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.     

The dependence of fatigue crack growth on hydrogen in warm-rolled 316 austenitic stainless steel

The fatigue crack growth rate of warm-rolled AISI 316 austenitic stainless steel was investigated by controlling rolling strain and temperature in argon and hydrogen gas atmospheres. The fatigue crack growth rates of warm-rolled 316 specimens tested in hydrogen decreased with increasing rolling temperature, especially 400 °C. By controlling the deformation temperature and strain, the influences of microstructure (including dislocation structure, deformation twins and α′ martensite) and its evolution on hydrogen-induced degradation of mechanical properties were separately discussed. Deformation twins deceased and dislocations became more uniform with the increase in rolling temperature, inhibiting the formation of dynamic α′ martensite during the crack propagation. In the cold-rolled 316 specimens, deformation twins accelerated hydrogen-induced crack growth due to the α′ martensitic transformation at the crack tip. In the warm-rolled specimens, the formation of α′ martensite around the crack tip was completely inhibited, which greatly reduced the fatigue crack growth rate in hydrogen atmosphere.     

Collagen network as the scaffold for spontaneously distributed optical resonators

The idea behind this work was to acquire one dimensional lasing in the Rhodamine 6G dye doped collagen fibers with the control of random lasing phenomenon properties by changing the dye molecular arrangement. We show that a simple manipulation of the dye concentration in biopolymeric fibril matrix bulk and an additional use of α-cyclodextrin (α-CD) molecules determine formation of specific dye aggregates and as a consequence the shift of the random lasing emission wavelength in the desired direction. The analysis of the light transport mean free path in function of the dye and (α-CD) concentration was done with the use of coherent back scattering technique.     

Influence of Composition on Self-toughening and Oxidation Properties of Y-α-Sialons

Y-α-sialon ceramics with different compositions were hot-press sintered. Varying the m or n value in theα-Sialon general formula, both the α-sialon grain morphology and phase assemblages present diversification, therefore, affecting the toughness and hardness. Meanwhile, varying the compositional parameters also influenced the composition and structure of the intergranular glass phase, as well as its oxidation behavior at 1100-1200 ℃. The oxidation of the intergranular phase Mt in the Y-α-sialon ceramics was significantly enhanced with further rising the oxidation temperature to 1300 ℃.     

Response surface optimization of supercritical CO2 extraction of α-tocopherol from gel and skin of Aloe vera and almond leaves

Supercritical fluid extraction (SFE) was studied as an alternative technology in the pharmaceutical industry for the separation of α-tocopherol from gel and skin of Aloe vera and almond leaves. The influence of operating conditions was investigated on the recovery of supercritical carbon dioxide (SC-CO₂) extraction of α-tocopherol from three-year old Aloe vera (Aloe barbadensis Miller) leaf gel. The obtained results were compared with the conventional Soxhlet extraction. Response surface methodology (RSM) was applied to optimize effective variables on the extracted recovery of α-tocopherol. The maximum α-tocopherol recovery of 53.41% from Aloe vera gel was obtained with employing RSM predicted optimal operating conditions of 32 MPa, 45.91 °C, 0.84 ml SC-CO₂/min and 140 min for extraction. The α-tocopherol extraction yield for gel and skin of Aloe vera and almond leaves at these optimal operating conditions were obtained 1.53, 16.29 and 2.61 mg/100 g dry sample, respectively.     

pH and heat-induced structural changes of bovine apo-α-lactalbumin

The effects of pH and thermal treatments on conformation and association state of Ca²⁺-depleted bovine α-lactalbumin (apo-α-LA) have been studied by fluorescence spectroscopy, and molecular modelling. The experimental results demonstrate a third-state model for heat-induced unfolding of apo-α-LA, at pH 2.0, and an all-or-none transition of apo-α-LA, at pH 4.5 and 7.0, respectively. The heat-induced changes in the secondary and tertiary structure of α-LA were outlined after running molecular dynamics simulations at 25 °C and 80 °C, at neutral pH, therefore supporting the experimental observations. Our data provides insight into the mechanism of pH- and heat-dependent structural changes and oligomerization of α-LA, and will be helpful in understanding the ability of this protein to interact with certain compounds of biological interest.     

Molecular modeling on HIF-2α–ARNT dimer destabilization caused by R171A and/or V192D mutations in HIF-2α

Oxygen homeostasis in normal and tumor cells is mediated by hypoxia-inducible factors (HIFs), which are active as heterodimer complexes, such as HIF-2α–aryl hydrocarbon receptor nuclear translocator (ARNT) and HIF-1α–ARNT. A series of mutations on the interfaces between HIF-2α and ARNT and on the domain–domain interface within HIF-2α has been reported to exert varying effects on HIF-2α–ARNT dimerization. In the present study, molecular dynamic simulations were conducted to evaluate HIF-2α mutations, namely R171A, V192D, and R171A/V192D, which are not involved in the interaction with ARNT but impede HIF-2α–ARNT dimerization. Our results indicate that these mutations induct local conformation leading to a shortened (by V192D) or widened (by R171A and R171A/V192D) Y91–E346 separation distance, where E346 and Y91 are located on the HIF-2α and interact with ARNT according to electrostatic and geometrical shape complementarity, respectively.     

Theoretical study of the zero-gap organic conductor α-(BEDT-TTF)2I3

Abstract

The quasi-two-dimensional molecular conductor α-(BEDT-TTF)₂I₃ exhibits anomalous transport phenomena where the temperature dependence of resistivity is weak but the ratio of the Hall coefficient at 10 K to that at room temperature is of the order of 10⁴. These puzzling phenomena were solved by predicting massless Dirac fermions, whose motions are described using the tilted Weyl equation with anisotropic velocity. α-(BEDT-TTF)₂I₃ is a unique material among several materials with Dirac fermions, i.e. graphene, bismuth, and quantum wells such as HgTe, from the view-points of both the structure and electronic states described as follows. α-(BEDT-TTF)₂I₃ has the layered structure with highly two-dimensional massless Dirac fermions. The anisotropic velocity and incommensurate momenta of the contact points, ±k₀, originate from the inequivalency of the BEDT-TTF sites in the unit cell, where ±k₀ moves in the first Brillouin zone with increasing pressure. The massless Dirac fermions exist in the presence of the charge disproportionation and are robust against the increase in pressure. The electron densities on those inequivalent BEDT-TTF sites exhibit anomalous momentum distributions, reflecting the angular dependences of the wave functions around the contact points. Those unique electronic properties affect the spatial oscillations of the electron densities in the vicinity of an impurity. A marked behavior of the Hall coefficient, where the sign of the Hall coefficient reverses sharply but continuously at low temperatures around 5 K, is investigated by treating the interband effects of the magnetic field exactly. It is shown that such behavior is possible by assuming the existence of the extremely small amount of electron doping. The enhancement of the orbital diamagnetism is also expected. The results of the present research shed light on a new aspect of Dirac fermion physics, i.e. the emergence of unique electronic properties owing to the structure of the material.