Biology subjects

Asgharpour, S.

Publications and source records attributed to Asgharpour, S..

3 recordsLinked to original sources

bioRxiv2023

Atomistic molecular insight on Angiotensin-(1-7) inter-peptide interactions

Angiotensin-(1-7) is an endogenous peptide with vaso-protective, anti-oxidant, and anti-inflammatory effects which has been proposed as a potential therapeutic agent in a wide range of clinical conditions. Angiotensin-(1-7) presents a pH-dependent physical instability in aqueous solutions; however, it still lacks a proper atomistic study that provides insights into this behavior and its potential implications. Hence, we studied the formation of early Angiotensin-(1-7) oligomeric aggregates in an aqueous environment under acidic and neutral conditions; physiological and high ionic strength; and high and low peptide concentrations using all-atom Molecular Dynamics simulations. Our main findings are: 1) at acidic pH, there is a poor level of Angiotensin-(1-7) clustering, while, 2) at neutral pH, peptides aggregate in a unique cluster, in good trend with experimental physical instability reports and 3) an increase in salt concentration at acidic pH gives place to aggregation similar to the case at neutral pH. Our results open the route for the modulation of Angiotensin-(1-7) aggregation through a combination of salt concentration and pH conditions. Our protocol (MD + cluster analysis + amino acids interaction map analysis) is general and could be applied to other peptides to study the inter-peptide interaction mechanisms.

biophysics↗

bioRxiv2023

Phosphoproteomics of cellular mechanosensing reveals NFATC4 as a regulator of myofibroblast activity

Feedback connections between tissue stiffness and cellular contractile forces can instruct cell identity and activity via a process referred to as mechanosensing. Specific phosphoproteome changes during mechanosensing are poorly characterized. In this work, we chart the global phosphoproteome dynamics of primary human lung fibroblasts sensing the stiffness of injury relevant fibronectin coated Poly(dimethylsiloxane) substrates. We discovered a key signaling threshold at a Youngs modulus of eight kPa stiffness, above which cells activated a large number of pathways including RhoA, CK2A1, PKA, AMPK, AKT1, and Hippo-YAP1/TAZ mediated signaling. Time-resolved phosphoproteomics of cell spreading on stiff substrates revealed the temporal dynamics of these stiffness-sensitive signaling pathways. ECM substrate stiffness above eight kPA induced fibroblast contractility, cytoskeletal rearrangements, ECM secretion, and a fibroblast to myofibroblast transition. Our data indicate that phosphorylation of the transcriptional regulator NFATC4 at S213/S217 enhances myofibroblast activity, which is the key hallmark of fibrotic diseases. NFATC4 knock down cells display reduced stiffness induced collagen secretion, cell contractility, nuclear deformation and invasion, suggesting NFATC4 as a novel target for antifibrotic therapy. SynopsisHow tissue stiffness regulates identity and activity of tissue fibroblasts is unclear. Mass spectrometry based analysis of tissue stiffness dependent phosphoproteome changes reveals how primary lung fibroblasts sense the mechanical properties of their environment and identifies NFATC4 as a novel regulator of the stiffness dependent transition of fibroblasts to ECM secreting myofibroblasts. O_LIMass spectrometry analysis reveals the signaling landscape of fibroblast mechanosensing C_LIO_LITime-resolved phosphoproteomic analysis of cell spreading on fibronectin C_LIO_LINFATC4 regulates myofibroblast collagen secretion, cell contractility and invasion C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=38 SRC="FIGDIR/small/528335v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@329c68org.highwire.dtl.DTLVardef@ba7513org.highwire.dtl.DTLVardef@15c32c4org.highwire.dtl.DTLVardef@90b96_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2022

Unveiling the G4-PAMAM capacity to bind and protect Ang-(1-7) bioactive peptide

New therapies that allow natural healing processes are required. Such as the endogenous peptide called Angiotensin-(1-7), a safe and eff e drug, which is able to re-balance the Renin-Angiotensin system affected during several pathologies, including the new COVID-19; cardiovascular, renal, and pulmonary disease; diabetes; neuropathic pain; Alzheimer and cancer. However, one of the limiting factors for its application is its unfavorable pharmacokinetic profile. In this work, we propose the coupling of Angiotensin-(1-7) to PAMAM dendrimers in order to evaluate the capacity of the nanocarrier to improve isolated peptide features and to gain insight into the structural as well as the energetic basis of its molecular binding. The In Silico tests were performed in acidic and neutral pH conditions as well as amino-terminated and hydroxyl-terminated PAMAM dendrimers. High-rigor computational approaches, such as molecular dynamics and metadynamics simulations were used. We found that, at neutral pH, PAMAM dendrimers with both terminal types are able to interact stably with 3 Angioteinsin-(1-7) peptides through ASP1, TYR4 and PRO7 key aminoacids, however, there are some differences in the binding sites of the peptides. In general, they bind on the surface in the case of the hydroxyl-terminated compact dendrimer and in the internal zone in the case of the amino-terminated open dendrimer. At acidic pH, PAMAM dendrimers with both terminal groups are still able to interact with peptides either internalized or in its periphery, however, the number of contacts, the percentage of coverage and the number of HBs are lesser than at neutral pH, suggesting a state for peptide release. In summary, amino-terminated PAMAM dendrimer showed slightly better features to bind, load and protect Angiotensin-(1-7) peptides.

biophysics↗