Targeting Y220C mutated p53 by Foeniculum vulgare-derived phytochemicals as cancer therapeutics.

CONTEXT: The mutations in the TP53 gene are the most frequent (50-60% of human cancer) genetic alterations in cancer cells, indicating the critical role of wild-type p53 in the regulation of cell proliferation and apoptosis upon oncogenic stress. Most missense mutations are clustered in the DNA-binding core domain, disrupting DNA binding ability. However, some mutations like Y220C occur outside the DNA binding domain and are associated with p53 structure destabilization. Overall, the results of these mutations are single amino acid substitutions in p53 and the production of dysfunctional p53 protein in large amounts, consequently allowing the escape of apoptosis and rapid progression of tumor growth. Thus, therapeutic targeting of mutant p53 in tumors to restore its wild-type tumor suppression activity has immense potential for translational cancer research. Various molecules have been discovered with modern scientific techniques to reactivate mutant p53 by reverting structural changes and/or DNA binding ability. These compounds include small molecules, various peptides, and phytochemicals. TP53 protein is long thought of as a potential target; however, its translation for therapeutic purposes is still in its infancy. The study comprehensively analyzed the therapeutic potential of small phytochemicals from Foeniculum vulgare (Fennel) with drug-likeness and capability to reactivate mutant p53 (Y220C) through molecular docking simulation. The docking study and the stable molecular dynamic simulations revealed juglalin (- 8.6 kcal/mol), retinol (- 9.14 kcal/mol), and 3-nitrofluoranthene (- 8.43 kcal/mol) significantly bind to the mutated site suggesting the possibility of drug designing against the Y220C mutp53. The study supports these compounds for further animal based in vivo and in vitro research to validate their efficacy. METHODS: For the purposes of drug repurposing, recently in-silico methods have presented with opportunity to rule out many compounds which have less probability to act as a drug based on their structural moiety and interaction with the target macromolecule. The study here utilizes molecular docking via Autodock 4.2.6 and molecular dynamics using Schrodinger 2021 to find potential therapeutic options which are capable to reactive the mutated TP53 protein.

SARS-CoV-2 origins: zoonotic Rhinolophus vs contemporary models.

The question of the origin of coronavirus spread like wildfire ever since it wreaked havoc among humankind, and ever since the scientific community has worked tirelessly to trace the history of the virus. In this review, we have tried to compile relevant literature pertaining to the different theories of origin of SARS-CoV-2, hopefully without any bias, and we strongly support the zoonotic origin of the infamous SARS-CoV-2 in bats and its transfer to human beings through the most probable evolutionary hosts, pangolins and minks. We also support the contemporary 'Circulation Model' that simply mirrors the concept of evolution to explain the origin of the virus which, the authors believe, is the most rational school of thought. The most recent variant of SARS-CoV-2, Omicron, has been taken as an example to clarify the concept. We recommend the community to refer to this model for further understanding and delving deep into this mystery of the origin of SARS-CoV-2.

Disease-associated dysbiosis and potential therapeutic role of Akkermansia muciniphila, a mucus degrading bacteria of gut microbiome.

The unique functionality of Akkermansia muciniphila in gut microbiota indicates it to be an indispensable microbe for human welfare. The importance of A. muciniphila lies in its potential to convert mucin into beneficial by-products, regulate intestinal homeostasis and maintain gut barrier integrity. It is also known to competitively inhibit other mucin-degrading bacteria and improve metabolic functions and immunity responses in the host. It finds a pivotal perspective in various diseases and their treatment. It has future as a promising probiotic, disease biomarker and therapeutic agent for chronic diseases. Disease-associated dysbiosis of A. muciniphila in the gut microbiome makes it a potential candidate as a biomarker for some diseases and can provide future theranostics by suggesting ways of diagnosis for the patients and best treatment method based on the screening results. Manipulation of A. muciniphila in gut microbiome may help in developing a novel personalized therapeutic action and can be a suitable next generation medicine. However, the actual pathway governing A. muciniphila interaction with hosts remains to be investigated. Also, due to the limited availability of products containing A. muciniphila, it is not exploited to its full potential. The present review aims at highlighting the potential of A. muciniphila in mucin degradation, contribution towards the gut health and host immunity and management of metabolic diseases such as obesity and type 2 diabetes, and respiratory diseases such as cystic fibrosis and COVID-19.

Toxicity and immunomodulatory efficacy of biosynthesized silver myconanosomes on pathogenic microbes and macrophage cells.

