A novel peptide-based tau aggregation inhibitor as a potential therapeutic for Alzheimer's disease and other tauopathies.

Introduction: As aggregation underpins Tau toxicity, aggregation inhibitor peptides may have disease-modifying potential. They are therefore currently being designed and target either the VQIVYK aggregation-promoting hotspot found in all Tau isoforms or the VQIINK aggregation-promoting hotspot found in 4R isoforms. However, for any Tau aggregation inhibitor to potentially be clinically relevant for other tauopathies, it should target both hotspots to suppress aggregation of Tau isoforms, be stable, cross the blood-brain barrier, and rescue aggregation-dependent Tau phenotypes in vivo.

Aggregation Kinetics and Filament Structure of a Tau Fragment Are Influenced by the Sulfation Pattern of the Cofactor Heparin.

A pathological signature of Alzheimer's disease (AD) is the formation of neurofibrillary tangles comprising filamentous aggregates of the microtubule associated protein tau. Tau self-assembly is accelerated by polyanions including heparin, an analogue of heparan sulfate. Tau filaments colocalize with heparan sulfate proteoglycans (HSPGs) in vivo, and HSPGs may also assist the transcellular propagation of tau aggregates.

Circular Dichroism Spectroscopy Identifies the β-Adrenoceptor Agonist Salbutamol As a Direct Inhibitor of Tau Filament Formation .

Potential drug treatments for Alzheimer's disease (AD) may be found by identifying compounds that block the assembly of the microtubule-associated protein tau into neurofibrillar tangles associated with neuron destabilization and cell death. Here, a small library of structurally diverse compounds was screened for the ability to inhibit tau aggregation, using high-throughput synchrotron radiation circular dichroism as a novel tool to monitor the structural changes in the protein as it assembles into filaments. The catecholamine epinephrine was found to be the most effective tau aggregation inhibitor of all 88 screened compounds.

Bioactive silver phosphate/polyindole nanocomposites.

Materials capable of releasing reactive oxygen species (ROS) can display antibacterial and anticancer activity, and may also have anti-oxidant capacity if they suppress intracellular ROS ( nitric oxide, NO) resulting in anti-inflammatory activity. Herein we report silver phosphate (AgPO)/polyindole (Pln) nanocomposites which display antibacterial, anticancer and anti-inflammatory activity, and have therefore potential for a variety of biomedical applications.

Standardization of complex biologically derived spectrochemical datasets.

Spectroscopic techniques such as Fourier-transform infrared (FTIR) spectroscopy are used to study interactions of light with biological materials. This interaction forms the basis of many analytical assays used in disease screening/diagnosis, microbiological studies, and forensic/environmental investigations. Advantages of spectrochemical analysis are its low cost, minimal sample preparation, non-destructive nature and substantially accurate results.

An analysis of benign human prostate offers insights into the mechanism of apocrine secretion and the origin of prostasomes.

The structure and function of normal human prostate is still not fully understood. Herein, we concentrate on the different cell types present in normal prostate, describing some previously unreported types and provide evidence that prostasomes are primarily produced by apocrine secretion. Patients (n = 10) undergoing TURP were prospectively consented based on their having a low risk of harbouring CaP.

Development of proteolytically stable N-methylated peptide inhibitors of aggregation of the amylin peptide implicated in type 2 diabetes.

Islet amyloid polypeptide, also known as amylin, is the main component of the amyloid deposits present in approximately 90% of people with type 2 diabetes mellitus (T2DM). In this disease, amylin aggregates into multimeric β-pleated sheet structures which cause damage to pancreatic islet β-cells. Inhibitors of early-stage amylin aggregation could therefore provide a disease-modifying treatment for T2DM.

A Surgical Cryoprobe for Targeted Transcorneal Freezing and Endothelial Cell Removal.

Purpose: To examine the effects of transcorneal freezing using a new cryoprobe designed for corneal endothelial surgery.

Methods: A freezing console employing nitrous oxide as a cryogen was used to cool a series of different cryoprobe tip designs made of silver for high thermal conductivity. In vitro studies were conducted on 426 porcine corneas, followed by preliminary in vivo investigations on three rabbit corneas.

