The lysyl oxidase like 2/3 enzymatic inhibitor, PXS-5153A, reduces crosslinks and ameliorates fibrosis.

Fibrosis is characterized by the excessive deposition of extracellular matrix and crosslinked proteins, in particular collagen and elastin, leading to tissue stiffening and disrupted organ function. Lysyl oxidases are key players during this process, as they initiate collagen crosslinking through the oxidation of the ε-amino group of lysine or hydroxylysine on collagen side-chains, which subsequently dimerize to form immature, or trimerize to form mature, collagen crosslinks. The role of LOXL2 in fibrosis and cancer is well documented, however the specific enzymatic function of LOXL2 and LOXL3 during disease is less clear. Herein, we describe the development of PXS-5153A, a novel mechanism based, fast-acting, dual LOXL2/LOXL3 inhibitor, which was used to interrogate the role of these enzymes in models of collagen crosslinking and fibrosis. PXS-5153A dose-dependently reduced LOXL2-mediated collagen oxidation and collagen crosslinking in vitro. In two liver fibrosis models, carbon tetrachloride or streptozotocin/high fat diet-induced, PXS-5153A reduced disease severity and improved liver function by diminishing collagen content and collagen crosslinks. In myocardial infarction, PXS-5153A improved cardiac output. Taken together these results demonstrate that, due to their crucial role in collagen crosslinking, inhibition of the enzymatic activities of LOXL2/LOXL3 represents an innovative therapeutic approach for the treatment of fibrosis.

Comparative Evaluation of TRAIL, FGF-2 and VEGF-A-Induced Angiogenesis In Vitro and In Vivo.

Tumor necrosis-factor-related apoptosis-inducing ligand (TRAIL) has been implicated in angiogenesis; the growth of new blood vessels from an existing vessel bed. Our aim was to compare pro-angiogenic responses of TRAIL, vascular endothelial growth-factor-A (VEGF-A) and fibroblast growth-factor-2 (FGF-2) either separately (10 ng/mL) or in combination, followed by the assessment of proliferation, migration and tubule formation using human microvascular endothelial-1 (HMEC-1) cells in vitro. Angiogenesis was also measured in vivo using the Matrigel plug assay. TRAIL and FGF-2 significantly augmented HMEC-1 cell proliferation and migration, with combination treatment having an enhanced effect on cell migration only. In contrast, VEGF-A did not stimulate HMEC-1 migration at 10 ng/mL. Tubule formation was induced by all three factors, with TRAIL more effective compared to VEGF-A, but not FGF-2. TRAIL at 400 ng/mL, but not VEGF-A, promoted CD31-positive staining into the Matrigel plug. However, FGF-2 was superior, stimulating cell infiltration and angiogenesis better than TRAIL and VEGF-A in vivo. These findings demonstrate that each growth factor is more effective at different processes of angiogenesis in vitro and in vivo. Understanding how these molecules stimulate different processes relating to angiogenesis may help identify new strategies and treatments aimed at inhibiting or promoting dysregulated angiogenesis in people.

A DFT study for improving the photovoltaic performance of organic solar cells by designing symmetric non-fullerene acceptors by quantum chemical modification on pre-existed LC81 molecule.

Minimizing the energy loss and improving the open circuit voltage of organic solar cells is still a primary concern for scientists working in this field. With the aim to enhance the photovoltaic performance of organic solar cells by minimizing energy loss and improving open circuit voltage, seven new acceptor molecules (LC1-LC7) are presented in this work. These molecules are designed by modifying the terminal acceptors of pre-existed "LC81" molecule based on an indacinodithiophene (IDT) fused core. The end-group modification approach is very fruitful in ameliorating the efficacy and optoelectric behavior of OSCs. The newly developed molecules presented remarkable improvements in performance-related parameters and optoelectronic properties. Among all designed molecules, LC7 exhibited the highest absorption maxima (λmax = 869 nm) with the lowest band-gap (1.79 eV), lowest excitation energy (Ex = 1.42 eV), lowest binding energy, and highest excited state lifetime (0.41 ns). The newly designed molecules LC2, LC3, and LC4 exhibited remarkably improved Voc that was 1.84 eV, 1.82 eV, and 1.79 eV accordingly, compared to the LC81 molecule with Voc of 1.74 eV LC2 molecule showed significant improvement in fill factor compared to the previously presented LC81 molecule. LC2, LC6, and LC7 showed a remarkable reduction in energy loss by showing Eloss values of 0.26 eV, 0.18 eV, and 0.25 eV than LC81 molecule (0.37 eV). These findings validate the supremacy of these developed molecules (especially LC2) as potential components of future OSCs.

