RESUMEN
The present study evaluated the growth, self-flocculation, lipid content, and pollutants removal by Limnothrix sp. BASMWW-9 isolated from municipal wastewater treatment system and cultivated in municipal wastewater. The biomass yield and lipid content after 6 days of cultivation were 1.07 g dw/L and 27.34 %dw, respectively. In addition, its self-flocculating ability reached up to 90 % after harvesting time of 180 min. Moreover, COD,NH3-N, TN, and TP removalefficiencies were 71.65 %, 81.89 %, 74.64 %, and 80.16 %, respectively. The self-flocculation performance of Limnothrix sp. was greatly associated to its morphology and production of extracellular polymeric substances (EPS), with significant positive impact of the high calcium and magnesium content in municipal wastewater. Interestingly, blue light irradiation during harvest enhanced the aggregation and floc formation as a floating biomat, which was attributed to enhanced polysaccharides production. This study provides innovative harvest method for Limnothrix sp. BASMWW-9 cultivated in wastewater using blue light for enhanced lipid recovery.
Asunto(s)
Cianobacterias , Microalgas , Purificación del Agua , Aguas Residuales , Nitrógeno , Biomasa , LípidosRESUMEN
Self-assembly is a fundamental concept and a powerful approach in molecular science. However, creating functional materials with the desired properties through self-assembly remains challenging. In this work, through a combination of experimental and computational approaches, the self-assembly of small amphiphilic dendrons into nanosized supramolecular dendrimer micelles with a degree of structural definition similar to traditional covalent high-generation dendrimers is reported. It is demonstrated that, with the optimal balance of hydrophobicity and hydrophilicity, one of the self-assembled nanomicellar systems, totally devoid of toxic side effects, is able to deliver small interfering RNA and achieve effective gene silencing both in cells - including the highly refractory human hematopoietic CD34(+) stem cells - and in vivo, thus paving the way for future biomedical implementation. This work presents a case study of the concept of generating functional supramolecular dendrimers via self-assembly. The ability of carefully designed and gauged building blocks to assemble into supramolecular structures opens new perspectives on the design of self-assembling nanosystems for complex and functional applications.
Asunto(s)
Dendrímeros/química , Silenciador del Gen/fisiología , ARN Interferente Pequeño/química , Animales , Línea Celular Tumoral , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Ratones , Ratones Desnudos , Micelas , Estructura Molecular , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Various arylvinyltriazole nucleoside analogues were synthesized using Pd-catalyzed oxidative Heck reaction. This method affords the corresponding and otherwise difficult to achieve arylvinyltriazole nucleosides with good yields and large functional group compatibility. These results further advocate the potential and practicality of this oxidative C-H alkenylation method for generating structurally challenging chemical entities in organic synthesis.
Asunto(s)
Alquenos/química , Nucleósidos/química , Nucleósidos/síntesis química , Paladio/química , Triazoles/química , Catálisis , Técnicas de Química Sintética , Oxidación-ReducciónRESUMEN
RNA interference (RNAi) with small interfering RNA (siRNA) is expected to offer an attractive means to specifically and efficiently silence disease-associated genes for treating various diseases provided that safe and efficient delivery systems are available. In this study, we have established an arginine-decorated amphiphilic dendrimer composed of a hydrophobic alkyl chain and a hydrophilic PAMAM dendron bearing arginine terminals as nonviral vector for siRNA delivery. Indeed, this dendrimer proved to be very effective at delivering siRNAs in human prostate cancer PC-3 cells and in human hematopoietic CD34+ stem cells, leading to improved gene silencing compared to the corresponding nonarginine decorated dendrimer. Further investigation confirmed that this dendrimer was granted with the capacity to form stable nanoparticles with siRNA and significantly enhance cellular uptake of siRNA. In addition, this dendrimer revealed no discernible cytotoxicity. All these findings demonstrate that decoration of the dendrimer surface with arginine residues is indeed a useful strategy to improve the delivery ability of dendrimers.
Asunto(s)
Arginina/química , Dendrímeros/química , ARN Interferente Pequeño/química , Antígenos CD34/metabolismo , Línea Celular Tumoral , Proteínas de Choque Térmico HSP27/antagonistas & inhibidores , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Microscopía Fluorescente , Nanopartículas/química , Interferencia de ARN , ARN Interferente Pequeño/metabolismoRESUMEN
siRNA delivery remains a major challenge in RNAi-based therapy. Here, we report for the first time that an amphiphilic dendrimer is able to self-assemble into adaptive supramolecular assemblies upon interaction with siRNA, and effectively delivers siRNAs to various cell lines, including human primary and stem cells, thereby outperforming the currently available nonviral vectors. In addition, this amphiphilic dendrimer is able to harness the advantageous features of both polymer and lipid vectors and hence promotes effective siRNA delivery. Our study demonstrates for the first time that dendrimer-based adaptive supramolecular assemblies represent novel and versatile means for functional siRNA delivery, heralding a new age of dendrimer-based self-assembled drug delivery in biomedical applications.
