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1.
Mediators Inflamm ; 2018: 2547918, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30013451

RESUMO

MT-III, a snake venom GIIA sPLA2, which shares structural and functional features with mammalian GIIA sPLA2s, activates macrophage defense functions including lipid droplet (LDs) formation, organelle involved in both lipid metabolism and inflammatory processes. Macrophages (MΦs) loaded with LDs, termed foam cells, characterize early blood vessel fatty-streak lesions during atherosclerosis. However, the factors involved in foam cell formation induced by a GIIA sPLA2 are still unknown. Here, we investigated the participation of lipid homeostasis-related factors in LD formation induced by MT-III in macrophages. We found that MT-III activated PPAR-γ and PPAR-ß/δ and increased the protein levels of both transcription factors and CD36 in macrophages. Pharmacological interventions evidenced that PPAR-γ, PPAR-ß/δ, and CD36 as well as the endoplasmic reticulum enzymes ACAT and DGAT are essential for LD formation. Moreover, PPAR-ß/δ, but not PPAR-γ, is involved in MT-III-induced PLIN2 protein expression, and both PPAR-ß/δ and PPAR-γ upregulated CD36 protein expression, which contributes to MT-III-induced COX-2 expression. Furthermore, production of 15-d-PGJ2, an activator of PPARs, induced by MT-III, was dependent on COX-1 being LDs an important platform for generation of this mediator.


Assuntos
Células Espumosas/efeitos dos fármacos , Homeostase , Lipídeos/química , Fosfolipases A2/farmacologia , Venenos de Serpentes/enzimologia , Animais , Antígenos CD36/metabolismo , Retículo Endoplasmático/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos , PPAR alfa/metabolismo , PPAR delta/metabolismo , PPAR gama/metabolismo , PPAR beta/metabolismo , Prostaglandina D2/análogos & derivados , Prostaglandina D2/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Regulação para Cima
2.
Toxicon ; 238: 107568, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38110040

RESUMO

Most anti-inflammatory drugs currently adopted to treat chronic inflammatory joint diseases can alleviate symptoms but they do not lead to remission. Therefore, new and more efficient drugs are needed to block the course of joint inflammatory diseases. Animal venoms, rich in bioactive compounds, can contribute as valuable tools in this field of research. In this study, we first demonstrate the direct action of venoms on cells that constitute the articular joints. We established a platform consisting of cell-based assays to evaluate the release of cytokines (IL-6, IL-8, TNFα, IL-1ß, and IL-10) by human chondrocytes, synoviocytes and THP1 macrophages, as well as the release of neuropeptides (substance-P and ß-endorphin) by differentiated sensory neuron-like cells, 24 h after stimulation of cells with 21 animal venoms from snake and arthropod species, sourced from different taxonomic families and geographic origins. Results demonstrated that at non-cytotoxic concentrations, the venoms activate at varying degrees the secretion of inflammatory mediators involved in the pathology of articular diseases, such as IL-6, IL-8, and TNF-α by chondrocytes, synoviocytes, and macrophages and of substance P by neuron-like cells. Venoms of the Viperidae snake family were more inflammatory than those of the Elapidae family, while venoms of Arthropods were less inflammatory than snake venoms. Notably, some venoms also induced the release of the anti-inflammatory IL-10 by macrophages. However, the scorpion Buthus occitanus venom induced the release of IL-10 without increasing the release of inflammatory cytokines by macrophages. Since the cell types used in the experiments are crucial elements in joint inflammatory processes, the results of this work may guide future research on the activation of receptors and inflammatory signaling pathways by selected venoms in these particular cells, aiming at discovering new targets for therapeutic intervention.


Assuntos
Animais Peçonhentos , Venenos de Artrópodes , Artrópodes , Artropatias , Venenos de Escorpião , Escorpiões , Viperidae , Animais , Humanos , Interleucina-10 , Interleucina-6 , Interleucina-8 , Venenos de Serpentes/química , Citocinas , Fator de Necrose Tumoral alfa , Anti-Inflamatórios
3.
Artigo em Inglês | MEDLINE | ID: mdl-35432496

