[show abstract][hide abstract] ABSTRACT: Fluorescent and biotinylated squalene–gemcitabine prodrug nanoparticles exhibiting high drug payloads have been prepared and successfully used to target different cancer cell lines, resulting in increased cell uptake and improved anticancer efficiency, which represents the first targeted system derived from the squalenoylation approach.
[show abstract][hide abstract] ABSTRACT: Spurred by recent progress in materials chemistry and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).
[show abstract][hide abstract] ABSTRACT: A new paclitaxel (Ptx) prodrug was designed by coupling a single terpene unit (MIP) to the hydroxyl group in position 2' of the drug molecule. Using a squalene derivative of polyethylene glycol (SQ-PEG) as surface active agent, the resulting bioconjugate (PtxMIP) self-assembled in water leading to the formation of stable nanoparticles (PtxMIP_SQ-PEG NPs) with an impressively high drug loading (82%). In vivo, the anticancer activity of this novel Ptx nanoassembled prodrug was compared to the conventional Cremophor-containing formulation (Taxol) on a murine model of breast cancer lung metastasis induced by intravenous injection of 4T1 tumor cells, genetically modified to stably express firefly luciferase. Cell growth was assessed noninvasively by bioluminescence imaging (BLI) which enabled monitoring tumor metastatic burden in the same animals. PtxMIP_SQ-PEG nanoparticles slowed metastatic spread and were better tolerated than the Cremophor-containing formulation (i.e., free drug), thus demonstrating the potential of terpene-based nanoassembled prodrugs in the improvement of the therapeutic index of Ptx in balb/c mice.
[show abstract][hide abstract] ABSTRACT: Unprotected thioglycosides were effective nucleophiles for Ni(0) -catalyzed CS bond-forming reaction with functionalized (hetero)aryl, alkenyl, and alkynyl halides. The functional-group tolerance on the electrophilic partner was typically high and the anomeric selectivities of the thioglycosides were high in all cases. The efficiency of this general procedure was well-demonstrated by the synthesis of 4-methyl-7-thioumbelliferyl-β-D-cellobioside (MUS-CB).
[show abstract][hide abstract] ABSTRACT: Cell migration is dependent on a series of integrated cellular events including the membrane recycling of the extracellular matrix receptor integrins. In this paper, we investigate the role of autophagy in regulating cell migration. In a wound-healing assay, we observed that autophagy was reduced in cells at the leading edge than in cells located rearward. These differences in autophagy were correlated with the robustness of MTOR activity. The spatial difference in the accumulation of autophagic structures was not detected in rapamycin-treated cells, which had less migration capacity than untreated cells. In contrast, the knockdown of the autophagic protein ATG7 stimulated cell migration of HeLa cells. Accordingly, atg3(-/-) and atg5(-/-) MEFs have greater cell migration properties than their wild-type counterparts. Stimulation of autophagy increased the co-localization of β1 integrin-containing vesicles with LC3-stained autophagic vacuoles. Moreover, inhibition of autophagy slowed down the lysosomal degradation of internalized β1 integrins and promoted its membrane recycling. From these findings, we conclude that autophagy regulates cell migration, a central mechanism in cell development, angiogenesis, and tumor progression, by mitigating the cell surface expression of β1 integrins.
[show abstract][hide abstract] ABSTRACT: Introduction: Sildenafil citrate is a potent, selective phosphodiesterase type 5 inhibitor approved for the treatment of pulmonary arterial hypertension (PAH) and plays an important role in the management of the disease. Areas covered: In this review, we focus on the current available information on the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of sildenafil citrate in PAH through a MEDLINE literature search. Comparison of sildenafil citrate with tadalafil, another phosphodiesterase type 5 inhibitor was also performed. Expert opinion: In the last few years, considerable progress has been made in the understanding and treatment of PAH. Sildenafil citrate has multiple advantages and whether it is first-line treatment alone or in combination for the mild form of the disease, it is one of the treatments of choice. In terms of its future use, more studies are still needed to better evaluate the benefit/risk balance of sildenafil citrate in pediatric populations.
Expert Opinion on Drug Metabolism & Toxicology 09/2013; 9(9):1193-205.
[show abstract][hide abstract] ABSTRACT: SUMMARY Hosts are protected from attack by potentially harmful enteric microorganisms, viruses, and parasites by the polarized fully differentiated epithelial cells that make up the epithelium, providing a physical and functional barrier. Enterovirulent bacteria interact with the epithelial polarized cells lining the intestinal barrier, and some invade the cells. A better understanding of the cross talk between enterovirulent bacteria and the polarized intestinal cells has resulted in the identification of essential enterovirulent bacterial structures and virulence gene products playing pivotal roles in pathogenesis. Cultured animal cell lines and cultured human nonintestinal, undifferentiated epithelial cells have been extensively used for understanding the mechanisms by which some human enterovirulent bacteria induce intestinal disorders. Human colon carcinoma cell lines which are able to express in culture the functional and structural characteristics of mature enterocytes and goblet cells have been established, mimicking structurally and functionally an intestinal epithelial barrier. Moreover, Caco-2-derived M-like cells have been established, mimicking the bacterial capture property of M cells of Peyer's patches. This review intends to analyze the cellular and molecular mechanisms of pathogenesis of human enterovirulent bacteria observed in infected cultured human colon carcinoma enterocyte-like HT-29 subpopulations, enterocyte-like Caco-2 and clone cells, the colonic T84 cell line, HT-29 mucus-secreting cell subpopulations, and Caco-2-derived M-like cells, including cell association, cell entry, intracellular lifestyle, structural lesions at the brush border, functional lesions in enterocytes and goblet cells, functional and structural lesions at the junctional domain, and host cellular defense responses.
