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Vitamin C and Somatic Cell Reprogramming
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
A subsequent independent study found that vitamin C could promote DNA demethylation in ESCs at genomic loci known to undergo widespread loss of methylation during the reprogramming of somatic cells into iPSCs [24]. Furthermore, Stadtfeld and colleagues [14] showed that vitamin C prevents DNA hypermethylation and maintains the active chromatin state and normal maternal expression of the paternally imprinted Dlk1-Dio3 gene cluster. Loss of imprinting at this locus due to DNA hypermethylation was known to cause the abnormal development of mice generated from iPSCs [10]. The ability of vitamin C to increase the efficiency of reprogramming and improve the quality of iPSCs has therefore been attributed to its ability to modulate the epigenome (Figure 6.1a).
Biochemistry
Published in Burkhard Madea, Asphyxiation, Suffocation,and Neck Pressure Deaths, 2020
In extrathyroidal tissues, conversion of the pro-hormone T4 to the active form T3 (by iodine atom removal from the outer ring of T4), as well as T3 and T4 metabolism to inactive products (by removal of an inner-ring iodine atom) are mediated by three selenoenzymes called type 1, type 2 and type 3 deiodinase. All deiodinases are membrane-anchored proteins of 29–33 kDa that share substantial sequence homology and catalytic properties, and contain selenocysteine as the key residue within their catalytic centre. Expression levels and activities of type 1 deiodinase (D1 or DIO1, which is preferentially expressed in the thyroid gland, liver and kidney) and type 2 deiodinase (D2 or DIO2) vary among tissues, leading to tissue-specific differences in circulating levels of T3. Type 1 deiodinase catalyzes the removal of inner- or outer-ring iodine atoms in equimolar proportion to generate T3, 3,3′,5′-triiodothyronine (reverse triiodothyronine or rT3) or 3,3′-diiodothyronine (T2), depending on the substrate. Most of the circulating T3 is derived from T4 to T3 conversion by D1 action. Type 2 deiodinase, which is considerably more efficient than D1, catalyzes only outer-ring iodine atom removal from T4, generating the active product T3. D2 is mainly active in the brain, pituitary and skeletal muscle. Type 3 deiodinase (D3 or DIO3) irreversibly inactivates T3, or prevents T4 activation by catalyzing the removal of an inner-ring iodine atom to generate T2 or rT3 respectively. Given these functions, D3 is considered the major physiological inactivator and terminator of thyroid hormone action at the peripheral level [4,6,11,15,47,61,72,76].
Selective thyroid hormone receptor beta agonist, GC-1, is capable to reduce growth of colorectal tumor in syngeneic mouse models
Published in Journal of Receptors and Signal Transduction, 2022
Katayoun Pourvali, Ghazaleh Shimi, Arman Ghorbani, Azam Shakery, Farshad Hosseini Shirazi, Hamid Zand
To investigate the expression of THRB in normal colon tissue and tumor cells, and examine the probable influence of GC-1 on its expression, we performed a quantitative reverse transcription-polymerase chain reaction (qRT-PCR). As higher ΔCT values indicate lower gene expression, these results imply that normal colon tissue has higher expression of THRB (ΔCT = 3.89 ± 0.55) and tumoral tissue has a significant reduction of THRB gene expression (ΔCT = 10.59 ± 1.80) (p < .05). GC-1 injection for 8 d significantly increased THRB expression in tumor tissue (ΔCT = 6.25 ± 2.40) compared to the untreated tumor cells (p < .05) (Figure 4(A)). Figure 4(B) shows that there was no difference in THRA mRNA levels among normal colon tissue, untreated tumor cells, and GC-1 treated tumors. Although the expression of DIO2 gene was not significantly different among normal, untreated, and treated tumor tissues, the expression of DIO3 was induced in mouse model tumor but the results were not statistically significant. Administration of GC-1 for 8 d at selected doses in this study decreased the mRNA level of DIO3; however, the results were not statistically significant (p > .05) (Figure 4(C,D)).
