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1.
J Thromb Haemost ; 21(12): 3317-3328, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38000851

RESUMO

Antiplatelet therapy plays a critical role in the prevention and treatment of major cardiovascular diseases triggered by thrombosis. Since the 1900s, significant progress in reducing morbidity and death caused by cardiovascular diseases has been made. However, despite the development and approval of drugs that specifically target the platelet, including inhibitors for cycloxygenase-1, P2Y12 receptor, integrin αIIbß3, phosphodiesterases, and protease-activated receptor 1, the risk of recurrent thrombotic events remains high, and the increased risk of bleeding is a major concern. Scientific advances in our understanding of the role of platelets in haemostasis and thrombosis have revealed novel targets, such as protease-activated receptor 4 (PAR4), glycoprotein Ib (GPIb)-V-IX complex, glycoprotein VI, and 12-lipoxygenase. The antithrombotic effects and safety of the pharmacologic inhibition of these targets are currently under investigation in clinical studies. This review provides an overview of drugs in early development to target the platelet and those in current use in clinical practice. Furthermore, it describes the emerging drug targets being developed and studied to reduce platelet activity and outlines potential novel therapeutic targets in the platelet.


Assuntos
Doenças Cardiovasculares , Trombose , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Plaquetas , Hemorragia/tratamento farmacológico , Trombose/tratamento farmacológico , Trombose/prevenção & controle
2.
Blood ; 142(18): 1556-1569, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37624927

RESUMO

Cardiovascular disease remains the primary cause of morbidity and mortality globally. Platelet activation is critical for maintaining hemostasis and preventing the leakage of blood cells from the vessel. There has been a paucity in the development of new drugs to target platelet reactivity. Recently, the oxylipin 12(S)-hydroxy-eicosatrienoic acid (12-HETrE), which is produced in platelets, was shown to limit platelet reactivity by activating the prostacyclin receptor. Here, we demonstrated the synthesis of a novel analog of 12-HETrE, known as CS585. Human blood and mouse models of hemostasis and thrombosis were assessed for the ability of CS585 to attenuate platelet activation and thrombosis without increasing the risk of bleeding. Human platelet activation was assessed using aggregometry, flow cytometry, western blot analysis, total thrombus formation analysis system, microfluidic perfusion chamber, and thromboelastography. Hemostasis, thrombosis, and bleeding assays were performed in mice. CS585 was shown to potently target the prostacyclin receptor on the human platelet, resulting in a highly selective and effective mechanism for the prevention of platelet activation. Furthermore, CS585 was shown to inhibit platelet function in human whole blood ex vivo, prevent thrombosis in both small and large vessels in mouse models, and exhibit long-lasting prevention of clot formation. Finally, CS585 was not observed to perturb coagulation or increase the risk of bleeding in the mouse model. Hence, CS585 represents a new validated target for the treatment of thrombotic diseases without the risk of bleeding or off-target activation observed with other prostaglandin receptor agonists.


Assuntos
Oxilipinas , Trombose , Animais , Humanos , Camundongos , Receptores de Epoprostenol , Oxilipinas/farmacologia , Oxilipinas/uso terapêutico , Ativação Plaquetária , Plaquetas , Hemostasia , Hemorragia , Agregação Plaquetária
3.
Pharmacol Res Perspect ; 11(1): e01056, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36708179

RESUMO

The antiplatelet effect of polyunsaturated fatty acids is primarily attributed to its metabolism to bioactive metabolites by oxygenases, such as lipoxygenases (LOX). Platelets have demonstrated the ability to generate 15-LOX-derived metabolites (15-oxylipins); however, whether 15-LOX is in the platelet or is required for the formation of 15-oxylipins remains unclear. This study seeks to elucidate whether 15-LOX is required for the formation of 15-oxylipins in the platelet and determine their mechanistic effects on platelet reactivity. In this study, 15-HETrE, 15-HETE, and 15-HEPE attenuated collagen-induced platelet aggregation, and 15-HETrE inhibited platelet aggregation induced by different agonists. The observed anti-aggregatory effect was due to the inhibition of intracellular signaling including αIIbß3 and protein kinase C activities, calcium mobilization, and granule secretion. While 15-HETrE inhibited platelets partially through activation of peroxisome proliferator-activated receptor ß (PPARß), 15-HETE also inhibited platelets partially through activation of PPARα. 15-HETrE, 15-HETE, or 15-HEPE inhibited 12-LOX in vitro, with arachidonic acid as the substrate. Additionally, a 15-oxylipin-dependent attenuation of 12-HETE level was observed in platelets following ex vivo treatment with 15-HETrE, 15-HETE, or 15-HEPE. Platelets treated with DGLA formed 15-HETrE and collagen-induced platelet aggregation was attenuated only in the presence of ML355 or aspirin, but not in the presence of 15-LOX-1 or 15-LOX-2 inhibitors. Expression of 15-LOX-1, but not 15-LOX-2, was decreased in leukocyte-depleted platelets compared to non-depleted platelets. Taken together, these findings suggest that 15-oxylipins regulate platelet reactivity; however, platelet expression of 15-LOX-1 is low, suggesting that 15-oxylipins may be formed in the platelet through a 15-LOX-independent pathway.