RESUMO

Background: Endogenous phospholipases A2 (PLA2) play a fundamental role in inflammation, neurodegenerative diseases, apoptosis and cellular senescence. Neurotoxins with PLA2 activity are found in snake venoms from the Elapidae and Viperidae families. The mechanism of action of these neurotoxins have been studied using hippocampal and cerebellar neuronal cultures showing [Ca2+]i increase, mitochondrial depolarization and cell death. Astrocytes are rarely used as a model, despite being modulators at the synapses and responsible for homeostasis and defense in the central nervous system. Preserving the cell division ability, they can be utilized to study the cell proliferation process. In the present work cultured astrocytes and glioblastoma cells were employed to characterize the action of ß-micrustoxin (previously named Mlx-9), a PLA2 isolated from Micrurus lemniscatus snake venom. The ß-micrustoxin structure was determined and the cell proliferation, cell cycle phases and the regulatory proteins p53, p21 and p27 were investigated. Methods: ß-micrustoxin was characterized biochemically by a proteomic approach. Astrocytes were obtained by dissociation of pineal glands from Wistar rats; glioblastoma tumor cells were purchased from ATCC and Sigma and cultured in DMEM medium. Cell viability was evaluated by MTT assay; cell proliferation and cell cycle phases were analyzed by flow cytometry; p53, p21 and p27 proteins were studied by western blotting and immunocytochemistry. Results: Proteomic analysis revealed fragments on ß-micrustoxin that aligned with a PLA2 from Micrurus lemniscatus lemniscatus previously identified as transcript ID DN112835_C3_g9_i1/m.9019. ß-micrustoxin impaired the viability of astrocytes and glioblastoma tumor cells. There was a reduction in cell proliferation, an increase in G2/M phase and activation of p53, p21 and p27 proteins in astrocytes. Conclusion: These findings indicate that ß-micrustoxin from Micrurus lemniscatus venom could inhibit cell proliferation through p53, p21 and p27 activation thus imposing cell cycle arrest at the checkpoint G2/M.

4.
Toxins (Basel) ; 13(12)2021 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-34941706

RESUMO

Phospholipases A2s (PLA2s) constitute one of the major protein groups present in the venoms of viperid and crotalid snakes. Snake venom PLA2s (svPLA2s) exhibit a remarkable functional diversity, as they have been described to induce a myriad of toxic effects. Local inflammation is an important characteristic of snakebite envenomation inflicted by viperid and crotalid species and diverse svPLA2s have been studied for their proinflammatory properties. Moreover, based on their molecular, structural, and functional properties, the viperid svPLA2s are classified into the group IIA secreted PLA2s, which encompasses mammalian inflammatory sPLA2s. Thus, research on svPLA2s has attained paramount importance for better understanding the role of this class of enzymes in snake envenomation and the participation of GIIA sPLA2s in pathophysiological conditions and for the development of new therapeutic agents. In this review, we highlight studies that have identified the inflammatory activities of svPLA2s, in particular, those from Bothrops genus snakes, which are major medically important snakes in Latin America, and we describe recent advances in our collective understanding of the mechanisms underlying their inflammatory effects. We also discuss studies that dissect the action of these venom enzymes in inflammatory cells focusing on molecular mechanisms and signaling pathways involved in the biosynthesis of lipid mediators and lipid accumulation in immunocompetent cells.


Assuntos
Venenos de Crotalídeos/enzimologia , Venenos de Crotalídeos/toxicidade , Inflamação , Fosfolipases A2/toxicidade , Animais , Bothrops , Humanos , Mediadores da Inflamação , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/imunologia , Transdução de Sinais
5.
Front Immunol ; 10: 2082, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572356

RESUMO

Envenomation by viperid snakes is characterized by systemic thrombotic syndrome and prominent local inflammation. To date, the mechanisms underlying inflammation and blood coagulation induced by Viperidae venoms have been viewed as distinct processes. However, studies on the mechanisms involved in these processes have revealed several factors and signaling molecules that simultaneously act in both the innate immune and hemostatic systems, suggesting an overlap between both systems during viper envenomation. Moreover, distinct classes of venom toxins involved in these effects have also been identified. However, the interplay between inflammation and hemostatic alterations, referred as to thromboinflammation, has never been addressed in the investigation of viper envenomation. Considering that platelets are important targets of viper snake venoms and are critical for the process of thromboinflammation, in this review, we summarize the inflammatory effects and mechanisms induced by viper snake venoms, particularly from the Bothrops genus, which strongly activate platelet functions and highlight selected venom components (metalloproteases and C-type lectins) that both stimulate platelet functions and exhibit pro-inflammatory activities, thus providing insights into the possible role(s) of thromboinflammation in viper envenomation.