Effect of sodium selenite on synaptic plasticity and neurogenesis impaired by hypothyroidism
Published in International Journal of Neuroscience, 2022
Ercan Babur, Özlem Canöz, Burak Tan, Cem Süer, Nurcan Dursun
Selenium is known primarily for its antioxidant activity and has a role in thyroid hormone metabolism. Selenium deficiency impairs thyroid hormone metabolism by inhibiting the synthesis and activity of the iodothyronine deiodinases, which convert T4 to the more metabolically active T3. Deiodinases (DIO1, DIO2 and DIO3) are selenoenzymes that can up- or down-regulate thyroid hormone signaling on a cell-specific basis, independently of circulating thyroid hormone levels [18]. Recently, we have shown that deficiency of selenium impairs the LTP and hippocampus-dependent learning [19] and the administration of selenium to hypothyroid rats is partially able to attenuate impairment of LTP [20]. Although no study has examined direct relationship between Se deficiency and adult neurogenesis, it has been shown that selenomethionine, an amino acid containing selenium, has promoted hippocampal neurogenesis via the PI3K-Akt-GSK3β-Wnt pathway in a Mouse Model of Alzheimer's Disease [21]. Selenium effectively inhibited ROS-mediated apoptotic neural precursor cell death in vitro and in vivo in traumatic brain injury [22]. It has been suggested that altered neurogenesis may contribute to the cognitive and behavioral deficits associated with adult-onset hypothyroidism [14,16]. However, no study has examined whether chronic selenium administration can reverse the reduced neurogenesis observed in hypothyroidism. With the thought that selenium may positively affect deiodinase enzyme activity, in this study, we examined if selenium supplementation may ameliorate the deterioration of learning and memory processes induced by hypothyroidism.
Effects of maternal exposure to BDE209 on neuronal development and transcription of iodothyronine deiodinase in offspring mice
Published in Toxicology Mechanisms and Methods, 2019
Bo Qian, Chengqiang Wang, Chaochao Zhao, Rongjuan Jiang, Jiale Song
dio1 and dio2 are not the only TH-regulated genes affected in BDE209-induced TH disruption. Previous studies revealed that the THs change induced by BDE209 was a result of multiple gene damage, including dio1 and dio2 (Li et al. 2014; Han et al. 2017). The inhibition of dio1 and dio2 transcriptions can only partly explain the increased THs in circulation. dio3 is the main enzyme for deactivating T3 and T4 in the serum to protect tissues from excess active THs (Marsili et al. 2011). The inactivation pathways of THs are very limited, and our previous study showed a significant negative correlation between dio3 gene transcription in the placenta and prenatal exposure dose of BDE209 (Bo et al. 2014). Thus, it may be helpful to examine the gene/protein of dio3 to understand the mechanisms of THs disruption. In the current study, reduced mRNA level of dio3 was noted in the livers and brains of offspring after BDE209 exposure. Consistent with us, dio3 mRNA levels of the chicken embryos were reported obviously reduced in vitro and in vivo upon exposure to an environmentally realistic concentration of PBDEs (Egloff et al. 2011). This study is one of only a few that has concentrated on PBDEs-induced changes in dio3 gene transcription. The protein levels of dio3 observed in the liver and brain were consistent with the dio3 mRNA level change, suggest that decreased gene transcriptional response of dio3 has translated to a detectable decrease in the dio3 protein of offspring mice. dio3 is the major TH-deactivating enzyme to convert the T3 into T2 and T4 into rT3 (Marsili et al. 2011), which makes it a sensitive regulator of serum THs homeostasis. In dio3-deficient mice, T3 concentrations in the serum and brain were reported to elevate differently (Hernandez et al. 2010). Thus, the decrease in mRNA and protein levels of dio3 might be the main reason participated in increased T3 and T4 of serum in offspring mice. Hence, dio3 might be the potential toxic target in TH disruption induced by BDE209.