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1.
Adv Exp Med Biol ; 1274: 223-258, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894513

RESUMO

G protein-coupled receptors (GPCRs) have seven transmembrane spanning domains and comprise the largest superfamily with ~800 receptors in humans. GPCRs are attractive targets for drug discovery because they transduce intracellular signaling in response to endogenous ligands via heterotrimeric G proteins or arrestins, resulting in a wide variety of physiological and pathophysiological responses. The endogenous ligands for GPCRs are highly chemically diverse and include ions, biogenic amines, nucleotides, peptides, and lipids. In this review, we follow the KonMari method to better understand druggable lipid GPCRs. First, we have a comprehensive tidying up of lipid GPCRs including receptors for prostanoids, leukotrienes, specialized pro-resolving mediators (SPMs), lysophospholipids, sphingosine 1-phosphate (S1P), cannabinoids, platelet-activating factor (PAF), free fatty acids (FFAs), and sterols. This tidying up consolidates 46 lipid GPCRs and declutters several perplexing lipid GPCRs. Then, we further tidy up the lipid GPCR-directed drugs from the literature and databases, which identified 24 clinical drugs targeting 16 unique lipid GPCRs available in the market and 44 drugs under evaluation in more than 100 clinical trials as of 2019. Finally, we introduce drug designs for GPCRs that spark joy, such as positive or negative allosteric modulators (PAM or NAM), biased agonism, functional antagonism like fingolimod, and monoclonal antibodies (MAbs). These strategic drug designs may increase the efficacy and specificity of drugs and reduce side effects. Technological advances will help to discover more endogenous lipid ligands from the vast number of remaining orphan GPCRs and will also lead to the development novel lipid GPCR drugs to treat various diseases.


Assuntos
Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Arrestinas/metabolismo , Doença , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Humanos , Ligantes , Lipídeos/farmacologia , Lipídeos/uso terapêutico , Receptores Acoplados a Proteínas-G/metabolismo
2.
PLoS One ; 15(7): e0233252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32701962

RESUMO

Phthiocerol dimycocerosates (PDIMs) are a class of mycobacterial lipids that promote virulence in Mycobacterium tuberculosis and Mycobacterium marinum. It has recently been shown that PDIMs work in concert with the M. tuberculosis Type VII secretion system ESX-1 to permeabilize the phagosomal membranes of infected macrophages. As the zebrafish-M. marinum model of infection has revealed the critical role of PDIM at the host-pathogen interface, we set to determine if PDIMs contributed to phagosomal permeabilization in M. marinum. Using an ΔmmpL7 mutant defective in PDIM transport, we find the PDIM-ESX-1 interaction to be conserved in an M. marinum macrophage infection model. However, we find PDIM and ESX-1 mutants differ in their degree of defect, with the PDIM mutant retaining more membrane damaging activity. Using an in vitro hemolysis assay-a common surrogate for cytolytic activity, we find that PDIM and ESX-1 differ in their contributions: the ESX-1 mutant loses hemolytic activity while PDIM retains it. Our observations confirm the involvement of PDIMs in phagosomal permeabilization in M. marinum infection and suggest that PDIM enhances the membrane disrupting activity of pathogenic mycobacteria and indicates that the role they play in damaging phagosomal and red blood cell membranes may differ.


Assuntos
Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Lipídeos/farmacologia , Macrófagos/citologia , Mycobacterium marinum/metabolismo , Fagossomos/efeitos dos fármacos , Linhagem Celular , Humanos , Macrófagos/efeitos dos fármacos , Mycobacterium marinum/fisiologia , Permeabilidade/efeitos dos fármacos , Fagossomos/metabolismo
3.
Food Chem ; 332: 127384, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32615384

RESUMO

Dairy polar lipids (PL) seem to exhibit antiplatelet effects. However, it is not known what molecular species may be responsible. In this study, we confirmed using C30 reversed-phase (C30RP) ultra-high-performance liquid chromatography (UHPLC) coupled to high resolution accurate mass tandem mass spectrometry (HRAM-MS/MS) that fermentation of yoghurts from ovine milk using specific starter cultures altered the PL composition. These lipid alterations occurred concomitant with increased antithrombotic properties of the yoghurts PL fractions against platelet-activating factor (PAF) and thrombin-induced platelet aggregation. Specifically, elevation in phosphatidylethanolamine (PE), sphingomyelin (SM), phosphatidylcholine (PC) and their molecular species were observed following yoghurt fermentation. Furthermore, PC(18:0/18:1), PE(18:1/18:2), SM(d18:0/22:0) and several other molecular species were significantly inversely correlated with the inhibition of PAF and thrombin. These molecular species were abundant in the most bioactive yoghurts fermented by S. thermophilus and L. acidophilus, which suggest that fermentation by these microorganisms increases the antithrombotic properties of ovine milk PL.