Assuntos
Ácidos Graxos , Oxilipinas , Araquidonato 15-Lipoxigenase , Eicosanoides , Inibidores de Lipoxigenase/farmacologia , Receptores Depuradores Classe E
4.
Arch Physiol Biochem ; 129(3): 810-820, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33502908

RESUMO

Present study investigated which diet, high-carbohydrate (HCD) or high-fat (HFD), most effectively induces classical characteristics of obesity in mice. Mice were fed commercial chow (control), an HCD, or an HFD for 12 weeks. HFD and HCD increased body weight, fat mass, and glycaemia, whereas the HFD augmented insulinemia. In the kidney, the HFD caused albuminuria, and reductions in fractional Na+ excretion, Thromboxane B2 (TXB2) excretion, and urinary flow, whereas the HCD reduced glomerular filtration, plasma osmolality, and TXB2 and Prostaglandin E2 excretion. The consumption of HFD and HCD modified parameters that indicate histopathological changes, such as proliferation (proliferating-cell-nuclear antigen), inflammation (c-Jun N-terminal-protein), and epithelial-mesenchymal transition (vimentin, and desmin) in renal tissue, but the HCD group presents fewer signals of glomerular hypertrophy or tubule degeneration. In summary, the HCD generated the metabolic and renal changes required for an obesity model, but with a delay in the development of these modifications concerning the HFD.


Assuntos
Dieta Hiperlipídica , Obesidade , Camundongos , Animais , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Peso Corporal , Rim/metabolismo , Carboidratos , Camundongos Endogâmicos C57BL
5.
Arch Biochem Biophys ; 733: 109472, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36442529

RESUMO

Human platelet 12-lipoxygenase (h12-LOX) is responsible for the formation of oxylipin products that play an important role in platelet aggregation. Single nucleotide polymorphisms (SNPs) of h12-LOX have been implicated in several diseases. In this study, we investigate the structural, dynamical, and functional impact of a h12-LOX SNP that generates a tyrosine-to-cysteine mutation at a buried site (Y649C h12-LOX) and was previously ascribed with reduced levels of 12(S)-hydroxyeicosatetraenoic acid (12S-HETE) production in isolated platelets. Herein, in vitro Michaelis-Menten kinetics show reduced catalytic rates for Y649C compared to WT h12-LOX at physiological or lower temperatures. Both proteins exhibited similar melting temperatures, metal content, and oligomerization state. Liposome binding for both proteins was also dependent upon the presence of calcium, temperature, and liposome composition; however, the Y649C variant was found to have lowered binding capacity to liposomes compared to WT at physiological temperatures. Further, hydrogen-deuterium exchange mass spectrometry (HDX-MS) experiments revealed a regional defined enhancement in the peptide mobility caused by the mutation. This increased instability for the mutation stemmed from a change in an interaction with an arched helix that lines the substrate binding site, located ≥15 Å from the mutation site. Finally, differential scanning calorimetry demonstrated a reduced protein (un)folding enthalpy, consistent with the HDX results. Taken together, these results demonstrate remarkable similarity between the mutant and WT h12-LOX, and yet, subtle changes in activity, membrane affinity and protein stability may be responsible for the significant physiological changes that the Y649C SNP manifests in platelet biology.