Assuntos
Inflamação/imunologia , Mordeduras de Serpentes/imunologia , Venenos de Serpentes/imunologia , Trombose/imunologia , Animais , Coagulação Sanguínea , Hemostasia , Humanos , Lectinas Tipo C/metabolismo , Metaloproteases/metabolismo , Ativação Plaquetária , Viperidae
6.
Toxicon, v. 238, 107568, fev. 2024
Artigo em Inglês | SES-SP, SESSP-IBPROD, SES-SP | ID: bud-5249

RESUMO

Most anti-inflammatory drugs currently adopted to treat chronic inflammatory joint diseases can alleviate symptoms but they do not lead to remission. Therefore, new and more efficient drugs are needed to block the course of joint inflammatory diseases. Animal venoms, rich in bioactive compounds, can contribute as valuable tools in this field of research. In this study, we first demonstrate the direct action of venoms on cells that constitute the articular joints. We established a platform consisting of cell-based assays to evaluate the release of cytokines (IL-6, IL-8, TNFα, IL-1β, and IL-10) by human chondrocytes, synoviocytes and THP1 macrophages, as well as the release of neuropeptides (substance-P and β-endorphin) by differentiated sensory neuron-like cells, 24 h after stimulation of cells with 21 animal venoms from snake and arthropod species, sourced from different taxonomic families and geographic origins. Results demonstrated that at non-cytotoxic concentrations, the venoms activate at varying degrees the secretion of inflammatory mediators involved in the pathology of articular diseases, such as IL-6, IL-8, and TNF-α by chondrocytes, synoviocytes, and macrophages and of substance P by neuron-like cells. Venoms of the Viperidae snake family were more inflammatory than those of the Elapidae family, while venoms of Arthropods were less inflammatory than snake venoms. Notably, some venoms also induced the release of the anti-inflammatory IL-10 by macrophages. However, the scorpion Buthus occitanus venom induced the release of IL-10 without increasing the release of inflammatory cytokines by macrophages. Since the cell types used in the experiments are crucial elements in joint inflammatory processes, the results of this work may guide future research on the activation of receptors and inflammatory signaling pathways by selected venoms in these particular cells, aiming at discovering new targets for therapeutic intervention.

7.
Chem Biol Interact ; 291: 120-127, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29908986

RESUMO

The genesis of rheumatoid arthritis (RA) is complex and dependent on genetic background and exposure to environmental xenobiotic. Indeed, smoking is associated to developing and worsening pre-existing RA. Nevertheless, the mechanisms and cigarette compounds involved in the harmful processes have not been elucidated. Here, we investigated if the exposure to hydroquinone (HQ), an abundant pro-oxidative compound of cigarette and benzene metabolite, could worsen the ongoing RA. Hence, collagen-induced arthritis (CIA) was induced in male Wistar rats by s.c. injection of 400 µg (200 µL) of bovine collagen type II emulsified in complete Freund's adjuvant on day 1, and a booster injection was performed on day 7. Exposures to nebulized HQ (25 ppm), saline solution or HQ vehicle solution (5% ethanol in saline) were carried out for 1 h, once a day, on days 21-27 after CIA induction. On day 27, animals were euthanized and samples were collected for further analyses. Exposure to HQ caused loss of weight, intensified paw edema, enhanced levels of tumor necrosis factor-α (TNF-α) and anti-citrullinated protein antibody (ACPA) in the serum; augmented synoviocyte proliferation and influx of aril hydrocarbon receptor (AhR) positive cells into the synovial membrane, altered collagen fibre rearrangement in the synovia, and synoviocytes isolated from HQ exposed rats secreted higher levels of pro-inflammatory cytokines, TNF-α and interleukin-1ß. Associated, we point out HQ as an environmental pollutant that aggravates RA, suggesting its participation on worsening RA in smoking patients.


Assuntos
Artrite Reumatoide/patologia , Hidroquinonas/toxicidade , Animais , Anticorpos Antiproteína Citrulinada/sangue , Artrite Experimental/sangue , Artrite Experimental/patologia , Artrite Reumatoide/sangue , Bovinos , Separação Celular , Extremidades/patologia , Inflamação/patologia , Interleucina-1beta/metabolismo , Masculino , Ratos Wistar , Receptores de Hidrocarboneto Arílico/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia , Fator de Necrose Tumoral alfa/metabolismo
8.
Toxicology ; 408: 22-30, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29935983

