Nanoparticles in cancer immunotherapies: An innovative strategy

Cancer has been one of the most significant causes of mortality, worldwide. Cancer immunotherapy has recently emerged as a competent, cancer-fighting clinical strategy. Nevertheless, due to the difficulty of such treatments, costs, and off-target adverse effects, the implementation of cancer immunotherapy described by the antigen-presenting cell (APC) vaccine and chimeric antigen receptor T cell therapy ex vivo in large clinical trials have been limited. Nowadays, the nanoparticles theranostic system as a promising target-based modality provides new opportunities to improve cancer immunotherapy difficulties and reduce their adverse effects. Meanwhile, the appropriate engineering of nanoparticles taking into consideration nanoparticle characteristics, such as, size, shape, and surface features, as well as the use of these physicochemical properties for suitable biological interactions, provides new possibilities for the application of nanoparticles in cancer immunotherapy. In this review article, we focus on the latest state-of-the-art nanoparticle-based antigen/adjuvant delivery vehicle strategies to professional APCs and engineering specific T lymphocyte required for improving the efficiency of tumor-specific immunotherapy.     

Draft Genome Sequence of Ureibacillus thermosphaericus Strain Thermo-BF, Isolated from Ramsar Hot Springs in Iran

Ureibacillus thermosphaericus strain Thermo-BF is an aerobic, thermophilic bacillus which has been characterized to biosynthesize gold nanoparticles. Here we present the draft genome sequence of Ureibacillus thermosphaericus strain Thermo-BF which consists of a 2,864,162-bp chromosome. This is the first report of a shotgun sequenced draft genome of a species in the Ureibacillus genus.     

Maintaining hepatocyte differentiation in vitro through co-culture with hepatic stellate cells

Primary hepatocytes lose their differentiated functions rapidly when in culture. Our aim was to maintain the differentiated status of hepatocytes in vitro by means of vital hepatic stellate cells (HSCs), their soluble and particulate factors and lipid extracts. Hepatocytes were placed into collagen-coated culture dishes in the presence of HSCs at different ages of pre-culture, with or without direct cell to cell contacts, at different cell ratios and in monoculture with cellular HSC components in place of vital cells. Changes in morphology and enhancement of phosphoenolpyruvate carboxykinase (PCK) activity by glucagon were used to determine the differentiated status of hepatocytes in 2d-short-term culture. HSCs proved able to maintain the differentiated function of hepatocytes in co-culture either by direct cell contacts or via factors derived from HSC-conditioned medium. In comparison, however, without cellular contact to hepatocytes five to ten times as many HSCs were necessary to increase the PCK activity to the same degree as in the presence of intercellular contacts. Whereas stimulation in the presence of HSC/hepatocyte contacts was independent of HSC culture age only quiescent, resting HSCs (precultured for 1–2 d) were able to stimulate hepatocytes significantly via soluble factors. Culturing of hepatocytes with a lipid extract or a particulate fraction from HSCs clearly displayed a very strong beneficial effect on enzyme activity and morphology. HSCs maintain hepatocyte function and structure through preferentially cell-bound signalling and transfer of lipids.     

Structure, Evolutionary Conservation, and Conformational Dynamics of Homo sapiens Fascin-1, an F-actin Crosslinking Protein

Eukaryotes have several highly conserved actin-binding proteins that crosslink filamentous actin into compact ordered bundles present in distinct cytoskeletal processes, including microvilli, stereocilia and filopodia. Fascin is an actin-binding protein that is present predominantly in filopodia, which are believed to play a central role in normal and aberrant cell migration. An important outstanding question regards the molecular basis for the unique localization and functional properties of fascin compared with other actin crosslinking proteins. Here, we present the crystal structure of full-length Homo sapiens fascin-1, and examine its packing, conformational flexibility, and evolutionary sequence conservation. The structure reveals a novel arrangement of four tandem β-trefoil domains that form a bi-lobed structure with approximate pseudo 2-fold symmetry. Each lobe has internal approximate pseudo 2-fold and pseudo 3-fold symmetry axes that are approximately perpendicular, with β-hairpin triplets located symmetrically on opposite sides of each lobe that mutational data suggest are actin-binding domains. Sequence conservation analysis confirms the importance of hydrophobic core residues that stabilize the β-trefoil fold, as well as interfacial residues that are likely to stabilize the overall fascin molecule. Sequence conservation also indicates highly conserved surface patches near the putative actin-binding domains of fascin, which conformational dynamics analysis suggests to be coupled via an allosteric mechanism that might have important functional implications for F-actin crosslinking by fascin.     

