10 research outputs found
Mesoglycan connects Syndecan-4 and VEGFR2 through Annexin A1 and formyl peptide receptors to promote angiogenesis in vitro.
Mesoglycan is a mixture of glycosaminoglycans (GAG) with fibrinolytic effects and the potential to enhance skin wound repair. Here, we have used endothelial cells isolated from Wild Type (WT) and Syndecan-4 null (Sdc4-/-) C57BL/6 mice to demonstrate that mesoglycan promotes cell motility and in vitro angiogenesis acting on the co-receptor Syndecan-4 (SDC4). This latter is known to participate in the formation and release of extracellular vesicles (EVs). We characterized EVs released by HUVECs and assessed their effect on angiogenesis. Particularly, we focused on Annexin A1 (ANXA1) containing EVs, since they may contribute to tube formation via interactions with Formyl peptide receptors (FPRs). In our model, the bond ANXA1-FPRs stimulates the release of vascular endothelial growth factor (VEGF-A) that interacts with vascular endothelial receptor-2 (VEGFR2) and activates the pathway enhancing cell motility in an autocrine manner, as shown by Wound-Healing/invasion assays, and the induction of Endothelial to Mesenchymal Transition (EndMT). Thus, we have shown for the first time that mesoglycan exerts its pro-angiogenic effects in the healing process triggering the activation of the three interconnected molecular axis: mesoglycan-SDC4, EVs-ANXA1-FPRs and VEGF-A-VEGFR2
Exploring the molecular interactions and binding affinity of resveratrol and calcitriol with RAGE and its intracellular proteins and kinases involved in colorectal cancer
Colorectal cancer (CRC) burden is progressively increasing in young population due to dietary and lifestyle pattern. Advanced glycation end products (AGEs), one of the dietary compounds, form complex aggregates with proteins, lipids, and nucleic acids distorting their structure and function. AGE’s pro-tumorigenic role is mediated through the receptor for AGEs (RAGE) triggering an array of signaling pathways. The current study aimed to target AGE-RAGE axis signaling proteins and kinases at multiple levels with calcitriol (CAL) and trans-resveratrol (RES) through in silico analysis using molecular docking (MD), molecular dynamic simulation(MDS), MM-PBSA analysis, and in vitro study. In silico analysis of CAL and RES showed significant binding affinity toward RAGE and its signaling proteins such as NF-kB, PI3K/AKT, ERK1/2, and PKC compared to its reference inhibitors through better hydrogen, hydrophobic, pi-pi stacking interactions. MD and MDS studies have revealed stable and compact protein-ligand complexes. Binding free energies of protein-ligand complex were estimated using MM/PBSA analysis thatprovided an assessment of overall interacting free energies of complexes and revealed the presence of low binding energy within the active site. Furthermore, in the in vitro study, methylglyoxal (MG), an AGE-precursor showed a proliferative effect on HCT116, however, CAL and RES showed an inhibitory effect against MG induced effect with an IC50 value of 51 nM and 110 µM respectively. Thus, the study suggests the possible target binding sites of AGE-RAGE signaling proteins and kinases with CAL and RES, thereby exploiting it for developing CAL with RES as adjuvant therapy along with chemo drug for CRC. Communicated by Ramaswamy H. Sarma</p
Insights on the structural perturbations in human MTHFR Ala222Val mutant by protein modeling and molecular dynamics
Methylenetetrahydrofolate reductase (MTHFR) protein catalyzes the only biochemical reaction which produces methyltetrahydrofolate, the active form of folic acid essential for several molecular functions. The Ala222Val polymorphism of human MTHFR encodes a thermolabile protein associated with increased risk of neural tube defects and cardiovascular disease. Experimental studies have shown that the mutation does not affect the kinetic properties of MTHFR, but inactivates the protein by increasing flavin adenine dinucleotide (FAD) loss. The lack of completely solved crystal structure of MTHFR is an impediment in understanding the structural perturbations caused by the Ala222Val mutation; computational modeling provides a suitable alternative. The three-dimensional structure of human MTHFR protein was obtained through homology modeling, by taking the MTHFR structures from Escherichia coli and Thermus thermophilus as templates. Subsequently, the modeled