RESUMO

BACKGROUND: Phospholipase A2 (PLA2) is a large family of enzymes involved in the inflammatory process that catalyzes the hydrolysis of membrane phospholipids, leading to the production of free fatty acids and lysophospholipids, starting the arachidonic acid cascade. Their expression has been related to the behavior of several cancers. Our objective is to search for PLA2 expression in prostate cancer (PCa) tissue that correlates with prognosis and survival. METHODS: Using qRT-PCR, we analyzed the expression levels of PLA2G1B, PLA2G2A, PLA2G2D, PLA2G4A, PLA2G4B, PLA2G4C, PLA2G4D, PLA2G4E, PLA2G4F, PLA2G6, PLA2G7, PLA2G16, PNPLA1, and PNPLA2 in PCa tissue from 108 patients submitted to radical prostatectomy, followed by a mean time of 163 months. RESULTS: All PLA2 was overexpressed in PCa compared to normal tissue. Interestingly, higher expression of some PLA2 was related to favorable prognostic factors: lower levels of PSA (PLA2G2A, PLA2G4D), lower rates of lymph node metastasis (PLA2G16 and PLA2G1B), and organ-confined disease (PLA2G4A). Most importantly, PLAG4B was independently related to longer disease-free survival. CONCLUSION: This is the first study exploring comprehensively the expression levels of PLA2 in PCa, showing that the higher expression of some PLA2 should be used as biomarkers of good prognosis and longer disease-free survival.

RESUMO

Phospholipases A2 (PLA2) comprise a superfamily of enzymes that specifically catalyze hydrolysis of the ester bond at the sn-2 position of glycerophospholipids, generating lysophospholipids and fatty acids. In Rhodnius prolixus, one of the main vectors of the Chagas's disease etiologic agent Trypanosoma cruzi, it was previously shown that lysophosphatidylcholine, a bioactive lipid, found in the insect's saliva, contributes to the inhibition of platelet aggregation, and increases the production of nitric oxide, an important vasodilator. Due to its role in potentially generating LPC, here we studied the PLA2 present in the salivary glands of R. prolixus. PLA2 activity is approximately 100 times greater in the epithelium than in the contents of salivary glands. Our study reveals the role of the RpPLA2XIIA gene in the insect feeding performance and in the fatty acids composition of phospholipids extracted from the salivary glands. Knockdown of RpPLA2XIIA significantly altered the relative amounts of palmitic, palmitoleic, oleic and linoleic acids. A short-term decrease in the expression of RpPLA2III and RpPLA2XIIA in the salivary glands of R. prolixus was evident on the third day after infection by T. cruzi. Taken together, our results contribute to the understanding of the role of PLA2 in the salivary glands of hematophagous insects and show that the parasite is capable of modulating even tissues that are not colonized by it.

Assuntos

Fosfolipases A2 , Rhodnius , Glândulas Salivares , Trypanosoma cruzi , Animais , Rhodnius/parasitologia , Rhodnius/enzimologia , Rhodnius/genética , Glândulas Salivares/parasitologia , Glândulas Salivares/enzimologia , Glândulas Salivares/metabolismo , Trypanosoma cruzi/genética , Trypanosoma cruzi/enzimologia , Fosfolipases A2/metabolismo , Fosfolipases A2/genética , Ácidos Graxos/metabolismo , Doença de Chagas/parasitologia , Insetos Vetores/parasitologia , Insetos Vetores/enzimologia

RESUMO

Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor (LEPR), suppressor of cytokine signaling 3 (SOCS3), sterol regulatory element-binding transcription factor 1 (SREBF1), stearoyl-CoA desaturase-1 (SCD1), and patatin-like phospholipase domain-containing protein 2 (PNPLA2), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1. In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes (p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT-liver crosstalk and the complications of MASLD in humans.

Assuntos

Tecido Adiposo , Fígado Gorduroso , Leptina , Fígado , Omento , Humanos , Leptina/metabolismo , Feminino , Masculino , Fígado/metabolismo , Pessoa de Meia-Idade , Omento/metabolismo , Omento/patologia , Tecido Adiposo/metabolismo , Adulto , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Receptores para Leptina/metabolismo , Receptores para Leptina/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Resistência à Insulina , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Estearoil-CoA Dessaturase/metabolismo , Estearoil-CoA Dessaturase/genética

