RESUMEN

BACKGROUND: Phosphatidylcholine (PC) and Omega-3 fatty acid (Omega-3) are promising therapeutic molecules for treating inflammatory bowel disease (IBD). PURPOSE: Based on the IBD therapeutic potential of nanoparticles, we herein sought to develop Omega-3-incorporated PC nanoparticles (liposomes) as an orally administrable vehicle for treating IBD. METHODS: Liposomes prepared with or without Omega-3 incorporation were compared in terms of colloidal stability and anitiinflammatory effects. RESULTS: The incorporation of free Omega-3 (alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid) into liposomes induced time-dependent membrane fusion, resulting in particle size increase from nm to µm during storage. In contrast, krill oil incorporation into liposomes (KO liposomes) did not induce the fusion and the particle size maintained <250 nm during storage. KO liposomes also maintained colloidal stability in simulated gastrointestinal conditions and exhibited a high capacity to entrap the IBD drug, budesonide (BDS). KO liposomes greatly suppressed the lipopolysaccharide-induced production of pro-inflammatory cytokines in cultured macrophages and completely restored inflammation-impaired membrane barrier function in an intestinal barrier model. In mice subjected to dextran sulfate sodium-induced colitis, oral administration of BDS-entrapped KO liposomes suppressed tumor necrosis factor-α production (by 84.1%), interleukin-6 production (by 35.3%), and the systemic level of endotoxin (by 96.8%), and slightly reduced the macroscopic signs of the disease. CONCLUSION: Taken together, KO liposomes may have great potential as a nanovehicle for oral delivery of IBD drugs.

Asunto(s)

Antiinflamatorios no Esteroideos/farmacología , Colitis/tratamiento farmacológico , Euphausiacea/química , Liposomas/farmacología , Aceites/química , Animales , Antiinflamatorios no Esteroideos/química , Budesonida/química , Budesonida/farmacología , Células CACO-2 , Colitis/inducido químicamente , Citocinas/metabolismo , Sulfato de Dextran/toxicidad , Ácidos Grasos Omega-3/química , Femenino , Humanos , Lipopolisacáridos/farmacología , Liposomas/química , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL

RESUMEN

Orthogonal frequency division multiple access (OFDMA) uplink in a passive optical network (PON) requires the delay alignment for OFDMA symbols from remotely distributed optical network units (ONUs). In this paper, we experimentally demonstrate and analyze the performance of a Zadoff-Chu (ZC) sequence-based upstream ranging scheme in an intensity modulation/direct detection (IM/DD)-based OFDMA-PON. The experimental results show that the proposed scheme can achieve upstream synchronization with only marginal inter-carrier interference (ICI) and requires no additional bandwidths in a typical OFDMA transmission with cyclic prefix (CP).

RESUMEN

The efficacy of T-cell therapy is inhibited by various tumor-associated immunosuppressive ligands and soluble factors. Such inhibitory signals turn specific T-cell signaling pathways on or off, impeding the anticancer functions of T cells. Many studies have focused on PD-1 or CTLA-4 blockade to invigorate T-cell functions through CD28/B7 signaling, but obtaining robust clinical outcomes remains challenging. In this study, we use CRISPR/Cas9 to potentiate T-cell function by increasing CD3 signaling via knockout of diacylglycerol kinase (DGK), an enzyme that metabolizes diacylglycerol to phosphatidic acid. Knockout of DGK augmented the effector functions of CAR-T cells in vitro via increased TCR signaling. DGK knockout from CAR-T cells rendered them resistant to soluble immunosuppressive factors such as TGFß and prostaglandin E2 and sustained effector functions under conditions of repeated tumor stimulation. Moreover, DGK knockout caused significant regression of U87MGvIII glioblastoma tumors through enhanced effector functions in a xenograft mouse model. Collectively, our study shows that knockout of DGK effectively enhances the effector functions of CAR-T cells, suggesting that CRISPR/Cas9-mediated knockout of DGK could be applicable as part of a multifaceted clinical strategy to treat solid cancers.Significance: This novel study demonstrates efficient ablation of diacylglycerol kinase in human CAR-T cells that leads to improved antitumor immunity and may have significant impact in human cancer immunotherapy. Cancer Res; 78(16); 4692-703. ©2018 AACR.

Asunto(s)

Diacilglicerol Quinasa/genética , Inmunoterapia Adoptiva , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , Animales , Antígenos CD28/genética , Antígenos CD28/inmunología , Sistemas CRISPR-Cas/genética , Sistemas CRISPR-Cas/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Línea Celular Tumoral , Diacilglicerol Quinasa/inmunología , Técnicas de Inactivación de Genes , Humanos , Ligandos , Ratones , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Chemokine (C-X3-C motif) ligand 1 (CX3CL1, also known as fractalkine) and its receptor chemokine (C-X3-C motif) receptor 1 (CX3CR1) are widely expressed in immune cells and non-immune cells throughout organisms. However, their expression is mostly cell type-specific in each tissue. CX3CR1 expression can be found in monocytes, macrophages, dendritic cells, T cells, and natural killer (NK) cells. Interaction between CX3CL1 and CX3CR1 can mediate chemotaxis of immune cells according to concentration gradient of ligands. CX3CR1 expressing immune cells have a main role in either pro-inflammatory or anti-inflammatory response depending on environmental condition. In a given tissue such as bone marrow, brain, lung, liver, gut, and cancer, CX3CR1 expressing cells can maintain tissue homeostasis. Under pathologic conditions, however, CX3CR1 expressing cells can play a critical role in disease pathogenesis. Here, we discuss recent progresses of CX3CL1/CX3CR1 in major tissues and their relationships with human diseases.