RESUMO
2-Hydroxyoleic acid (2-OHOA) has gained attention as a membrane lipid therapy (MLT) anti-cancer drug. However, in the viewpoint of anti-cancer drug, 2-OHOA shows poor water solubility and its effectiveness still has space for improvement. Thus, this study aimed to overcome the problems by formulating 2-OHOA into liposome dosage form. Furthermore, in the context of MLT reagents, the influence of 2-OHOA on the biophysical properties of the cytoplasmic membrane remains largely unexplored. To bridge this gap, our study specifically focused the alterations in cancer cell membrane fluidity and lipid packing characteristics before and after treatment. By using a two-photon microscope and the Laurdan fluorescence probe, we noted that liposomes incorporating 2-OHOA induced a more significant reduction in cancer cell membrane fluidity, accompanied by a heightened rate of cellular apoptosis when compared to the non-formulated 2-OHOA. Importantly, the enhanced efficacy of 2-OHOA within the liposomal formulation demonstrated a correlation with its endocytic uptake mechanism. In conclusion, our findings underscore the significant influence of 2-OHOA on the biophysical properties of cancer plasma membranes, emphasizing the potential of liposomes as an optimized delivery system for 2-OHOA in anti-cancer therapy.
Assuntos
Membrana Celular , Lipossomos , Fluidez de Membrana , Lipossomos/química , Humanos , Membrana Celular/metabolismo , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Fluidez de Membrana/efeitos dos fármacos , 2-Naftilamina/análogos & derivados , 2-Naftilamina/química , Apoptose/efeitos dos fármacos , Lauratos/química , Microscopia de Fluorescência por Excitação Multifotônica , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Ácidos Oleicos/química , Corantes Fluorescentes/químicaRESUMO
Growing evidence indicates that the intake of trans fatty acids (TFAs) increases the risk of numerous diseases, such as cardiovascular diseases. Recently, our group found that certain natural sulfur compounds (allyl isothiocyanate [AITC] and diallyl disulfide [DADS]) promote cis to trans isomerization of fatty acid esters during heat treatment. However, little information is available on the fatty acid isomerization with them. In this study, we investigated the effects of oxygen and α-tocopherol (antioxidant) on isomerization of oleic acid (18:1) methyl ester (OA-ME) in the presence of AITC and DADS. Furthermore, the effect of the simultaneous use of AITC and DADS was evaluated. Our results indicate that oxygen enhances the AITC-induced trans isomerization, and DADS was found to promote trans isomerization but inhibit AITC-induced trans isomerization during heating. Both AITC- and DADS-induced trans isomerization were inhibited by α-tocopherol. These results indicate that the trans isomerization of fatty acids induced by sulfur compounds can be controlled by devising a cooking process and the food ingredients used together.
Assuntos
Dissulfetos , Isotiocianatos , Ácidos Oleicos , alfa-Tocoferol , Isomerismo , alfa-Tocoferol/química , Dissulfetos/química , Ácidos Oleicos/química , Isotiocianatos/química , Compostos Alílicos/química , Oxigênio/química , Antioxidantes/química , Temperatura Alta , Compostos de Enxofre/química , Culinária , Ácido Oleico/química , Ácidos Graxos trans/química , Ésteres/química , Estereoisomerismo , Cisteína/análogos & derivadosRESUMO
[123I]ß-methyl-p-iodophenyl-pentadecanoic acid ([123I]BMIPP), which is used for nuclear medicine imaging of myocardial fatty acid metabolism, accumulates in cancer cells. However, the mechanism of accumulation remains unknown. Therefore, this study aimed to elucidate the accumulation and accumulation mechanism of [123I]BMIPP in cancer cells. We compared the accumulation of [123I]BMIPP in cancer cells with that of [18F]FDG and found that [123I]BMIPP was a much higher accumulation than [18F]FDG. The accumulation of [123I]BMIPP was evaluated in the presence of sulfosuccinimidyl oleate (SSO), a CD36 inhibitor, and lipofermata, a fatty acid transport protein (FATP) inhibitor, under low-temperature conditions and in the presence of etomoxir, a carnitine palmitoyl transferase I (CPT1) inhibitor. The results showed that [123I]BMIPP accumulation was decreased in the presence of SSO and lipofermata in H441, LS180, and DLD-1 cells, suggesting that FATPs and CD36 are involved in [123I]BMIPP uptake in cancer cells. [123I]BMIPP accumulation in all cancer cell lines was significantly decreased at 4 °C compared to that at 37 °C and increased in the presence of etomoxir in all cancer cell lines, suggesting that the accumulation of [123I]BMIPP in cancer cells is metabolically dependent. In a biological distribution study conducted using tumor-bearing mice transplanted with LS180 cells, [123I]BMIPP highly accumulated in not only LS180 cells but also normal tissues and organs (including blood and muscle). The tumor-to-intestine or large intestine ratios of [123I]BMIPP were similar to those of [18F]FDG, and the tumor-to-large-intestine ratios exceeded 1.0 during 30 min after [123I]BMIPP administration in the in vivo study. [123I]BMIPP is taken up by cancer cells via CD36 and FATP and incorporated into mitochondria via CPT1. Therefore, [123I]BMIPP may be useful for imaging cancers with activated fatty acid metabolism, such as colon cancer. However, the development of novel imaging radiotracers based on the chemical structure analog of [123I]BMIPP is needed.
