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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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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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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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Perspectives of Reprogramming Breast Cancer Metabolism.
Wang, YP, Lei, QY
Advances in experimental medicine and biology. 2017;:217-232
Abstract
Reprogramming of cellular metabolism is one of the hallmarks of breast cancer. Breast cancer cells remodel metabolic network to maintain their transformed state and survive in a harsh tumor microenvironment. Dysregulated metabolism further interacts with cellular signaling and epigenetics to promote breast cancer development. Meanwhile, breast cancer stem cells exhibit unique metabolic features, which are critical for therapeutic resistance and tumor recurrence. Besides, aberrant metabolism of breast cancer cells reshapes tumor microenvironment, such as promoting cancer vascularization and sabotaging tumor immunity, to accelerate tumor progression. These special metabolic traits not only open vulnerabilities of breast cancer by targeting essential metabolic pathways but also provide promising diagnostic and prognostic biomarkers to facilitate clinical investigations. Studies in the last few decades have significantly advanced our understanding of mechanisms underlying the reprogramming of breast cancer metabolism and metabolic regulation of breast cancer biology. Targeting tumor metabolism serves as a potentially effective therapeutic approach to suppress breast cancer.
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Review: Metabolic Control of Immune System Activation in Rheumatic Diseases.
Perl, A
Arthritis & rheumatology (Hoboken, N.J.). 2017;(12):2259-2270
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Abstract
Metabolic pathways mediate lineage specification within the immune system through the regulation of glucose utilization, a process that generates energy in the form of ATP and synthesis of amino acids, nucleotides, and lipids to enable cell growth, proliferation, and survival. CD4+ T cells, a proinflammatory cell subset, preferentially produce ATP through glycolysis, whereas cells with an antiinflammatory lineage, such as memory and regulatory T cells, favor mitochondrial ATP generation. In conditions of metabolic stress or a shortage of nutrients, cells rely on autophagy to secure amino acids and other substrates, while survival depends on the sparing of mitochondria and maintenance of a reducing environment. The pentose phosphate pathway acts as a key gatekeeper of inflammation by supplying ribose-5-phosphate for cell proliferation and NADPH for antioxidant defenses. Increased lysosomal catabolism, accumulation of branched amino acids, glutamine, kynurenine, and histidine, and depletion of glutathione and cysteine activate the mechanistic target of rapamycin (mTOR), an arbiter of lineage development within the innate and adaptive immune systems. Mapping the impact of susceptibility genes to metabolic pathways allows for better understanding and therapeutic targeting of disease-specific expansion of proinflammatory cells. Therapeutic approaches aimed at glutathione depletion and mTOR pathway activation appear to be safe and effective for treating lupus, while an opposing intervention may be of benefit in rheumatoid arthritis. Environmental sources of origin for metabolites within immune cells may include microbiota and plants. Thus, a better understanding of the pathways of immunometabolism could provide new insights into the pathogenesis and treatment of the rheumatic diseases.