Immune Cells on the Corneal Endothelium of an Allogeneic Corneal Transplantation Rabbit Model.

Purpose: Corneal endothelial cell density undergoes a progressive decrease for many years after transplantation, eventually threatening patients with late endothelial failure. The purpose of this study was to investigate the possibility of an immunologic response in successfully grafted corneal endothelium.

Methods: The corneal endothelium of patients who had undergone corneal transplantation was evaluated by specular microscopy.

Development of functional human oral mucosal epithelial stem/progenitor cell sheets using a feeder-free and serum-free culture system for ocular surface reconstruction.

Ocular surface reconstruction (OSR) using tissue-engineered cultivated oral mucosal epithelial cell sheets (COMECS) is a promising newly developed treatment for patients with severe ocular surface disease. Until now, this technique has used exogenic and undefined components such as mouse-derived 3T3 feeder cells and fetal bovine serum. To minimize associated risks of zoonotic infection or transmission of unknown pathogens and so establish a safe and effective protocol for the next generation of treatment modality, we developed a novel technique for the COMECS protocol, using a feeder-free and serum-free (FFSF) culture system.

Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer's Aβ peptide.

Aggregation of amyloid-β peptide (Aβ) is a key event in the pathogenesis of Alzheimer's disease (AD). We investigated the effects of nanoliposomes decorated with the retro-inverso peptide RI-OR2-TAT (Ac-rGffvlkGrrrrqrrkkrGy-NH) on the aggregation and toxicity of Aβ. Remarkably low concentrations of these peptide inhibitor nanoparticles (PINPs) were required to inhibit the formation of Aβ oligomers and fibrils in vitro, with 50% inhibition occurring at a molar ratio of ~1:2000 of liposome-bound RI-OR2-TAT to Aβ.

Diet-sourced carbon-based nanoparticles induce lipid alterations in tissues of zebrafish (Danio rerio) with genomic hypermethylation changes in brain.

With rising environmental levels of carbon-based nanoparticles (CBNs), there is an urgent need to develop an understanding of their biological effects in order to generate appropriate risk assessment strategies. Herein, we exposed zebrafish via their diet to one of four different CBNs: C fullerene (C), single-walled carbon nanotubes (SWCNT), short multi-walled carbon nanotubes (MWCNTs) or long MWCNTs. Lipid alterations in male and female zebrafish were explored post-exposure in three target tissues (brain, gonads and gastrointestinal tract) using 'omic' procedures based in liquid chromatography coupled with mass spectrometry (LC-MS) data files.

Using Raman spectroscopy to characterize biological materials.

Raman spectroscopy can be used to measure the chemical composition of a sample, which can in turn be used to extract biological information. Many materials have characteristic Raman spectra, which means that Raman spectroscopy has proven to be an effective analytical approach in geology, semiconductor, materials and polymer science fields. The application of Raman spectroscopy and microscopy within biology is rapidly increasing because it can provide chemical and compositional information, but it does not typically suffer from interference from water molecules.

Low-dose carbon-based nanoparticle-induced effects in A549 lung cells determined by biospectroscopy are associated with increases in genomic methylation.

Nanotechnology has introduced many manufactured carbon-based nanoparticles (CNPs) into our environment, generating a debate into their risks and benefits. Numerous nanotoxicology investigations have been carried, and nanoparticle-induced toxic effects have been reported. However, there remain gaps in our knowledge, primarily regarding mechanism.

Rho-Associated Kinase Inhibitor Eye Drop (Ripasudil) Transiently Alters the Morphology of Corneal Endothelial Cells.

Purpose: Ripasudil (Glanatec), a selective Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, was approved in Japan in September 2014 for the treatment of glaucoma and ocular hypertension. The purpose of this study was to investigate the effect of ripasudil eye drops on corneal endothelial morphology, as ROCK signaling is known to modulate the actin cytoskeleton.

Methods: Morphological changes in the corneal endothelium were evaluated in human subjects by specular and slit-lamp microscopy, following topical administration of ripasudil.

Distinguishing nuclei-specific benzo[a]pyrene-induced effects from whole-cell alterations in MCF-7 cells using Fourier-transform infrared spectroscopy.