Assuntos
Neoplasias do Colo , Iodobenzenos , Animais , Humanos , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Camundongos , Linhagem Celular Tumoral , Iodobenzenos/química , Antígenos CD36/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Radioisótopos do Iodo , Ácidos Oleicos/química , Miocárdio/metabolismo , Distribuição Tecidual , Proteínas de Transporte de Ácido Graxo/metabolismo , Fluordesoxiglucose F18/química , Fluordesoxiglucose F18/metabolismo , Ácidos GraxosRESUMO
To determine the performance of a sophorolipid biosurfactant production process, it is important to have accurate and specific analytical techniques in place. Among the most popular are the anthrone assay, gravimetric quantification (hexane:ethyl acetate extraction), and high-performance liquid chromatography (HPLC). The choice of analytical tool varies depending on cost, availability, and ease of use; however, these techniques have never been compared directly against one another. In this work, 75 fermentation broths with varying product/substrate concentrations were comprehensively tested with the 3 techniques and compared. HPLC-ultraviolet detection (198 nm) was capable of quantifying C18:1 subterminal hydroxyl diacetylated lactonic sophorolipid down to a lower limit of 0.3 g/L with low variability (<3.21%). Gravimetric quantification of the broths following liquid:liquid extraction with hexane and ethyl acetate showed some linearity (R2 = .658) when compared to HPLC but could not quantify lower than 11.06 g/L, even when no sophorolipids were detected in the sample, highlighting the non-specificity of the method to co-extract non-sophorolipid components in the final gravimetric measure. The anthrone assay showed no linearity (R2 = .129) and was found to cross-react with media components (rapeseed oil, corn steep liquor, glucose), leading to consistent overestimation of sophorolipid concentration. The appearance of poor biomass separation during sample preparation with centrifugation was noted and resolved with a novel sample preparation method with pure ethanol. Extensive analysis and comparisons of the most common sophorolipid quantification techniques are explored and the limitations/advantages are highlighted. The findings provide a guide for scientists to make an informed decision on the suitable quantification tool that meets their needs, exploring all aspects of the analysis process from harvest, sample preparation, and analysis.
