RESUMO
Breast cancer remains a serious threat to women's physical and emotional health. The combination therapies can overcome the deficiency of single therapy, enhance the therapeutic effects and reduce the side effects at the same time. In this study, we synthesize a novel nanomedicine that enhanced the therapeutic effects of breast cancer treatment by combining photodynamic therapy and chemotherapy. The doxorubicin (DOX) and photosensitizer methyl pyropheophorbide-a (MPPa) are loaded into the nano-drug delivery system as DPSPFA/MPPa/DOX. In response to near-infrared (NIR) laser, the drugs were quickly released to the cancer cells. The MPPa produces reactive oxygen species (ROS) under the action of photodynamics. Unsaturated fatty acids with ROS promotes lipid peroxidation and the combination of chemotherapy and photodynamic therapy. The data shows that the DPSPFA/MPPa/DOX has a spherical shape, good dispersibility and stability, and the particle size is roughly 200â¯nm. The drug loading capability of DOX is about 13â¯%. Both of MCF7 cell model in vitro and breast cancer model in vivo, DPSPFA/MPPa/DOX showed an excellent anti-tumor effect of 86.9â¯% and without any obvious side effects. These findings might offer potential for a new approach for breast cancer treatment.
Assuntos
Neoplasias da Mama , Ácidos Docosa-Hexaenoicos , Doxorrubicina , Peroxidação de Lipídeos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio , Humanos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/química , Células MCF-7 , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Animais , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/síntese química , Camundongos , Clorofila/análogos & derivados , Clorofila/química , Clorofila/farmacologia , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Sobrevivência Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , PorfirinasRESUMO
This review article assembles key recent advances in the synthetic chemistry and biology of specialised pro-resolving mediators (SPMs). The major medicinal chemistry developments in the design, synthesis and biological evaluation of synthetic SPM analogues of lipoxins and resolvins have been discussed. These include variations in the top and bottom chains, as well as changes to the triene core, of lipoxins, all changes intended to enhance the metabolic stability whilst retaining or improving biological activity. Similar chemical modifications of resolvins are also discussed. The biological evaluation of these synthetic SPMs is also described in some detail. Original investigations into the biological activity of endogenous SPMs led to the pairing of these ligands with the FPR2/LX receptor, and these results have been challenged in more recent work, leading to conflicting results and views, which are again discussed.
Assuntos
Lipoxinas , Humanos , Lipoxinas/metabolismo , Lipoxinas/química , Animais , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/síntese química , Receptores de Formil Peptídeo/metabolismoRESUMO
This manuscript describes our third generation, gram-scale synthesis of very long chain-polyunsaturated fatty acids (VLC-PUFAs), a unique and increasingly important class of lipids. Critical to this work and what makes it different from our previous approach to this family was the avoidance of oxidation sequences. Central to accomplishing this involved the use of a Negishi coupling reaction between the acid chloride derived from DHA and a saturated alkyl zinc reaction. Overall, the general approach required 6 synthetic transformations from DHA and was accomplished with an overall yield of 40%.
Assuntos
Ácidos Graxos Insaturados , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/síntese química , Estrutura Molecular , Zinco/química , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/síntese químicaRESUMO
Marine organisms are an important source of natural products with unique and diverse chemical structures that may hold the key for the development of novel drugs. Docosahexaenoic acid (DHA) is an omega-3 fatty acid marine natural product playing a crucial regulatory role in the resolution of inflammation and acting as a precursor for the biosynthesis of the anti-inflammatory specialized pro-resolving mediators (SPMs) resolvins, protectins, and maresins. These metabolites exert many beneficial actions including neuroprotection, anti-hypertension, or anti-tumorigenesis. As dysregulation of SPMs is associated with diseases of prolonged inflammation, the disclosure of their bioactivities may be correlated with anti-inflammatory and pro-resolving capabilities, offering new targets for drug design. The availability of these SPMs from natural resources is very low, but the evaluation of their pharmacological properties requires their access in larger amounts, as achieved by synthetic routes. In this report, the first review of the total organic syntheses carried out for resolvins, protectins, and maresins is presented. Recently, it was proposed that DHA-derived pro-resolving mediators play a key role in the treatment of COVID-19. In this work we also review the current evidence on the structures, biosynthesis, and functional and new-found roles of these novel lipid mediators of disease resolution.