RESUMO

Robust correlation between the severity of rheumatoid arthritis (RA) and cigarette smoking has been clinically demonstrated. Nevertheless, cigarette compounds responsible for this toxic effect and their mechanisms have not been described. Considering that hydroquinone (HQ) is an abundant, pro-oxidative compound of the matter particle phase of cigarette smoke, we investigated whether HQ exposure during the initial phase of collagen-induced arthritis (CIA) could aggravate the disease. For this purpose, male Wistar rats were exposed to aerosolized HQ (25 ppm), saline or 5% ethanol solution (HQ vehicle) for 1 h per day during 14 days. CIA was induced through s.c. injection of bovine collagen Type II (0.4 mg/100 µL) at days seven and 14 of exposure. Clinical signs of disease and the cell profile and chemical mediators in the synovial fluid and membrane were analysed at day 35 after the beginning of exposure. HQ exposure aggravated CIA-related paw edema and increased the cell infiltrate and interleukin-6 (IL-6) levels in the synovial fluid, promoted intense tissue collagen deposition and enhanced synoviocyte proliferation and higher frequency of aryl hydrocarbon receptor (AhR+) and interleukin (IL-17+) neutrophils in the synovial membrane. in vitro data also highlighted that neutrophils expressed increased levels of AhR, IL-17 and reactive oxygen species (ROS) generation. However, only AhR expression and ROS generation were blocked by in vitro treatment with AhR antagonist. Therefore, we conclude that in vivo HQ exposure at the early phase of AR onset worsens RA, leading to high frequency of AhR/IL-17+ neutrophils into the joint.


Assuntos
Artrite Experimental/induzido quimicamente , Colágeno Tipo II , Hidroquinonas/toxicidade , Membrana Sinovial/efeitos dos fármacos , Sinoviócitos/efeitos dos fármacos , Aerossóis , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hidroquinonas/administração & dosagem , Mediadores da Inflamação/metabolismo , Exposição por Inalação , Interleucina-17/metabolismo , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Líquido Sinovial/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Fatores de Tempo
9.
J Venom Anim Toxins Trop Dis, v. 28, e20210094, abr. 2022
Artigo em Inglês | SES-SP, SESSP-IBPROD, SES-SP | ID: bud-4301

RESUMO

Background: Endogenous phospholipases A2 (PLA2) play a fundamental role in inflammation, neurodegenerative diseases, apoptosis and cellular senescence. Neurotoxins with PLA2 activity are found in snake venoms from the Elapidae and Viperidae families. The mechanism of action of these neurotoxins have been studied using hippocampal and cerebellar neuronal cultures showing [Ca2+]i increase, mitochondrial depolarization and cell death. Astrocytes are rarely used as a model, despite being modulators at the synapses and responsible for homeostasis and defense in the central nervous system. Preserving the cell division ability, they can be utilized to study the cell proliferation process. In the present work cultured astrocytes and glioblastoma cells were employed to characterize the action of β-micrustoxin (previously named Mlx-9), a PLA2 isolated from Micrurus lemniscatus snake venom. The β-micrustoxin structure was determined and the cell proliferation, cell cycle phases and the regulatory proteins p53, p21 and p27 were investigated. Methods: β-micrustoxin was characterized biochemically by a proteomic approach. Astrocytes were obtained by dissociation of pineal glands from Wistar rats; glioblastoma tumor cells were purchased from ATCC and Sigma and cultured in DMEM medium. Cell viability was evaluated by MTT assay; cell proliferation and cell cycle phases were analyzed by flow cytometry; p53, p21 and p27 proteins were studied by western blotting and immunocytochemistry. Results: Proteomic analysis revealed fragments on β-micrustoxin that aligned with a PLA2 from Micrurus lemniscatus lemniscatus previously identified as transcript ID DN112835_C3_g9_i1/m.9019. β-micrustoxin impaired the viability of astrocytes and glioblastoma tumor cells. There was a reduction in cell proliferation, an increase in G2/M phase and activation of p53, p21 and p27 proteins in astrocytes. Conclusion: These findings indicate that β-micrustoxin from Micrurus lemniscatus venom could inhibit cell proliferation through p53, p21 and p27 activation thus imposing cell cycle arrest at the checkpoint G2/M.

10.
J. venom. anim. toxins incl. trop. dis ; 28: e20210094, 2022. graf, tab, ilus
Artigo em Inglês | VETINDEX | ID: biblio-1395948