Assuntos
Lipídeos/análise , Leite/metabolismo , Inibidores da Agregação de Plaquetas/análise , Iogurte/análise , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Cromatografia Líquida de Alta Pressão , Fermentação , Lipídeos/farmacologia , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Ovinos , Esfingomielinas/metabolismo , Espectrometria de Massas em Tandem , Trombina/farmacologia
4.
J Food Sci ; 85(4): 1223-1230, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32147836

RESUMO

The present study aims to study the antibacterial activity of food-grade lipidic nanoemulsion (noncationized/cationized) against Bacillus subtilis (BS). Bactericidal activity was ascertained by studying the morphological transitions on BS using transmission electron microscopy (TEM), atomic force microscopy (AFM), and scanning electron microscopy (SEM). Morphological changes were witnessed by cell wall breakage, oozing out of cellular contents, loss of cell turgidity and contour. Furthermore, aggregation of cationic nanoemulsion (CaNM) was preferentially observed at apical side of BS construing comparatively more electrostatic attraction between electronegative apical side and CaNM. Resistance response of BS exhibited by apical cell-wall thickening was not able to protect the bacteria due to leakage of cellular content. AFM corroborated its importance in bacteriology, wherein the fragmented cell wall can be "piece-by-piece" identified and sutured back to its appropriate vacant places, thereby, completing the cell wall contour of the ghost cell. Such postmortem analysis of bacterial cell using AFM studies can throw light toward mechanism of cell fragmentation of bacterial cells. SEM study also demonstrated the deformed, fragmented, and amorphous nature of BS construing the bactericidal effect of prepared nanoemulsion.


Assuntos
Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Lipídeos/farmacologia , Bacillus subtilis/crescimento & desenvolvimento , Bacillus subtilis/ultraestrutura , Parede Celular/efeitos dos fármacos , Parede Celular/ultraestrutura , Emulsões/química , Emulsões/farmacologia , Lipídeos/química , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão
5.
J Nanobiotechnology ; 18(1): 43, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164731

RESUMO

BACKGROUND: Metastasis causes the most breast cancer-related deaths in women. Here, we investigated the antitumor effect of solid lipid nanoparticles (SLN-DTX) when used in the treatment of metastatic breast tumors using 4T1-bearing BALB/c mice. RESULTS: Solid lipid nanoparticles (SLNs) were produced using the high-energy method. Compritol 888 ATO was selected as the lipid matrix, and Pluronic F127 and Span 80 as the surfactants to stabilize nanoparticle dispersion. The particles had high stability for at least 120 days. The SLNs' dispersion size was 128 nm, their polydispersity index (PDI) was 0.2, and they showed a negative zeta potential. SLNs had high docetaxel (DTX) entrapment efficiency (86%), 2% of drug loading and showed a controlled drug-release profile. The half-maximal inhibitory concentration (IC50) of SLN-DTX against 4T1 cells was more than 100 times lower than that of free DTX after 24 h treatment. In the cellular uptake test, SLN-DTX was taken into the cells significantly more than free DTX. The accumulation in the G2-M phase was significantly higher in cells treated with SLN-DTX (73.7%) than in cells treated with free DTX (23.0%), which induced subsequent apoptosis. TEM analysis revealed that SLN-DTX internalization is mediated by endocytosis, and fluorescence microscopy showed DTX induced microtubule damage. In vivo studies showed that SLN-DTX compared to free docetaxel exhibited higher antitumor efficacy by reducing tumor volume (p < 0.0001) and also prevented spontaneous lung metastasis in 4T1 tumor-bearing mice. Histological studies of lungs confirmed that treatment with SLN-DTX was able to prevent tumor. IL-6 serum levels, ki-67 and BCL-2 expression were analyzed and showed a remarkably strong reduction when used in a combined treatment. CONCLUSIONS: These results indicate that DTX-loaded SLNs may be a promising carrier to treat breast cancer and in metastasis prevention.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Docetaxel/farmacologia , Lipídeos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Portadores de Fármacos/farmacologia , Ácidos Graxos/farmacologia , Feminino , Hexoses/farmacologia , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Tamanho da Partícula , Poloxâmero/farmacologia
6.
J Agric Food Chem ; 68(7): 1948-1957, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32009394