Assuntos
Araquidonato 12-Lipoxigenase , Plaquetas , Humanos , Araquidonato 12-Lipoxigenase/genética , Araquidonato 12-Lipoxigenase/metabolismo , Plaquetas/metabolismo , Polimorfismo de Nucleotídeo Único , Deutério , Medição da Troca de Deutério , Lipossomos/metabolismo , Hidrogênio/metabolismo
6.
Front Pharmacol ; 13: 997403, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36238558

RESUMO

Polyunsaturated fatty acids (PUFAs) are structural components of membrane phospholipids in cells. PUFAs regulate cellular function through the formation of derived lipid mediators termed eicosanoids. The oxygenation of 20-carbon PUFAs via the oxygenases cyclooxygenases, lipoxygenases, or cytochrome P450, generates a class of classical eicosanoids including prostaglandins, thromboxanes and leukotrienes, and also the more recently identified hydroxy-, hydroperoxy-, epoxy- and oxo-eicosanoids, and the specialized pro-resolving (lipid) mediators. These eicosanoids play a critical role in the regulation of inflammation in the blood and the vessel. While arachidonic acid-derived eicosanoids are extensively studied due to their pro-inflammatory effects and therefore involvement in the pathogenesis of inflammatory diseases such as atherosclerosis, diabetes mellitus, hypertension, and the coronavirus disease 2019; in recent years, several eicosanoids have been reported to attenuate exacerbated inflammatory responses and participate in the resolution of inflammation. This review focused on elucidating the biosynthesis and the mechanistic signaling of eicosanoids in inflammation, as well as the pro-inflammatory and anti-inflammatory effects of these eicosanoids in the blood and the vascular wall.

7.
Clin Transl Sci ; 15(10): 2378-2391, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35791734

RESUMO

Postmenopausal women are at increased risk for a cardiovascular event due to platelet hyperactivity. There is evidence suggesting that ω-3 polyunsaturated fatty acids (PUFAs) and ω-6 PUFAs have cardioprotective effects in these women. However, a mechanistic understanding of how these fatty acids regulate platelet function is unknown. In this study, we supplemented postmenopausal women with fish oil (ω-3 fatty acids) or evening primrose oil (ω-6 fatty acids) and investigated the effects on their platelet activity. The effects of fatty acid supplementation on platelet aggregation, dense granule secretion, and activation of integrin αIIbß3 at basal levels and in response to agonist were tested in postmenopausal women following a supplementation and washout period. Supplementation with fish oil or primrose oil attenuated the thrombin receptor PAR4-induced platelet aggregation. Supplementation with ω-3 or ω-6 fatty acids decreased platelet dense granule secretion and attenuated basal levels of integrin αIIbß3 activation. Interestingly, after the washout period following supplementation with primrose oil, platelet aggregation was similarly attenuated. Additionally, for either treatment, the observed protective effects post-supplementation on platelet dense granule secretion and basal levels of integrin activation were sustained after the washout period, suggesting a long-term shift in platelet reactivity due to fatty acid supplementation. These findings begin to elucidate the underlying mechanistic effects of ω-3 and ω-6 fatty acids on platelet reactivity in postmenopausal women. Hence, this study supports the beneficial effects of fish oil or primrose oil supplementation as a therapeutic intervention to reduce the risk of thrombotic events in postmenopausal women. https://clinicaltrials.gov/ct2/show/NCT02629497.


Assuntos
Ácidos Graxos Ômega-3 , Ácidos Graxos Ômega-6 , Óleos de Peixe , Feminino , Suplementos Nutricionais , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Graxos Ômega-6/farmacologia , Ácidos Graxos Ômega-6/uso terapêutico , Óleos de Peixe/farmacologia , Óleos de Peixe/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas , Pós-Menopausa , Receptores de Trombina , Humanos
8.
Biochemistry ; 60(22): 1741-1754, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34029049