RESUMO

Background: Endogenous phospholipases A2 (PLA2 ) play a fundamental role in inflammation, neurodegenerative diseases, apoptosis and cellular senescence. Neurotoxins with PLA2 activity are found in snake venoms from the Elapidae and Viperidae families. The mechanism of action of these neurotoxins have been studied using hippocampal and cerebellar neuronal cultures showing [Ca2+]i increase, mitochondrial depolarization and cell death. Astrocytes are rarely used as a model, despite being modulators at the synapses and responsible for homeostasis and defense in the central nervous system. Preserving the cell division ability, they can be utilized to study the cell proliferation process. In the present work cultured astrocytes and glioblastoma cells were employed to characterize the action of ß-micrustoxin (previously named Mlx-9), a PLA2 isolated from Micrurus lemniscatus snake venom. The ß-micrustoxin structure was determined and the cell proliferation, cell cycle phases and the regulatory proteins p53, p21 and p27 were investigated. Methods: ß-micrustoxin was characterized biochemically by a proteomic approach. Astrocytes were obtained by dissociation of pineal glands from Wistar rats; glioblastoma tumor cells were purchased from ATCC and Sigma and cultured in DMEM médium. Cell viability was evaluated by MTT assay; cell proliferation and cell cycle phases were analyzed by flow cytometry; p53, p21 and p27 proteins were studied by western blotting and immunocytochemistry. Results: Proteomic analysis revealed fragments on ß-micrustoxin that aligned with a PLA2 from Micrurus lemniscatus lemniscatus previously identified as transcript ID DN112835_C3_g9_i1/m.9019. ß-micrustoxin impaired the viability of astrocytes and glioblastoma tumor cells. There was a reduction in cell proliferation, an increase in G2/M phase and activation of p53, p21 and p27 proteins in astrocytes. Conclusion: These findings indicate that ß-micrustoxin from Micrurus lemniscatus venom could inhibit cell proliferation through p53, p21 and p27 activation thus imposing cell cycle arrest at the checkpoint G2/M.(AU)


Assuntos
Venenos de Serpentes/toxicidade , Bioquímica , Glioblastoma , Neurotoxinas
11.
Int Immunopharmacol ; 6(3): 415-25, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16428077

RESUMO

Cyclosporin, an immunosuppressive drug, is known to affect macrophage and to exert a nephrotoxic effect. Aminopeptidases play important roles for renal and macrophage functions. In this work, we attempt to test the hypothesis that the aminopeptidases participate within macrophage and renal effects induced by cyclosporin. Macrophage and renal aminopeptidase activities of cyclosporin-treated and control mice were evaluated, as well as renal caspase 3 activity, hematocrit, urinary protein and plasma osmolality, creatinine and uric acid concentrations. Cyclosporin treatment increased caspase 3 activity, hematocrit and osmolality, while urinary protein, creatinine and uric acid were unaltered. Soluble and particulate aminopeptidases in resident and elicited macrophages were unaffected by cyclosporin. The treatment with cyclosporin increased neutral, basic, cystyl, prolyl imino and pyroglutamyl soluble aminopeptidase activities in the renal cortex. Acid and basic soluble aminopeptidase activities increased in the renal medulla. Increased levels of particulate form in the cortex were detected for acid and pyroglutamyl aminopeptidase activities. Cyclosporin increased cortical soluble while decreased medullar particulate prolyl dipeptidyl aminopeptidase IV activity. With the exception of prolyl dipeptidyl aminopeptidase IV, particulate aminopeptidase activities returned to levels similar to controls after fifteen days of cyclosporin withdrawal, and soluble aminopeptidase activities did not regress. Our data indicate that the adopted regimen of cyclosporin treatment produced mild renal impairment with consistent changes on the levels of renal but not macrophage aminopeptidase activities. The obtained profiles of macrophage and renal aminopeptidase activities should be considered into the elaboration of new potential strategies for preventing nephrotoxicity during the treatment with cyclosporin.


Assuntos
Aminopeptidases/metabolismo , Ciclosporina/farmacologia , Imunossupressores/farmacologia , Rim/efeitos dos fármacos , Rim/enzimologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Animais , Ciclosporina/administração & dosagem , Ativação Enzimática/efeitos dos fármacos , Imunossupressores/administração & dosagem , Córtex Renal/efeitos dos fármacos , Córtex Renal/enzimologia , Medula Renal/efeitos dos fármacos , Medula Renal/enzimologia , L-Lactato Desidrogenase/urina , Masculino , Camundongos
12.
Toxicon ; 47(5): 549-59, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16529786