RESUMO

As one of six dietary nutrients, lipid derived from different food matrices has been extensively studied and has an appropriate application in food, medicine, and cosmetic industry. Egg is a richly nutritive food, of which proteins and lipids possess excellent functional characteristics and biological activities. In recent years, egg yolk lipid has been successively separated and investigated, such as egg yolk oil, phospholipids, and fatty acids, which have anti-inflammatory activity, antioxidant activity, cardiovascular protection, and memory improvement, involving the regulation of cell function and physiological homeostatic balance. In this paper, the biological activities and underlying benefit of egg yolk lipids and fat-soluble components have been highlighted and summarized. Meanwhile, the quantitative data of egg yolk lipids needed to achieve any of the described biological effects and recommended concentrations relevant for dietary intake are reviewed. Finally, current challenges and crucial issues of high-efficiency utilization of egg yolk lipids are also discussed.


Assuntos
Gema de Ovo/química , Lipídeos/farmacologia , Animais , Galinhas , Humanos , Lipídeos/química
7.
Mater Sci Eng C Mater Biol Appl ; 108: 110462, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923986

RESUMO

Breast cancer is a serious public health problem that causes thousands of deaths annually. Chemotherapy continues to play a central role in the management of breast cancer but is associated with extreme off-target toxicity. Therefore, treatments that directly target the tumor and display reduced susceptibility to resistance could improve the outcome and quality of life for patients suffering from this disease. Photodynamic therapy is a targeted treatment based on the use of light to activate a photosensitizer (PS) that then interacts with molecular oxygen and other biochemical substrates to generate cytotoxic levels of Reactive Oxygen Species. Currently approved PS also tends to have poor aqueous solubility that can cause problems when delivered intravenously. In order to circumvent this limitation, in this manuscript, we evaluate the potential of a phthalocyanine-loaded nanostructured lipid carrier (NLC) functionalized with folic acid (FA). To prepare the FA labelled NLC, the polymer PF127 was first esterified with FA and emulsified with an oil phase containing polyoxyethylene 40 stearate, capric/caprylic acid triglycerides, ethoxylated hydrogenated castor oil 40 and the PS zinc phthalocyanine. The resulting PS loaded FA-NLC had a hydrodynamic diameter of 180 nm and were stable in suspension for >90 days. Interestingly, the amount of singlet oxygen generated upon light activation for the PS loaded FA-NLC was substantially higher than the free PS, yet at a lower PS concentration. The PS was released from the NLC in a sustained manner with 4.13 ±â€¯0.58% and 27.7 ±â€¯3.16% after 30 min and 7 days, respectively. Finally, cytotoxicity assays showed that NLC in the concentrations of 09.1 µM of PS present non-toxic with >80 ±â€¯6.8% viable and after 90 s of the light-exposed the results show a statistically significant decrease in cell viability (57 ±â€¯4%). The results obtained allow us to conclude that the functionalized NLC incorporated with PS associated with the PDT technique have characteristics that make them potential candidates for the alternative treatment of breast cancer.


Assuntos
Portadores de Fármacos , Ácido Fólico , Indóis , Lipídeos , Nanoestruturas , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Ácido Fólico/química , Ácido Fólico/farmacocinética , Ácido Fólico/farmacologia , Humanos , Indóis/química , Indóis/farmacocinética , Indóis/farmacologia , Lipídeos/química , Lipídeos/farmacocinética , Lipídeos/farmacologia , Células MCF-7 , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia , Poloxâmero/química , Poloxâmero/farmacocinética , Poloxâmero/farmacologia
8.
Chem Commun (Camb) ; 56(11): 1661-1664, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31939463

