47 research outputs found

    Folate Decorated Dual Drug Loaded Nanoparticle: Role of Curcumin in Enhancing Therapeutic Potential of Nutlin-3a by Reversing Multidrug Resistance

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    Retinoblastoma is the most common intraocular tumor in children. Malfunctioning of many signaling pathways regulating cell survival or apoptosis, make the disease more vulnerable. Notably, resistance to chemotherapy mediated by MRP-1, lung-resistance protein (LRP) is the most challenging aspect to treat this disease. Presently, much attention has been given to the recently developed anticancer drug nutlin-3a because of its non-genotoxic nature and potency to activate tumor suppressor protein p53. However, being a substrate of multidrug resistance protein MRP1 and Pgp its application has become limited. Currently, research has step towards reversing Multi drug resistance (MDR) by using curcumin, however its clinical relevance is restricted by plasma instability and poor bioavailability. In the present investigation we tried to encapsulate nutlin-3a and curcumin in PLGA nanoparticle (NPs) surface functionalized with folate to enhance therapeutic potential of nutlin-3a by modulating MDR. We document that curcumin can inhibit the expression of MRP-1 and LRP gene/protein in a concentration dependent manner in Y79 cells. In vitro cellular cytotoxicity, cell cycle analysis and apoptosis studies were done to compare the effectiveness of native drugs (single or combined) and single or dual drug loaded nanoparticles (unconjugated/folate conjugated). The result demonstrated an augmented therapeutic efficacy of targeted dual drug loaded NPs (Fol-Nut-Cur-NPs) over other formulation. Enhanced expression or down regulation of proapoptotic/antiapoptotic proteins respectively and down-regulation of bcl2 and NFΞΊB gene/protein by Fol-Nut-Cur-NPs substantiate the above findings. This is the first investigation exploring the role of curcumin as MDR modulator to enhance the therapeutic potentiality of nutlin-3a, which may opens new direction for targeting cancer with multidrug resistance phenotype

    Interplay between CD8Ξ±+ Dendritic Cells and Monocytes in Response to Listeria monocytogenes Infection Attenuates T Cell Responses

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    During the course of a microbial infection, different antigen presenting cells (APCs) are exposed and contribute to the ensuing immune response. CD8Ξ±+ dendritic cells (DCs) are an important coordinator of early immune responses to the intracellular bacteria Listeria monocytogenes (Lm) and are crucial for CD8+ T cell immunity. In this study, we examine the contribution of different primary APCs to inducing immune responses against Lm. We find that CD8Ξ±+ DCs are the most susceptible to infection while plasmacytoid DCs are not infected. Moreover, CD8Ξ±+ DCs are the only DC subset capable of priming an immune response to Lm in vitro and are also the only APC studied that do so when transferred into Ξ²2 microglobulin deficient mice which lack endogenous cross-presentation. Upon infection, CD11b+ DCs primarily secrete low levels of TNFΞ± while CD8Ξ±+ DCs secrete IL-12 p70. Infected monocytes secrete high levels of TNFΞ± and IL-12p70, cytokines associated with activated inflammatory macrophages. Furthermore, co-culture of infected CD8Ξ±+ DCs and CD11b+ DCs with monocytes enhances production of IL-12 p70 and TNFΞ±. However, the presence of monocytes in DC/T cell co-cultures attenuates T cell priming against Lm-derived antigens in vitro and in vivo. This suppressive activity of spleen-derived monocytes is mediated in part by both TNFΞ± and inducible nitric oxide synthase (iNOS). Thus these monocytes enhance IL-12 production to Lm infection, but concurrently abrogate DC-mediated T cell priming

    Vascular Normalization in Cerebral Angiogenesis: Friend or Foe?

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    Current antiangiogenic therapies have led to the observation that such agents can lead to improved tumor vessel structure and function termed β€œvascular normalization” which reduces tumor burden. However, vessel normalization is a transient process, and patients often develop resistance/poor response to anti-vascular strategies that remains an important clinical challenge. Therefore, increasing effort has been made to better understand the cellular and molecular mechanisms of vascular normalization and its contribution to immunomodulation. Herein, we summarize the recent effort to better understand the cellular and molecular mechanisms of vascular normalization with a focus on preclinical genetic models. These studies remain important directions for a mechanistic understanding of the complexities of the maintenance of BBB integrity and the impact of its breakdown on tumor dissemination and pharmaco-distribution of therapeutics
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