Silver myconanosomes prepared from Alternaria brassicae may exhibit potential antimicrobial and immunomodulatory activity due to their inimitable character. The prepared myconanosomes were characterized by using differential light scattering, zeta potential, UV-visible spectroscopy and transmission electron microscopic analyses. Mycologically produced AgNPs were found as spherical and irregular shaped measuring size range between 55.4 and 70.23 nm. The antimicrobicidal activity of these AgNPs against pathogenic microbes was evaluated by agar well diffusion method. Results showed that AgNPs inhibit the growth of various bacteria and fungi, which may be due to the disruption of cell membranes, leakage of cytoplasm and DNA degradation. Cytotoxicity analysis of AgNPs on cell lines revealed its dose dependent effect. Moreover, significant increase of intracellular reactive oxygen species was characterized in AgNPs treated cells after 4 h of incubation. Thus, AgNPs may have a significant advantage over conventional antibiotics as microorganisms are acquiring resistance against the broad range of available antibiotics.

Genetic Diversity Analysis of Medicinally Important Horticultural Crop Aegle marmelos by ISSR Markers.

Inter simple sequence repeat (ISSR) markers help in identifying and determining the extent of genetic diversity in cultivars. Here, we describe their application in determining the genetic diversity of bael (Aegle marmelos Corr.). Universal ISSR primers are selected and their marker characteristics such as polymorphism information content, effective multiplex ratio and marker index have been evaluated. ISSR-PCR is then performed using universal ISSR primers to generate polymorphic bands. This information is used to determine the degree of genetic similarity among the bael varieties/accessions by cluster analysis using unweighted pair-group method with arithmetic averages (UPGMA). This technology is valuable for biodiversity conservation and for making an efficient choice of parents in breeding programs.

Extracellular mycosynthesis of silver nanoparticles and their microbicidal activity.

Myconanotechnology, a combination of mycology and nanotechnology that deals with the synthesis of nanoparticles using fungi or their metabolites, has great potential in the area of agriculture owing to the high surface-to-volume ratio and excellent biomedical, electronic, mechanical and physicochemical properties of these myconanoparticles. Extracellular mycosynthesis of Aspergillus flavus (KF934407) silver nanoparticles (AgNPs) was performed, which were produced by redox reaction. Furthermore, the extracellular synthesised AgNPs were characterised by ultraviolet/visible spectrophotometry, differential light scattering (DLS) and transmission electron microscopy. The bactericidal and fungicidal actions of synthesised silver myconanoparticles (myco-AgNPs) were studied against pathogenic bacteria and fungi. The formulated myco-AgNPs were spherical in shape, with a size in the range of 50nm and DLS at an intensity of 107.8nm. The myco-AgNPs showed effective antimicrobial properties against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Trichoderma spp. at high concentrations. In conclusion, AgNPs have a prolonged microbicidal effect as a result of continuous release of Ag+ at sufficient concentrations. Thus, A. flavus-based myco-AgNPs have the potential to be used as a non-toxic and cheap antimicrobial agent against various pathogenic bacteria and fungi.

Antimicrobial and immunomodulatory efficacy of extracellularly synthesized silver and gold nanoparticles by a novel phosphate solubilizing fungus Bipolaris tetramera.

BACKGROUND: Particulates of nanometers size have occupied a significant area in the field of medicinal and agricultural purposes due to their large surface-to-volume ratio and exceptional physicochemical, electronic and mechanical properties. Myconanotechnology, an interface between mycology and nanotechnology is budding nowadays for nanoparticle-fabrication using fungus or its metabolites. In the present study, we have isolated and characterized a novel phosphate solubilizing fungus B. tetramera KF934408 from rhizospheric soil. This phosphatase releasing fungus was subjected to extracellular synthesis of metal nanoparticles by redox reaction. RESULTS: Silver (AgNPs) and gold nanoparticles (AuNPs) were characterized by dynamic light scattering and transmission electron microscopic analysis. The formulated AgNPs were irregular shaped with a size ranging between 54.78 nm to 73.49 nm whereas AuNPs were spherical or hexagonal, with a size of 58.4 and 261.73 nm, respectively. The nanoparticles were assessed for their antibacterial and antifungal efficacy. The results showed effective antimicrobial activity of AgNPs against Bacillus cereus, Staphylococcus aureus, Enterobacter aeroginosa and Trichoderma sp. at higher concentrations, however, AuNPs possessed only moderate antibacterial efficacy while they found no antifungal activity. Cytotoxicity analysis of nanoparticles on J774 and THP1 α cell lines revealed the dose dependence in case of AgNPs, while AuNPs were non-toxic at both low and high doses. Furthermore, significant elevation of intracellular ROS was observed after 4 h of incubation with both the nanoparticles. The capping of fungal proteins on the particulates might be involved in the activities demonstrated by these inert metal nanoparticles. CONCLUSION: In conclusion, the findings showed that the metal nanoparticles synthesized by fungus B. tetramera could be used as an antimicrobial agents as well as cost effective and nontoxic immunomodulatory delivery vehicle.