Assuntos
Anti-Inflamatórios/uso terapêutico , Ácidos Docosa-Hexaenoicos/metabolismo , Inflamação/prevenção & controle , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , COVID-19/virologia , Ácidos Docosa-Hexaenoicos/biossíntese , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/uso terapêutico , Desenho de Fármacos , Humanos , Inflamação/patologia , SARS-CoV-2/isolamento & purificação , Tratamento Farmacológico da COVID-19RESUMO
BACKGROUND: Persistent inflammation following vascular injury drives neointimal hyperplasia (NIH). Specialized lipid mediators (SPM) mediate resolution which attenuates inflammation and downstream NIH. We investigated the effects of a synthetic analogue of resolvin D1 (RvD1) on vascular cells and in a model of rat carotid angioplasty. METHODS: Human venous VSMC and endothelial cells (EC) were employed in migration, cell shape, toxicity, proliferation and p65 nuclear translocation assays. Murine RAW 264.7 cells were utilized to test the effect of pro-resolving compounds on phagocytic activity. A model of rat carotid angioplasty was used to evaluate the effects of 17R/S-benzo-RvD1 (benzo-RvD1) and 17R-RvD1 applied to the adventitia via 25% Pluronic gel. Immunostaining was utilized to examine Ki67 expression and leukocyte recruitment. Morphometric analysis was performed on arteries harvested 14 days after injury. RESULTS: Exposure to benzo-RvD1 attenuated PDGF- stimulated VSMC migration across a range of concentrations (0.1-100 nM), similar to that observed with 17R-RvD1. Pre-treatment with either Benzo-RvD1 or 17R-RvD1 (10, 100nM) attenuated PDGF-BB-induced VSMC cytoskeletal changes to nearly baseline dimensions. Benzo-RvD1 demonstrated modest anti-proliferative activity on VSMC and EC at various concentrations, without significant cytotoxicity. Benzo-RvD1 (10nM) inhibited p65 nuclear translocation in cytokine-stimulated EC by 21% (p<0.05), similar to 17R-RvD1. Consistent with pro-resolving activities of other SPM, both 17R-RvD1 and benzo-RvD1 increased the phagocytic activity of RAW 264.7 cells against S. Aureus and Zymosan particles. There were no significant differences in Ki-67 or CD45 staining observed on day 3 after angioplasty. Periadventitial treatment with benzo-RvD1 reduced carotid neointimal area at 14 days compared to control (0.08 mm2 v. 0.18 mm2; p<0.05), with similar efficacy to 17R-RvD1. CONCLUSIONS: 17R/S-benzo-RvD1 and 17R-RvD1 exhibit similar pro-resolving and anti-migratory activity in cell-based assays, and both compounds attenuated NIH following acute arterial injury in rats. Further studies of the mechanisms of resolution following vascular injury, and the translational potential of SPM analogues, are indicated.