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Dendrímeros/química , Silenciador del Gen/inmunología , ARN Interferente Pequeño/inmunología , HumanosRESUMEN
An ingenious and specific affinity resin designed to capture the 2-oxoglutaric acid (2-OG) binding proteins was constructed by appending a 2-OG tag to the solid resin via a Cu-catalyzed Huisgen "click" reaction. The so-obtained affinity resin was able to recognize, retain and separate the established 2-OG binding protein NtcA in both the pure form and crude cellular extract, thus constituting a valuable means of searching for novel 2-OG receptors with a view to exploring the signalling pathways of 2-OG, a key Krebs cycle intermediate with unprecedented signalling functions.
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Proteínas Portadoras/química , Ácidos Cetoglutáricos/química , Proteínas Portadoras/genética , Química Clic , Estructura MolecularRESUMEN
Small interfering RNAs (siRNA) are emerging as novel therapeutic agents, providing competent delivery systems that are available. Dendrimers, a special family of synthetic macromolecules, represent an exciting delivery platform by virtue of their well-defined dendritic structure and unique multivalency and cooperativity confined within a nanoscale volume. Here, we report a Dicer-substrate siRNA (dsiRNA) which, when delivered using a structurally flexible triethanolamine-core poly(amidoamine) dendrimer of generation 5 as the nanocarrier, gives rise to a much greater RNAi response than that produced with conventional siRNA. Further decoration of the dsiRNA/dendrimer complexes with a dual targeting peptide simultaneously promoted cancer cell targeting through interacting with integrins and cell penetration via the interaction with neuropilin-1 receptors, which led to improved gene silencing and anticancer activity. Altogether, our results disclosed here open a new avenue for therapeutic implementation of RNAi using dendrimer nanovector based targeted delivery. FROM THE CLINICAL EDITOR: This study demonstrates superior therapeutic properties of siRNA when combined with a dendrimer-based targeted nano-delivery system. Similar approaches may eventually gain clinical utility following additional studies determining safety and efficacy.
Asunto(s)
Dendrímeros/química , Péptidos/química , ARN Interferente Pequeño/genética , Apoptosis/genética , Apoptosis/fisiología , Línea Celular Tumoral , Proliferación Celular , ARN Helicasas DEAD-box/genética , Citometría de Flujo , Silenciador del Gen , Vectores Genéticos , Humanos , Microscopía Confocal , Interferencia de ARN , Ribonucleasa III/genéticaRESUMEN
2-Oxoglutaric acid (2-OG) has gained considerable attention because of its newly discovered signalling role in addition to its established metabolic functions. With the aim of further exploring the signalling function of 2-OG, here we present a structure-activity relationship study using 2-OG probes bearing different carbon chain lengths and terminal groups. Our results highlight the importance of the five-membered carbon molecular skeleton and of the two carboxylic terminals in maintaining the signalling functions of the parent molecule 2-OG. These findings provide valuable information for designing new, effective molecular probes able to dissect and discriminate the newly discovered, complex signalling role of 2-OG from its canonical activity in metabolism.
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Ácidos Cetoglutáricos/metabolismo , Sondas Moleculares/química , Sondas Moleculares/metabolismo , Transducción de Señal , Anabaena/metabolismo , ADN/metabolismo , Simulación de Dinámica Molecular , Sondas Moleculares/síntesis química , Espectroscopía de Protones por Resonancia Magnética , Relación Estructura-Actividad , Termodinámica , Factores de Transcripción/metabolismoRESUMEN
Successful therapeutic implementation of RNA interference critically depends on systems able to safely and efficiently deliver small interfering RNA (siRNA). Dendrimers are emerging as appealing nanovectors for siRNA delivery by virtue of their unique well-defined dendritic nanostructure within which is confined an intriguing cooperativity and multivalency. We have previously demonstrated that structurally flexible triethanolamine (TEA) core poly(amidoamine) (PAMAM) dendrimers of high generations are effective nanovectors for siRNA delivery in vitro and in vivo. In the present study, we have developed arginine-terminated dendrimers with the aim of combining and harnessing the unique siRNA delivery properties of the TEA-core PAMAM dendrimer and the cell-penetrating advantages of the arginine-rich motif. A generation 4 dendrimer of this family (G4Arg) formed stable dendriplexes with siRNA, leading to improved cell uptake of siRNA by comparison with its nonarginine bearing dendrimer counterpart. Moreover, G4Arg was demonstrated to be an excellent nanocarrier for siRNA delivery, yielding potent gene silencing and anticancer effects in prostate cancer models both in vitro and in vivo with no discernible toxicity. Consequently, importing an arginine residue on the surface of a dendrimer is an appealing option to improve delivery efficiency, and at the same time, the dendrimer G4Arg constitutes a highly promising nanovector for efficacious siRNA delivery and holds great potential for further therapeutic applications.