RESUMO

The inflammatory events induced by BaP1, a 22.7 kDa metalloproteinase isolated from Bothrops asper snake venom, were studied. BaP1 i.p. injection in mice induced a marked inflammatory cell infiltrate into peritoneal cavity of animals with predominance of neutrophils in the early phase followed by mononuclear cells in the late period. Inhibition of enzymatic activity of BaP1 by chelation with EDTA resulted in a drastic reduction of this effect. In addition, BaP1 induced a significant increase of blood neutrophil numbers before its accumulation in peritoneal cavity, thus suggesting a stimulatory action of BaP1 on mechanisms of cell mobilization from bone marrow reserve compartments. A reduction in the number of neutrophils was observed in the exudate when antibodies against LECAM-1, CD18 and LFA-1 were used, suggesting the involvement of these adhesion molecules in the effects of BaP1. In contrast, there was no effect with antibodies against ICAM-1 and PECAM-1. Moreover, a conspicuous increment in the levels of IL-1 and TNF-alpha, but not of LTB4, was observed in peritoneal washes collected from mice injected with BaP1. It is concluded that BaP1 induces in vivo a marked leukocyte influx, which parallels an increased number of these cells in the blood, and is associated to the expression of specific leukocyte adhesion molecules and release of chemotactic inflammatory cytokines. Since BaP1 is a P-I class metalloproteinase, these results indicate that the proteolytic domain of metalloproteinases per se can trigger specific inflammatory events.


Assuntos
Bothrops/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Venenos de Crotalídeos/química , Citocinas/metabolismo , Leucócitos/efeitos dos fármacos , Metaloproteases/isolamento & purificação , Metaloproteases/farmacologia , Animais , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/metabolismo , Leucócitos/citologia , Leucócitos/metabolismo , Masculino , Metaloproteases/química , Camundongos , Fatores de Tempo
13.
Scientific Reports ; 10: 3269, 2020.
Artigo em Inglês | SES-SP, SESSP-IBPROD, SES-SP | ID: but-ib17457

RESUMO

Inflammatory joint conditions are characterized by synovial inflammation, which involves activation of fibroblast-like synoviocytes (FLSs) and production of inflammatory mediators and matrix metalloproteases (MMPs) in joints. This study showed that the snake venom metalloprotease (SVMP) BaP1 activates FLSs to produce PGE2 by a mechanism dependent on COX-2, mPGES-1 and iPLA2s. BaP1 also induces IL-1ß release, which up-regulates the production of PGE2 at a late stage of the stimulation. Expression of COX-2 and mPGES-1 are induced by BaP1 via activation of NF-capaB pathway. While NF-capaB p50 and p65 subunits are involved in up-regulation of COX-2 expression, only p65 is involved in BaP1-induced mPGES-1 expression. In addition, BaP1 up-regulates EP4 receptor expression. Engagement of this receptor by PGE2 triggers a positive feedback loop for its production by up-regulating expression of key components of the PGE2 biosynthetic cascade (COX-2, mPGES-1 and the EP4 receptor), thus contributing to amplification of BaP1-induced effects in FLSs. These data highlight the importance of FLS as a target for metalloproteases in joint inflammation and provide new insights into the roles of MMPs in inflammatory joint diseases. Moreover, our results may give insights into the importance of the catalytic domain, of MMPs for the inflammatory activity of these enzymes.

14.
Toxins, v. 13, n. 12, 868, dez. 2021
Artigo em Inglês | SES-SP, SESSP-IBPROD, SES-SP | ID: bud-4071

RESUMO

Phospholipases A2s (PLA2s) constitute one of the major protein groups present in the venoms of viperid and crotalid snakes. Snake venom PLA2s (svPLA2s) exhibit a remarkable functional diversity, as they have been described to induce a myriad of toxic effects. Local inflammation is an important characteristic of snakebite envenomation inflicted by viperid and crotalid species and diverse svPLA2s have been studied for their proinflammatory properties. Moreover, based on their molecular, structural, and functional properties, the viperid svPLA2s are classified into the group IIA secreted PLA2s, which encompasses mammalian inflammatory sPLA2s. Thus, research on svPLA2s has attained paramount importance for better understanding the role of this class of enzymes in snake envenomation and the participation of GIIA sPLA2s in pathophysiological conditions and for the development of new therapeutic agents. In this review, we highlight studies that have identified the inflammatory activities of svPLA2s, in particular, those from Bothrops genus snakes, which are major medically important snakes in Latin America, and we describe recent advances in our collective understanding of the mechanisms underlying their inflammatory effects. We also discuss studies that dissect the action of these venom enzymes in inflammatory cells focusing on molecular mechanisms and signaling pathways involved in the biosynthesis of lipid mediators and lipid accumulation in immunocompetent cells.