Assuntos
Artérias Carótidas , Movimento Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos , Neointima , Lesões do Sistema Vascular , Animais , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperplasia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Neointima/metabolismo , Neointima/patologia , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Lesões do Sistema Vascular/tratamento farmacológico , Lesões do Sistema Vascular/metabolismo , Lesões do Sistema Vascular/patologiaRESUMO
Fatty acid esters of hydroxy fatty acids (FAHFAs) are a new class of endogenous lipids with interesting physiological functions in mammals. Despite their structural diversity and links with nuclear factor erythroid 2-related factor 2 (NRF2) biosynthesis, FAHFAs are less explored as NRF2 activators. Herein, we examined for the first time the synthetic docosahexaenoic acid esters of 12-hydroxy stearic acid (12-DHAHSA) or oleic acid (12-DHAHOA) against NRF2 activation in cultured human hepatoma-derived cells (C3A). The effect of DHA-derived FAHFAs on lipid metabolism was explored by the nontargeted lipidomic analysis using liquid chromatography-mass spectrometry. Furthermore, their action on lipid droplet (LD) oxidation was investigated by the fluorescence imaging technique. The DHA-derived FAHFAs showed less cytotoxicity compared to their native fatty acids and activated the NRF2 in a dose-dependent pattern. Treatment of 12-DHAHOA with C3A cells upregulated the cellular triacylglycerol levels by 17-fold compared to the untreated group. Fluorescence imaging analysis also revealed the suppression of the degree of LDs oxidation upon treatment with 12-DHAHSA. Overall, these results suggest that DHA-derived FAHFAs as novel and potent activators of NRF2 with plausible antioxidant function.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Ácidos Graxos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Oleico/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/farmacologia , Ésteres/síntese química , Ésteres/farmacologia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Triglicerídeos/metabolismo , Células Tumorais CultivadasRESUMO
In this work, a novel DHA-loaded nanoparticle with PLGA and chitosan (PCSDNP) was successfully prepared. The structure of PCSDNP and DHA-loaded PLGA nanoparticles was measured by transmission electron microscope, scanning electron microscope, and differential scanning calorimeter. The interaction strength between DHA, PLGA, and chitosan was evaluated through Fourier transform infrared spectroscopy. The curves of controlled DHA release and stabilities for different environmental factors of two NPs were evaluated. Importantly, two NPs were almost regularly spherical and the interactions were hydrogen bonds and electrostatic interactions between PLGA and chitosan. These NPs had a good encapsulation rate (80.45%) and high-water solubility than the free DHA molecule. In simulated gastrointestinal fluid, two NPs showed a controlled-release pattern. Overall, PCSDNP had better stability and controlled-release effect with the synergy between CS and PLGA under the conditions of pH (2- 7), ionic strength (0- 500 mM), storage time (0- 42 d), and temperature (30- 80 °C).
Assuntos
Quitosana/química , Ácidos Docosa-Hexaenoicos/síntese química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Preparações de Ação Retardada , Ácidos Docosa-Hexaenoicos/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Ligação de Hidrogênio , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Nanopartículas , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The resolution of inflammation is a biosynthetically active process controlled by the interplay between oxygenated polyunsaturated mediators and G-protein coupled receptor-signaling pathways. These enzymatically oxygenated polyunsaturated fatty acids belong to distinct families of specialized pro-resolving autacoids. The protectin family of mediators has attracted an interest because of their potent pro-resolving and anti-inflammatory actions verified in several in vivo disease models. Herein, we present the stereoselective synthesis and biological evaluations of 3-oxa-PD1n-3 DPA, a protectin D1 analog. Results from mouse models indicate that the mediators protectin D1, PD1n-3 DPA and the new analog 3-oxa-PD1n-3 DPA all relieved streptozotocin-induced diabetic neuropathic pain at doses of 90 and 300 pmol, equivalent to 30 and 100 ng, respectively, following intrathecal (I.T.) injection. Of interest, at a low dose of only 30 pmol (10 ng; I.T.) only 3-oxa PD1n-3 DPA was able to alleviate neuropathic pain, directly compared to vehicle controls. Moreover, using a chronic itch model of cutaneous T-cell lymphoma (CTCL), all three compounds at 300 pmol (100 ng) showed a significant reduction in itching for several hours. The biomolecular information on the structure-functions of the protectins and the new synthetic analog 3-oxa-PD1n-3 DPA is of interest towards developing new immunoresolvents.
