Understanding amyloid structures and disease: A continuing challenge in health research

Neurodegenerative disorders (NDDs), including Alzheimer's, Parkinson's, and Huntington's diseases, are a highly prevalent class of disorders that share the presence of aberrant aggregates called amyloids in the nervous system [...]

Study on the Production and Re-use of Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) and Extracellular Polysaccharide by the Archaeon Haloferax mediterranei Strain DSM 1411

The halobacterium Haloferax mediterranei was used to study the production of two types of biopolymers: The biopolyester poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) was accumulated as intracellular granules, whereas an extracelluar polysaccharide was excreted in parallel to biopolyester synthesis. After production, microbial re-use and degradation of these polymers under different conditions were investigated to assess the requirements for handling the product-rich fermentation broth prior to the downstream processing for product recovery. Degradation kinetics of the polymers and the impact of different storage conditions on molar mass of PHBV were studied. It turned out that the biotechnological fermentation process can be run without any sterility precautions. No major product losses were observed without pasteurization of fermentation broth after the stop of fermentation. In addition, neither PHBV nor EPS are re-utilized by the cells for biomass formation even if the culture is maintained under conditions of carbon starvation for an extended time

Transthyretin stabilization: An emerging strategy for the treatment of alzheimer’s disease?

Transthyretin (TTR), previously named prealbumin is a plasma protein secreted mainly by the liver and choroid plexus (CP) that is a carrier for thyroid hormones (THs) and retinol (vitamin A). The structure of TTR, with four monomers rich in β-chains in a globular tetrameric protein, accounts for the predisposition of the protein to aggregate in fibrils, leading to a rare and severe disease, namely transthyretin amyloidosis (ATTR). Much effort has been made and still is required to find new therapeutic compounds that can stabilize TTR (“kinetic stabilization”) and prevent the amyloid genetic process. Moreover, TTR is an interesting therapeutic target for neurodegenerative diseases due to its recognized neuroprotective properties in the cognitive impairment context and interestingly in Alzheimer’s disease (AD). Much evidence has been collected regarding the neuroprotective effects in AD, including through in vitro and in vivo studies as well as a wide range of clinical series. Despite this supported hypothesis of neuroprotection for TTR, the mechanisms are still not completely clear. The aim of this review is to highlight the most relevant findings on the neuroprotective role of TTR, and to summarize the recent progress on the development of TTR tetramer stabilizers

Collecting data through high throughput in vitro early toxicity and off-target liability assays to rapidly identify limitations of novel thyromimetics

In order to rapidly identify the phenotypic profile and possible off-target liability effects of novel synthesized thyromimetics for selection of lead compounds for further optimization studies, we performed in vitro screening on a new small library of synthetic thyromimetics. A comprehensive panel of early toxicity assays comprising cytotoxicity on 4 different cell lines (osteosarcoma, U2OS; lung fibroblast, hTERT; human breast adenocarcinoma, MCF7; human embryonic kidney, HEK293), hERG liability, cytochrome P450 inhibition (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isoforms), and off-target liability against selected proteins (Aurora B kinase and phosphodiesterase PDE4C1) and epigenetic enzymes (HDAC4, HDAC6, HDAC8, HDAC9 & SIRT7). All the compounds were screened at 10 μM in at least triplicate using well-established in vitro assays with readouts in luminescence or fluorescence polarization mode. The raw data were processed using Microsoft Excel and the Z′ for each assay was calculated (acceptable Z' >0.40). The processed and normalized data were organized in tables and visualized using spider plots. The results which are reported in the present manuscript can be used in prediction studies of early toxicity and off-target liabilities of other thyromimetics using in silico methods. The data reported herein support our research article entitled “Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-Toxicity analysis” by Runfola M., Sestito S., et al. [1

The cytotoxic activity of diiron bis-cyclopentadienyl complexes with bridging c3-ligands