Assuntos
Tensoativos , Tensoativos/química , Cromatografia Líquida de Alta Pressão/métodos , Fermentação , Ácidos Oleicos/análise , Ácidos Oleicos/química , Meios de Cultura/químicaRESUMO
The oleic acid/alpha-lactalbumin complex HAMLET (human alpha-lactalbumin made lethal to tumors) is cytotoxic to various cancerous cell lines and is assembled from alpha-lactalbumin (ALA) and free oleic acid (OA). HAMLET is also cytotoxic to normal immature intestinal cells. It remains unclear if HAMLET, experimentally assembled with OA and heat, can spontaneously assemble in frozen human milk over time. To approach this issue, we used a set of timed proteolytic experiments to evaluate the digestibility of HAMLET and native ALA. The purity of HAMLET in human milk was confirmed by ultra high performance liquid chromatography coupled to tandem mass spectrometry and western blot to resolve the ALA and OA components. Timed proteolytic experiments were used to identify HAMLET in whole milk samples. Structural characterization of HAMLET was performed by Fournier transformed infrared spectroscopy and indicated a transformation of secondary structure with increased alpha-helical character of ALA upon binding to OA.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Ácido Oleico/química , Leite Humano/metabolismo , Lactalbumina/química , Neoplasias/patologia , Antineoplásicos/química , Digestão , Ácidos Oleicos/químicaRESUMO
This investigation developed a novel strategy for efficiently preparing glucolipids (GLs) by chemically modifying crude sophorolipids. Running this strategy, crude sophorolipids were effectively transformed into GLs through deglycosylation and de-esterification, with a yield of 54.1%. The acquired GLs were then purified via stepwise extractions, and 66.2% of GLs with 95% purity was recovered. GLs are more hydrophobic and present a stronger surface activity than acidic sophorolipids (ASLs). More importantly, these GLs displayed a superior antimicrobial activity to that of ASLs against the tested Gram-positive food pathogens, with a minimum inhibitory concentration of 32-64 mg/L, except against E. coli . This activity of GLs is pH-dependent and especially more powerful under acidic conditions. The mechanism involved is possibly associated with the more efficient adsorption of GLs, as demonstrated by the hydrophobicity of the cell membrane. These GLs could be used as antimicrobial agents for food preservation and health in the food industry.
Assuntos
Escherichia coli , Tensoativos , Tensoativos/química , Escherichia coli/metabolismo , Ácidos Oleicos/química , Indústria Alimentícia , Glicolipídeos/químicaRESUMO
Biological amphiphiles derived from natural resources are presently being investigated in the hope that they will someday replace current synthetic surfactants, which are known pollutants of soils and water resources. Sophorolipids constitute one of the main classes of glycosylated biosurfactants that have attracted interest because they are synthesized by non-pathogenic yeasts from glucose and vegetable oils at high titers. In this work, the self-assembly properties of several sophorolipids in water at high concentrations (20-80 wt %), a range so far mostly uncharted, have been investigated by polarized-light microscopy and X-ray scattering. Some of these compounds were found to show lyotropic liquid-crystalline behavior as they display lamellar or hexagonal columnar mesophases. X-ray scattering data shows that the structure of the lamellar phase is almost fully interdigitated, which is likely due to the packing difference between the bulky hydrophilic tails and the more compact aliphatic chains. A tentative representation of the molecular organization of the columnar phase is also given. Moreover, some of these compounds display thermotropic liquid-crystalline behavior, either pure or in aqueous mixtures. In addition, small domains of the lamellar phase can easily be aligned by applying onto them a moderate a.c. electric field, which is a rather unusual feature for lyotropic liquid crystals. Altogether, our work explored the self-assembly liquid-crystalline behavior of sophorolipids at high concentration, which could shed light on the conditions of their potential industrial applications as well as on their biological function.
Assuntos
Cristais Líquidos , Interações Hidrofóbicas e Hidrofílicas , Cristais Líquidos/química , Ácidos Oleicos/química , Tensoativos/química , Água/químicaRESUMO
BACKGROUND: 10-Hydroxy-cis-12-octadecenoic acid (10-HOE, 10-OH C18:1), an emerging functional fatty acid, has anti-fungal and anti-inflammatory effects. 10-HOE is synthesized by bacterial 10-linoleic acid hydratase (10-LHT) with linoleic acid as the substate. However, the characterization of 10-LHT and its targeted synthesis of 10-HOE have been rarely reported. In this study, the recombinant 10-LHT from Lactiplantibacillus plantarum ZS2058 was characterized, and the biocatalysis of 10-HOE using crude enzyme was optimized. RESULTS: The recombinant 10-LHT catalyzed the conversion of linoleic acid (C18:2) to 10-HOE as identified using gas chromatography-mass spectrometry (GC-MS). It showed a molecular weight of about 70 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and was a flavin adenine dinucleotide (FAD)-dependent enzyme. The activity of 10-LHT was optimal at pH 6.5 and 25 °C, and it was pH-stable but thermo-sensitive. The optimal condition for the 10-HOE biosynthesis using crude enzyme was 5 g L-1 linoleic acid (C18:2), 148.0 U mL-1 10-LHT, 0.05 mmol L-1 FAD, 2% methanol and 100 mmol L-1 sodium chloride at 25 °C and pH 6.5. A conversion yield of 47.8 ± 1.5% and the corresponding 10-HOE concentration of 2.4 ± 0.1 g L-1 were achieved at 48 h under the optimal reaction conditions. CONCLUSION: This work achieved the highest conversion yield of 10-HOE with the highest substrate concentration, and provides some useful information for the industrial production of 10-HOE. © 2021 Society of Chemical Industry.
