New Insights Into Pyridoxal Kinase Inhibitors and Their Antileukemic Effects.

Pyridoxal kinase (PDXK) plays a pivotal role as an essential enzyme in cellular processes. It catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine to generate pyridoxal 5'-phosphate (PLP), the bioactive form of vitamin B6. An intriguing link has emerged between elevated expression levels of PDXK and PLP and various types of carcinomas, including leukemia. Leukemic cells have an increased need for vitamin B6 to sustain their survival and rapid growth, highlighting the potential of targeting PDXK-PLP as a promising therapeutic target in cancer treatment. To discover a novel and promising PDXK inhibitor, we conducted a comprehensive screening of compounds derived from both natural sources and drug-like databases. Our approach involved employing structure-based virtual screening and molecular docking techniques to attenuate the phosphorylation of PLP. Among the top six compounds, ZINC095099376 (referred to as C03) emerged as the most potent inhibitor of PDXK, primarily due to its exceptional binding affinity and remarkable specificity for the target protein. Furthermore, our investigation revealed that compound C03 establishes crucial interactions with key residues within the substrate binding site, indicating that it binds at the same site as the co-crystallized ligand. Remarkably, compound C03 inhibited the endogenous PDXK expression, showed anti-proliferative activity, and triggered an intrinsic pathway for apoptosis via the activation of key apoptotic factors in leukemic cells. In summary, these findings strongly indicate that compound C03 holds promise as a novel inhibitor of PDXK, offering the potential for the development of effective treatments for leukemia.

Identification of high-affinity pyridoxal kinase inhibitors targeting cancer therapy: an integrated docking and molecular dynamics simulation approach.

Pyridoxal kinase (PDXK) is a vitamin B6-dependent transferase enzyme encoded by the PDXK gene, crucial for leukemic cell proliferation. Disruption of its activity causes altered metabolism and reduced levels of nucleotides and polyamines. PDXK and pyridoxal 5'-phosphate (PLP) are overexpressed in various carcinomas, making them promising targets for drug design against cancer. Targeting PDXK may hold promise as a therapeutic approach for cancer treatment. This study focused on discovering potential inhibitors that could selectively interrupt the binding of pyridoxal phosphate (PLP) to pyridoxal kinase (PDXK). A commercially available library of 7,28,747 natural and druglike compounds was virtually screened using a molecular docking approach to target the substrate binding pocket of PDXK. Six promising inhibitors were identified, and all-atom molecular dynamics simulations were conducted on the PDXK-ligand complexes for 100 ns to assess their binding conformational stability. The simulation results indicated that the binding of ZINC095099376, ZINC01612996, ZINC049841390, ZINC095098959, ZINC01482077, and ZINC03830976 induced a slight structural change and stabilized the PDXK structure. This analysis provided valuable information about the critical residues involved in the PDXK-PLP complex formation and can be utilized in designing specific and effective PDXK inhibitors. According to this study, these compounds could be developed as anticancer agents targeting PDXK as a potential candidate for further study.Communicated by Ramaswamy H. Sarma.

Expression of Regucalcin, a calcium-binding protein is regulated by hypoxia-inducible factor-1α.

Regucalcin (RGN) regulates intracellular Ca2+ homeostasis and the activity of several proteins involved in intracellular signaling pathways, which highlights its importance in cell biology. Regucalcin has cytoprotective effects reducing intracellular levels of oxidative stress, also playing a crucial role in the control of cell survival and apoptosis. In an effort to assess its gene regulation, we initially identified the expression of Regucalcin in rat lungs treated with hypoxia at various time points. Previously, HIF-1α expression was also reported to be upregulated in hypoxia. Interestingly hypoxic induced Regucalcin expression in a fashion similar to that of HIF-1α expression in rat lungs. Sequence analysis of the Regucalcin promoter region revealed the presence of putative HRE binding motifs. Further analysis of the 1 kb Regucalcin promoter region with 5' deletion and point mutants of HRE binding motif showed that the HRE binding site was critical for high promoter activity. In addition, HIF-1α protein binds directly to the HRE binding motifs within the Regucalcin promoter in-vivo, and regulates Regucalcin gene expression. All together, these findings suggest that Regucalcin is the novel target gene of HIF-1α and that Regucalcin gene expression in hypoxia may be regulated by the control of HIF-1α expression.

