Identification of Natural Products as Potential Pharmacological Chaperones for Protein Misfolding Diseases

Defective protein folding and accumulation of misfolded proteins is associated with neurodegenerative, cardiovascular, secretory, and metabolic disorders. Efforts are being made to identify small-molecule modulators or structural-correctors for conformationally destabilized proteins implicated in various protein aggregation diseases. Using a metastable-reporter-based primary screen, we evaluated pharmacological chaperone activity of a diverse class of natural products. We found that a flavonoid glycoside ( C-10 , chrysoeriol-7-O-β-D-glucopyranoside) stabilizes metastable proteins, prevents its aggregation, and remodels the oligomers into protease-sensitive species. Data was corroborated with additional secondary screen with disease-specific pathogenic protein. In vitro and cell-based experiments showed that C-10 inhibits α-synuclein aggregation which is implicated in synucleinopathies-related neurodegeneration. C-10 interferes in its structural transition into β-sheeted fibrils and mitigates α-synuclein aggregation-associated cytotoxic effects. Computational modeling suggests that C-10 binds to unique sites in α-synuclein which may interfere in its aggregation amplification. These findings open an avenue for comprehensive SAR development for flavonoid glycosides as pharmacological chaperones for metastable and aggregation-prone proteins implicated in protein conformational diseases.     

Angiogenic potential of boron-containing bioactive glasses: in vitro study

Boron-containing bioactive glasses (BGs) are being extensively researched for the treatment and regeneration of bone defects because of their osteostimulatory and neovascularization potential. In this study, we report the effects of the ionic dissolution products (IDPs) of different boron-doped, borosilicate, and borate BG scaffolds on mouse bone marrow stromal cells in vitro, using an angiogenesis assay. Five different BG scaffolds of the system SiO₂–Na₂O–K₂O–MgO–CaO–P₂O₅–B₂O₃ (with varying amounts of SiO₂ and B₂O₃) were fabricated by the foam replication technique. Bone marrow stromal cells were cultivated in contact with the IDPs of the boron-containing BG scaffolds at different concentrations for 48 h. The expression and secretion of vascular endothelial growth factor (VEGF) from the cultured cells was measured quantitatively using the VEGF ELISA Kit. Cell viability and cell morphology were determined using WST-8 assay and H&E staining, respectively. The cellular response was found to be dependent on boron content and the B release profile from the glasses corresponded to the positive or negative biological activity of the BGs.     

CryptoCT: towards privacy preserving color transfer and storage over cloud

Multimedia Tools and Applications - Current trend toward cloud computing coupled with emerging technologies such as high definition images/videos and 360-degree videos, has led the requirement of...     

Pluronic lecithin organogel of 5-aminosalicylic acid for wound healing

5-Aminosalicylic acid (5-ASA) is an aminosalicylate anti-inflammatory drug, which is also known as mesalazine or mesalamine. Currently employed in treating inflammatory bowel disease, ulcerative colitis, inflamed anus or rectum, and maintain remission in Crohn's disease. Evidence from the researchers highlighted its significant re-epithelization in allergic asthma, aphthous, and gastric ulcerative conditions. The objective of the study was to formulate the pluronic lecithin organogel (PLO) containing 5-ASA and evaluate its wound-healing ability in a full thickness excision wound rat model. The data obtained from in silico docking studies revealed 5-ASA is having an affinity towards the transforming growth factor-beta (TGF-β) specifically towards beta1. Among various formulations prepared (F1 to F8), F1, and F6 have shown a maximum in vitro drug release with optimum pH and viscosity. From MTT assay it was found that selected PLO formulations showed no toxicity and enhanced cell proliferation in HaCaT cell lines. In vivo wound-healing studies in albino Wistar rats has revealed that PLO accelerates wound closure and reepithelization to the statistically significant level on day 3 (p?相似文献   

Synthesis and characterization studies of ZnSe quantum dots

ZnSe QDs have been synthesized by wet chemical, template free process by zinc acetate and elemental selenium powder in presence of ethylene glycol, hydrazine hydrate and a defined amount of water at 90 °C. The product was in strong quantum confinement regime, having yield as high as 50 %. The transmission electron microscopy image indicated that the particles were well dispersed and spherical in shape. The X-ray diffraction analysis showed that the ZnSe nanoparticles were of the Cubic structure, with average particle diameter of about 3.50 nm. The FTIR characteristic indicates that the N₂H₄ molecule has intercalated into the complex and formed a molecular precursor.     

