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Thyroid peroxidase as a dual active site enzyme: Focus on biosynthesis, hormonogenesis and thyroid disorders of autoimmunity and cancer.
Godlewska, M, Banga, PJ
Biochimie. 2019;:34-45
Abstract
Thyroid peroxidase (TPO) is the key enzyme involved in thyroid hormone synthesis. Autoantibodies to TPO (TPOAbs) are a hallmark of autoimmune thyroid disease (AITD). Here, we highlight recent progress over several years in understanding TPO biochemistry and function in various pathologies. TPO undergoes complex post-translational modifications as a dimer in endoplasmic reticulum during secretory pathway to apical membrane of thyrocytes. In silico modelling of TPO dimer has provided new information into the two enzyme active site regions and autoantigenic determinants. TPO and hydrogen peroxide generating DUOX and caveolin-1 form a complex known as thyroxisome to bring together in close proximity the components of hormone synthesis in apical membrane. Autoimmunity to TPO is characterised by autoantibodies and T cell reactivity in Hashimoto's disease and Graves' disease. TPOAbs are directed predominantly to two immunodominant determinants (IDR) termed IDR-A and IDR-B regions, with the latter antibodies more predominant in autoimmune disease. Strong genetic risk has been shown to be associated with TPOAbs for AITD development. A different antibody with unusual features of bispecificity for both TPO and thyroglobulin may play protective role in Hashimoto's disease. In the context of TPO biology in human cancer, thyroid tumor tissue and breast cancer differ in TPO expression and isoform composition. In thyroid cancer, TPO expression is decreased partly by the BRAF(V600E) mutation, with direct impact on significant hormone production. TPOAbs may play a protective role in breast cancer development. An understanding of TPO and its unique two enzymatic active sites and autoantigenic determinants continues to add new knowledge on the biochemistry and immunology of this enzyme.
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2.
Diagnosis and treatment of hypothyroidism in the elderly.
Duntas, LH, Yen, PM
Endocrine. 2019;(1):63-69
Abstract
The global population is aging with millions of people today living into their 90 s. Thyroid disease, particularly hypothyroidism, is widespread among all age groups, and it is expected to steadily increase as the population gets older. Clinical diagnosis of hypothyroidism is challenging, as the TSH reference range needs to be evaluated according to age, while evaluation of TSH levels must also take into account body weight and other variants such as polypharmacy, comorbidities, and general health condition. Since thyroid hormone has a potent regulatory effect on cholesterol metabolism, the possibility of thyroid dysfunction should be considered in cases of unexplained dyslipidemia. Once hypothyroidism has been confirmed, treatment requires caution, frequent cardiovascular monitoring, and individualized (precision) medicine. Treatment of subclinical hypothyroidism (SCH) in the elderly should be undertaken with care, guided by age and the degree of SCH: a TSH higher than 10 mU/l seems a reasonable threshold, though it should be regularly re-evaluated, while the LT4 dose needs to be tailored, taking into account the patient's health condition and the potential presence of dyslipidemia as well as other metabolic derangements.
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3.
Combined docosahexaenoic acid and thyroid hormone supplementation as a protocol supporting energy supply to precondition and afford protection against metabolic stress situations.