RESUMO

In this paper, human platelet 12-lipoxygenase [h12-LOX (ALOX12)], human reticulocyte 15-lipoxygenase-1 [h15-LOX-1 (ALOX15)], and human epithelial 15-lipoxygenase-2 [h15-LOX-2 (ALOX15B)] were observed to react with docosahexaenoic acid (DHA) and produce 17S-hydroperoxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid (17S-HpDHA). The kcat/KM values with DHA for h12-LOX, h15-LOX-1, and h15-LOX-2 were 12, 0.35, and 0.43 s-1 µM-1, respectively, which demonstrate h12-LOX as the most efficient of the three. These values are comparable to their counterpart kcat/KM values with arachidonic acid (AA), 14, 0.98, and 0.24 s-1 µM-1, respectively. Comparison of their product profiles with DHA demonstrates that the three LOX isozymes produce 11S-HpDHA, 14S-HpDHA, and 17S-HpDHA, to varying degrees, with 17S-HpDHA being the majority product only for the 15-LOX isozymes. The effective kcat/KM values (kcat/KM × percent product formation) for 17S-HpDHA of the three isozymes indicate that the in vitro value of h12-LOX was 2.8-fold greater than that of h15-LOX-1 and 1.3-fold greater than that of h15-LOX-2. 17S-HpDHA was an effective substrate for h12-LOX and h15-LOX-1, with four products being observed under reducing conditions: protectin DX (PDX), 16S,17S-epoxy-4Z,7Z,10Z,12E,14E,19Z-docosahexaenoic acid (16S,17S-epoxyDHA), the key intermediate in neuroprotection D1 biosynthesis [NPD1, also known as protectin D1 (PD1)], 11,17S-diHDHA, and 16,17S-diHDHA. However, h15-LOX-2 did not react with 17-HpDHA. With respect to their effective kcat/KM values, h12-LOX was markedly less effective than h15-LOX-1 in reacting with 17S-HpDHA, with a 55-fold lower effective kcat/KM in producing 16S,17S-epoxyDHA and a 27-fold lower effective kcat/KM in generating PDX. This is the first direct demonstration of h15-LOX-1 catalyzing this reaction and reveals an in vitro pathway for PDX and NPD1 intermediate biosynthesis. In addition, epoxide formation from 17S-HpDHA and h15-LOX-1 was negatively affected via allosteric regulation by 17S-HpDHA (Kd = 5.9 µM), 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12S-HETE) (Kd = 2.5 µM), and 17S-hydroxy-13Z,15E,19Z-docosatrienoic acid (17S-HDTA) (Kd = 1.4 µM), suggesting a possible regulatory pathway in reducing epoxide formation. Finally, 17S-HpDHA and PDX inhibited platelet aggregation, with EC50 values of approximately 1 and 3 µM, respectively. The in vitro results presented here may help advise in vivo PDX and NPD1 intermediate (i.e., 16S,17S-epoxyDHA) biosynthetic investigations and support the benefits of DHA rich diets.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Lipoxigenases/metabolismo , Regulação Alostérica , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Ácido Araquidônico/metabolismo , Ácidos Araquidônicos/metabolismo , Vias Biossintéticas , Plaquetas/metabolismo , Ácidos Docosa-Hexaenoicos/farmacocinética , Ácidos Docosa-Hexaenoicos/farmacologia , Humanos , Lipoxigenase/metabolismo , Lipoxigenases/biossíntese
9.
Thromb Res ; 200: 64-71, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33540294

RESUMO

INTRODUCTION: Despite the great promise for therapies using antisense oligonucleotides (ASOs), their adverse effects, which include pro-inflammatory effects and thrombocytopenia, have limited their use. Previously, these effects have been linked to the phosphorothioate (PS) backbone necessary to prevent rapid ASO degradation in plasma. The main aim of this study was to assess the impact of the nucleic acid portion of an ASO-type drug on platelets and determine if it may contribute to thrombosis or thrombocytopenia. METHODS: Platelets were isolated from healthy donors and men with advanced prostate cancer. Effects of antisense oligonucleotides (ASO), oligonucleotides, gDNA, and microRNA on platelet activation and aggregation were evaluated. A mouse model of lung thrombosis was used to confirm the effects of PS-modified oligonucleotides in vivo. RESULTS: Platelet exposure to gDNA, miRNA, and oligonucleotides longer than 16-mer at a concentration above 8 mM resulted in the formation of hypersensitive platelets, characterized by an increased sensitivity to low-dose thrombin (0.1 nM) and increase in p-Selectin expression (6-8 fold greater than control; p < 0.001). The observed nucleic acid (NA) effects on platelets were toll-like receptor (TLR) -7 subfamily dependent. Injection of a p-Selectin inhibitor significantly (p = 0.02) reduced the formation of oligonucleotide-associated pulmonary microthrombosis in vivo. CONCLUSION: Our results suggest that platelet exposure to nucleic acids independent of the presence of a PS modification leads to a generation of hypersensitive platelets and requires TLR-7 subfamily receptors. ASO studies conducted in cancer patients may benefit from testing the ASO effects on platelets ex vivo before initiation of patient treatment.


