The summarized amalgam of internal
relaxation modulations and external
forces like pH, temperature, and solvent conditions determine the
protein structure, stability, and function. In a free-energy landscape,
although conformers are arranged in vertical hierarchy, there exist
several adjacent parallel sets with conformers occupying equivalent
energy cleft. Such conformational states are pre-requisites for the
functioning of proteins that have oscillating environmental conditions.
As these conformational changes have utterly small re-arrangements,
nuclear magnetic resonance (NMR) spectroscopy is unique in elucidating
the structure–dynamics–stability–function relationships
for such conformations. Helicobacter pylori survives and causes gastric cancer at extremely low pH also. However,
least is known as to how the genome of the pathogen is protected from
reactive oxygen species (ROS) scavenging in the gut at low pH under
acidic stress. In the current study, biophysical characteristics of H. pylori DNA binding protein (Hup) have been elucidated
at pH 2 using a combination of circular dichroism, fluorescence, NMR
spectroscopy, and molecular dynamics simulations. Interestingly, the
protein was found to have conserved structural features, differential
backbone dynamics, enhanced stability, and DNA binding ability at
low pH as well. In summary, the study suggests the partaking of Hup
protein even at low pH in DNA protection for maintaining the genome
integrity.
Owing to the astounding
biological properties, dietary plant flavonoids
have received considerable attention toward developing unique supplementary
food sources to prevent various ailments. Chemokines are chemotactic
proteins involved in leukocyte trafficking through their interactions
with G-protein-coupled receptors and cell surface glycosaminoglycans
(GAGs). CCL2 chemokine, a foremost member of CC chemokines, is associated
with the pathogenesis of various inflammatory infirmities, thus making
the CCL2-Receptor (CCR2)/GAG axis a potential pharmacological target.
The current study is designed to unravel the structural details of
CCL2–flavonol interactions. Molecular interactions between
flavonols (kaempferol, quercetin, and myricetin) with human/murine
CCL2 orthologs and their monomeric/dimeric variants were systematically
investigated using a combination of biophysical approaches. Fluorescence
studies have unveiled that flavonols interact with CCL2 orthologs
specifically but with differential affinities. The dissociation constants
(
K
d
) were in the range of 10
–5
–10
–7
μM. The NMR- and computational
docking-based outcomes have strongly suggested that the flavonols
interact with CCL2, comprising the N-terminal and β1- and β3-sheets.
It has also been observed that the number of hydroxyl groups on the
annular ring-B imposed a significant cumulative effect on the binding
affinities of flavonols for CCL2 chemokine. Further, the binding surface
of these flavonols to CCL2 orthologs was observed to be extensively
overlapped with that of the receptor/GAG-binding surface, thus suggesting
attenuation of CCL2-CCR2/GAG interactions in their presence. Considering
the pivotal role of CCL2 during monocyte/macrophage trafficking and
the immunomodulatory features of these flavonols, their direct interactions
highlight the promising role of flavonols as nutraceuticals.
The present study employed nanoparticle tracking analysis, transmission electron microscopy, immunoblotting, RNA sequencing, and quantitative real-time PCR validation to characterize serum-derived small extracellular vesicles (sEVs) from RB patients and age-matched controls. Bioinformatics methods were used to analyze functions, and regulatory interactions between coding and non-coding (nc) sEVs RNAs. The results revealed that the isolated sEVs are round-shaped with a size < 150 nm, 5.3 × 1011 ± 8.1 particles/mL, and zeta potential of 11.1 to −15.8 mV, and expressed exosome markers CD9, CD81, and TSG101. A total of 6514 differentially expressed (DE) mRNAs, 123 DE miRNAs, and 3634 DE lncRNAs were detected. Both miRNA-mRNA and lncRNA-miRNA-mRNA network analysis revealed that the cell cycle-specific genes including CDKNI1A, CCND1, c-MYC, and HIF1A are regulated by hub ncRNAs MALAT1, AFAP1-AS1, miR145, 101, and 16-5p. Protein-protein interaction network analysis showed that eye-related DE mRNAs are involved in rod cell differentiation, cone cell development, and retinol metabolism. In conclusion, our study provides a comprehensive overview of the RB sEV RNAs and regulatory interactions between them.
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