Asunto(s)
Antineoplásicos/farmacología , Dendrímeros/farmacología , Portadores de Fármacos/farmacología , Sistemas de Liberación de Medicamentos , Nanoestructuras/química , Poliaminas/farmacología , ARN Interferente Pequeño/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Arginina/química , Proliferación Celular/efectos de los fármacos , Dendrímeros/síntesis química , Dendrímeros/química , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Silenciador del Gen/efectos de los fármacos , Humanos , Estructura Molecular , Poliaminas/síntesis química , Poliaminas/química , ARN Interferente Pequeño/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A 2-oxoglutaric acid (2-OG) probe bearing a methylene group introduced at the C4 position and a vinyl group to replace the carbonyl group at the C2 position elicited characteristic affinity for NtcA, the 2-OG receptor, while maintaining the signaling function of the parent natural metabolite 2-OG. This discovery opens new perspectives in the design, synthesis, and implementation of specific 2-OG analogues as molecular probes for investigating the complex 2-OG signaling pathways.
Asunto(s)
Ácidos Cetoglutáricos/química , Ácidos Cetoglutáricos/síntesis química , Anabaena/metabolismo , Estructura Molecular , Transducción de Señal/fisiología , Relación Estructura-ActividadRESUMEN
A bola-phospholipid probe, carrying a tetrafluorophenylazido chromophore in the middle of the transmembrane diacyl chain, was synthesized and characterized with a view to studying biomembranes by a photolabeling approach. This probe shows the advantageous stability of bola-lipids in giant vesicle formation alongside excellent photochemical properties conferred by the tetrafluorophenylazido chromophore, and thus constitutes a promising probe for biomembrane photolabeling studies.
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Azidas/química , Colorantes Fluorescentes/química , Proteínas de la Membrana/química , Fosfolípidos/química , Colorantes Fluorescentes/análisis , Colorantes Fluorescentes/síntesis química , Proteínas de la Membrana/análisis , Estructura Molecular , Fosfolípidos/análisis , Procesos FotoquímicosRESUMEN
An amphiphilic dendrimer bearing a hydrophobic alkyl chain and hydrophilic poly(amidoamine) dendrons is able to combine the advantageous features of lipid and dendrimer vectors to deliver a heat shock protein 27 siRNA and produce potent gene silencing and anticancer activity in vitro and in vivo in a prostate cancer model. This dendrimer can be used alternatively for treating various diseases.
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Dendrímeros/administración & dosificación , Dendrímeros/química , Silenciador del Gen , Vectores Genéticos/administración & dosificación , Vectores Genéticos/química , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , Dendrímeros/síntesis química , Terapia Genética/métodos , Vectores Genéticos/genética , Proteínas de Choque Térmico HSP27/genética , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , ARN Interferente Pequeño/genéticaRESUMEN
A novel bitriazolyl acyclonucleoside was discovered to exhibit powerful antiproliferative effects on different cancer cell lines through caspase-dependent apoptosis and at the same time stimulate the immune response in dendritic cells via Toll-like receptor 7 (TLR7) signaling. This promising compound with dual anticancer and immunomodulatory activity may represent a new generation of highly efficacious drug candidates for use in cancer therapy.
Asunto(s)
Antineoplásicos/síntesis química , Factores Inmunológicos/síntesis química , Nucleósidos/síntesis química , Triazoles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Factores Inmunológicos/química , Factores Inmunológicos/farmacología , Interleucina-6/biosíntesis , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Noqueados , Nucleósidos/química , Nucleósidos/farmacología , Relación Estructura-Actividad , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Triazoles/química , Triazoles/farmacologíaRESUMEN
A bola-lipid bearing tetrafluorophenylazido chromophore in the diacyl chain displayed puzzling (19)F NMR, leading to the evidence and rationalization of a F···S weak interaction that is important for altering molecular structures and imposing novel and special properties on fluorinated compounds.