Assuntos
Anti-Inflamatórios/farmacologia , Neuropatias Diabéticas/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Neuralgia/tratamento farmacológico , Prurido/tratamento farmacológico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Linhagem Celular Tumoral , Doença Crônica , Neuropatias Diabéticas/induzido quimicamente , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/química , Feminino , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos NOD , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neuralgia/induzido quimicamente , Prurido/induzido quimicamente , Estreptozocina/administração & dosagemRESUMO
In recent years, docosahexaenoic acid-containing phospholipids (DHA-PLs) have attracted much attention because of theirs unique health benefits. Compared with other forms of docosahexaenoic acid (DHA), DHA-PLs possess superior biological effects (e.g., anticancer, lipid metabolism regulation, visual development, and brain and nervous system biochemical reactions), more intricate metabolism mechanisms, and a stronger attraction to consumer. The production of DHA-PLs is hampered by several challenges associated with the limited content of DHA-PLs in natural sources, incomplete utilization of by-products, few microorganisms for DHA-PLs production, high cost, and complex process of artificial preparation of DHA-PLs. In this article, the sources, biological activities, and commercial applications of DHA-PLs were summarized, with intensive discussions on advantages of DHA-PLs over DHA, isomerism of DHA in phospholipids (PLs), and brain health. The excellent biological characteristics of DHA-PLs are primarily concerned with DHA and PLs. The metabolic fate of different DHA-PLs varies from the position of DHA in PLs to polar groups in DHA-PLs. Overall, well understanding of DHA-PLs about their sources and characteristics is critical to accelerate the production of DHA-PLs, economically enhance the value of DHA-PLs, and improve the applicability of DHA-PLs and the acceptance of consumers.
Assuntos
Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/farmacologia , Fosfolipídeos/farmacologia , Encéfalo/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/metabolismo , Humanos , Isomerismo , Fosfolipídeos/química , Fosfolipídeos/metabolismoRESUMO
Omega-3 polyunsaturated fatty acids (PUFAs) have been known to have beneficial effects in the prevention of various diseases. Recently, it was identified that the bioactivities of omega-3 are related to lipid mediators, called pro-resolving lipid mediators (SPMs), converted from PUFAs, so they have attracted much attention as potential pharmaceutical targets. Here, we aimed to build an efficient production system composed of enzymatic and chemical catalysis that converts docosahexaenoic acid (DHA) into lipid mediators. The cyanobacterial lipoxygenase, named Osc-LOX, was identified and characterized, and the binding poses of enzyme and substrates were predicted by ligand docking simulation. DHA was converted into three lipid mediators, a 17S-hydroxy-DHA, a 7S,17S-dihydroxy-DHA (RvD5), and a 7S,15R-dihydroxy-16S,17S-epoxy-DPA (new type), by an enzymatic reaction and deoxygenation. Also, two lipid mediators, 7S,15R,16S,17S-tetrahydroxy-DPA (new type) and 7S,16R,17S-trihydroxy-DHA (RvD2), were generated from 7S,15R-dihydroxy-16S,17S-epoxy-DPA by a chemical reaction. Our study suggests that discovering new enzymes that have not been functionally characterized would be a powerful strategy for producing various lipid mediators. Also, this combination catalysis approach including biological and chemical reactions could be an effective production system for the manufacturing lipid mediators.
Assuntos
Ácidos Docosa-Hexaenoicos/síntese química , Mediadores da Inflamação/síntese química , Inflamação/tratamento farmacológico , Lipídeos/síntese química , Catálise , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Ômega-3/síntese química , Ácidos Graxos Ômega-3/química , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/farmacologia , Humanos , Inflamação/patologia , Mediadores da Inflamação/química , Mediadores da Inflamação/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/química , Lipídeos/farmacologia , Lipoxigenase/químicaRESUMO
While survival rates have markedly improved following cardiac ischemia-reperfusion (IR) injury, the resulting heart damage remains an important issue. Preserving mitochondrial quality and limiting NLRP3 inflammasome activation is an approach to limit IR injury, in which the mitochondrial deacetylase sirtuin 3 (SIRT3) has a role. Recent data demonstrate cytochrome P450 (CYP450)-derived epoxy metabolites, epoxydocosapentaenoic acids (EDPs), of docosahexaenoic acid (DHA), attenuate cardiac IR injury. EDPs undergo rapid removal and inactivation by enzymatic and non-enzymatic processes. The current study hypothesizes that the cardioprotective effects of the synthetic EDP surrogates AS-27, SA-26 and AA-4 against IR injury involve activation of SIRT3. Isolated hearts from wild type (WT) mice were perfused in the Langendorff mode with vehicle, AS-27, SA-26 or AA-4. Improved postischemic functional recovery, maintained cardiac ATP levels, reduced oxidative stress and attenuation of NLRP3 activation were observed in hearts perfused with the analogue SA-26. Assessment of cardiac mitochondria demonstrated SA-26 preserved SIRT3 activity and reduced acetylation of manganese superoxide dismutase (MnSOD) suggesting enhanced antioxidant capacity. Together, these data demonstrate that the cardioprotective effects of the EDP analogue SA-26 against IR injury involve preservation of mitochondrial SIRT3 activity, which attenuates a detrimental innate NLRP3 inflammasome response.