RESUMO

We describe a novel class of stimuli-sensitive sulfonium-based synthetic lipids, which exhibit several favorable biophysical properties of phospholipids. The potent sulfonium-based lipid was successfully disassembled by glutathione to release the encapsulated drug molecules in a controlled manner. The cationic lipid also showed lower cytotoxicity against mammalian cells and displayed moderate antibacterial activities.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos/farmacologia , Compostos de Sulfônio/farmacologia , Antibacterianos/síntese química , Antibacterianos/toxicidade , Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacologia , Derivados de Benzeno/toxicidade , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Escherichia coli/efeitos dos fármacos , Humanos , Lipídeos/síntese química , Lipídeos/farmacologia , Lipídeos/toxicidade , Staphylococcus aureus/efeitos dos fármacos , Compostos de Sulfônio/síntese química , Compostos de Sulfônio/toxicidade
9.
J Microencapsul ; 37(2): 160-169, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31916886

RESUMO

The aim of this study was to develop levosulpiride-loaded solid lipid nanoparticles (SLNs) with enhanced solubilisation and bioavailability. The levosulpiride loaded-SLNs were composed of levosulpiride, stearic acid, and tween 80 in their respective weight ratios of (1, 5, and 1.5 mg) dissolved in 1 ml distilled water. Physicochemical properties of the SLNs such as particle size, shape, crystallinity, and chemical interaction were evaluated. Further, the in vitro drug dissolution, pharmacokinetic and stability studies of the SLNs were performed. The SLNs were rounded shaped stable nanoparticles with average diameter of 200 nm. They demonstrate 1.5- and 3-fold better drug dissolution when compared with the commercial product and levosulpiride powder, respectively. The SLNs enhanced the bioavailability of levosulpiride 3 times and 7 times, respectively, when compared with the commercial product and levosulpiride powder. It can be concluded that SLNs are capable to improve the dissolution and bioavailability of levosulpiride, even more than the commercial product.


Assuntos
Portadores de Fármacos , Lipídeos , Nanopartículas/química , Sulpirida/análogos & derivados , Animais , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Lipídeos/química , Lipídeos/farmacocinética , Lipídeos/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Sulpirida/química , Sulpirida/farmacocinética , Sulpirida/farmacologia
10.
Nanoscale ; 12(3): 1875-1885, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31903467

RESUMO

Tumor associated macrophages (TAMs) play an important role in initiating the immunosuppressive environment that negatively impacts the immunotherapy efficacy and has long been linked with cancer progression. On the other hand, activated macrophages display immense phagocytic potential and can be used as an effector cell for cancer therapy. But, activating TAMs to effectively phagocytose cancer cells is challenging. Cancer cells upregulate CD47, a "don't eat me" receptor that ligates with SIRPα present on macrophages to downregulate the phagocytosis. Since phagocytosis is a physical phenomenon based on engulfment of aberrant cells, we hypothesized that the phagocytic function of macrophages can be enhanced by blocking both CD47 and SIRPα in tandem and at the same time, engaging both macrophages and cancer cells can favor increased macrophage-cancer cellular interactions. Here, we demonstrate that a simple approach of anti-CD47 and anti-SIRPα antibodies conjugated lipid-based phagocytosis nanoenhancer (LPN) can perform both of these functions. The LPNs were stable in both physiological and biologically relevant conditions, bound to both macrophages and cancer cells and significantly enhanced phagocytosis of cancer cells as compared to combination of free antibodies. LPN treatment showed significant tumor growth inhibition and increased survival in B16F10 melanoma tumor bearing mice with no systemic toxicity. Mechanistic analysis of efficacy revealed an increase in intra-tumoral infiltration of effector T cells and NK cells. Cytokine analysis revealed increased secretion of intracellular iNOS, a hallmark of activated macrophages. This study shows that LPN can simultaneously block both CD47 and SIRPα and can effectively engage macrophage and cancer cell in close proximity. Combining these facets provide a simple approach to enhance phagocytosis and improve anti-cancer macrophage immunotherapy.


