Targeting chemokine-receptor mediated molecular signaling by ethnopharmacological approaches.

ETHNOPHARMACOLOGICAL RELEVANCE: Infection and inflammation are critical to global human health status and the goal of current pharmacological interventions intends formulating medications/preventives as a measure to deal with this situation. Chemokines and their cognate receptors are major regulatory molecules in many of these ailments. Natural products have been a keen source to the drug development industry, every year contributing significantly to the growing list of FDA approved drugs. A multiverse of natural resource is employed as a part of curative regimen in folk/traditional/ethnomedicine which can be employed to discover, repurpose, and design potent medications for the diseases of clinical concern. AIM OF THE STUDY: This review aims to systematically document the ethnopharmacologically active agents targeting the infectious-inflammatory diseases through the chemokine-receptor nexus. MATERIALS AND METHODS: Articles related to chemokine/receptor modulating ethnopharmacological anti-inflammatory, anti-infectious natural sources, bioactive compounds, and formulations have been examined with special emphasis on women related diseases. The available literature has been thoroughly scrutinized for the application of traditional medicines in chemokine associated experimental methods, their regulatory outcomes, and pertinence to women's health wherever applicable. Moreover, the potential traditional regimens under clinical trials have been critically assessed. RESULTS: A systematic and comprehensive review on the chemokine-receptor targeting ethnopharmaceutics from the available literature has been provided. The article discusses the implication of traditional medicine in the chemokine system dynamics in diverse infectious-inflammatory disorders such as cardiovascular diseases, allergic diseases, inflammatory diseases, neuroinflammation, and cancer. On this note, critical evaluation of the available data surfaced multiple diseases prevalent in women such as osteoporosis, rheumatoid arthritis, breast cancer, cervical cancer and urinary tract infection. Currently there is no available literature highlighting chemokine-receptor targeting using traditional medicinal approach from women's health perspective. Moreover, despite being potent in vitro and in vivo setups there remains a gap in clinical translation of these formulations, which needs to be strategically and scientifically addressed to pave the way for their successful industrial translation. CONCLUSIONS: The review provides an optimistic global perspective towards the applicability of ethnopharmacology in chemokine-receptor regulated infectious and inflammatory diseases with special emphasis on ailments prevalent in women, consecutively addressing their current status of clinical translation and future directions.

Protein-Based Nanocarriers and Nanotherapeutics for Infection and Inflammation.

Infectious and inflammatory diseases are one of the leading causes of death globally. The status quo has become more prominent with the onset of the coronavirus disease 2019 (COVID-19) pandemic. To combat these potential crises, proteins have been proven as highly efficacious drugs, drug targets, and biomarkers. On the other hand, advancements in nanotechnology have aided efficient and sustained drug delivery due to their nano-dimension-acquired advantages. Combining both strategies together, the protein nanoplatforms are equipped with the advantageous intrinsic properties of proteins as well as nanoformulations, eloquently changing the field of nanomedicine. Proteins can act as carriers, therapeutics, diagnostics, and theranostics in their nanoform as fusion proteins or as composites with other organic/inorganic materials. Protein-based nanoplatforms have been extensively explored to target the major infectious and inflammatory diseases of clinical concern. The current review comprehensively deliberated proteins as nanocarriers for drugs and nanotherapeutics for inflammatory and infectious agents, with special emphasis on cancer and viral diseases. A plethora of proteins from diverse organisms have aided in the synthesis of protein-based nanoformulations. The current study specifically presented the proteins of human and pathogenic origin to dwell upon the field of protein nanotechnology, emphasizing their pharmacological advantages. Further, the successful clinical translation and current bottlenecks of the protein-based nanoformulations associated with the infection-inflammation paradigm have also been discussed comprehensively. SIGNIFICANCE STATEMENT: This review discusses the plethora of promising protein-based nanocarriers and nanotherapeutics explored for infectious and inflammatory ailments, with particular emphasis on protein nanoparticles of human and pathogenic origin with reference to the advantages, ADME (absorption, distribution, metabolism, and excretion parameters), and current bottlenecks in development of protein-based nanotherapeutic interventions.

A review on structural mechanisms of protein-persistent organic pollutant (POP) interactions.

With the advent of the industrial revolution, the accumulation of persistent organic pollutants (POPs) in the environment has become ubiquitous. POPs are halogen-containing organic molecules that accumulate, and remain in the environment for a long time, thus causing toxic effects in living organisms. POPs exhibit a high affinity towards biological macromolecules such as nucleic acids, proteins and lipids, causing genotoxicity and impairment of homeostasis in living organisms. Proteins are essential members of the biological assembly, as they stipulate all necessary processes for the survival of an organism. Owing to their stereochemical features, POPs and their metabolites form energetically favourable complexes with proteins, as supported by biological and dose-dependent toxicological studies. Although individual studies have reported the biological aspects of protein-POP interactions, no comprehensive study summarizing the structural mechanisms, thermodynamics and kinetics of protein-POP complexes is available. The current review identifies and classifies protein-POP interaction according to the structural and functional basis of proteins into five major protein targets, including digestive and other enzymes, serum proteins, transcription factors, transporters, and G-protein coupled receptors. Further, analysis detailing the molecular interactions and structural mechanism evidenced that H-bonds, van der Waals, and hydrophobic interactions essentially mediate the formation of protein-POP complexes. Moreover, interaction of POPs alters the protein conformation through kinetic and thermodynamic processes like competitive inhibition and allostery to modulate the cellular signalling processes, resulting in various pathological conditions such as cancers and inflammations. In summary, the review provides a comprehensive insight into the critical structural/molecular aspects of protein-POP interactions.

Comprehensive Analysis of Serum Small Extracellular Vesicles-Derived Coding and Non-Coding RNAs from Retinoblastoma Patients for Identifying Regulatory Interactions.

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.

Molecular Insights into Conformational Heterogeneity and Enhanced Structural Integrity of Helicobacter pylori DNA Binding Protein Hup at Low pH.

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.

Anti-quorum sensing and biofilm inhibitory activity of Apium graveolens L. oleoresin.

Apium graveolens L. (Apiaceae) is a dietary herb used as a spice, condiment and medicine. A. graveolens (Celery) has been studied for its antimicrobial property and for its application as flavours in food industry. The present study investigated the Apium graveolens oleoresin as an anti-quorum sensing and antibiofilm agent. The quorum sensing and biofilm inhibition study was carried out using biosensor strains Chromobacterium violaceum CV12472 and Pseudomonas aeruginosa PAO1. The MIC of celery oleoresin against C. violaceum CV12472 and P. aeruginosa PAO1 was 10 and 25% v/v, respectively. Inhibition of violacein and biofilm formation was tested at concentrations of oleoresins ranging from 1.56 and 50% v/v. The oleoresins showed a concentration dependent QS inhibitory activity and at sub-MIC of 6.25 and 12.5% v/v, the oleoresins significantly inhibited violacein production and biofilm formation (p < 0.05). Similarly, the celery oleoresin had significant QS modulatory effect on swimming, swarming and twitching motility in P. aeruginosa PAO1 at 12.5% v/v (p < 0.05). The major phytoconstituents present in celery oleoresin as analysed by GC-MS were eicosadiene, benzenemethanol and methyl ester which have not been previously reported. The findings suggest that celery has QS and biofilm inhibitory potential against gram negative pathogens and can find application as food intervention techniques.