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Interactions between Radiation and One-Carbon Metabolism.
Korimerla, N, Wahl, DR
International journal of molecular sciences. 2022;(3)
Abstract
Metabolic reprogramming is a hallmark of cancer. Cancer cells rewire one-carbon metabolism, a central metabolic pathway, to turn nutritional inputs into essential biomolecules required for cancer cell growth and maintenance. Radiation therapy, a common cancer therapy, also interacts and alters one-carbon metabolism. This review discusses the interactions between radiation therapy, one-carbon metabolism and its component metabolic pathways.
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Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential.
Zhao, LN, Björklund, M, Caldez, MJ, Zheng, J, Kaldis, P
Oncogene. 2021;(13):2339-2354
Abstract
Most of the drugs currently prescribed for cancer treatment are riddled with substantial side effects. In order to develop more effective and specific strategies to treat cancer, it is of importance to understand the biology of drug targets, particularly the newly emerging ones. A comprehensive evaluation of these targets will benefit drug development with increased likelihood for success in clinical trials. The folate-mediated one-carbon (1C) metabolism pathway has drawn renewed attention as it is often hyperactivated in cancer and inhibition of this pathway displays promise in developing anticancer treatment with fewer side effects. Here, we systematically review individual enzymes in the 1C pathway and their compartmentalization to mitochondria and cytosol. Based on these insight, we conclude that (1) except the known 1C targets (DHFR, GART, and TYMS), MTHFD2 emerges as good drug target, especially for treating hematopoietic cancers such as CLL, AML, and T-cell lymphoma; (2) SHMT2 and MTHFD1L are potential drug targets; and (3) MTHFD2L and ALDH1L2 should not be considered as drug targets. We highlight MTHFD2 as an excellent therapeutic target and SHMT2 as a complementary target based on structural/biochemical considerations and up-to-date inhibitor development, which underscores the perspectives of their therapeutic potential.
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3.
Current progress of PM-localized protein functions in jasmonate pathway.
Qi, X, Gu, P, Shan, X
Plant signaling & behavior. 2021;(6):1906573
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Abstract
Jasmonate (JA), a class of lipid-derived phytohormone, regulates diverse developmental processes and responses to abiotic or biotic stresses. The biosynthesis and signaling of JA mainly occur in various organelles, except for the plasma membrane (PM). Recently, several PM proteins have been reported to be associated with the JA pathway. This mini-review summarized the recent progress on the functional role of PM-localized proteins involved in JA transportation, JA-related defense responses, and JA-regulated endocytosis.
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Host cell glutamine metabolism as a potential antiviral target.
Hirabara, SM, Gorjao, R, Levada-Pires, AC, Masi, LN, Hatanaka, E, Cury-Boaventura, MF, da Silva, EB, Santos-Oliveira, LCD, Sousa Diniz, VL, Serdan, TAD, et al
Clinical science (London, England : 1979). 2021;(2):305-325
Abstract
A virus minimally contains a nucleic acid genome packaged by a protein coat. The genome and capsid together are known as the nucleocapsid, which has an envelope containing a lipid bilayer (mainly phospholipids) originating from host cell membranes. The viral envelope has transmembrane proteins that are usually glycoproteins. The proteins in the envelope bind to host cell receptors, promoting membrane fusion and viral entry into the cell. Virus-infected host cells exhibit marked increases in glutamine utilization and metabolism. Glutamine metabolism generates ATP and precursors for the synthesis of macromolecules to assemble progeny viruses. Some compounds derived from glutamine are used in the synthesis of purines and pyrimidines. These latter compounds are precursors for the synthesis of nucleotides. Inhibitors of glutamine transport and metabolism are potential candidate antiviral drugs. Glutamine is also an essential nutrient for the functions of leukocytes (lymphocyte, macrophage, and neutrophil), including those in virus-infected patients. The increased glutamine requirement for immune cell functions occurs concomitantly with the high glutamine utilization by host cells in virus-infected patients. The development of antiviral drugs that target glutamine metabolism must then be specifically directed at virus-infected host cells to avoid negative effects on immune functions. Therefore, the aim of this review was to describe the landscape of cellular glutamine metabolism to search for potential candidates to inhibit glutamine transport or glutamine metabolism.
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Mechanisms and individuality in chromium toxicity in humans.
Pavesi, T, Moreira, JC
Journal of applied toxicology : JAT. 2020;(9):1183-1197
Abstract
With regards to health, chromium (Cr) is an ambiguous chemical element. Although it is considered to be an important micronutrient, it also is connected with several pathologies, including carcinogenicity. The mechanism of action of Cr and its compounds in humans is not yet fully understood. Currently, three possible mechanisms have been proposed for carcinogenesis: Cr(VI)-induced multistage carcinogenesis, genomic instability, and epigenetic modification. Therefore, in addition to the toxicity of this metal and its ions, human susceptibility to Cr-induced pathologies depends on external factors and individual characteristics, such as enzymatic polymorphisms, carriers, endogenous reducing system, adduct formation and stability, and efficiency of DNA repair mechanisms, among other factors. In fact, the variability of individual molecular constitutive factors, such as individual polymorphisms, creates an individualized environment for Cr toxicity. This mini-review contemplates the essential variables in this process.