Diiron bis-cyclopentadienyl bis-carbonyl cationic complexes with a bridging vinylim-inium ligand, [Fe2Cp2 (CO)(µ-CO){µ-η1:η3-C3 (R′)C2HC1NMe(R′′)}]CF3SO3 (R = Xyl = 2,6-C6H3Me2, R′ = Ph, R′′ = H, 2a; R = Xyl, R′ = R′′ = Me, 2b; R = R′ = Me, R′′ = H, 2c; R = Me, R′ = 2-naphthyl, R′′ = H, 2d; R = Me, R′ = R′′ = Ph, 2e), are easily available from commercial chemicals, robust in aqueous media and exert a variable in vitro cytotoxicity against cancer cell lines depending on the nature of the substituents on the vinyliminium ligand. The anticancer activity is, at least in part, associated to fragmentation reactions, leading to iron oxidation and active neutral and well-defined monoiron species. We report an innovative synthetic procedure for the preparation of 2a,c,d, and a facile method to access the monoiron derivative of 2a, i.e., [FeCp(CO){C1 (NMeXyl)C2HC3 (Ph)C(O)}] (3a). According to IC50 analyses at different times of incubation of the complexes, 3a is significantly faster in inhibiting cell viability compared to its diiron precursor 2a. The neutral complexes [Fe2Cp2 (CO)(µ-CO){µ-k1N:k1C:k1C-C3 (R′)C2 (Se)C1 (NMe2)C4 (CO2Y)C5 (CO2Y)}] (R′ = Y = Me, 4a; R′ = Pr, Y =tBu, 4b; R′ = Y = Et, 4c) are obtained via the two-step modification of the vinyliminium moiety and comprise a bridging selenophene-decorated alkylidene ligand. The antiproliferative activity exhibited by 4a-c is moderate but comparable on the ovarian cancer cell line A2780 and the corresponding cisplatin resistant cell line, A2780cisR. Complexes 4a-c in aqueous solutions undergo progressive release of the alkylidene ligand as a functionalized selenophene, this process being slower in cell culture medium. Since the released selenophenes SeC1 {C(O)R′ }C2 (NMe2)C3 (CO2Y)C4 (CO2Y) (R′ = Y = Me, 5a; R′ = Pr, Y =tBu, 5b) are substantially not cytotoxic, it is presumable that the activity of 4a-c is largely ascribable to the {Fe2Cp2 (CO)2 } scaffold

Perspectives on alternatives to phthalate plasticized poly(vinyl chloride) in medical devices applications

Poly(vinyl chloride) (PVC) is one of the most important polymeric materials available today and is used to manufacture many items, ranging from packaging and toys to healthcare devices. PVC is per se a rigid material but it is made softer by compounding with plasticizers, particularly phthalate esters such as di-(2-ethylhexyl) phthalate (DEHP). In flexible plasticizer PVC (P-PVC), phthalates are not chemically bound to PVC and they are released into the external environment. In particular, prolonged contact of P-PVC based medical devices with body fluids or tissues has been shown to be associated with severe health risks. Major concerns regarding the safety of P-PVC in medical plastic items have been raised, and several alternatives to phthalates and to P-PVC itself as well as chemical/physical treatments of P-PVC to reduce DEHP migration have been proposed. This review outlines recent scientific approaches for preventing DEHP contamination of humans by P-PVC medical devices, highlighting the impact of the proposed alternative materials on human health and strategies for implementing them

Selective thyroid hormone analogs

Selective thyroid hormone agonists are disclosed that are highly selective for the TR.beta. subtype with high binding affinity. Methods of using such agonists and pharmaceutical compositions containing them are also disclosed, as are novel procedures for their preparation

2-methylene-(20S,25S)-19,27-dinor-(22E)-vitamin D analogs

This invention discloses 2-methylene-(20S,25S)-19,27-dinor-(22E)-vitamin D analogs, and specifically 2-methylene-(20S,25S)-19,27-dinor-(22E)-1.alpha.,25-dihydroxyvitamin D.sub.3, and pharmaceutical uses therefor. This compound exhibits pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent and for the treatment of skin diseases such as psoriasis as well as skin conditions such as wrinkles, slack skin, dry skin and insufficient sebum secretion. This compound also has little, if any, calcemic activity and therefore may be used to treat autoimmune disorders or inflammatory diseases in humans as well as renal osteodystrophy. This compound may also be used for the treatment or prevention of obesity

3-iodothyronamine affects thermogenic substrates’ mobilization in brown adipocytes

We investigated the effect of 3-iodothyronamine (T1AM) on thermogenic substrates in brown adipocytes (BAs). BAs isolated from the stromal fraction of rat brown adipose tissue were exposed to an adipogenic medium containing insulin in the absence (M) or in the presence of 20 nM T1AM (M+T1AM) for 6 days. At the end of the treatment, the expression of p-PKA/PKA, p-AKT/AKT, p-AMPK/AMPK, p-CREB/CREB, p-P38/P38, type 1 and 3 beta adrenergic receptors (β1–β3AR), GLUT4, type 2 deiodinase (DIO2), and uncoupling protein 1 (UCP-1) were evaluated. The effects of cell conditioning with T1AM on fatty acid mobilization (basal and adrenergic-mediated), glucose uptake (basal and insulin-mediated), and ATP cell content were also analyzed in both cell populations. When compared to cells not exposed, M+T1AM cells showed increased p-PKA/PKA, p-AKT/AKT, p-CREB/CREB, p-P38/P38, and p-AMPK/AMPK, downregulation of DIO2 and β1AR, and upregulation of glycosylated β3AR, GLUT4, and adiponectin. At basal conditions, glycerol release was higher for M+T1AM cells than M cells, without any significant differences in basal glucose uptake. Notably, in M+T1AM cells, adrenergic agonists failed to activate PKA and lipolysis and to increase ATP level, but the glucose uptake in response to insulin exposure was more pronounced than in M cells. In conclusion, our results suggest that BAs conditioning with T1AM promote a catabolic condition promising to fight obesity and insulin resistance