15.
Toxicon ; 46(7): 806-13, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16198389

RESUMO

Bothrops asper venom (BaV) causes systemic and local effects characterized by an acute inflammatory reaction with accumulation of leukocytes and release of endogenous mediators. In this study, the effects of BaV on the release of the cytokines IL-1, IL-6 and TNF-alpha and the eicosanoids LTB4 and TXA2 in the peritoneal cavity of mice were analyzed. We also investigated the participation of beta2 integrin chain, l-selectin, LFA-1, ICAM-1 and PECAM-1 adhesion molecules in the BaV-induced leukocyte accumulation. Levels of proinflammatory cytokines IL-6 and TNF-alpha, as well as eicosanoids LTB4 and TXA2 were significantly increased after BaV injection (250 microg/kg), whereas no increment in IL-1 was observed. Anti-mouse l-selectin, LFA-1, ICAM-1, PECAM-1 and beta2 integrin chain monoclonal antibodies resulted in a reduction of neutrophil accumulation induced by BaV injection compared with isotype-matched control injected animals. These data suggest that BaV is able to induce the activation of leukocytes and endothelium to express adhesion molecules involved in the recruitment of neutrophils into the inflammed site. Furthermore, these results showed that BaV induces the release of cytokines and eicosanoids in the local of the venom injection; these inflammatory mediators may be important for the initiation and amplification of the inflammatory reaction characteristic from Bothrops sp envenomation.


Assuntos
Bothrops , Moléculas de Adesão Celular/genética , Quimiotaxia de Leucócito/efeitos dos fármacos , Venenos de Crotalídeos/toxicidade , Citocinas/metabolismo , Eicosanoides/metabolismo , Mediadores da Inflamação/metabolismo , Animais , Bothrops/imunologia , Moléculas de Adesão Celular/metabolismo , Venenos de Crotalídeos/administração & dosagem , Venenos de Crotalídeos/imunologia , Citocinas/imunologia , Eicosanoides/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/imunologia , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucotrieno B4/metabolismo , Masculino , Camundongos , Tromboxano A2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Front. immunol. ; 10(2082)2019.
Artigo em Inglês | SES-SP, SESSP-IBPROD, SES-SP | ID: but-ib17193

RESUMO

Envenomation by viperid snakes is characterized by systemic thrombotic syndrome and prominent local inflammation. To date, the mechanisms underlying inflammation and blood coagulation induced by Viperidae venoms have been viewed as distinct processes. However, studies on the mechanisms involved in these processes have revealed several factors and signaling molecules that simultaneously act in both the innate immune and hemostatic systems, suggesting an overlap between both systems during viper envenomation. Moreover, distinct classes of venom toxins involved in these effects have also been identified. However, the interplay between inflammation and hemostatic alterations, referred as to thromboinflammation, has never been addressed in the investigation of viper envenomation. Considering that platelets are important targets of viper snake venoms and are critical for the process of thromboinflammation, in this review, we summarize the inflammatory effects and mechanisms induced by viper snake venoms, particularly from the Bothrops genus, which strongly activate platelet functions and highlight selected venom components (metalloproteases and C-type lectins) that both stimulate platelet functions and exhibit pro-inflammatory activities, thus providing insights into the possible role(s) of thromboinflammation in viper envenomation.

17.
Scientific Reports, v. 10, 3269, fev. 2020
Artigo em Inglês | SES-SP, SESSP-IBPROD, SES-SP | ID: bud-2949

RESUMO

Inflammatory joint conditions are characterized by synovial inflammation, which involves activation of fibroblast-like synoviocytes (FLSs) and production of inflammatory mediators and matrix metalloproteases (MMPs) in joints. This study showed that the snake venom metalloprotease (SVMP) BaP1 activates FLSs to produce PGE2 by a mechanism dependent on COX-2, mPGES-1 and iPLA2s. BaP1 also induces IL-1ß release, which up-regulates the production of PGE2 at a late stage of the stimulation. Expression of COX-2 and mPGES-1 are induced by BaP1 via activation of NF-capaB pathway. While NF-capaB p50 and p65 subunits are involved in up-regulation of COX-2 expression, only p65 is involved in BaP1-induced mPGES-1 expression. In addition, BaP1 up-regulates EP4 receptor expression. Engagement of this receptor by PGE2 triggers a positive feedback loop for its production by up-regulating expression of key components of the PGE2 biosynthetic cascade (COX-2, mPGES-1 and the EP4 receptor), thus contributing to amplification of BaP1-induced effects in FLSs. These data highlight the importance of FLS as a target for metalloproteases in joint inflammation and provide new insights into the roles of MMPs in inflammatory joint diseases. Moreover, our results may give insights into the importance of the catalytic domain, of MMPs for the inflammatory activity of these enzymes.