structure was docked with FAD using Glide, which revealed a very good binding affinity, authenticated by a Glide XP score of-10.3983 (kcal mol-1). The MTHFR was mutated by changing Alanine 222 to Valine. The wild-type MTHFR-FAD complex and the Ala222Val mutant MTHFR-FAD complex were subjected to molecular dynamics simulation over 50 ns period. The average difference in backbone root mean square deviation (RMSD) between wild and mutant variant was found to be ~.11 Å. The greater degree of fluctuations in the mutant protein translates to increased conformational stability as a result of mutation. The FAD-binding ability of the mutant MTHFR was also found to be significantly lowered as a result of decreased protein grip caused by increased conformational flexibility. The study provides insights into the Ala222Val mutation of human MTHFR that induces major conformational changes in the tertiary structure, causing a significant reduction in the FAD-binding affinity
Explaining the food safety behaviours of food handlers using theories of behaviour change: a systematic review
A tale of two regions: Methane emissions from oil and gas production in offshore/onshore Mexico
We use atmospheric observations to quantify methane (CH4) emissions from Mexico’s most important onshore and offshore oil and gas production regions which account for 95% of oil production and 78% of gas production. We use aircraft-based top-down measurements at the regional and facility-levels to determine emissions. Satellite data (TROPOMI CH4 data and VIIRS night-time flare data) provide independent estimates of emissions over 2 years. Our airborne estimate of the offshore region’s emissions is 2800 kg CH4 h−1 (95% confidence interval (CI): 1700–3900 kg CH4 h−1), more than an order of magnitude lower than the Mexican national greenhouse gas inventory estimate. In contrast, emissions from the onshore study region are 29 000 kg CH4 h−1 (95% CI: 19 000–39 000 kg CH4 h−1), more than an order of magnitude higher than the inventory. One single facility—a gas processing complex that receives offshore associated gas—emits 5700 kg CH4 h−1 (CI: 3500–7900 kg CH4 h−1), with the majority of those emissions related to inefficient flaring and representing as much as half of Mexico’s residential gas consumption. This facility was responsible for greater emissions than the entirety of the largest offshore production region, suggesting that offshore-produced associated gas is being transported onshore where it is burned and in the process some released to the atmosphere. The satellite-based data suggest even higher emissions for the onshore region than did the temporally constrained aircraft data (>20 times higher than the inventory). If the onshore production region examined is representative of Mexican production generally, then total CH4 emissions from Mexico’s oil and gas production would be similar to, or higher than, the official inventory, despite the large overestimate of offshore emissions. The main driver of inaccuracies in the inventory is the use of generic, non-Mexican specific emission factors. Our work highlights the need for local empirical characterization of emissions if effective emissions mitigation is to be undertaken
Analysis of Patterns and Treatment Strategies for Mandibular Condyle Fractures: Review of 175 Condyle Fractures with Review of Literature
Proceedings of the 6th International Conference on Modeling and Simulation in Civil Engineering
This conference proceedings contains articles on the various research ideas of the academic community and technical researchers presented at the 6th International Conference on Modeling and Simulation in Civil Engineering (ICMSC 2022). ICMSC 2022 was organized by the Department of Civil Engineering, TKM College of Engineering, Kollam, Kerala, India on December 1-3, 2022. The main aim of this conference is to bring together leading academicians, researchers, technocrats, practitioners, and students to exchange and share their experiences and research outputs on all aspects of Civil Engineering, especially related to the modeling and simulation in Civil Engineering.
Conference Title: 6th International Conference on Modeling and Simulation in Civil EngineeringConference Acronym: ICMSC 2022Conference Date: 1-3 December 2022Conference Location: IndiaConference Organizer: Department of Civil Engineering, TKM College of Engineering, Kollam, Kerala, Indi