Synergistic modification of end groups in Quinoxaline fused core-based acceptor molecule to enhance its photovoltaic characteristics for superior organic solar cells.

The competence of organic solar cells (OSCs) could be enhanced by improving the light absorption capabilities as well as the open-circuit voltage (Voc) of utilized molecules. To upgrade overall functionality of OSCs, seven new molecules were designed in this work using an end-cap alteration technique on Quinoxaline fused core-based non-fullerene acceptor (Qx-2) molecule. This technique is known to be quite advantageous in terms of improvement of the effectiveness and optoelectrical behavior of various OSCs. Critical parameters like the absorption maximum, frontier molecular orbitals, excitation energy, exciton binding energy, Voc, and fill factor of molecules were considered for the molecules thus designed. All newly designed molecules showed outstanding improvement in optoelectronic as well as performance-related properties. Out of all scrutinized molecules, Q1 exhibited highest wavelength of absorption peak (λmax = 779 nm) with the reduced band gap (1.90 eV), least excitation energy (Ex = 1.59 eV), along with the highest dipole moment (17.982950 D). Additionally, the newly designed compounds Q4, Q5, and Q6 exhibited significantly improved Vocs that were 1.55, 1.47, and 1.50 eV accordingly, as compared to the 1.37 eV of Qx-2 molecule. These molecules also showed remarkable improvement in fill factor attributed to direct correspondence of Voc with it. Inclusively, these results support the superiority of these newly developed molecules as prospective constituents of upgraded OSCs.

Alteration of the central core of a DF-PCIC chromophore to boost the photovoltaic applications of non-fullerene acceptor based organic solar cells.

Modifying the central core is a very efficient strategy to boost the performance of non-fullerene acceptors. Herein five non-fullerene acceptors (M1-M5) of A-D-D'-D-A type were designed by substituting the central acceptor core of the reference (A-D-A'-D-A type) with different strongly conjugated and electron donating cores (D') to enhance the photovoltaic attributes of OSCs. All the newly designed molecules were analyzed through quantum mechanical simulations to compute their optoelectronic, geometrical, and photovoltaic parameters and compare them to the reference. Theoretical simulations of all the structures were carried out through different functionals with a carefully selected 6-31G(d,p) basis set. Absorption spectra, charge mobility, dynamics of excitons, distribution pattern of electron density, reorganization energies, transition density matrices, natural transition orbitals and frontier molecular orbitals, respectively of the studied molecules were evaluated at this functional. Among the designed structures in various functionals, M5 showed the most improved optoelectronic properties, such as the lowest band gap (2.18 e V), highest maximum absorption (720 nm), and lowest binding energy (0.46 eV) in chloroform solvent. Although the highest photovoltaic aptitude as acceptors at the interface was perceived to be of M1, its highest band gap and lowest absorption maxima lowered its candidature as the best molecule. Thus, M5 with its lowest electron reorganization energy, highest light harvesting efficiency, and promising open-circuit voltage (better than the reference), amongst other favorable features, outperformed the others. Conclusively, each evaluated property commends the aptness of designed structures to augment the power conversion efficiency (PCE) in the field of optoelectronics in one way or another, which reveals that a central un-fused core having an electron-donating capability with terminal groups being significantly electron withdrawing, is an effective configuration for the attainment of promising optoelectronic parameters, and thus the proposed molecules could be utilized in future NFAs.

Measurement of Collagen Cross-Links from Tissue Samples by Mass Spectrometry.

All tissues contain an extracellular matrix (ECM) which is constantly and dynamically remodeled, either in physiological or pathological processes, such as fibrosis or cancer. One of the key contributors in the establishment of a fibrotic state is the abnormal deposition of extracellular matrix and cross-linked proteins, in particular collagen, leading to tissue stiffening and disruption of organ function. The precise and sensitive measurement of these cross-links by LC-MS/MS is a very powerful tool for providing a quantitative and qualitative analysis of fibrosis and is a key requirement in the study of this state, as well as in the development of drugs for this unmet clinical need.