Assuntos
Ácido Linoleico , Ácidos Oleicos , Hidrolases , Ácidos Oleicos/químicaRESUMO
Biosurfactants are natural surfactants produced by a variety of microorganisms. In recent years, biosurfactants have garnered a lot of interest due to their biomedical and pharmaceutical applications. Sophorolipids are glycolipid types of biosurfactants produced by selected nonpathogenic yeasts. In addition to the detergent activity (reduction in surface and interfacial tension), which is commonly utilized by biomedical applications, sophorolipids have shown some unique properties such as, antiviral activity against enveloped viruses, immunomodulation, and anticancer activity. Considering their antiviral activity, the potential of sophorolipids as an antiviral therapy for the treatment of COVID-19 is discussed in this review. Being a surfactant molecule, sophorolipid could solubilize the lipid envelope of SARS-CoV-2 and inactivate it. As an immunomodulator, sophorolipid could attenuate the cytokine storm caused by the SARS-CoV-2 upon infection, and inhibit the progression of COVID-19 in patients. Sophorolipids could also be used as an effective treatment strategy for COVID-19 patients suffering from cancer. However, there is limited research on the use of sophorolipid as a therapeutic agent for the treatment of cancer and viral diseases, and to modulate the immune response. Nevertheless, the multitasking capabilities of sophorolipids make them potential therapeutic candidates for the bench-to-bedside research for the treatment of COVID-19.
Assuntos
Tratamento Farmacológico da COVID-19 , Ácidos Oleicos/química , Ácidos Oleicos/farmacologia , Tensoativos/química , Adjuvantes Imunológicos , Animais , Antineoplásicos/farmacologia , Antivirais/farmacologia , Linhagem Celular Tumoral , Síndrome da Liberação de Citocina , Citocinas/metabolismo , Desenho de Fármacos , Glicolipídeos , Humanos , Imunomodulação , Lipídeos/química , Ratos , SARS-CoV-2RESUMO
The main obstacle in the treatment of cancer patients has been resistance to multiple drugs, leading to the need to develop molecules with a higher specificity target. The liposomal formulation DODAC/2-AEH2P has antitumor potential, inducing apoptosis in several tumor types. Human chronic myeloid leukemia K-562 and K-562 Lucena (MDR+) cells were treated with the DODAC carrier and the liposomal formulation 2-AEH2P. Viability, cell cycle phases, apoptosis, marker expression and mitochondrial potential were analyzed. Significant reduction in viability was observed for all treatments. Changes in the distribution of the cell cycle phases and expression of markers involved in the apoptosis pathways were observed. Reduction of the mitochondrial electrical potential mediated by Bcl-2, being regulated by the reduction of the MTCH2 protein linked to the progression of myeloid leukemia and an increase in the pro-apoptotic proteins Bad and Bax, dependent on p53. This study demonstrated a significant therapeutic potential through apoptotic effects in leukemic cells, regardless of the molecular resistance profile (MDR+).