Traditional Nutritional and Health Practices Targeting Lifestyle Behavioral Changes in Humans.

In this 21st century who isn't enticed by the glamorous and appealing life in the fast lane? We are surrounded by wonders, something we could never have imagined erstwhile. We have everything just a click or a call away. This alluring lifestyle comes with its own perils, the biggest one being concerned with health which is often compromised with check ins and home delivered food but the problem doesn't just lie with the outside food but also with all those chemical enriched engineered expensive food items. The industry often tempers with our food to make it "More Attractive" to the consumer. However, in modern era, availability of drugs and fancy powders has led to imbalance of health and nutrition, contrary to the previous era when home gardening was very common and people preferred fresh-foods which didn't contain added chemicals. They even used to treat some of the health problems with the natural ways that we nowadays refer to DIYs (Do-it-yourselves). Since Ayurveda used natural herbs and plant extracts for treatment, the earth was fresher and less-polluted which led to greater life expectancy. The modern era also has its own benefits like excellences in allopathy medicine has brought a cure to many untreatable diseases of the ancient times, and have even eradicated certain diseases like smallpox and polio. To summarize, both the time had their own pros and cons, so it would be better if we take both of their advantages into consideration and work ahead to live a healthy life.

The heteropolysaccharide of Mangifera indica fruit: Isolation, chemical profile, complexation with ß-lactoglobulin and antioxidant activity.

A 91 kDa heteropolysaccharide (F2) was isolated from Mangifera indica fruit via extraction with H2O, purification by C2H5OH, starch removal and ion exchange chromatography. This polymer was made up mostly of Ara, Gal, Glc, Rha, Xyl, and GalA in a 37: 29: 9:3:2:19 molar proportion. It inherited a small backbone containing GalpA and Rhap units substituted with very large side chains containing differently linked Ara and Gal units plus esterified gallic acid (GA) residue. Several enzymes generated oligosaccharides including (i) Ara2-10Ac6-22, (ii) Gal1-8Ac5-26 and (iii) GA1Gal1Ac7 were characterized. This polysaccharide, which showed dose dependent antioxidant activity, exhibited synergism with gallic acid, and formed a complex (K = 1.2 × 106 M-1) with ß-lactoglobulin. Accordingly, H2O treatment produces a polysaccharide with desired biochemical properties; this could be effective in designing innovative functional food with flexible makeup.

Polysaccharides from Thymus vulgaris leaf: Structural features, antioxidant activity and interaction with bovine serum albumin.

Thymus vulgaris is used for various health benefits and culinary, nevertheless, report on its macromolecules is absent. Here, we report chemical compositions of the polysaccharides isolated from its leaf by sequential extraction with inorganic solvents. In particular, chemical profile of a unique rhamnogalacturonan I type polysaccharide containing ester linked phenolic acids has been described. Sugar compositional, TLC, UV-spectrometric and ESI-MS analyses of oligosaccharides generated from this polysaccharide by enzyme digestion, controlled acid hydrolysis and Smith degradation revealed atypical fine structural details. Biochemical analysis demonstrated dose-dependent antioxidant activity. A combination of large neutral side chains of the ramified region and ester linked phenolic acids are regarded as the functional sites. Ultraviolet spectrometric and fluorimetric analyses showed that this polysaccharide forms a homogeneous water-soluble complex with bovine serum albumin (binding constant, K = 2.91 × 106/M). Consequently, water extraction affords a polysaccharide which induces pharmacological effect; this underlines the impact of thyme as natural dietetic antioxidant.