Microbiology and molecular biology reviews: MMBR 09/2013; 77(3):380-439.
[show abstract][hide abstract] ABSTRACT: Antidepressant drugs such as the serotonin (5-HT)/norepinephrine (NE) and/or dopamine (DA) reuptake inhibitors have been shown to activate the monoaminergic neurotransmission in various brain regions such as the amygdala, frontal cortex or hippocampus. Although this property is well established, the post-synaptic mechanisms by which these pharmacological agents would exert their therapeutic activity in major depressive disorders (MDD) is as yet not fully understood. Recent clinical and preclinical studies indicate that the density and reactivity of glia and more particularly of astrocytes are reduced in MDD patients. This data along with the fact that astrocytes express monoaminergic transporters and receptors make these cells putative targets for antidepressant treatments. Accordingly, in vitro evidence demonstrates that the application of various classes of antidepressant drugs on rodents primary cultures of astrocytes elicits a wide spectrum of responses from the rise in cytosolic calcium concentrations, as a marker of cellular activity, to the release of glucose metabolites, gliotransmitters and neurotrophic factors. Remarkably, antidepressant drugs also have the peculiarity to attenuate the release of inflammatory molecules from reactive astrocytes or microglia suggesting that part of their beneficial effects in depressed patients or animal models of depression might result from their ability to regulate the synthesis and release of psychoactive substances acting on both pre- and post-synaptic neurons. Among the many long-term targets of antidepressant drugs, brain-derived neurotrophic factor (BDNF) has been well studied owing to its positive influence on adult hippocampal neurogenesis, synaptogenesis and local serotonergic tone. The present review will illustrate how the concept of the tripartite synapse, classically associated to different forms of plasticity involving glutamate, may be expanded to the monoaminergic systems to regulate antidepressant drug responses? An emphasis will be given on recent in vivo data supporting that hippocampal astrocytes may act in concert with neurons to release BDNF under pharmacological conditions and thereby regulate different facets of anxiolytic-/antidepressant-like activities through neurogenesis-dependent and independent mechanisms.
[show abstract][hide abstract] ABSTRACT: Covering: 2005 to 2013This review focuses on recent applications of the aza-Michael reaction in alkaloids total synthesis with a special emphasis on stereoselectivity. The report highlights achievements and challenges over the past five years and describes stereoselective intra- and inter-molecular conjugate addition of nitrogen-containing nucleophiles, including tandem and cascade processes. Total asymmetric syntheses of natural scaffolds, such as pyrrolidine, piperidine and "izidine" families, are depicted. Multi-step syntheses of highly challenging natural products are further detailed, assessing the scope of the stereocontrolled aza-Michael reaction as a powerful tool in alkaloid chemistry.
[show abstract][hide abstract] ABSTRACT: Clostridium difficile is currently the major cause of nosocomial intestinal diseases associated with antibiotic therapy in adults. In order to improve our knowledge on C. difficile-host interactions, we analysed the genome-wide temporal expression of C. difficile 630 genes during the first 38 hours of mouse colonization, to identify genes whose expression is modulated in vivo, suggesting that they may play a role to facilitate the colonization process. In the ceaca of the C. difficile-monoassociated mice, 549 genes of the C. difficile genome were differentially expressed when compared to in vitro growth, and were distributed in several functional categories. Overall, our results emphasize the roles of genes involved in host adaptation. Colonization results in a metabolic shift with genes responsible for the fermentation as well as several other metabolic pathways inversely regulated to those involved in carbon metabolism. In addition, several genes involved in stress responses, such as ferrous iron uptake or response to oxidative stress, were regulated in vivo. Interestingly, many genes encoding conserved hypothetical proteins (CHP) were highly and specifically up-regulated in vivo. Moreover, genes for all stages of sporulation were quickly induced in vivo, highlighting that sporulation is central to the persistence of C. difficile in the gut and to its ability to spread in the environment. Finally, we inactivated two genes differentially expressed in vivo, and evaluated the relative colonization fitness of the wild type and the mutant strains in co-infection experiments. We identified a CHP as a putative colonization factor, supporting that the in vivo transcriptomics approach can unravel new C. difficile virulence genes.
Infection and immunity 07/2013;
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