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Organofosfatos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Lipossomos/química , Lipossomos/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ácidos Oleicos/química , Ácidos Oleicos/farmacologia , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologiaRESUMO
We developed an alternative whipping cream fat using shea butter but with low saturation. Enriched stearic-oleic-stearic (SOS) solid fat was obtained from shea butter via solvent fractionation. Acyl migration reactant, which mainly contains asymmetric SSO triacylglycerol (TAG), was prepared through enzymatic acyl migration to obtain the creaming quality derived from the ß'-crystal form. Through enzymatic acyl migration, we obtained a 3.4-fold higher content of saturated-saturated-unsaturated (SSU) TAG than saturated-unsaturated-saturated (SUS) TAG. The acyl migration reactant was refined to obtain refined acyl migration reactant (RAMR). An alternative fat product was prepared by blending RAMR and hydrogenated palm kernel oil (HPKO) at a ratio of 4:6 (w/w). The melting points, solid fat index (SFI), and melting curves of the alternative products were similar to those of commercial whipping cream fat. The alternative fat had a content of total unsaturated fatty acids 20% higher than that of HPKO. The atherogenic index (AI) of alternative fat was 3.61, much lower than those of whipping cream fat (14.59) and HPKO (1220.3), because of its low atherogenic fatty acid content and high total unsaturated fatty acids. The polymorphic crystal form determined by X-ray diffraction spectroscopy showed that the ß'-crystal form was predominant. Therefore, the alternative fat is comparable with whipping cream that requires creaming quality, and has a reduced saturated fat content.
Assuntos
Gorduras na Dieta/análise , Ácidos Graxos Insaturados/química , Tecnologia de Alimentos/métodos , Ácidos Oleicos/química , Óleos de Plantas/química , Fracionamento Químico , Cristalização , Ácidos Graxos Insaturados/análise , Humanos , Ácido Oleico/análise , Ácido Oleico/química , Ácidos Oleicos/análise , Óleo de Palmeira/análise , Óleo de Palmeira/química , Óleos de Plantas/análise , Ácidos Esteáricos/análise , Ácidos Esteáricos/química , Triglicerídeos/análise , Triglicerídeos/químicaRESUMO
Over the last decade, upconversion nanoparticles (UCNP) have been widely investigated in nanomedicine due to their high potential as imaging agents in the near-infrared (NIR) optical window of biological tissues. Here, we successfully develop active targeted UCNP as potential probes for dual NIR-NIR fluorescence and radioactive-guided surgery of prostate-specific membrane antigen (PSMA)(+) prostate cancers. We designed a one-pot thermolysis synthesis method to obtain oleic acid-coated spherical NaYF4:Yb,Tm@NaYF4 core/shell UCNP with narrow particle size distribution (30.0 ± 0.1 nm, as estimated by SAXS analysis) and efficient upconversion luminescence. Polyethylene glycol (PEG) ligands bearing different anchoring groups (phosphate, bis- and tetra-phosphonate-based) were synthesized and used to hydrophilize the UCNP. DLS studies led to the selection of a tetra-phosphonate PEG(2000) ligand affording water-dispersible UCNP with sustained colloidal stability in several aqueous media. PSMA-targeting ligands (i.e., glutamate-urea-lysine derivatives called KuEs) and fluorescent or radiolabelled prosthetic groups were grafted onto the UCNP surface by strain-promoted azide-alkyne cycloaddition (SPAAC). These UCNP, coated with 10 or 100% surface density of KuE ligands, did not induce cytotoxicity over 24 h incubation in LNCaP-Luc or PC3-Luc prostate cancer cell lines or in human fibroblasts for any of the concentrations evaluated. Competitive binding assays and flow cytometry demonstrated the excellent affinity of UCNP@KuE for PSMA-positive LNCaP-Luc cells compared with non-targeted UCNP@CO2H. Furthermore, the binding of UCNP@KuE to prostate tumour cells was positively correlated with the surface density of PSMA-targeting ligands and maintained after 125I-radiolabelling. Finally, a preliminary biodistribution study in LNCaP-Luc-bearing mice demonstrated the radiochemical stability of non-targeted [125I]UCNP paving the way for future in vivo assessments.