Assuntos
Ácidos Nucleicos , Preparações Farmacêuticas , Animais , Plaquetas , Humanos , Camundongos , Oligonucleotídeos Antissenso , Oligonucleotídeos Fosforotioatos
10.
J Thromb Haemost ; 19(3): 839-851, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33222370

RESUMO

BACKGROUND: The effects of docosahexaenoic acid (DHA) on cardiovascular disease are controversial and a mechanistic understanding of how this omega-3 polyunsaturated fatty acid (ω-3 PUFA) regulates platelet reactivity and the subsequent risk of a thrombotic event is warranted. In platelets, DHA is oxidized by 12-lipoxygenase (12-LOX) producing the oxidized lipids (oxylipins) 11-HDHA and 14-HDHA. We hypothesized that 12-LOX DHA-oxylipins may be involved in the beneficial effects observed in dietary supplemental treatment with ω-3 PUFAs or DHA itself. OBJECTIVES: To determine the effects of DHA, 11-HDHA, and 14-HDHA on platelet function and thrombus formation, and to elucidate the mechanism by which these ω-3 PUFAs regulate platelet activation. METHODS AND RESULTS: DHA, 11-HDHA, and 14-HDHA attenuated collagen-induced human platelet aggregation, but only the oxylipins inhibited ⍺IIbß3 activation and decreased ⍺-granule secretion. Furthermore, treatment of whole blood with DHA and its oxylipins impaired platelet adhesion and accumulation to a collagen-coated surface. Interestingly, thrombus formation was only diminished in mice treated with 11-HDHA or 14-HDHA, and mouse platelet activation was inhibited following acute treatment with these oxylipins or chronic treatment with DHA, suggesting that under physiologic conditions, the effects of DHA are mediated through its oxylipins. Finally, the protective mechanism of DHA oxylipins was shown to be mediated via activation of protein kinase A. CONCLUSIONS: This study provides the first mechanistic evidence of how DHA and its 12-LOX oxylipins inhibit platelet activity and thrombus formation. These findings support the beneficial effects of DHA as therapeutic intervention in atherothrombotic diseases.


Assuntos
Ácidos Docosa-Hexaenoicos , Trombose , Animais , Ácidos Docosa-Hexaenoicos/farmacologia , Camundongos , Oxilipinas , Ativação Plaquetária , Transdução de Sinais , Trombose/tratamento farmacológico
11.
Biochemistry ; 59(42): 4118-4130, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33048542

RESUMO

The oxylipins, 5S,12S-dihydroxy-6E,8Z,10E,14Z-eicosatetraenoic acid (5S,12S-diHETE) and 5S,15S-dihydroxy-6E,8Z,11Z,13E-eicosatetraenoic acid (5S,15S-diHETE), have been identified in cell exudates and have chemotactic activity toward eosinophils and neutrophils. Their biosynthesis has been proposed to occur by sequential oxidations of arachidonic acid (AA) by lipoxygenase enzymes, specifically through oxidation of AA by h5-LOX followed by h12-LOX, h15-LOX-1, or h15-LOX-2. In this work, h15-LOX-1 demonstrates altered positional specificity when reacting with 5S-HETE, producing 90% 5S,12S-diHETE, instead of 5S,15S-diHETE, with kinetics 5-fold greater than that of h12-LOX. This is consistent with previous work in which h15-LOX-1 reacts with 7S-HDHA, producing the noncanonical, DHA-derived, specialized pro-resolving mediator, 7S,14S-diHDHA. It is also determined that oxygenation of 5S-HETE by h15-LOX-2 produces 5S,15S-diHETE and its biosynthetic kcat/KM flux is 2-fold greater than that of h15-LOX-1, suggesting that h15-LOX-2 may have a greater role in lipoxin biosynthesis than previously thought. In addition, it is shown that oxygenation of 12S-HETE and 15S-HETE by h5-LOX is kinetically slow, suggesting that the first step in the in vitro biosynthesis of both 5S,12S-diHETE and 5S,15S-diHETE is the production of 5S-HETE.


Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Lipoxinas/metabolismo , Ácido Araquidônico/metabolismo , Ácidos Araquidônicos/metabolismo , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo
12.
Blood Adv ; 4(18): 4522-4537, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32946570

RESUMO

Arterial thrombosis is the underlying cause for a number of cardiovascular-related events. Although dietary supplementation that includes polyunsaturated fatty acids (PUFAs) has been proposed to elicit cardiovascular protection, a mechanism for antithrombotic protection has not been well established. The current study sought to investigate whether an omega-6 essential fatty acid, docosapentaenoic acid (DPAn-6), and its oxidized lipid metabolites (oxylipins) provide direct cardiovascular protection through inhibition of platelet reactivity. Human and mouse blood and isolated platelets were treated with DPAn-6 and its 12-lipoxygenase (12-LOX)-derived oxylipins, 11-hydroxy-docosapentaenoic acid and 14-hydroxy-docosapentaenoic acid, to assess their ability to inhibit platelet activation. Pharmacological and genetic approaches were used to elucidate a role for DPA and its oxylipins in preventing platelet activation. DPAn-6 was found to be significantly increased in platelets following fatty acid supplementation, and it potently inhibited platelet activation through its 12-LOX-derived oxylipins. The inhibitory effects were selectively reversed through inhibition of the nuclear receptor peroxisome proliferator activator receptor-α (PPARα). PPARα binding was confirmed using a PPARα transcription reporter assay, as well as PPARα-/- mice. These approaches confirmed that selectivity of platelet inhibition was due to effects of DPA oxylipins acting through PPARα. Mice administered DPAn-6 or its oxylipins exhibited reduced thrombus formation following vessel injury, which was prevented in PPARα-/- mice. Hence, the current study demonstrates that DPAn-6 and its oxylipins potently and effectively inhibit platelet activation and thrombosis following a vascular injury. Platelet function is regulated, in part, through an oxylipin-induced PPARα-dependent manner, suggesting that targeting PPARα may represent an alternative strategy to treat thrombotic-related diseases.


Assuntos
Araquidonato 12-Lipoxigenase , Plaquetas , Animais , Araquidonato 12-Lipoxigenase/genética , Araquidonato 12-Lipoxigenase/farmacologia , Lipídeos , Camundongos , PPAR alfa/genética , PPAR alfa/farmacologia , Proliferadores de Peroxissomos/farmacologia
13.
Pak J Pharm Sci ; 31(1): 1-8, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29348077

RESUMO

Macrophages have been considered an elusive yet emerging therapeutic target in tumor development since they are an important component in tumor microenvironment. The purpose of the present study was to evaluate the effect of C. sinensis on macrophage function (a component of tumor microenvironment which can alter the virulence of cancer) in high-fat diet fed rats. IMR-32 human neuroblastoma cell cytotoxicity was also investigated. The following parameters were observed to evaluate macrophage function: superoxide anion, hydrogen peroxide, nitric oxide, lysosomal volume and phagocytic capacity. High fat diet (HFD) plus C. sinensis supplementation promoted a decreased superoxide anion and hydrogen peroxide levels as well as lysosomal volume and phagocytic capacity. Nitric oxide was increased in the same group. In summary, C. sinensis offered an important anti-tumoral perspective from the standpoint of the tumor microenvironment and in vitro IMR-32 cytotoxicity.


Assuntos
Antineoplásicos/farmacologia , Cordyceps , Dieta Hiperlipídica , Hiperlipidemias/fisiopatologia , Macrófagos Peritoneais/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Animais , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cordyceps/química , Humanos , Peróxido de Hidrogênio/metabolismo , Hiperlipidemias/etiologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/fisiologia , Masculino , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Óxido Nítrico/metabolismo , Ratos Wistar , Superóxidos/metabolismo , Microambiente Tumoral/efeitos dos fármacos
14.
Nutr Cancer ; 68(8): 1369-1380, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27652719

RESUMO

OBJECTIVE: Polyunsaturated fatty acids n-3 (PUFA n-3) have shown effects in reducing tumor growth, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) abundantly present in fish oil (FO). When these fatty acids are provided in the diet, they alter the functions of the cells, particularly in tumor and immune cells. However, the effects of α-linolenic fatty acid (ALA), which is the precursor of EPA and DHA, are controversial. Thus, our objective was to test the effect of this parental fatty acid. METHODS: Non-tumor-bearing and tumor-bearing Wistar rats (70 days) were supplemented with 1 g/kg body weight of FO or Oro Inca® (OI) oil (rich in ALA). Immune cells function, proliferation, cytokine production, and subpopulation profile were evaluated. RESULTS: We have shown that innate immune cells enhanced phagocytosis capacity, and increased processing and elimination of antigens. Moreover, there was a decrease in production of pro-inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6)) by macrophages. Lymphocytes showed decreased proliferation capacity, increased cluster of differentiation 8 (CD8+) subpopulation, and increased TNF-α production. CONCLUSIONS: Oil rich in ALA caused similar immune modulation in cancer when compared with FO.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Óleos de Peixe/farmacologia , Ácido alfa-Linolênico/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Suplementos Nutricionais , Óleos de Peixe/química , Interleucina-6/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Fagocitose/efeitos dos fármacos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
15.
Lipids Health Dis ; 14: 94, 2015 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-26303118