RESUMO

The Loxosceles genus represents one of the main arachnid genera of medical importance in Brazil. Despite the gravity of Loxosceles-related accidents, just a handful of species are deemed medically important and only a few have undergone comprehensive venom characterization. Loxosceles amazonica is a notable example of a potentially dangerous yet understudied Loxosceles species. While there have been limited reports of accidents involving L. amazonica to date, accidents related to Loxosceles are increasing in the North and Northeast regions of Brazil, where L. amazonica has been reported. In this work, we provide a complementary biochemical and immunological characterization of L. amazonica venom, considering its most relevant enzymatic activities and its immunorecognition and neutralization by current therapeutic antivenoms. Additionally, a cDNA library enriched with phospholipase D (PLD) sequences from L. amazonica venom glands was built and subsequently sequenced. The results showed that L. amazonica venom is well immunorecognised by all the tested antibodies. Its venom also displayed proteolytic, hyaluronidase, and sphingomyelinase activities. These activities were at least partially inhibited by available antivenoms. With cDNA sequencing of PLDs, seven new putative isoforms were identified in the venom of L. amazonica. These results contribute to a better knowledge of the venom content and activities of a synanthropic, yet understudied, Loxosceles species. In vivo assays are essential to confirm the medical relevance of L. amazonica, as well as to assess its true toxic potential and elucidate its related pathophysiology.

RESUMO

Calcium (Ca2+) is a highly versatile intracellular messenger that regulates several cellular processes. Although it is unclear how a single-second messenger coordinates various effects within a cell, there is growing evidence that spatial patterns of Ca2+ signals play an essential role in determining their specificity. Ca2+ signaling patterns can differ in various cell regions, and Ca2+ signals in the nuclear and cytoplasmic compartments have been observed to occur independently. The initiation and function of Ca2+ signaling within the nucleus are not yet fully understood. Receptor tyrosine kinases (RTKs) induce Ca2+ signaling resulting from phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis and inositol 1,4,5-trisphosphate (InsP3) formation within the nucleus. This signaling mechanism may be responsible for the effects of specific growth factors on cell proliferation and gene transcription. This review highlights the recent advances in RTK trafficking to the nucleus and explains how these receptors initiate nuclear calcium signaling.

Assuntos

Sinalização do Cálcio , Núcleo Celular , Receptores Proteína Tirosina Quinases , Humanos , Núcleo Celular/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/genética , Animais , Cálcio/metabolismo , Inositol 1,4,5-Trifosfato/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo

RESUMO

Crotalus neutralizing factor (CNF) is an endogenous glycoprotein from Crotalus durissus terrificus snake blood that inhibits secretory phospholipases A2 (sPLA2) from the Viperid but not from Elapid venoms (subgroups IA and IIA, respectively). In the present study, we demonstrated that CNF can inhibit group III-PLA2 from bee venom by forming a stable enzyme-inhibitor complex. This finding opens up new possibilities for the potential use of CNF and/or CNF-based derivatives in the therapeutics of bee stings.

Assuntos

Venenos de Abelha , Crotalus , Serpentes Peçonhentas , Animais , Venenos de Abelha/farmacologia , Inibidores de Fosfolipase A2/farmacologia , Venenos de Crotalídeos/antagonistas & inibidores , Abelhas , Fosfolipases A2 , Glicoproteínas/farmacologia , Fosfolipases A2 Secretórias/antagonistas & inibidores

RESUMO

BACKGROUND: Loxoscelism is a toxic clinical condition caused by the bite of spiders of the genus Loxosceles, with wide distribution throughout the world.1 Phospholipase D is responsible for dermonecrosis, inflammation, platelet aggregation, hemolysis, alteration of vascular permeability, cytotoxicity, nephrotoxicity, acute renal failure, among other symptoms involved with this protein. CASE REPORT: 27-year-old male patient, who began with a sudden episode of intense pain in the right hand, in the metacarpus and metacarpophalangeal joints. On clinical examination, the upper extremity was noted to have increased volume, extensive edema, hyperemia, and increased local temperature; The lesion progressed to extensive necrosis. Fasciotomies were performed, from distal to proximal, and release of the second and third finger compartment through longitudinal radial and ulnar incisions. A skin autograft was placed, obtained from the anterior surface of the right thigh. Opioid analgesics, non-steroidal anti-inflammatory drugs, corticosteroids, and antibiotics were administered. The skin biopsy reported: inflammatory infiltrate with neutrophils, ulceration, and bacterial colonies. After 27 days he had a favorable evolution, so he was discharged to his home, with follow-up by staff from the Outpatient Service. CONCLUSION: Cutaneous loxoscelism, as a cause of acute compartment syndrome of the hand, is rare, but should be considered in an area endemic for Loxosceles spp. Surgical decompression of the affected compartments represents a decisive factor in the treatment of patients.

