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1.
Influence of graphene on the multiple metabolic pathways of Zea mays roots based on transcriptome analysis.
Chen, Z, Zhao, J, Song, J, Han, S, Du, Y, Qiao, Y, Liu, Z, Qiao, J, Li, W, Li, J, et al
PloS one. 2021;(1):e0244856
Abstract
Graphene reportedly exerts positive effects on plant root growth and development, although the corresponding molecular response mechanism remains to be elucidated. Maize seeds were randomly divided into a control and experimental group, and the roots of Zea mays L. seedlings were watered with different concentrations (0-100 mg/L) of graphene to explore the effects and molecular mechanism of graphene on the growth and development of Z. mays L. Upon evaluating root growth indices, 50 mg/L graphene remarkably increased total root length, root volume, and the number of root tips and forks of maize seedlings compared to those of the control group. We observed that the contents of nitrogen and potassium in rhizosphere soil increased following the 50 mg/L graphene treatment. Thereafter, we compared the transcriptome changes in Z. mays roots in response to the 50 mg/L graphene treatment. Transcriptional factor regulation, plant hormone signal transduction, nitrogen and potassium metabolism, as well as secondary metabolism in maize roots subjected to graphene treatment, exhibited significantly upregulated expression, all of which could be related to mechanisms underlying the response to graphene. Based on qPCR validations, we proposed several candidate genes that might have been affected with the graphene treatment of maize roots. The transcriptional profiles presented here provide a foundation for deciphering the mechanism underlying graphene and maize root interaction.
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2.
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.
Subtelomeric assembly of a multi-gene pathway for antimicrobial defense compounds in cereals.
Li, Y, Leveau, A, Zhao, Q, Feng, Q, Lu, H, Miao, J, Xue, Z, Martin, AC, Wegel, E, Wang, J, et al
Nature communications. 2021;(1):2563
Abstract
Non-random gene organization in eukaryotes plays a significant role in genome evolution. Here, we investigate the origin of a biosynthetic gene cluster for production of defence compounds in oat-the avenacin cluster. We elucidate the structure and organisation of this 12-gene cluster, characterise the last two missing pathway steps, and reconstitute the entire pathway in tobacco by transient expression. We show that the cluster has formed de novo since the divergence of oats in a subtelomeric region of the genome that lacks homology with other grasses, and that gene order is approximately colinear with the biosynthetic pathway. We speculate that the positioning of the late pathway genes furthest away from the telomere may mitigate against a 'self-poisoning' scenario in which toxic intermediates accumulate as a result of telomeric gene deletions. Our investigations reveal a striking example of adaptive evolution underpinned by remarkable genome plasticity.
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4.
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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5.
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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6.
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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7.
Identification and analysis of 35 genes associated with vitamin D deficiency: A systematic review to identify genetic variants.
Sepulveda-Villegas, M, Elizondo-Montemayor, L, Trevino, V
The Journal of steroid biochemistry and molecular biology. 2020;:105516
Abstract
Vitamin D deficiency is a public health concern associated with, but not limited to, skeletal anomalies, chronic diseases, immune conditions, and cancer, among others. Hypovitaminosis D is mainly associated with environmental and lifestyle factors that affect sunlight exposure. However, genetic factors also influence 25-hydroxyvitamin D (25[OH]D) serum concentration. Although there is available information of genes with clear biological relevance or markers identified by Genome-Wide Association Studies, an overall view and screening tool to identify known genetic causes of altered serum levels of 25(OH)D is lacking. Moreover, there are no studies including the total genetic evidence associated with abnormal serum concentration of 25(OH)D. Therefore, we conducted a de-novo systematic literature review to propose a set of genes comprehensive of all genetic variants reported to be associated with deficiency of vitamin D. Abstracts retrieved from PubMed search were organized by gene and curated one-by-one using the PubTerm web tool. The genes identified were classified according to the type of genetic evidence associated with serum 25(OH)D levels and were also compared with the few commonly screened genes related to vitamin D status. This strategy allowed the identification of 35 genes associated with serum 25(OH)D concentrations, 27 (75%) of which are not commercially available and are not, therefore, analyzed in clinical practice for genetic counseling, nor are they sufficiently studied for research purposes. Functional analysis of the genes identified confirmed their role in vitamin D pathways and diseases. Thus, the list of genes is an important source to understand the genetic determinants of 25(OH)D levels. To further support our findings, we provide a map of the reported functional variants and SNPs not included in ClinVar, minor allelic frequencies, SNP effect sizes, associated diseases, and an integrated overview of the biological role of the genes. In conclusion, we identified a comprehensive candidate list of genes associated with serum 25(OH)D concentrations, most of which are not commercially available, but would prove of importance in clinical practice in screening for patients that should respond to supplementation because of alterations in absorption, patients that would have little benefit because alterations in the downstream metabolism of vitamin D, and to study non-responsiveness to supplementation with vitamin D.
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Untargeted Metabolomics Identifies Key Metabolic Pathways Altered by Thymoquinone in Leukemic Cancer Cells.
AlGhamdi, AA, Mohammed, MRS, Zamzami, MA, Al-Malki, AL, Qari, MH, Khan, MI, Choudhry, H
Nutrients. 2020;(6)
Abstract
Thymoquinone (TQ), a naturally occurring anticancer compound extracted from Nigella sativa oil, has been extensively reported to possess potent anti-cancer properties. Experimental studies showed the anti-proliferative, pro-apoptotic, and anti-metastatic effects of TQ on different cancer cells. One of the possible mechanisms underlying these effects includes alteration in key metabolic pathways that are critical for cancer cell survival. However, an extensive landscape of the metabolites altered by TQ in cancer cells remains elusive. Here, we performed an untargeted metabolomics study using leukemic cancer cell lines during treatment with TQ and found alteration in approximately 335 metabolites. Pathway analysis showed alteration in key metabolic pathways like TCA cycle, amino acid metabolism, sphingolipid metabolism and nucleotide metabolism, which are critical for leukemic cell survival and death. We found a dramatic increase in metabolites like thymine glycol in TQ-treated cancer cells, a metabolite known to induce DNA damage and apoptosis. Similarly, we observed a sharp decline in cellular guanine levels, important for leukemic cancer cell survival. Overall, we provided an extensive metabolic landscape of leukemic cancer cells and identified the key metabolites and pathways altered, which could be critical and responsible for the anti-proliferative function of TQ.
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Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study.
Mahajan, UV, Varma, VR, Griswold, ME, Blackshear, CT, An, Y, Oommen, AM, Varma, S, Troncoso, JC, Pletnikova, O, O'Brien, R, et al
PLoS medicine. 2020;(1):e1003012
Abstract
BACKGROUND There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. METHODS AND FINDINGS We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators. CONCLUSIONS In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.
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10.
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.