No abstract
Enhancement of glycolysis and glutaminolysis are the two most common modalities associated with metabolic reprogramming in rheumatoid arthritis (RA). This enhancement is concomitant to the upregulation of hexokinase 2 (HK2) and glutaminase 1 (GLS1). Hence, the current study was undertaken to identify potential phytobiological inhibitors against HK2 and GLS1, from Dracaena (Sansevieria) trifasciata, an indigenous ethnomedicinal plant found in Pakistan, using computational analysis. Phytobiologics from Dracaena trifasciata were assessed for their ability to co-inhibit HK2 and GLS1 via molecular docking and molecular dynamics simulations. The results underscored seven phytobiologics with promising binding affinities for both HK2 and GLS1. Molecular dynamics simulations further elucidated that all seven identified phytobiologics inhibited HK2 by forming stable complexes but only five amongst the seven had the potential to form stable complexes with GLS1 in real time, thereby implying the potential of co-inhibition for these five compounds. Compound 28MS exhibited an equally strong binding profile for both HK2 (−8.19 kcal/mol) and GLS1 (−8.99 kcal/mol). Furthermore, it exhibited a similar trend in stability during simulation for both targets. Our results serve as a primer for a more lucid understanding towards co-inhibition of HK2 and GLS1 using multiple computational approaches. The identified phytobiologics should undergo in-vitro and in-vivo validation to corroborate their therapeutic potential in RA.
Chromatin remodeling, ubiquitylation, and DNA damage repair may be regarded as three discrete processes, but in fact, they are three extremely important interlinked processes that are imperative for the sustenance for life. Discrepancies in one will have outcomes that will affect the other processes direly. Exogenous and endogenous factors persistently affect the DNA by inducing damage and modifications. To sustain the integrity of life, these challenges need to be combated efficiently. For the preservation of the structural and functional components of the genome, nature has allowed them to evolve numerous pathways that constantly work to repair the induced damage. This sort of response is termed as DDR (DNA damage response) that include BER and NER (base excision and nucleotide excision repair, respectively) and non-homologous end joining and homologous recombination (NHEJ & HR). Since the DNA in cells is exceedingly organized and compressed, hence any process that utilizes DNA as its substrate requires essential remodeling of the chromatin structure. The chapter emphasizes on the phenomenon of chromatin remodeling and ubiquitylation which subsequently affects the integral process of DNA damage repair.
Bioethics are usually associated with ethical issues that emerge from advances in medical sciences and practices. These basically include the ethical guidelines that should be followed during any research or medical procedure or practice that is to be conducted. The genetic material present in the form of DNA, which encodes guidelines for cellular life, is termed as genome. Genome of many organisms has been sequenced completely and with this genetic manipulation is possible. To characterize and manipulate the genome many techniques and procedures have been developed like Whole Genome Sequencing (WGS) and genome editing respectively. Some other techniques that come under the umbrella of functional genomics generate huge amount of data that can be characterized and manipulated according to the requirement. These new procedures and approaches have raised many ethical concerns and issues that are being addressed in this review.
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