Assuntos
Anticorpos Antineoplásicos , Imunoterapia , Lipídeos , Macrófagos , Melanoma Experimental , Nanopartículas , Fagocitose , Animais , Anticorpos Antineoplásicos/química , Anticorpos Antineoplásicos/farmacologia , Humanos , Lipídeos/química , Lipídeos/farmacologia , Macrófagos/imunologia , Macrófagos/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico
11.
Eur J Med Chem ; 186: 111854, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31753515

RESUMO

Small Conductance Calcium (Ca2+)-activated potassium (K+) channels (SKCa) are now proved to be involved in many cancer cell behaviors such as proliferation or migration. The SK3 channel isoform was particularly described in breast cancer where it can be associated with the Orai1 Ca2+ channel to form a complex that regulates the Ca2+ homeostasis during tumor development and acts as a potent mediator of bone metastases development in vivo. Until now, very few specific blockers of Orai1 and/or SK3 have been developed as potential anti-metastatic compounds. In this study, we illustrated the synthesis of new families of lipophilic pyridine and tetrahydropyridine derivatives designed as potential modulators of SK3 channel. The toxicity of the newly synthesized compounds and their migration effects were evaluated on the breast cancer cell line MDA-MB-435s. Two molecules (7a and 10c) demonstrated a significant decrease in the SK3 channel-dependent migration as well as the SK3/Orai1-related Ca2+ entry. Current measurements showed that these compounds are more likely SK3-selective. Taken all together these results suggest that such molecules could be considered as promising anti-metastatic drugs in breast cancer.


Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Lipídeos/farmacologia , Pirrolidinas/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Alcaloides/síntese química , Alcaloides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Lipídeos/química , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Relação Estrutura-Atividade
12.
Am J Physiol Gastrointest Liver Physiol ; 318(2): G254-G264, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31709828

RESUMO

The small intestine regulates barrier function to absorb nutrients while avoiding the entry of potentially harmful substances or bacteria. Barrier function is dynamically regulated in part by the enteric nervous system (ENS). The role of the ENS in regulating barrier function in response to luminal nutrients is not well understood. We hypothesize that the ENS regulates intestinal permeability and ion flux in the small intestine in response to luminal nutrients. Segments of jejunum and ileum from mice were mounted in Ussing chambers. Transepithelial electrical resistance (TER), short-circuit current (Isc), and permeability to 4-kDa FITC-dextran (FD4) were recorded after mucosal stimulation with either glucose, fructose, glutamine (10 mM), or 5% Intralipid. Mucosal lipopolysaccharide (1 mg/mL) was also studied. Enteric neurons were inhibited with tetrodotoxin (TTX; 0.5 µM) or activated with veratridine (10 µM). Enteric glia were inhibited with the connexin-43 blocker Gap26 (20 µM). Glucose, glutamine, Intralipid, and veratridine acutely modified Isc in the jejunum and ileum, but the effect of nutrients on Isc was insensitive to TTX. TTX, Gap26, and veratridine treatment did not affect baseline TER or permeability. Intralipid acutely decreased permeability to FD4, while LPS increased it. TTX pretreatment abolished the effect of Intralipid and exacerbated the LPS-induced increase in permeability. Luminal nutrients and enteric nerve activity both affect ion flux in the mouse small intestine acutely but independently of each other. Neither neuronal nor glial activity is required for the maintenance of baseline intestinal permeability; however, neuronal activity is essential for the acute regulation of intestinal permeability in response to luminal lipids and lipopolysaccharide.NEW & NOTEWORTHY Luminal nutrients and enteric nerve activity both affect ion transport in the mouse small intestine acutely, but independently of each other. Activation or inhibition of the enteric neurons does not affect intestinal permeability, but enteric neural activity is essential for the acute regulation of intestinal permeability in response to luminal lipids and lipopolysaccharide. The enteric nervous system regulates epithelial homeostasis in the small intestine in a time-dependent, region- and stimulus-specific manner.


Assuntos
Sistema Nervoso Entérico/fisiologia , Absorção Intestinal/fisiologia , Intestino Delgado/metabolismo , Transporte de Íons/fisiologia , Nutrientes , Animais , Impedância Elétrica , Sistema Nervoso Entérico/metabolismo , Íleo/metabolismo , Técnicas In Vitro , Absorção Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Transporte de Íons/efeitos dos fármacos , Jejuno/metabolismo , Lipídeos/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Neurônios/metabolismo , Neurônios/fisiologia
13.
Gut ; 69(3): 487-501, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31189655