Assuntos
Antígenos de Superfície/metabolismo , Materiais Revestidos Biocompatíveis/química , Glutamato Carboxipeptidase II/metabolismo , Nanopartículas de Magnetita/química , Animais , Antígenos de Superfície/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/metabolismo , Materiais Revestidos Biocompatíveis/farmacologia , Materiais Revestidos Biocompatíveis/uso terapêutico , Reação de Cicloadição , Fluoretos/química , Glutamato Carboxipeptidase II/química , Humanos , Ligantes , Nanopartículas de Magnetita/uso terapêutico , Nanopartículas de Magnetita/toxicidade , Masculino , Camundongos , Ácidos Oleicos/química , Imagem Óptica , Tamanho da Partícula , Polietilenoglicóis/química , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Túlio/química , Distribuição Tecidual , Itérbio/química , Ítrio/químicaRESUMO
Curcumin, a polyphenolic compound isolated from turmeric, exhibits various biological activities. The application of this nutraceutical in foods, however, is limited due to its extreme hydrophobicity, inferior stability, and poor bioaccessibility. The purpose of this paper is to prepare alcohol-free curcumin-loaded zein/sophorolipid nanoparticles (Cur-Z/SNPs) by one-step self-assembly to overcome the abovementioned challenges of curcumin. In detail, Cur-Z/SNPs were formed by mixing curcumin, zein, and sophorolipid under neutral conditions without any organic reagents or high energy equipment. The encapsulation efficiency and loading capacity of Cur-Z/SNPs were 94.08% and 11.50%, respectively. The spherical shape of Cur-Z/SNPs was observed by using a transmission electron microscope. The self-assembly mechanism involved hydrogen bonding, hydrophobic and electrostatic interactions, and the crystalline nature of curcumin changed to amorphous during self-assembly. Cur-Z/SNPs enhanced the zein denaturation resistance. They exhibited complete redispersibility and improved the aqueous solubility by approximately 246 times compared with free curcumin. The fresh Cur-Z/SNPs exhibited physicochemical stability at pH 5.0-8.0, ionic strength within 250 mM, and storage at 25 °C and 4 °C for 30 days. Notably, Cur-Z/SNPs could achieve excellent storage stability at room temperature as compared to those at refrigeration. Furthermore, lyophilization had a positive effect on storage stability, did not change the pH stability, and slightly reduced the ionic strength stability. Besides, Cur-Z/SNPs increased the 1,1-diphenyl-2-picrylhydrazyl free radical (DPPHË) scavenging capacity compared to free curcumin. The bioaccessibility of curcumin was increased by about 6 times by Cur-Z/SNPs. These findings provided new insight into the application of hydrophobic nutrients in alcohol-free functional foods.
Assuntos
Curcumina/química , Nanopartículas/química , Ácidos Oleicos/química , Zeína/química , Antioxidantes , Fenômenos Químicos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Concentração Osmolar , Tamanho da Partícula , Solubilidade , Eletricidade EstáticaRESUMO
Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.
Assuntos
Peptídeos/química , Peptídeos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Sequência de Aminoácidos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Endocitose/efeitos dos fármacos , Determinação de Ponto Final , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ácidos Oleicos/química , Peptídeos/farmacologia , Placebos , Conformação Proteica , Espectroscopia de Prótons por Ressonância Magnética , Termodinâmica , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
Sophorolipids (SLs) are glycolipids that consist of a hydrophilic sophorose head group covalently linked to a hydrophobic fatty acid tail. They are produced by fermentation of non-pathogenic yeasts such as Candida Bombicola. The fermentation products predominantly consist of the diacetylated lactonic form that coexists with the open-chain acidic form. A systematic series of modified SLs were prepared by ring opening of natural lactonic SL with n-alkanols of varying chain length under alkaline conditions and lipase-selective acetylation of sophorose primary hydroxyl groups. The antimicrobial activity of modified SLs against Gram-positive human pathogens was a function of the n-alkanol length, as well as the degree of sophorose acetylation at the primary hydroxyl sites. Modified SLs were identified with promising antimicrobial activities against Gram-positive human pathogens with moderate selectivity (therapeutic index, TI = EC50/MICB. cereus = 6-33). SL-butyl ester exhibited the best antimicrobial activity (MIC = 12 µM) and selectivity (TI = 33) among all SLs tested. Kinetic studies revealed that SL-ester derivatives kill B. cereus in a time-dependent manner resulting in greater than a 3-log reduction in cell number within 1 h at 2×MIC. In contrast, lactonic SL required 3 h to achieve the same efficiency.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Ácidos Oleicos/química , Ácidos Oleicos/farmacologia , Ésteres/química , Testes de Sensibilidade Microbiana , Modelos Biológicos , Relação Estrutura-AtividadeRESUMO