Bio-accumulation of metals on reef associated organisms of Lakshadweep Archipelago

Tissue samples of marine organisms from the coastal waters of Agatti Island were subjected to analysis of metals (cadmium, cobalt, copper, iron, magnesium, manganese, nickel, lead and zinc), using Inductively Coupled Plasma Optical Emission Spectrometer (ICP-OES) for the assessment of the present condition of the Island ecosystem and compiling the baseline data for future monitoring, with respect of metal accumulation of marine organisms. Tissue samples of fish, shellfish and seaweed revealed that the metals have different levels of accumulation viz. Cd = 0.08-0.14, Co = 0.01-0.02, Cu = 0.16-0.98, Fe = 3.19-5.3, Mg = 86.73-152.45, Mn = 0.17-0.55, Ni = 0.06-0.26, Pb = 0.11-0.46 and Zn = 3.26-14.2 μg g⁻¹ dry wt. Metal concentrations were more in shellfish and less in finfish. Concentrations of toxic metals such as Cd, Co, Ni and Pb were well below the permissible limits proposed by the World Health Organization.     

Stable Synthetic Bacteriochlorins for Photodynamic Therapy: Role of Dicyano Peripheral Groups,Central Metal Substitution (2H,Zn, Pd), and Cremophor EL Delivery

A series of four stable synthetic bacteriochlorins was tested in vitro in HeLa cells for their potential in photodynamic therapy (PDT). The parent bacteriochlorin (BC), dicyano derivative (NC)₂BC and corresponding zinc chelate (NC)₂BC–Zn and palladium chelate (NC)₂BC–Pd were studied. Direct dilution of a solution of bacteriochlorin in an organic solvent (N,N‐dimethylacetamide) into serum‐containing medium was compared with the dilution of bacteriochlorin in Cremophor EL (CrEL; polyoxyethylene glycerol triricinoleate) micelles into the same medium. CrEL generally reduced aggregation (as indicated by absorption and fluorescence) and increased activity up to tenfold (depending on bacteriochlorin), although it decreased cellular uptake. The order of PDT activity against HeLa human cancer cells after 24 h incubation and illumination with 10 J cm^?2 of near‐infrared (NIR) light is (NC)₂BC–Pd (LD₅₀=25 nM ) > (NC)₂BC > (NC)₂BC–Zn ≈ BC. Subcellular localization was determined to be in the endoplasmic reticulum, mitochondria and lysosomes, depending on the bacteriochlorin. (NC)₂BC–Pd showed PDT‐mediated damage to mitochondria and lysosomes, and the greatest production of hydroxyl radicals as determined using a hydroxyphenylfluorescein probe. The incorporation of cyano substituents provides an excellent motif for the enhancement of the photoactivity and photostability of bacteriochlorins as PDT photosensitizers.     

Influence of plastic deformation in flexible pad laser shock forming – experimental and numerical analysis

Flexible Pad Laser Shock Forming (FPLSF) is a new microforming process using laser-induced shock pressure and a hyperelastic flexible pad to induce high strain-rate (~10⁵ s^?1) plastic deformation on metallic foils to produce 3D microcraters. This paper studies the effect of two significant process parameters of FPLSF, flexible pad material and its thickness, on the deformation characteristics of the metal foils using experiments and finite element analysis. A finite element model is developed to simulate the FPLSF process. The stress-strain distribution across the foil and the flexible pad at different process stages of FPLSF are studied using FE analysis. Flexible pad materials including silicone rubber, polyurethane rubber, and natural rubber with thicknesses ranging between 300 μm and 3000 μm have been investigated in detail. Experimental results highlight that both the hardness and thickness of the flexible pad significantly influence the deformed crater geometry, thickness distribution across the formed crater and surface hardness at the crater surfaces. The experimental results are correlated with the stress-strain distributions from finite element analysis to study the underlying behaviors.     

Nitroarenes as Antitubercular Agents: Stereoelectronic Modulation to Mitigate Mutagenicity

Nitroarenes are less preferred in drug discovery due to their potential to be mutagenic. However, several nitroarenes were shown to be promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro group in these compounds is activated through different mechanisms, both enzymatic and non‐enzymatic, in mycobacteria prior to binding to the target of interest. From a whole‐cell screening program, we identified a novel lead nitrobenzothiazole (BT) series that acts by inhibition of decaprenylphosphoryl‐β‐d ‐ribose 2′‐epimerase (DprE1) of Mycobacterium tuberculosis (Mtb). The lead was found to be mutagenic to start with. Our efforts to mitigate mutagenicity resulted in the identification of 6‐methyl‐7‐nitro‐5‐(trifluoromethyl)‐1,3‐benzothiazoles (cBTs), a novel class of antitubercular agents that are non‐mutagenic and exhibit an improved safety profile. The methyl group ortho to the nitro group decreases the electron affinity of the series, and is hence responsible for the non‐mutagenic nature of these compounds. Additionally, the co‐crystal structure of cBT in complex with Mtb DprE1 established the mode of binding. This investigation led to a new non‐mutagenic antitubercular agent and demonstrates that the mutagenic nature of nitroarenes can be solved by modulation of stereoelectronic properties.