Videla, LA
IUBMB life. 2019;(9):1211-1220
Abstract
Liver preconditioning (PC) refers to the development of an enhanced tolerance to injuring stimuli. For example, the protection from ischemia-reperfusion (IR) in the liver that is obtained by previous maneuvers triggering beneficial molecular and functional changes. Recently, we have assessed the PC effects of thyroid hormone (T3; single dose of 0.1 mg/kg) and n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs; daily doses of 450 mg/kg for 7 days) that abrogate IR injury to the liver. This feature is also achieved by a combined T3 and the n-3 LCPUFA docosahexaenoic acid (DHA) using a reduced period of supplementation of the FA (daily doses of 300 mg/kg for 3 days) and half of the T3 dosage (0.05 mg/kg). T3 -dependent protective mechanisms include (i) the reactive oxygen species (ROS)-dependent activation of transcription factors nuclear factor-κB (NF-κB), AP-1, signal transducer and activator of transcription 3, and nuclear factor erythroid-2-related factor 2 (Nrf2) upregulating the expression of protective proteins. (ii) ROS-induced endoplasmic reticulum stress affording proper protein folding. (iii) The autophagy response to produce FAs for oxidation and ATP supply and amino acids for protein synthesis. (iv) Downregulation of inflammasome nucleotide-bonding oligomerization domain leucine-rich repeat containing family pyrin containing 3 and interleukin-1β expression to prevent inflammation. N-3 LCPUFAs induce antioxidant responses due to Nrf2 upregulation, with inflammation resolution being related to production of oxidation products and NF-κB downregulation. Energy supply to achieve liver PC is met by the combined DHA plus T3 protocol through upregulation of AMPK coupled to peroxisome proliferator-activated receptor-γ coactivator 1α signaling. In conclusion, DHA plus T3 coadministration favors hepatic bioenergetics and lipid homeostasis that is of crucial importance in acute and clinical conditions such as IR, which may be extended to long-term or chronic situations including steatosis in obesity and diabetes. © 2019 IUBMB Life, 71(9):1211-1220, 2019.
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4.
Pyruvate kinase M2: A simple molecule with complex functions.
Alquraishi, M, Puckett, DL, Alani, DS, Humidat, AS, Frankel, VD, Donohoe, DR, Whelan, J, Bettaieb, A
Free radical biology & medicine. 2019;:176-192
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Abstract
Pyruvate kinase M2 is a critical enzyme that regulates cell metabolism and growth under different physiological conditions. In its metabolic role, pyruvate kinase M2 catalyzes the last glycolytic step which converts phosphoenolpyruvate to pyruvate with the generation of ATP. Beyond this metabolic role in glycolysis, PKM2 regulates gene expression in the nucleus, phosphorylates several essential proteins that regulate major cell signaling pathways, and contribute to the redox homeostasis of cancer cells. The expression of PKM2 has been demonstrated to be significantly elevated in several types of cancer, and the overall inflammatory response. The unusual pattern of PKM2 expression inspired scientists to investigate the unrevealed functions of PKM2 and the therapeutic potential of targeting PKM2 in cancer and other disorders. Therefore, the purpose of this review is to discuss the mechanistic and therapeutic potential of targeting PKM2 with the focus on cancer metabolism, redox homeostasis, inflammation, and metabolic disorders. This review highlights and provides insight into the metabolic and non-metabolic functions of PKM2 and its relevant association with health and disease.
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5.
PKM2, a potential target for regulating cancer.
Li, YH, Li, XF, Liu, JT, Wang, H, Fan, LL, Li, J, Sun, GP
Gene. 2018;:48-53
Abstract
Aberrated glucose metabolism is a key future of cancer cells. Unlike normal cells, tumor cells favor glycolysis even in the presence of sufficient oxygen. Pyruvate kinase (PK), a key glucose metabolic enzyme, converts phosphoenolpyruvate (PEP) to pyruvate by transferring the high-energy phosphate group to adenosine diphosphate (ADP) to produce adenosine triphosphate (ATP). Pyruvate kinase M2 (PKM2), one of the four isozyme of PK, which universally expressed in rapidly proliferating cells such as embryonic cells and cancer cells. Recent years, more and more research suggested PKM2 plays a crucial role in cancer progression through both metabolic and non-metabolic pathways. On the one hand, the middle product of glycolysis, such as amino acids, nucleotides, lipids is necessary to rapid growth of cancer cells. On the other hand, PKM2 supports tumor growth through regulating the expression of gene that involved in cell proliferation, migration and apoptosis. In this article, we review the recent advances to further understand the regulation and function of PKM2 in tumorigenesis. Given its multiple effects on cancer, PKM2 may be a potential target for cancer diagnosis and treatment.
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Thyrotropic hormones.
