, differentiation, membrane trafficking, and gene expression. In this review, we discuss the current understanding of phosphoinositide-specific phospholipase enzymes and their emerging roles in LC. Full article

One of the most important constituents of the cell membrane is arachidonic acid. Lipids forming part of the cellular membrane can be metabolized in a variety of cellular types of the body by a family of enzymes termed phospholipases: phospholipase A2, phospholipase C and phospholipase D. Phospholipase A2 is considered the most important enzyme type for the release of arachidonic acid. The latter is subsequently subjected to metabolization via different enzymes. Three enzymatic pathways, involving the enzymes cyclooxygenase, lipoxygenase and cytochrome P450, transform the lipid derivative into several bioactive compounds. Arachidonic acid itself plays a role as an intracellular signaling molecule. Additionally, its derivatives play critical roles in cell physiology and, moreover, are involved in the development of disease. Its metabolites comprise, predominantly, prostaglandins, thromboxanes, leukotrienes and hydroxyeicosatetraenoic acids. Their involvement in cellular responses leading to inflammation and/or cancer development is subject to intense study. This manuscript reviews the findings on the involvement of the membrane lipid derivative arachidonic acid and its metabolites in the development of pancreatitis, diabetes and/or pancreatic cancer. Full article

In Southeast Asia, the Malayan Pit Viper (Calloselasma rhodostoma) is a venomous snake species of medical importance and bioprospecting potential. To unveil the diversity of its toxin genes, this study de novo assembled and analyzed the venom gland transcriptome of C. rhodostoma from Malaysia. The expression of toxin genes dominates the gland transcriptome by 53.78% of total transcript abundance (based on overall FPKM, Fragments Per Kilobase Million), in which 92 non-redundant transcripts belonging to 16 toxin families were identified. Snake venom metalloproteinase (SVMP, PI > PII > PIII) is the most dominant family (37.84% of all toxin FPKM), followed by phospholipase A₂ (29.02%), bradykinin/angiotensin-converting enzyme inhibitor-C-type natriuretic peptide (16.30%), C-type lectin (CTL, 10.01%), snake venom serine protease (SVSP, 2.81%), L-amino acid oxidase (2.25%), and others (1.78%). The expressions of SVMP, CTL, and SVSP correlate with hemorrhagic, anti-platelet, and coagulopathic effects in envenoming. The SVMP metalloproteinase domains encode hemorrhagins (kistomin and rhodostoxin), while disintegrin (rhodostomin from P-II) acts by inhibiting platelet aggregation. CTL gene homologues uncovered include rhodocytin (platelet aggregators) and rhodocetin (platelet inhibitors), which contribute to thrombocytopenia and platelet dysfunction. The major SVSP is a thrombin-like enzyme (an ancrod homolog) responsible for defibrination in consumptive coagulopathy. The findings provide insight into the venom complexity of C. rhodostoma and the pathophysiology of envenoming. Full article