---

ANTECEDENTES: El loxoscelismo es un cuadro clínico tóxico provocado por la mordedura de arañas del género Loxosceles, con amplia distribución en todo el mundo.1 La fosfolipasa D es la responsable de la dermonecrosis, inflamación, agregación plaquetaria, hemólisis, alteración de la permeabilidad vascular, citotoxicidad, nefrotoxicidad, insuficiencia renal aguda, entre otros síntomas implicados con esta proteína. REPORTE DE CASO: Paciente masculino de 27 años, que inició con un cuadro repentino de dolor intenso en la mano derecha, en el metacarpo y las articulaciones metacarpofalángicas. Al examen clínico, la extremidad superior se percibió con aumento de volumen, edema extenso, hiperemia y aumento de la temperatura local; la lesión progresó a necrosis extensa. Se realizaron fasciotomías, de distal a proximal, y liberación del compartimento del segundo y tercer dedo a través de incisiones longitudinales radiales y cubitales. Se colocó un autoinjerto de piel, obtenido de la superficie anterior del muslo derecho. Se administraron analgésicos opioides, antiinflamatorios no esteroides, corticosteroides y antibióticos. La biopsia de piel reporto: infiltrado inflamatorio con neutrófilos, ulceración y colonias bacterianas. Luego de 27 días tuvo evolución favorable, por lo que se dio alta a su domicilio, con seguimiento por personal del servicio de Consulta externa. CONCLUSIÓN: El loxoscelismo cutáneo, como causa de síndrome compartimental agudo de la mano, es poco común, pero debe considerarse en un área endémica para Loxosceles spp. La descompresión quirúrgica de los compartimentos afectados representa un factor decisivo en el tratamiento de los pacientes.

Assuntos

Picada de Aranha , Humanos , Masculino , Adulto , Picada de Aranha/complicações , Doença Aguda , Síndromes Compartimentais/etiologia

RESUMO

Background: In Colombia, several species of Buthidae scorpions belonging to the genera Centruroides and Tityus coexist, and their stings are considered life-threatening to humans because of their venom neurotoxins. Despite previous studies focusing on neurotoxins from these scorpion genera, little is known about the enzymes present in their venoms and their relationship with whole venom toxicity. Methods: Here, using proteomic and biochemical protocols the enzymatic activities of the venoms of three Colombian scorpion species, C. margaritatus, T. pachyurus, and T. n. sp. aff. metuendus, were compared to establish the presence and absence of enzymes such as phospholipases, hyaluronidases, and proteases that could be related to venom toxicity. Results: C. margaritatus was positive for hyaluronidases, T. n. sp. aff. metuendus for proteases, and T. pachyurus exhibited activity for all three mentioned enzymes. Conclusion: This information provides valuable insights into the specific enzyme diversity of each species' venom and their potential role in venom toxicity, which could contribute to the development of better treatments and prevention strategies for scorpion envenomation.

RESUMO

Tityus serrulatus scorpion is responsible for a significant number of envenomings in Brazil, ranging from mild to severe, and in some cases, leading to fatalities. While supportive care is the primary treatment modality, moderate and severe cases require antivenom administration despite potential limitations and adverse effects. The remarkable proliferation of T. serrulatus scorpions, attributed to their biology and asexual reproduction, contributes to a high incidence of envenomation. T. serrulatus scorpion venom predominantly consists of short proteins acting as neurotoxins (α and ß), that primarily target ion channels. Nevertheless, high molecular weight compounds, including metalloproteases, serine proteases, phospholipases, and hyaluronidases, are also present in the venom. These compounds play a crucial role in envenomation, influencing the severity of symptoms and the spread of venom. This review endeavors to comprehensively understand the T. serrulatus scorpion venom by elucidating the primary high molecular weight compounds and exploring their potential contributions to envenomation. Understanding these compounds' mechanisms of action can aid in developing more effective treatments and prevention strategies, ultimately mitigating the impact of scorpion envenomation on public health in Brazil.

RESUMO

High-altitude hypoxia exposure can lead to phospholipase D-mediated lipid metabolism disorder in spleen tissues and induce ferroptosis. Nonetheless, the key genes underlying hypoxia-induced splenic phospholipase D and the ferroptosis pathway remain unclear. This study aimed to establish a hypoxia animal model. Combined transcriptomic and proteomic analyses showed that 95 predicted target genes (proteins) were significantly differentially expressed under hypoxic conditions. Key genes in phospholipase D and ferroptosis pathways under hypoxic exposure were identified by combining Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis techniques. Gene set enrichment analysis (GSEA) showed that the differential gene sets of the phospholipase D and ferroptosis signaling pathways were upregulated in the high-altitude hypoxia group. The genes in the phospholipase D signalling pathway were verified, and the expression levels of KIT and DGKG were upregulated in spleen tissues under hypoxic exposure. Subsequently, the mRNA and protein expression levels of genes from the exogenous pathway such as TFRC, SLC40A1, SLC7A11, TRP53, and FTH1 and those from the endogenous pathway such as GPX4, HMOX1, and ALOX15 differentials in the ferroptosis signalling pathway were verified, and the results indicated significant differential expression. In summary, exposure to high-altitude hypoxia mediated phospholipid metabolism disturbance through the phospholipase D signalling pathway and further induced ferroptosis, leading to splenic injury.