RESUMO

BACKGROUND: Several studies have been shown pro-apoptotic effects of fish oil (FO), rich in n-3 polyunsaturated fatty acids (n-3 PUFA) on cancer cells. Nevertheless, few in vivo experiments have provided data of its ability on apoptosis protein expression in tumor tissue. Thus, in this study we investigate the effect of FO supplementation on apoptosis protein expression in Walker 256 tumor bearing rats. Male Wistar rats were randomly assigned to three groups: fed with regular chow (W); fed regular chow supplemented with FO (WFO) or coconut fat (WCO) (1 g/kg body weight/daily). After thirty days, all animals were inoculated subcutaneously with Walker 256 tumor cells. FINDINGS: Protein expression was done by western blotting in Walker 256 tumor tissue samples. FO decreased the Bcl-2/Bax ratio (p < 0.05) and increased the p53 (p < 0.05), cleaved caspase-7 (p < 0.05) and cleaved caspase-3 (p < 0.05) in Walker 256 tumor tissue. CONCLUSIONS: Our data suggest that the pro-apoptotic effect of FO in Walker 256 tumor is related with specifics cleaved caspases.


Assuntos
Anticarcinógenos/farmacologia , Carcinoma 256 de Walker/dietoterapia , Suplementos Nutricionais , Óleos de Peixe/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carcinoma 256 de Walker/genética , Carcinoma 256 de Walker/metabolismo , Carcinoma 256 de Walker/patologia , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Óleo de Coco , Injeções Subcutâneas , Masculino , Óleos de Plantas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
16.
Nutr Cancer ; 67(5): 839-46, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26011096

RESUMO

Fish oil (FO) has been shown to affect cancer cachexia, tumor mass, and immunity cell. n-3 PUFA, specifically α-linolenic fatty acid (ALA), has controversial effects. We investigated this in nontumor-bearing Wistar rats fed regular chow (C), fed regular chow and supplemented with FO or Oro Inca oil (OI), and Walker 256 tumor-bearing rats fed regular chow (W), fed regular chow and supplemented with FO (WFO) or OI (WOI). Rats were supplemented (1g/kg body weight/day) during 4 wk and then the groups tumor-bearing were inoculated with Walker 256 tumor cells suspension and 14 days later the animals were killed. WFO increased EPA fivefold and DHA 1.5-fold in the tumor tissue compared to W (P < 0.05). OI supplementation increased of threefold of ALA when compared to W (P < 0.05). Tumor mass in WFO and OI was of 2.3-fold lower, as well as tumor cell proliferation of 3.0-fold tumor tissue lipoperoxidation increased of 76.6% and cox-2 expression was 20% lower. Cachexia parameters were attenuate, blood glucose (25% higher), Triacylglycerolemia (50% lower), and plasma TNF-α (65% lower; P < 0.05) and IL-6 (62.5% lower). OI, rich in ALA, caused the same effect on cancer as those seen in FO.


Assuntos
Caquexia/prevenção & controle , Carcinoma 256 de Walker/patologia , Proliferação de Células/efeitos dos fármacos , Óleos de Peixe/administração & dosagem , Ácido alfa-Linolênico/administração & dosagem , Animais , Linhagem Celular Tumoral , Suplementos Nutricionais , Inibidores do Crescimento/farmacologia , Masculino , Ratos , Ratos Wistar
17.
Nutr Cancer ; 64(2): 286-93, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22242972