RESUMO

OBJECTIVE: To investigate whether milk polar lipids (PL) impact human intestinal lipid absorption, metabolism, microbiota and associated markers of cardiometabolic health. DESIGN: A double-blind, randomised controlled 4-week study involving 58 postmenopausal women was used to assess the chronic effects of milk PL consumption (0, 3 or 5 g-PL/day) on lipid metabolism and gut microbiota. The acute effects of milk PL on intestinal absorption and metabolism of cholesterol were assessed in a randomised controlled crossover study using tracers in ileostomy patients. RESULTS: Over 4 weeks, milk PL significantly reduced fasting and postprandial plasma concentrations of cholesterol and surrogate lipid markers of cardiovascular disease risk, including total/high-density lipoprotein-cholesterol and apolipoprotein (Apo)B/ApoA1 ratios. The highest PL dose preferentially induced a decreased number of intestine-derived chylomicron particles. Also, milk PL increased faecal loss of coprostanol, a gut-derived metabolite of cholesterol, but major bacterial populations and faecal short-chain fatty acids were not affected by milk PL, regardless of the dose. Acute ingestion of milk PL by ileostomy patients shows that milk PL decreased cholesterol absorption and increased cholesterol-ileal efflux, which can be explained by the observed co-excretion with milk sphingomyelin in the gut. CONCLUSION: The present data demonstrate for the first time in humans that milk PL can improve the cardiometabolic health by decreasing several lipid cardiovascular markers, notably through a reduced intestinal cholesterol absorption involving specific interactions in the gut, without disturbing the major bacterial phyla of gut microbiota. TRIAL REGISTRATION NUMBER: NCT02099032 and NCT02146339; Results.


Assuntos
Doenças Cardiovasculares/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/farmacologia , Sobrepeso/metabolismo , Esfingomielinas/metabolismo , Animais , Apolipoproteína A-I/sangue , Apolipoproteína B-100/sangue , Colestanol/metabolismo , Colesterol/metabolismo , HDL-Colesterol/sangue , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Emulsificantes/farmacologia , Fezes/química , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Ileostomia , Absorção Intestinal/efeitos dos fármacos , Lipídeos/administração & dosagem , Lipídeos/análise , Pessoa de Meia-Idade , Leite/química , Pós-Menopausa , Fatores de Risco
14.
J Dairy Sci ; 103(1): 72-86, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31677836

RESUMO

The aim of this study was to characterize minor lipids in methanol fraction extracted from raw camel milk after loading it on a water-preconditioned short C18 open column and fractionating with a gradient of methanol/water. The C18 column showed high fractionation efficiency of minor lipids, such as glycosphingolipids, lipopolysaccharides, or oligosaccharides, when compared with other constituents, in particular polysaccharides, proteins, and free fatty acids. Liquid chromatography electrospray ionization tandem mass spectrometry in negative ion mode was used to identify 21 new glycosphingolipids, lipopolysaccharides, and oligosaccharides. Electrospray ionization tandem mass spectrometry was qualified to provide relevant data for recognizing the molecular mass, glycosylation sequences, and structure of saccharide moieties for the revealed compounds. The sequence of combinations of one selected lipopolysaccharide, which was considered the backbone of the remaining lipopolysaccharides, was confirmed in a density functional theory study. The obtained results showed that the tested fraction is a rich source of glycosphingolipids, lipopolysaccharides, and oligosaccharides with antioxidant activity.


Assuntos
Camelus , Lipídeos/farmacologia , Leite/química , Oligossacarídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray/veterinária , Animais , Humanos , Lipídeos/química , Oligossacarídeos/química , Plasma , Espectrometria de Massas por Ionização por Electrospray/métodos
15.
Molecules ; 24(23)2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31795131

RESUMO

The procedures for the extraction and separation of lipids and nutraceutics from microalgae using classic solvents have been frequently used over the years. However, these production methods usually require expensive and toxic solvents. Based on our studies involving the use of eco-sustainable methodologies and alternative solvents, we selected ethanol (EtOH) and cyclopentyl methyl ether (CPME) for extracting bio-oil and lipids from algae. Different percentages of EtOH in CPME favor the production of an oil rich in saturated fatty acids (SFA), useful to biofuel production or rich in bioactive compounds. The proposed method for obtaining an extract rich in saturated or unsaturated fatty acids from dry algal biomass is disclosed as eco-friendly and allows a good extraction yield. The method is compared both in extracted oil percentage yield and in extracted fatty acids selectivity to extraction by supercritical carbon dioxide (SC-CO2).