Trypanosomosis and helminthosis, considered as part of neglected tropical diseases, are parasitic infections of public health importance, especially in Africa. Medicinal plants have been used in most parts of Africa, to treat these parasitic infections. The study aims to determine the anti-trypanosomal and anthelminthic properties of Tetrapleura tetraptera (fruit and stembark). The aqueous extracts of T. tetraptera fruit (TTFaq) and stembark (TTSaq), as well as ethanol extracts of T. tetraptera fruit (TTFe) and stembark (TTSe), were screened for their in vitro anti-trypanosomal and anthelminthic activities against T. b. brucei and Pheretima posthuma worms, respectively. Preliminary phytochemical screening of all extracts and gas chromatography-mass spectrometry (GC-MS) analysis of most active extracts were conducted. TTFaq exhibited anti-trypanosomal activity with IC50 of 18.18 µg/mL. TTSe and TTFe had moderate anti-trypanosomal activity with IC50 of 34.76 and 34.84 µg/mL, respectively. TTSaq had relatively low activity against the parasite with IC50 of 55.03 µg/mL. The SI of T. tetraptera extracts was between the range of 0.14-2.09. TTFaq showed dose-dependent activity causing paralysis and death of the adult worms at all concentrations. At the least concentration of 0.625 mg/mL, TTFaq induced paralysis and death after 101.88 ± 0.8 and 242.64 ± 0.38 min of exposure, respectively compared with the negative control (p < 0.0001). TTFe, TTSe and TTSaq caused paralysis of worms after 318.32 ± 0.74, 422.5 ± 0.72, 422.20 ± 0.55 min of exposure at minimum concentrations of 2.5, 10 and 5 mg/mL, respectively (p < 0.0001). However, no death was observed in worms treated with TTFe, TTSe and TTSaq at all test concentrations. In the presence of sub-minimal inhibitory concentration of the extracts, TTFaq potentiated the anthelminthic activity of albendazole whiles TTFe, TTSaq and TTSe inhibited the activity of albendazole. Phytochemical screening revealed the presence of saponins, triterpenoids, reducing sugars, flavonoids (absent in TTFe), steroids (absent in TTFaq) and tannins (absent in TTSe and TTFe) in the extracts. GC-MS revealed the presence of 9-octadecenamide and betulic acid in TTFaq. Hence, there was evidence provided here that Tetrapleura tetraptera may be effective. This gives credence to their folkloric use. However, further study might be necessary to ascertain safety use in both humans and animals.
Assuntos
Albendazol/química , Anti-Helmínticos/farmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Tetrapleura/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Albendazol/farmacologia , Anti-Helmínticos/química , Etanol , Frutas/química , Cromatografia Gasosa-Espectrometria de Massas/veterinária , Ácidos Oleicos/química , Triterpenos Pentacíclicos/análise , Compostos Fitoquímicos/química , Casca de Planta/química , Extratos Vegetais/química , Caules de Planta/química , Plantas Medicinais , Tripanossomicidas/química , Água , Ácido BetulínicoRESUMO
trans-Fatty acids (TFAs), including elaidic acid and linoelaidic acid, are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. TFAs are not synthesized in the human body, but are taken into the body from various foods, which are mainly produced during industrial food manufacturing. Recent epidemiological studies have revealed that TFA consumption is a major risk factor for various disorders, such as atherosclerosis, cardiovascular diseases, allergic diseases, and dementia. However, the underlying pathogenic mechanisms of TFA-related disorders and the specific molecular targets evoking TFA toxicity are largely unknown. To elucidate the molecular mechanisms by which TFAs cause the cytotoxicity, we focused on cell death and inflammation, which are the main and common pathogenesis of the TFA-related diseases, and analyzed the effects of TFAs on cellular responses to various stimulations inducing cell death and inflammation. This review provides recent progress in our studies on the molecular mechanisms causing toxic actions of TFAs, which lead to diverse TFA-related disorders.
