China
Africa
Explore chapters and articles related to this topic
Micronutrients for Improved Management of Huntington’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Examination of autopsied samples human HD striatum showed increased levels carbonylation of proteins (a marker of protein oxidation). Oxidation of mitochondrial enzymes decreased catalytic activities, which reduced energy levels in HD, whereas oxidation of pyridoxal kinase and antiquitin-1 decreased the levels of pyridoxal 5-phosphate (vitamin B6). Using the Tet/HD94 conditional mouse HD model, it was shown that carbonylation (oxidation) of proteins in the striatum was dependent upon the expression of HD protein.120 Vitamin B6 acts as a cofactor for several biological processes including transaminases, and synthesis of glutathione, GABA, and dopamine; therefore, the reduction in the levels of vitamin B6 in HD may be responsible for reduction in the levels of dopamine and GABA in this disease.
Vitamin B6 and Other Inhibitors of Glucocorticoid Receptor Function and Cell Death of B16 Melanoma Cells
Published in Maryce M. Jacobs, Vitamins and Minerals in the Prevention and Treatment of Cancer, 2018
Gerald Litwack, Noreen M. Robertson, Andrew B. Maksymowych, Mahmut Celiker
In 1977 and 1978,1–6 we provided the first evidence that pyridoxal phosphate, the biologically active form of vitamin B6, interfered with the ability of the activated (DNA-binding form) glucocorticoid receptor to interact with DNA, thus opening the possibility that the cellular level of pyridoxal phosphate might regulate the functioning of the receptor mechanism. The precursor or pyridoxal phosphate is dietary vitamin B6, pyridoxine. This is metabolized to pyridoxal phosphate in two steps, the phosphorylation of pyridoxine to form pyridoxine phosphate and its subsequent oxidation to pyridoxal by a riboflavin catalyzed enzymic reaction.7 Pyridoxal, an alternative form of vitamin B6 can enter the cell and be converted to pyridoxal phosphate by pyridoxal kinase and ATP in a single step. Classically, pyridoxal phosphate is known to form a Schiff base with proteins through a side chain amino group of a lysine residue.8 Thus, it appeared that not only was pyridoxal phosphate able to form a Schiff base with lysine residues in the DNA binding domain and at or near the steroid binding site of the glucorticoid receptor, but it was likely that the dietary level of vitamin B6 could influence the cellular level of pyridoxal phosphate and exert some control over the glucocorticoid receptor mechanism that mediates stress adaptation at the cellular level.
Biochemical Effects in Animals
Published in Stephen P. Coburn, The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
Pyridoxal kinase (E.C. 2.7.1.35) has a broad specificity and may be referred by various names depending on the substrate used in a particular experiment. For consistency, we will use the term, pyridoxal kinase, throughout this discussion even though the original authors may have used an alternate name (e.g., pyridoxine kinase). Also, in the following review of the interaction between deoxypyridoxines and pyridoxal kinases, the reader should keep in mind the problems discussed in the preface in distinguishing between a substrate and a competitive inhibitor. The term competitive inhibitor is used below as used in the original articles and does not necessarily mean that the inhibitor was not a substrate for the enzyme. It is very likely that 4′-deoxypyridoxine was a substrate in every case.
Immunostimulatory effects of vitamin B5 improve anticancer immunotherapy
Published in OncoImmunology, 2022
Melanie Bourgin, Oliver Kepp, Guido Kroemer
Yet another example is provided by vitamin B6 (pyridoxine), the metabolism of which is linked to prognosis in non-small cell lung cancer (NSCLC). Thus, low levels of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, correlate with poor responses to cisplatin-based chemotherapy in mouse models and NSCLC patients,17 as well as with an infiltration of NSCLC by activated dendritic cells (DCs) expressing lysosomal associated membrane glycoprotein (DC-LAMP).18 Similarly, in patients with locally advanced cervical carcinoma, a positive correlation between PDXK expression and tumor infiltration by DC-LAMP+ cells has been observed.18 Conversely, supplementation of vitamin B6, if combined with cisplatin-based chemotherapy, stimulates anticancer immune responses by enhancing immunogenic stress and death of NSCLC cells.19 Altogether, these results support the idea that vitamin B6 stimulates anticancer immunosurveillance.
Recent progress in development of cyclin-dependent kinase 7 inhibitors for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2021
Hanzhi Liang, Jintong Du, Reham M. Elhassan, Xuben Hou, Hao Fang
Replacing the purine ring in the Roscovitine structure by a pyridomidazole ring, led in a discovery of a series of 3 H-imidazole [4,5-b]pyridine core derivatives, such as Perharidine A (2, Figure 2) [69]. Perharidine A was found to inhibit CDKs (CDK7: IC50 = 0.9 μM), and exhibited selectivity against pyridoxal kinase, which caused side effects [69,70]. The pyrazoline [1,5-a] pyrimidine core scaffold (3) was also used for the development of novel CDK inhibitors. Each position in this scaffold was expanded to investigate the structure-activity relationships [71]. Dinaciclib (3, SCH-727,965, Figure 2), which incorporates a 3-ethyl substituent, had an overall improved activity compared to the other analogs [71]. Dinaciclib inhibited the activity of multiple CDKs, including CDK7 (IC50 = 0.17 μM) [71,72], suppressed cell proliferation, and induced cancer cell apoptosis in a broad spectrum of human tumor cell lines, including AML, chronic lymphocytic leukemia, breast cancer, and Bcl-xL silenced cells [6,66,67,73].
Metabolic enzymes expressed by cancer cells impact the immune infiltrate
Published in OncoImmunology, 2019
Gautier Stoll, Margerie Kremer, Normal Bloy, Adrien Joseph, Maria Castedo, Guillaume Meurice, Christophe Klein, Lorenzo Galluzzi, Judith Michels, Guido Kroemer
Driven by these considerations, we decided to evaluate the impact of specific metabolic enzymes on the immune infiltrate of non-small cell lung carcinoma (NSCLC) lesions, the prognosis of which is known to be dictated by anticancer immune responses.20–28 Based on an admittedly cell-autonomous perspective of NSCLC, we previously reported that the expression or activity enzymes involved in (1) vitamin B6 metabolism, such as pyridoxal kinase (PDXK) and aldehyde dehydrogenase 7 family, member A1, (ALDH7A1), (2) lipid synthesis, such as lipase C, hepatic type (LIPC), or (3) poly-ADP ribosylation, such as poly(ADP-ribose) polymerase 1 (PARP1) would affect the response of NSCLC cells to chemotherapy in vitro and in vivo, and affect patient prognosis.29–35 However, we have not yet explored the impact of these enzymes on anticancer immune responses. Here, we investigated the possibility that such enzymes might affect natural or therapy-driven anticancer immunosurveillance using a bioinformatic approach.