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Targeting Cell Metabolism as Cancer Therapy.
Ngoi, NYL, Eu, JQ, Hirpara, J, Wang, L, Lim, JSJ, Lee, SC, Lim, YC, Pervaiz, S, Goh, BC, Wong, ALA
Antioxidants & redox signaling. 2020;(5):285-308
Abstract
Significance: Cancer cells exhibit altered metabolic pathways to keep up with biosynthetic and reduction-oxidation needs during tumor proliferation and metastasis. The common induction of metabolic pathways during cancer progression, regardless of cancer histio- or genotype, makes cancer metabolism an attractive target for therapeutic exploitation. Recent Advances: Emerging data suggest that these altered pathways may even result in resistance to anticancer therapies. Identifying specific metabolic dependencies that are unique to cancer cells has proved challenging in this field, limiting the therapeutic window for many candidate drug approaches. Critical Issues: Cancer cells display significant metabolic flexibility in nutrient-limited environments, hampering the longevity of suppressing cancer metabolism through any singular approach. Combinatorial "synthetic lethal" approaches may have a better chance for success and promising strategies are reviewed here. The dynamism of the immune system adds a level of complexity, as various immune populations in the tumor microenvironment often share metabolic pathways with cancer, with successive alterations during immune activation and quiescence. Decoding the reprogramming of metabolic pathways within cancer cells and stem cells, as well as examining metabolic symbiosis between components of the tumor microenvironment, would be essential to further meaningful drug development within the tumor's metabolic ecosystem. Future Directions: In this article, we examine evidence for the therapeutic potential of targeting metabolic alterations in cancer, and we discuss the drawbacks and successes that have stimulated this field.
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7.
One-carbon metabolism and folate transporter genes: Do they factor prominently in the genetic etiology of neural tube defects?
Steele, JW, Kim, SE, Finnell, RH
Biochimie. 2020;:27-32
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Abstract
Neural tube defects (NTDs) are a broad class of congenital birth defects that result from the failure of neural tube closure during neurulation. Folic acid supplementation has been shown to prevent the occurrence of NTDs by as much as 70% in some human populations, and folate deficiency in a pregnant woman is associated with increased risk for having an NTD affected infant. Thus, folate transport-related genes and genes involved in the subsequent folate-mediated one-carbon metabolic pathway have long been considered primary candidates to study the genetic etiology of human NTDs. Herein, we review the genes involved in folate transport and one-carbon metabolism thus far identified as contributing variants that influence human NTD risk, and place these findings in the context of our evolving understanding of the complex genetic architecture underlying these defects.
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Glycomacropeptide Bioactivity and Health: A Review Highlighting Action Mechanisms and Signaling Pathways.
Córdova-Dávalos, LE, Jiménez, M, Salinas, E
Nutrients. 2019;(3)
Abstract
Food-derived bioactive peptides are reported as beneficial and safe for human health. Glycomacropeptide (GMP) is a milk-protein-derived peptide that, in addition to its nutritional value, retains many biological properties and has therapeutic effects in several inflammatory disorders. GMP was shown under in vitro and in vivo conditions to exert a number of activities that regulate the physiology of important body systems, namely the gastrointestinal, endocrine, and immune systems. This review represents a comprehensive compilation summarizing the current knowledge and updated information on the major biological properties associated with GMP. GMP bioactivity is addressed with special attention on mechanisms of action, signaling pathways involved, and structural characteristics implicated. In addition, the results of various studies dealing with the effects of GMP on models of inflammatory diseases are reviewed and discussed.
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Role of cytochrome P450 polymorphisms and functions in development of ulcerative colitis.
Sen, A, Stark, H
World journal of gastroenterology. 2019;(23):2846-2862
Abstract
Cytochromes P450s (CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms (CYP1A1, CYP2D6, CYP2J2, CYP2R1, CYP3A5, CYP3A7, CYP4F3, CYP24A1, CYP26B1 and CYP27B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.
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10.
Gluconeogenesis in cancer cells - Repurposing of a starvation-induced metabolic pathway?
Grasmann, G, Smolle, E, Olschewski, H, Leithner, K
Biochimica et biophysica acta. Reviews on cancer. 2019;(1):24-36
Abstract
Cancer cells constantly face a fluctuating nutrient supply and interference with adaptive responses might be an effective therapeutic approach. It has been discovered that in the absence of glucose, cancer cells can synthesize crucial metabolites by expressing phosphoenolpyruvate carboxykinase (PEPCK, PCK1 or PCK2) using abbreviated forms of gluconeogenesis. Gluconeogenesis, which in essence is the reverse pathway of glycolysis, uses lactate or amino acids to feed biosynthetic pathways branching from glycolysis. PCK1 and PCK2 have been shown to be critical for the growth of certain cancers. In contrast, fructose-1,6-bisphosphatase 1 (FBP1), a downstream gluconeogenesis enzyme, inhibits glycolysis and tumor growth, partly by non-enzymatic mechanisms. This review sheds light on the current knowledge of cancer cell gluconeogenesis and its role in metabolic reprogramming, cancer cell plasticity, and tumor growth.