Assuntos
Ácidos Docosa-Hexaenoicos , Traumatismo por Reperfusão Miocárdica , Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 3/metabolismo , Animais , Ácidos Docosa-Hexaenoicos/análogos & derivados , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/farmacologia , Feminino , Masculino , Camundongos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologiaRESUMO
Triple-negative breast cancer (TNBC) tends to recur and metastasize following initial chemotherapy, which presents a treatment challenge. Here, we detail the anti-metastatic activity of phloridzin docosahexaenoate (PZ-DHA), synthesized from the natural polyphenol, phloridzin, and the ω-3 fatty acid, docosahexaenoic acid. Sub-cytotoxic PZ-DHA suppressed the migration of MDA-MB-231, SUM149, and 4T1 cells, as well as invasion by MDA-MB-231 and 4T1 cells. Sub-cytotoxic PZ-DHA also inhibited MDA-MB-231 expression of matrix metalloproteinase 2, and expression of epithelial-to-mesenchymal transition-associated transcription factors by MDA-MB-231 and SUM149â¯cells. Transforming growth factor-ß-induced Rho GTPase signaling in MDA-MB-231â¯cells and non-malignant MCF-10A mammary epithelial cells was suppressed by sub-cytotoxic PZ-DHA, which also inhibited Akt/phosphoinositide 3-kinase and extracellular signal-regulated kinase 1 and 2 signaling in MDA-MB-231â¯cells. Finally, intraperitoneal administration of PZ-DHA suppressed the metastasis of 4T1 and GFP-transfected MDA-MB-231â¯cells from the mammary fat pad to the lungs of BALB/c and NOD-SCID female mice, respectively, which was unrelated to any inhibition of primary tumor growth. There was no evidence of toxicity as PZ-DHA treatment did not affect liver or kidney function. We conclude that PZ-DHA might prevent or inhibit the progression of TNBC.
Assuntos
Ácidos Docosa-Hexaenoicos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Florizina/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções Intraperitoneais , Neoplasias Pulmonares/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PD1n-3 DPA belongs to the protectin family of specialized pro-resolving lipid mediators. The protectins are endogenously formed mediators that display potent anti-inflammatory properties and pro-resolving bioactivities and have attracted interest in drug discovery. However, few studies have been reported of the secondary metabolism of the protectins. To investigate the metabolic formation of the putative C22 mono-hydroxylated product, coined 22-OH-PD1n-3 DPA, a stereoselective synthesis was performed. LC/MS-MS data of synthetic 22-OH-PD1n-3 DPA matched the data for the biosynthetic formed product. Cellular studies revealed that 22-OH-PD1n-3 DPA is formed from n-3 docosapentaenoic acid in human serum, and we confirmed that 22-OH-PD1n-3 DPA is a secondary metabolite produced by ω-oxidation of PD1n-3 DPA in human neutrophils and in human monocytes. The results reported are of interest for enabling future structure-activity relationship studies and provide useful molecular insight of the metabolism of the protectin class of specialized pro-resolving mediators.