Asunto(s)
Azidas/química , Flúor/química , Fosfolípidos/química , Azufre/química , Modelos Moleculares , Conformación MolecularRESUMEN
Make it unique! A mixed-ligand system of Pd/Synphos/Xantphos promotes effective C-N coupling in the synthesis of various N-arylaminotriazole and N-arylaminopurine nucleoside analogues. This catalytic system is strikingly powerful and efficient, allowing for unparalleled substrate scope and high product yields as well as promotion of C-Cl bond activation for C-N coupling (see scheme).
Asunto(s)
Carbono/química , Nitrógeno/química , Nucleósidos/síntesis química , Paladio/química , Fosfinas/química , Triazoles/síntesis química , Xantenos/química , Catálisis , Cristalografía por Rayos X , Ligandos , Estructura Molecular , Nucleósidos/química , Triazoles/químicaRESUMEN
Issued from a lead optimization process, we have identified a novel triazole nucleoside analog which elicits potent anticancer activity on drug-resistant pancreatic cancer. Most importantly, this compound targets heat shock response pathways by down-regulation of heat shock transcription factor 1 and consequential down-regulation of multiple heat shock proteins HSP27, HSP70 and HSP90. Down-regulation of these proteins caused the shut-down of several oncogenic pathways and caspase-dependent apoptosis resulting in a potent anticancer effect in vitro and in vivo. These results demonstrate the potential rewards gained in searching for anticancer candidates with multimodal actions on heat shock response pathways via HSF1 down-regulation.
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Antineoplásicos/uso terapéutico , Proteínas de Choque Térmico/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Triazoles/uso terapéutico , Secuencia de Bases , Western Blotting , Cartilla de ADN , Regulación hacia Abajo , Resistencia a Antineoplásicos , Ensayo de Inmunoadsorción Enzimática , Humanos , Neoplasias Pancreáticas/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Successful achievement of RNA interference in therapeutic applications requires safe and efficient vectors for siRNA delivery. In the present study, we demonstrate that a triethanolamine (TEA)-core PAMAM dendrimer of generation 5 (G(5)) is able to deliver sticky siRNAs bearing complementary A(n)/T(n) 3'-overhangs effectively to a prostate cancer model in vitro and in vivo and produce potent gene silencing of the heat shock protein 27, leading to a notable anticancer effect. The complementary A(n)/T(n) (n = 5 or 7) overhangs characteristic of these sticky siRNA molecules help the siRNA molecules self-assemble into "gene-like" longer double-stranded RNAs thus endowing a low generation dendrimer such as G(5) with greater delivery capacity. In addition, the A(n)/T(n) (n = 5 or 7) overhangs act as protruding molecular arms that allow the siRNA molecule to enwrap the dendrimer and promote a better interaction and stronger binding, ultimately contributing toward the improved delivery activity of G(5). Consequently, the low generation dendrimer G(5) in combination with sticky siRNA therapeutics may constitute a promising gene silencing-based approach for combating castration-resistant prostate tumors or other cancers and diseases, for which no effective treatment currently exists.
Asunto(s)
Dendrímeros/química , Etanolaminas/química , Silenciador del Gen/fisiología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , ARN Interferente Pequeño/administración & dosificación , Animales , Apoptosis/genética , Apoptosis/fisiología , Western Blotting , Línea Celular Tumoral , Dendrímeros/administración & dosificación , Citometría de Flujo , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Microscopía Confocal , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Phospholipids bearing tetrafluorophenylazido chromophores were synthesized with perfectly conserved amphiphilicity and photochemical activity. Interestingly however, those phospholipids harboring the amine-linked chromophores exhibited unusual (19)F NMR signals which depended on the protonation state of the lipid headgroup. These probes may serve as powerful tools for studying various pH-dependent events in biomembranes.
Asunto(s)
Azidas/química , Fosfolípidos/química , Halogenación , Espectroscopía de Resonancia Magnética , Estructura Molecular , Procesos Fotoquímicos , ProtonesRESUMEN
A family of novel bitriazolyl acyclonucleosides were synthesized using a simple and convenient one-step synthetic procedure via the Huisgen reaction by addition of NaN(3) onto triazole nucleosides bearing internal alkynyl groups introduced at the 5-position of the triazole ring. Some of the compounds exhibited interesting antiviral activity against tobacco mosaic virus, demonstrating the importance of the bitriazolyl motif for the observed antiviral activity.