Mallya, M, Ogilvy-Stuart, AL
Best practice & research. Clinical endocrinology & metabolism. 2018;(1):17-25
Abstract
Thyroid hormones are crucial for normal cognition and neurodevelopment in children. The introduction of the screening programs for congenital hypothyroidism has decreased the incidence of untreated congenital hypothyroidism. As maternal thyroid disease is common, and may impact on thyroid gland development and function in the fetus, optimal management is crucial. This review discusses thyroid function and the impact of maternal thyroid disease on the fetus and neonate, as well as the influence of thyroid hormones, thyroid antibodies and the excretion of thyroid medication into breast milk on infant thyroid function.
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7.
The Physiology of Childhood Growth: Hormonal Regulation.
Benyi, E, Sävendahl, L
Hormone research in paediatrics. 2017;(1):6-14
Abstract
The growth patterns of a child changes from uterine life until the end of puberty. Height velocity is highest in utero and declines after birth until puberty when it rises again. Important hormonal regulators of childhood growth are growth hormone, insulin-like growth factor 1, sex steroids, and thyroid hormone. This review gives an overview of these hormonal regulators of growth and their interplay with nutrition and other key players such as inflammatory cytokines.
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"With a little help from my friends" - The role of microbiota in thyroid hormone metabolism and enterohepatic recycling.
Virili, C, Centanni, M
Molecular and cellular endocrinology. 2017;:39-43
Abstract
The gut microbiota is composed of over 1200 species of anaerobes and aerobes bacteria along with bacteriophages, viruses and fungal species. Increasing evidence indicates that the intestinal microbiota, beside digestive equilibrium, is also crucial for immunologic, hormonal and metabolic homeostasis. The intestinal microbiota interacts with distant organs by signals which may be part of the bacteria themselves or their metabolites. Dysbiosis has been observed in inflammatory or autoimmune disorders such as multiple sclerosis or type 1 diabetes as well as in obesity and type 2 diabetes. Functional thyroid disorders were associated with bacterial overgrowth and a different microbial composition. Although thyroid metabolism was apparently disregarded, the interference of microbiota on peripheral iodothyronine homeostasis is an intriguing issue. In this review we focused on the interactions of intestinal microbiota with thyroid-related micronutrients and with the metabolic steps of endogenous and exogenous iodothyronines.
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Thyroid Hormones, Metabolic Syndrome and Its Components.
Delitala, AP, Fanciulli, G, Pes, GM, Maioli, M, Delitala, G
Endocrine, metabolic & immune disorders drug targets. 2017;(1):56-62
Abstract
Metabolic syndrome is a clustering of various metabolic parameters, which include diabetes, low high-density lipoprotein cholesterol, elevated triglycerides, abdominal obesity, and hypertension. It has merged as a worldwide epidemic and a major public health care concern. However, due to the different criteria used for the assessment, the frequency of metabolic syndrome in the general population is variable but it is more common in the older people. Metabolic syndrome is closely linked to cardiovascular risk and increases cardiovascular outcomes and all-cause mortality. Recent evidences showed that alterations of the thyroid function could have an impact on the components of the metabolic syndrome, suggesting that thyroid hormones have a variety of effects on energy homeostasis, lipid and glucose metabolism, and blood pressure. In this review, we summarize available data on the action of thyroid hormone on the components of metabolic syndrome.
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10.
Disorder of thyroid hormone transport into the tissues.
Groeneweg, S, Visser, WE, Visser, TJ
Best practice & research. Clinical endocrinology & metabolism. 2017;(2):241-253
Abstract
Transport of thyroid hormone (TH) across the plasma membrane is essential for intracellular TH metabolism and action, and this is mediated by specific transporter proteins. During the last two decades several transporters capable of transporting TH have been identified, including monocarboxylate transporter 8 (MCT8), MCT10 and organic anion transporting polypeptide 1C1 (OATP1C1). In particular MCT8 and OATP1C1 are important for the regulation of local TH activity in the brain and thus for brain development. MCT8 is a protein containing 12 transmembrane domains, and is encoded by the SLC16A2 gene located on the X chromosome. It facilitates both TH uptake and efflux across the cell membrane. Male subjects with hemizygous mutations in MCT8 are afflicted with severe intellectual and motor disability, also known as the Allan-Herndon-Dudley syndrome (AHDS), which goes together with low serum T4 and high T3 levels. This review concerns molecular and clinical aspects of MCT8 function.