Assuntos
Ácidos Docosa-Hexaenoicos/química , Vias Biossintéticas , Técnicas de Química Sintética , Cromatografia Líquida , Ácidos Docosa-Hexaenoicos/biossíntese , Ácidos Docosa-Hexaenoicos/síntese química , Humanos , Conformação Molecular , Estrutura Molecular , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Relação Estrutura-Atividade , Espectrometria de Massas em TandemRESUMO
Our goal in this study is to improve the efficiency of docosahexaenoic acid (DHA) toward the enhancement of insulin signaling pathway in vivo via loading with zinc oxide nanoparticles (ZnO NPs). To this end, two consecutive steps were undertaken, preparation of ZnO NPs by one-step solid-state reaction in dry conditions and calcinated followed by loading DHA. Both developed nanoparticles, with and without DHA were then characterized by TEM, SEM, EDX, and Zetasizer. For comparison between free and loaded DHA, four groups of rats were prepared to receive different treatments. Group I; healthy rats (reference), group II; diabetes (streptozotocin-induced), group III and group IV are diabetes orally administered with free DHA and DHA-loaded ZnO NPs (10â¯mg/kgâ¯bw/day), respectively. Blood samples were collected and analyzed where the results demonstrated that fasting blood sugar and insulin resistance were significantly increased in diabetic group along with upgrading in oxidative stress parameters emphasizing the oxidative properties of streptozotocin. HPLC analysis of cell membrane fatty acids resulted in the reduction of omega-6 and 9 and elevation of omega-3 after free DHA and DHA-loaded ZnO NPs streptozotocin treatments. DHA-loaded ZnO NPs had high performance in enhancing insulin signaling pathway as expressed in changes of phosphatidylinositol 3-kinase (PI3K) levels.
Assuntos
Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Nanopartículas/química , Óxido de Zinco/síntese química , Óxido de Zinco/farmacologia , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Dano ao DNA , Insulina/sangue , Resistência à Insulina , Masculino , Lipídeos de Membrana/metabolismo , Nanopartículas/ultraestrutura , Tamanho da Partícula , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Difração de Raios XRESUMO
In this study, two capsaicin analogues, N-eicosapentaenoyl vanillylamine (EPVA) and N-docosahexaenoyl vanillylamine (DHVA), were enzymatically synthesized from their corresponding n-3 long chain polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both dietary relevant components. The compounds significantly reduced the production of some lipopolysaccharide (LPS)-induced inflammatory mediators, including nitric oxide (NO), macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1 or CCL2), by RAW264.7 macrophages. Next to this, only EPVA increased insulin secretion by pancreatic INS-1 832/13 ß-cells, while raising intracellular Ca2+ and ATP concentrations. This suggests that the stimulation of insulin release occurs through an increase in the intracellular ATP/ADP ratio in the first phase, while is calcium-mediated in the second phase. Although it is not yet known whether EPVA is endogenously produced, its potential therapeutic value for diabetes treatment merits further investigation.
Assuntos
Capsaicina/análogos & derivados , Capsaicina/farmacologia , Ácidos Docosa-Hexaenoicos/análogos & derivados , Ácido Eicosapentaenoico/análogos & derivados , Ácidos Graxos Ômega-3/química , Inflamação/metabolismo , Insulina/metabolismo , Macrófagos/efeitos dos fármacos , Animais , Benzilaminas , Cálcio/metabolismo , Capsaicina/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/síntese química , Ácido Eicosapentaenoico/química , Ácido Eicosapentaenoico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Células RAW 264.7 , RatosRESUMO
The first total synthesis of a lipid mediator derived from natural ω-3-fatty acid docosahexaenoic acid (DHA), 10 S,17 S-diHDHA (also referred to as protectin DX/PDX), was achieved in a convergent route (29 steps). The two chiral hydroxyl groups at C-10 and C-17 were derived from readily available ( S)-1,2,4-butanetriol and ( R)-glycidol, respectively. The two stereodefined E-double bonds were generated by a Takai olefination, and the skipped diene side chain was introduced with a stereocontrolled Wittig olefination. Importantly, the sensitive conjugated E, Z, E-triene intermediate was generated by a Boland reduction of the central triple bond of a E, E-dienyne. Overall, this synthetic strategy should allow the preparation of a larger quantity of PDX, which is inaccessible via previously reported biosynthetic approaches.