18.
Front immunol, v. 10, n. 2082, sep. 2019
Artigo em Inglês | SES-SP, SESSP-IBPROD, SES-SP | ID: bud-2836

RESUMO

Envenomation by viperid snakes is characterized by systemic thrombotic syndrome and prominent local inflammation. To date, the mechanisms underlying inflammation and blood coagulation induced by Viperidae venoms have been viewed as distinct processes. However, studies on the mechanisms involved in these processes have revealed several factors and signaling molecules that simultaneously act in both the innate immune and hemostatic systems, suggesting an overlap between both systems during viper envenomation. Moreover, distinct classes of venom toxins involved in these effects have also been identified. However, the interplay between inflammation and hemostatic alterations, referred as to thromboinflammation, has never been addressed in the investigation of viper envenomation. Considering that platelets are important targets of viper snake venoms and are critical for the process of thromboinflammation, in this review, we summarize the inflammatory effects and mechanisms induced by viper snake venoms, particularly from the Bothrops genus, which strongly activate platelet functions and highlight selected venom components (metalloproteases and C-type lectins) that both stimulate platelet functions and exhibit pro-inflammatory activities, thus providing insights into the possible role(s) of thromboinflammation in viper envenomation.

19.
Toxicology ; 408: p. 22-30, 2018.
Artigo em Inglês | SES-SP, SESSP-IBPROD, SES-SP | ID: but-ib15315

RESUMO

Robust correlation between the severity of rheumatoid arthritis (RA) and cigarette smoking has been clinically demonstrated. Nevertheless, cigarette compounds responsible for this toxic effect and their mechanisms have not been described. Considering that hydroquinone (HQ) is an abundant, pro-oxidative compound of the matter particle phase of cigarette smoke, we investigated whether HQ exposure during the initial phase of collagen-induced arthritis (CIA) could aggravate the disease. For this purpose, male Wistar rats were exposed to aerosolized HQ (25 ppm), saline or 5% ethanol solution (HQ vehicle) for 1 h per day during 14 days. CIA was induced through s.c. injection of bovine collagen Type II (0.4 mg/100 µL) at days seven and 14 of exposure. Clinical signs of disease and the cell profile and chemical mediators in the synovial fluid and membrane were analysed at day 35 after the beginning of exposure. HQ exposure aggravated CIA-related paw edema and increased the cell infiltrate and interleukin-6 (IL-6) levels in the synovial fluid, promoted intense tissue collagen deposition and enhanced synoviocyte proliferation and higher frequency of aryl hydrocarbon receptor (AhR+) and interleukin (IL-17+) neutrophils in the synovial membrane. in vitro data also highlighted that neutrophils expressed increased levels of AhR, IL-17 and reactive oxygen species (ROS) generation. However, only AhR expression and ROS generation were blocked by in vitro treatment with AhR antagonist. Therefore, we conclude that in vivo HQ exposure at the early phase of AR onset worsens RA, leading to high frequency of AhR/IL-17+ neutrophils into the joint.

20.
Chem.-Biol. Interact. ; 291: p. 120-127, 2018.
Artigo em Inglês | SES-SP, SESSP-IBPROD, SES-SP | ID: but-ib15295

RESUMO

The genesis of rheumatoid arthritis (RA) is complex and dependent on genetic background and exposure to environmental xenobiotic. Indeed, smoking is associated to developing and worsening pre-existing RA. Nevertheless, the mechanisms and cigarette compounds involved in the harmful processes have not been elucidated. Here, we investigated if the exposure to hydroquinone (HQ), an abundant pro-oxidative compound of cigarette and benzene metabolite, could worsen the ongoing RA. Hence, collagen-induced arthritis (CIA) was induced in male Wistar rats by s.c. injection of 400 lig (200 mu L) of bovine collagen type II emulsified in complete Freund's adjuvant on day 1, and a booster injection was performed on day 7. Exposures to nebulized HQ (25 ppm), saline solution or HQ vehicle solution (5% ethanol in saline) were carried out for 1 h, once a day, on days 21-27 after CIA induction. On day 27, animals were euthanized and samples were collected for further analyses. Exposure to HQ caused loss of weight, intensified paw edema, enhanced levels of tumor necrosis factor-alpha (TNF-alpha) and anti-citrullinated protein antibody (ACPA) in the serum; augmented synoviocyte proliferation and influx of aril hydrocarbon receptor (AhR) positive cells into the synovial membrane, altered collagen fibre rearrangement in the synovia, and synoviocytes isolated from HQ exposed rats secreted higher levels of proinflammatory cytokines, TNF-alpha and interleukin-15. Associated, we point out HQ as an environmental pollutant that aggravates RA, suggesting its participation on worsening RA in smoking patients.

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