Assuntos
Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Lipídeos/isolamento & purificação , Lipídeos/farmacologia , Microalgas/química , Produtos Biológicos/química , Fracionamento Químico , Cromatografia Gasosa-Espectrometria de Massas , Lipídeos/química
16.
Int J Med Sci ; 16(12): 1621-1630, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839750

RESUMO

The goal of this study was to examine the effect of lipid emulsion on the vasodilation induced in isolated endothelium-denuded rat aortae by a toxic dose of amlodipine. We examined the effects of lipid emulsion and verapamil on amlodipine-induced vasodilation. We also examined the effects of a mixture of lipid emulsion and amlodipine, as well as the centrifuged aqueous extract (CAE) obtained by ultracentrifuging such a mixture and then removing the upper lipid layer, on amlodipine-induced vasodilation. The effect of lipid emulsion on the amlodipine concentration was examined. Lipid emulsion attenuated amlodipine-induced vasodilation in isolated aortae. Both CAE and lipid emulsion containing amlodipine inhibited amlodipine-induced vasodilation. However, there was no significant difference in amlodipine-induced vasodilation between aortae treated with CAE and those treated with lipid emulsion containing amlodipine. Verapamil inhibited amlodipine-induced vasodilation. Lipid emulsion decreased the concentration of amlodipine. Lipid emulsion attenuated the vasodilation induced by a toxic amlodipine dose in NaF-precontracted aortae. The data show that lipid emulsion inhibited the vasodilation induced by a toxic amlodipine dose in isolated rat aortae by reducing the concentration of amlodipine. Amlodipine-induced vasodilation seems to be mediated mainly by blockade of L-type calcium channels and partially by inhibition of the Rho-kinase pathway.


Assuntos
Anlodipino/farmacologia , Aorta/efeitos dos fármacos , Lipídeos/farmacologia , Vasodilatação/efeitos dos fármacos , Anlodipino/toxicidade , Animais , Aorta/fisiopatologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/genética , Emulsões/farmacologia , Humanos , Lipídeos/antagonistas & inibidores , Lipídeos/química , Masculino , Técnicas de Cultura de Órgãos , Ratos , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/genética , Vasodilatação/fisiologia , Verapamil/farmacologia , Quinases Associadas a rho/genética
17.
Biomolecules ; 10(1)2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31878099

RESUMO

Nanoemulsion was formulated from membrane lipids of Trichoderma spp. with the non-ionic surfactant Tween 80 by the ultrasonic emulsification method. Nanoemulsion with a droplet diameter of 5 to 51 nm was obtained. The possible effects of membrane lipid nanoemulsion on pearl millet (PM) seed growth parameters and elicitation of downy mildew (DM) disease resistance in PM was analyzed to develop an eco-friendly disease management strategy. Seed priming with nanoemulsion illustrates significant protection and elevated levels of early defense gene expression. Lipid profiling of Trichoderma spp. reveals the presence of oleic acid as a major fatty acid molecule. The prominent molecule in the purified lipid fraction of T. brevicompactum (UP-91) responsible for the elicitation of induction of systemic resistance in PM host against DM pathogen was predicted as (E)-N-(1, 3-dihydroxyoctadec-4-en-2yl) acetamide. The results suggest that protection offered by the novel nanoemulsion formulation is systemic in nature and durable and offers a newer sustainable approach to manage biotrophic oomycetous pathogen.


Assuntos
Resistência à Doença/efeitos dos fármacos , Lipídeos/farmacologia , Nanoestruturas/química , Pennisetum/imunologia , Pennisetum/microbiologia , Peronospora/fisiologia , Doenças das Plantas/microbiologia , Emulsões , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Lipídeos/química , Pennisetum/citologia , Pennisetum/genética , Doenças das Plantas/imunologia , Sementes/efeitos dos fármacos , Sementes/microbiologia , Transdução de Sinais/efeitos dos fármacos , Trichoderma/química
18.
ACS Appl Mater Interfaces ; 11(50): 46585-46590, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31763806