Assuntos
Ácidos Docosa-Hexaenoicos/síntese química , Hipoglicemiantes/síntese química , Lipídeos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/uso terapêutico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Estrutura MolecularRESUMO
Stereoselective synthesis of Z-configured double bonds is central in organic synthesis due to the presence of such motifs in polyunsaturated fatty acids and many natural products. Traditionally, reductions of internal alkynes or Wittig, Ando or Still-Gennari reactions, are often used for preparing such compounds. The substrate scope is limited for both the Ando and the Still-Gennari reactions, while the Wittig reaction often gives low Z-selectivity for the synthesis of polyunsaturated Z-configured methylene interrupted (skipped) double bonds. Reductions of internal alkynes are challenging due to diminished Z-selectivity, poor catalyst reproducibility and over-reductions. An alternative and highly attractive approach is to employ naturally occurring and commercially available polyunsaturated fatty acids as starting materials. The main advantage of this strategy is the conservation of the multiple Z-configured double bonds present in the starting material, allowing a precise incorporation of the desired double bonds into the final product. In particular, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid have been used for the stereoselective synthesis of polyunsaturated fatty acids, their derivatives and other polyunsaturated natural products. Herein, such efforts are reviewed.
Assuntos
Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Ácidos Graxos Insaturados/síntese química , Alcinos/síntese química , Alcinos/química , Ácido Araquidônico/síntese química , Ácido Araquidônico/química , Produtos Biológicos/química , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/química , Ácido Eicosapentaenoico/síntese química , Ácido Eicosapentaenoico/química , Ácidos Graxos Insaturados/química , EstereoisomerismoRESUMO
Protectin D1 is a specialized pro-resolving mediator with potent pro-resolving and anti-inflammatory effects in vivo in several human disease models. Herein the preparation of the first synthetic analog of protectin D1, named 22-F-PD1, is presented together with data from in vivo investigations. This analog showed potent pro-resolving and anti-inflammatory properties. These results inspired the preparation of the radiotracer 22-[18F]F-PD1-ME that was used in a positron emission tomography proof of concept study. Altogether, the findings presented contribute to new knowledge on the biomolecular properties of protectin D1 analogs. In addition, an improved formal synthesis of the metabolite 22-OH-PD1 is reported.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/farmacologia , Animais , Anti-Inflamatórios/química , Encéfalo/diagnóstico por imagem , Técnicas de Química Sintética , Ácidos Docosa-Hexaenoicos/química , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Tomografia por Emissão de Pósitrons , Traçadores RadioativosRESUMO
ß-Oxidation of most fatty acids occurs in the mitochondria. However, ß-oxidation for ω-3 polyunsaturated fatty acids (PUFAs) is distinct from abundant fatty acids and occurs in the peroxisomes. Since little is known about peroxisomal ß-oxidation, here we report the synthesis of proposed intermediates of ω-3 PUFA ß-oxidation steps in free fatty acid form having a conjugated double bond, a ß-hydroxyl group, a ß-olefin and a ß-carbonyl group. These fatty acids can serve as authentic samples for biological experiments.
Assuntos
Ácidos Docosa-Hexaenoicos/química , Ácido Eicosapentaenoico/química , Ácidos Graxos Insaturados/química , Ácidos Docosa-Hexaenoicos/síntese química , Ligantes , Oxirredução , EstereoisomerismoRESUMO
Docosahexaenoic acid (DHA) is a semiessential polyunsaturated fatty acid (PUFA) for eukaryotic cells that is found in natural sources such as fish and algal oils and widely used as an ingredient for omega-3 containing foods or supplements. DHA effects are connected to its natural structure with six cis double bonds, but geometrical monotrans isomers can be formed during distillation or deodorization processes, as an unwanted event that alters molecular characteristics and annihilates health benefits. The characterization of the six monotrans DHA regioisomers is an open issue to address for analytical, biological, and nutraceutical applications. Here we report the preparation, separation, and first identification of each isomer by a dual approach consisting of the following: (i) the direct thiyl radical-catalyzed isomerization of cis-DHA methyl ester and (ii) the two-step synthesis from cis-DHA methyl ester via monoepoxides as intermediates, which are separated and identified by nuclear magnetic resonance spectroscopy, followed by elimination for the unequivocal assignment of the double bond position. This monotrans DHA isomer library with NMR and GC analytical characterization was also used to examine the products of thiyl-radical-catalyzed isomerization of a fish oil sample and to evaluate the trans isomer content in omega-3 containing supplements commercially available in Italy and Spain.