Microbial hydroxylation of rustmicin (galbonolide A) and galbonolide B, two antifungal products produced by Micromonospora sp.

In order to synthesize derivatives of galbonolide A and B with improved chemical stability and antifungal activity profiles, a panel of microorganisms consisting of various species of actinomycetes and fungi were screened. As a result, an organism, Streptomyces halstedii, was identified, which catalyzed the formation of two polar compounds, one from each of the galbonolides. The synthesis and the relative stability of these compounds were optimized by using washed cells, which had been prepared from the transforming organism, and reaction conditions, which included the usage of MES buffer with pH adjusted to 5.5 and incubation at 27°C. Under conditions thus established, two compounds were isolated and characterized by a combination of UV, mass, and NMR spectroscopic analysis. The data indicate the synthesis of 21-hydroxy derivatives of galbonolides A and B with reduced but still significant anti-fungal activity when compared to the parent galbonolides.     

L-type calcium channel blockade attenuates morphine withdrawal: in vivo interaction between L-type calcium channels and corticosterone

Both opioids and calcium channel blockers could affect hypothalamic-pituitary-adrenal (HPA) axis function. Nifedipine, as a calcium channel blocker, can attenuate the development of morphine dependence; however, the role of the HPA axis in this effect has not been elucidated. We examined the effect of nifedipine on the induction of morphine dependency in intact and adrenalectomized (ADX) male rats, as assessed by the naloxone precipitation test. We also evaluated the effect of this drug on HPA activity induced by naloxone. Our results showed that despite the demonstration of dependence in both groups of rats, nifedipine is more effective in preventing of withdrawal signs in ADX rats than in sham-operated rats. In groups that received morphine and nifedipine concomitantly, naloxone-induced corticosterone secretion was attenuated. Thus, we have shown the involvement of the HPA axis in the effect of nifedipine on the development of morphine dependency and additionally demonstrated an in vivo interaction between the L-type Ca2+ channels and corticosterone.     

Cdk5: a novel role in learning and memory

Learning and memory are processes by which organisms acquire, retain and retrieve information. They result in modifications of behavior in response to new or previously encountered stimuli thereby enabling adaptation to a permanently changing environment. Protein phosphorylation has long been known to play a key role in triggering synaptic changes underlying learning and memory. Although intracellular phosphorylation and dephosphorylation is orchestrated by a complex network of interactions between a number of protein kinases and phosphatases, significant advances in the understanding of neuronal mechanisms underlying learning and memory have been achieved by investigating the actions of individual molecules under defined experimental conditions, brain areas, neuronal cells and their subcellular compartments. On the basis of these approaches, the cyclic AMP protein kinase (PKA), protein kinase C (PKC) and extracellularly regulated protein kinases 1 and 2 (Erk-1/2) have been identified as the core signaling pathways in memory consolidation. Here we review recent findings demonstrating an important novel role for Cdk5 in learning and memory. We suggest that some of the well-characterized roles of Cdk5 during neurodevelopmental processes, such as interactions with distinct cytoplasmic and synaptic target molecules, may be also involved in synaptic plasticity underlying memory consolidation within the adult central nervous system.     

Detection of pathological zinc accumulation in neurons: methods for autopsy, biopsy, and cultured tissue.

It has been repeatedly shown that synaptically released zinc contributes to excitotoxic neuronal injury in ischemia, epilepsy, and mechanical head trauma. Such zinc-induced injury leaves an unmistakable "footprint" in the injured neurons, allowing an easy and unambiguous postmortem diagnosis. This footprint is the presence of weakly bound, histochemically reactive zinc in the cytoplasm of the perikaryon and proximal dendrites. Such staining appears to be a necessary and sufficient marker for zinc-induced neuronal injury. Here we show how to prepare and stain tissue from biopsy, autopsy, or experimental animal sources for maximal contrast and visibility of zinc-injured neurons.