Assuntos
Aterosclerose/etiologia , Doenças Cardiovasculares/etiologia , Morte Celular/efeitos dos fármacos , Ácidos Graxos trans/toxicidade , Isomerases de Ligação Dupla Carbono-Carbono , Ingestão de Alimentos , Humanos , Inflamação/etiologia , Ácidos Oleicos/efeitos adversos , Ácidos Oleicos/química , Ácidos Oleicos/toxicidade , Fatores de Risco , Ácidos Graxos trans/efeitos adversos , Ácidos Graxos trans/químicaRESUMO
Seaweed processing generates liquid fraction residual that could be used as a low-cost nutrient source for microbial production of metabolites. The Rhodotorula strain is able to produce antimicrobial compounds known as sophorolipids. Our aim was to evaluate sophorolipid production, with antibacterial activity, by marine Rhodotorula rubra using liquid fraction residual (LFR) from the brown seaweed Macrocystis pyrifera as the nutrient source. LFR having a composition of 32% w/w carbohydrate, 1% w/w lipids, 15% w/w protein and 52% w/w ash. The best culture condition for sophorolipid production was LFR 40% v/v, without yeast extract, artificial seawater 80% v/v at 15 °C by 3 growth days, with the antibacterial activity of 24.4 ± 3.1 % on Escherichia coli and 21.1 ± 3.8 % on Staphylococcus aureus. It was possible to identify mono-acetylated acidic and methyl ester acidic sophorolipid. These compounds possess potential as pathogen controllers for application in the food industry.
Assuntos
Macrocystis/química , Ácidos Oleicos/química , Extratos Vegetais/farmacologia , Rhodotorula/efeitos dos fármacos , Organismos Aquáticos/química , Ácidos Oleicos/farmacologia , Extratos Vegetais/química , Rhodotorula/patogenicidadeRESUMO
Solidification of self-microemulsifying drug delivery systems (SMEDDS) is one of the major trends to promote the transformation of self-microemulsion technology into industrialization. Here, a preliminary curcumin SMEDDS formulation was constructed to improve the druggability of curcumin, through the determination of equilibrium solubility determination, self-emulsifying grading assessment, and pseudo-ternary phase diagrams drafting. Furthermore, the optimal curcumin SMEDDS formulation consisted of 10% Ethyl oleate, 57.82% Cremophor RH 40, and 32.18% Transcutol P was obtained by the simplex lattice design. Besides, curcumin solid self-microemulsifying drug delivery system (S-SMEDDS) was developed by the extrusion and spheronization process to achieve the solidification of SMEDDS. The formulation of curcumin S-SMEDDS pellets was screened by the single factor experiment and the process parameters were investigated using the orthogonal optimization method. Subsequently, curcumin S-SMEDDS pellets were evaluated by apparent morphology characterization, redispersibility study, drug release behavior, and pharmacokinetic evaluation. Results from the pharmacokinetic study in rabbits showed that the AUC0-τ of the curcumin S-SMEDDS pellets and curcumin suspension were 5.91 ± 0.28 µg/mL·h and 2.05 ± 0.04 µg/mL·h, while the relative bioavailability was 289.30%. These studies demonstrated that S-SMEDDS pellets can be a promising strategy for curcumin industrialized outputs.
Assuntos
Curcumina/administração & dosagem , Sistemas de Liberação de Medicamentos , Excipientes/química , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Química Farmacêutica/métodos , Curcumina/farmacocinética , Liberação Controlada de Fármacos , Emulsões , Etilenoglicóis/química , Ácidos Oleicos/química , Polietilenoglicóis/química , Coelhos , Solubilidade , Tecnologia FarmacêuticaRESUMO
Sophorolipids (SLs) from Candida batistae has a unique structure that contains ω-hydroxy fatty acids, which can be used as a building block in the polymer and fragrance industries. To improve the production of this industrially important SLs, we optimized the culture medium of C. batistae for the first time. Using an optimized culture medium composed of 50 g/L glucose, 50 g/L rapeseed oil, 5 g/L ammonium nitrate and 5 g/L yeast extract, SLs were produced at a concentration of 24.1 g/L in a flask culture. Sophorolipids production increased by about 19% (28.6 g/L) in a fed-batch fermentation using a 5 L fermentor. Sophorolipids production more increased by about 121% (53.2 g/L), compared with that in a flask culture, in a fed-batch fermentation using a 50 L fermentor, which was about 787% higher than that of the previously reported SLs production (6 g/L). These results indicate that a significant increase in C. batistae-derived SLs production can be achieved by optimization of the culture medium composition and fed-batch fermentation. Finally, we successfully separated and purified the SLs from the culture medium. The improved production of SLs from C. batistae in this study will help facilitate the successful development of applications for the SLs.