RESUMO

Messenger RNA (mRNA) represents an emerging class of nucleic acid therapeutics for genome editing and genetic disease treatment. Delivering exogenous mRNA selectively to cells, however, remains a main challenge to broaden the biomedical application of mRNA and develop targeted gene therapy. Herein, we report cell-selective mRNA delivery and CRISPR/Cas9 genome editing by modulating the interface of phenylboronic acid (PBA) derived lipid nanoparticles (NPs) and cellular surface sialic acid (SA). We design a cationic lipid featuring a PBA group, PBA-BADP, to self-assemble with mRNA into nanoparticles via electrostatic interactions. Importantly, these nanoparticles present free PBA groups on their surface, showing an enhanced cellular uptake by SA-overexpressing cancer cells via the interfacial PBA/SA interaction. It is shown that PBA-BADP/mRNA NPs transfection results in 300 times higher luciferase reporter gene expression in cancer cells than that in noncancer cells. Moreover, we demonstrate that the delivery of tumor suppressor p53 mRNA using PBA-BADP selectively prohibits cancer cell growth, while PBA-BADP/Cas9 mRNA NPs delivery knocks out gene expression of HeLa cancer cells in a much higher efficiency than noncancer cells. We believe these findings could further extend the modulation of PBA and cellular SA interface to advance mRNA delivery and genome editing for new gene therapy.


Assuntos
Técnicas de Transferência de Genes , Lipídeos/farmacologia , Nanopartículas/química , RNA Mensageiro/farmacologia , Ácidos Borônicos/química , Sistemas CRISPR-Cas/efeitos dos fármacos , Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , Terapia Genética , Células HeLa , Humanos , Lipídeos/química , Ácido N-Acetilneuramínico/química , Ácido N-Acetilneuramínico/metabolismo , RNA Mensageiro/química , Transfecção/métodos
19.
Molecules ; 24(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694159

RESUMO

Two bacterial isolates from the Barents Sea, both belonging to the genus Algibacter, were found to yield extracts with anti-bacterial bioactivity. Mass spectrometry guided dereplication and purification of the active extracts lead to the isolation of the same active principle in both extracts. The structure of the bioactive compound was identified via mass spectrometry and nuclear resonance spectroscopy and it turned out to be the known lipopeptide Lipid 430. We discovered and determined its previously unknown anti-bacterial activity against Streptococcus agalactiae and revealed a cytotoxic effect against the A2058 human melanoma cell line at significantly lower concentrations compared to its anti-bacterial concentration. Flow cytometry and microscopy investigations of the cytotoxicity against the melanoma cell line indicated that Lipid 430 did not cause immediate cell lysis. The experiments with melanoma cells suggest that the compound functions trough more complex pathways than acting as a simple detergent.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , Flavobacteriaceae/química , Lipídeos/química , Lipídeos/farmacologia , Linhagem Celular Tumoral , Células HT29 , Humanos , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Melanoma/tratamento farmacológico , Streptococcus agalactiae/efeitos dos fármacos
20.
Molecules ; 24(21)2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31684021

RESUMO

Objectives: The study aimed to prepare carbamazepine in solid lipid nanoparticle form (CBZ-SLN) in order to enhance its anticonvulsant effect. Method: Eight formulations of CBZ-SLNs were prepared by homogenization and ultra-sonication techniques. Results: The prepared CBZ-SLN showed a high entrapment efficiency% (39.66 ± 2.42%-71.91 ± 1.21%), a small particle size (45.11 ± 6.72-760.7 ± 5.25 nm), and a negative zeta potential (from -21.5 ± 1.02 to -38.4 ± 1.32 mv). The in vitro release study showed the slow release of CBZ from SLNs compared to CBZ aqueous dispersion (p < 0.05). The infrared spectroscopy and the thermal analysis revealed the compatibility of the drug with other ingredients and the presence of drug in the more soluble amorphous estate, respectively. The in vivo study on mice revealed that the CBZ-SLN had a higher anticonvulsant efficacy than CBZ aqueous dispersion after a lethal and chronic dose of pentylenetetrazole (PTZ) (p < 0.05). The histopathological examination of the hippocampus revealed a decrease in the percentage of degeneration in mice treated with the CBZ-SLN compared to the PTZ and CBZ groups. Conclusion: CBZ can be formulated as SLN with higher anticonvulsant activity than free CBZ aqueous dispersion.


Assuntos
Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Composição de Medicamentos , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/química , Carbamazepina/química , Modelos Animais de Doenças , Humanos , Lipídeos/química , Lipídeos/farmacologia , Camundongos , Nanopartículas/química , Pentilenotetrazol/farmacologia
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