RESUMO

This study investigated the mechanisms by which ß-hydroxy-ß-methylbutyrate (HMB) administration in rats reduces Walker-256 tumor growth. Male Wistar rats were supplemented with HMB (76 mg/kg/day) (HW), or a placebo (W), during 8 wk by gavage. At the 6th wk, rats were inoculated with a suspension of Walker 256 tumor cells (3 × 10(7)/mL). Fifteen days after inoculation, the HW group showed higher glycemia (109.4 ± 5.53 vs. 89.87 ± 7.02 mg/dL, P < 0.05) and lower spleen (1.35 ± 0.05 vs. 1.65 ± 0.12 g, P < 0.05) and tumor weights (9.64 ± 1.07 vs. 13.55 ± 1.19 g, P < 0.05) compared to the W group. Tumor cells extracted from the HMB-treated rats displayed a 36.9% decrement in rates of proliferation ex vivo and a significant increase in the Bax/Bcl-2 protein expression ratio in comparison to those extracted from the placebo-treated rats (P < 0.05). Both phagocytic capacity and H(2)O(2) production rates were higher in polymorphnuclear cells that were obtained from the blood of the HW rats in comparison to those from the W rats (P < 0.05). Reduction of necrotic regions and an intense infiltration of leukocytes and activated granulocytes in HW were evident by transmission electron microscopy. Our findings suggest that HMB supplementation decreases tumor burden by modifying the inner environment of tumor cells and by interfering with blood leukocyte function.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma 256 de Walker/patologia , Neutrófilos/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Valeratos/administração & dosagem , Proteína X Associada a bcl-2/análise , Animais , Carcinoma 256 de Walker/química , Carcinoma 256 de Walker/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Masculino , Microscopia Eletrônica de Transmissão , Transplante de Neoplasias , Neutrófilos/efeitos dos fármacos , Ratos , Ratos Wistar
18.
EXCLI J ; 11: 767-775, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-27847459

RESUMO

This study investigated the effect of Cordyceps sinensis biomass supplementation obtained from submerged fermentation on blood lipid and low testosterone induced by high-fat diet (HFD). The experiments were carried out using a long-term intake of HFD and HFD plus Simvastatin or C. sinensis (4 months). Our results show that plasma cholesterol, triglycerides and LDL were decreased by Cordyceps sinensis biomass supplementation (CSBS). A long-term intake of HFD caused a significant liver damage which has been reverted by CSBS. CSBS normalized decreasing testosterone levels observed in high-fat diet feed rats. All these findings lead us to suggest that C. sinensis was able to decrease blood lipid concentration, increase hepatoprotective activity and normalize testosterone levels.

19.
Lipids Health Dis ; 10: 66, 2011 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-21526994

RESUMO

BACKGROUND: Obesity is commonly associated with diabetes, cardiovascular diseases and cancer. The purpose of this study was to determinate the effect of a lower dose of fish oil supplementation on insulin sensitivity, lipid profile, and muscle metabolism in obese rats. METHODS: Monosodium glutamate (MSG) (4 mg/g body weight) was injected in neonatal Wistar male rats. Three-month-old rats were divided in normal-weight control group (C), coconut fat-treated normal weight group (CO), fish oil-treated normal weight group (FO), obese control group (Ob), coconut fat-treated obese group (ObCO) and fish oil-treated obese group (ObFO). Obese insulin-resistant rats were supplemented with fish oil or coconut fat (1 g/kg/day) for 4 weeks. Insulin sensitivity, fasting blood biochemicals parameters, and skeletal muscle glucose metabolism were analyzed. RESULTS: Obese animals (Ob) presented higher Index Lee and 2.5 fold epididymal and retroperitoneal adipose tissue than C. Insulin sensitivity test (Kitt) showed that fish oil supplementation was able to maintain insulin sensitivity of obese rats (ObFO) similar to C. There were no changes in glucose and HDL-cholesterol levels amongst groups. Yet, ObFO revealed lower levels of total cholesterol (TC; 30%) and triacylglycerol (TG; 33%) compared to Ob. Finally, since exposed to insulin, ObFO skeletal muscle revealed an increase of 10% in lactate production, 38% in glycogen synthesis and 39% in oxidation of glucose compared to Ob. CONCLUSIONS: Low dose of fish oil supplementation (1 g/kg/day) was able to reduce TC and TG levels, in addition to improved systemic and muscle insulin sensitivity. These results lend credence to the benefits of n-3 fatty acids upon the deleterious effects of insulin resistance mechanisms.


Assuntos
Comportamento Alimentar/efeitos dos fármacos , Óleos de Peixe/administração & dosagem , Óleos de Peixe/farmacologia , Resistência à Insulina , Insulina/metabolismo , Lipídeos/sangue , Obesidade/metabolismo , Animais , Dieta , Ácidos Graxos/análise , Insulina/sangue , Masculino , Músculo Esquelético/metabolismo , Obesidade/sangue , Ratos , Ratos Wistar , Glutamato de Sódio/administração & dosagem
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