Exposure to chemicals such as benzo[a]pyrene (B[a]P) can generate intracellular toxic mechanisms. Fourier-transform infrared (FTIR) spectroscopy is a novel approach that allows the non-destructive analysis of underlying chemical bond alterations in patho-physiological processes. This study set out to examine whether B[a]P-induced whole cell alterations could be distinguished from effects on nuclei of exposed cells.

Gold nanoparticles as a substrate in bio-analytical near-infrared surface-enhanced Raman spectroscopy.

As biospectroscopy techniques continue to be developed for screening or diagnosis within a point-of-care setting, an important development for this field will be high-throughput optimization. For many of these techniques, it is therefore necessary to adapt and develop parameters to generate a robust yet simple approach delivering high-quality spectra from biological samples. Specifically, this is important for surface-enhanced Raman spectroscopy (SERS) wherein there are multiple variables that can be optimised to achieve an enhancement of the Raman signal from a sample.

Surface-enhanced Raman spectroscopy of the endothelial cell membrane.

We applied surface-enhanced Raman spectroscopy (SERS) to cationic gold-labeled endothelial cells to derive SERS-enhanced spectra of the bimolecular makeup of the plasma membrane. A two-step protocol with cationic charged gold nanoparticles followed by silver-intensification to generate silver nanoparticles on the cell surface was employed. This protocol of post-labelling silver-intensification facilitates the collection of SERS-enhanced spectra from the cell membrane without contribution from conjugated antibodies or other molecules.

Using Fourier transform IR spectroscopy to analyze biological materials.

IR spectroscopy is an excellent method for biological analyses. It enables the nonperturbative, label-free extraction of biochemical information and images toward diagnosis and the assessment of cell functionality. Although not strictly microscopy in the conventional sense, it allows the construction of images of tissue or cell architecture by the passing of spectral data through a variety of computational algorithms.

Infrared microspectroscopy identifies biomolecular changes associated with chronic oxidative stress in mammary epithelium and stroma of breast tissues from healthy young women: implications for latent stages of breast carcinogenesis.

Studies of the decades-long latent stages of breast carcinogenesis have been limited to when hyperplastic lesions are already present. Investigations of earlier stages of breast cancer (BC) latency have been stymied by the lack of fiducial biomarkers needed to identify where in histologically normal tissues progression toward a BC might be taking place. Recent evidence suggests that a marker of chronic oxidative stress (OxS), protein adducts of 4-hydroxy-2-nonenal (4HNE), can meet this need.

Dose-related alterations of carbon nanoparticles in mammalian cells detected using biospectroscopy: potential for real-world effects.

Nanotechnologies generate a wide range of engineered nanomaterials that enter into our ecosystem, especially carbon-based nanoparticles (CNPs). As these novel materials acquire ever increasing numbers of applications, they may pose a risk to organisms, including humans. However, our knowledge of nanoparticle-induced effects remains limited.

Sub-cellular spectrochemical imaging of isolated human corneal cells employing synchrotron radiation-based Fourier-transform infrared microspectroscopy.

Understanding stem cell (SC) biology remains challenging and one of the few human tissues within which their in situ location is well characterized is the cornea. Individual human corneal epithelial cells were isolated from biopsies of live tissues using fluorescence-activated cell sorting (FACS); these were divided into putative SCs, transit-amplifying (TA) cells and terminally-differentiated (TD) cells. Employing synchrotron radiation-based Fourier-transform infrared (SR-FTIR) microspectroscopy with a focal plane array (FPA), sub-cellular spatial resolution analysis of unstained isolated cells was achieved as a consequence of the brilliance of a 12 collimated beams arrangement allowing rapid spectral acquisition.

Classification of test agent-specific effects in the Syrian hamster embryo assay (pH 6.7) using infrared spectroscopy with computational analysis.

The Syrian hamster embryo (SHE) cell transformation assay (pH 6.7) has utility in the assessment of potential chemical carcinogenicity (both genotoxic and non-genotoxic mechanisms of action). The assay uses morphological transformation as an end point and has a reported sensitivity of 87%, specificity of 83% and overall concordance of 85% with in vivo rodent bioassay data.