-
Nutrients Apr 2024Bitterness from phenylthiocarbamide and 6-n-propylthiouracil (PROP) varies with polymorphisms in the gene. Three SNPs form two common (AVI, PAV) and four rare...
Bitterness from phenylthiocarbamide and 6-n-propylthiouracil (PROP) varies with polymorphisms in the gene. Three SNPs form two common (AVI, PAV) and four rare haplotypes (AAI, AAV, PVI, and PAI). AVI homozygotes exhibit higher detection thresholds and lower suprathreshold bitterness for PROP compared to PAV homozygotes and heterozygotes, and these differences may influence alcohol and vegetable intake. Within a diplotype, substantial variation in suprathreshold bitterness persists, and some AVI homozygotes report moderate bitterness at high concentrations. A second receptor encoded by a gene containing a functional polymorphism may explain this. Early work has suggested that PROP might activate TAS2R4 in vitro, but later work did not replicate this. Here, we identify three SNPs that result in three diplotypes-SLN/SLN, FVS/SLN, and FVS/FVS-which make up 25.1%, 44.9%, and 23.9% of our sample. These haplotypes show minimal linkage disequilibrium with so we examined the suprathreshold bitterness as a function of both. The participants ( = 243) rated five PROP concentrations in duplicate, interleaved with other stimuli. As expected, the haplotypes explained ~29% ( < 0.0001) of the variation in the bitterness ratings, with substantial variation within the haplotypes (AVI/AVI, PAV/AVI, and PAV/PAV). Notably, the diplotypes (independent of the haplotypes) explained ~7-8% of the variation in the bitterness ratings ( = 0.0001). Given this, we revisited if PROP could activate heterologously expressed TAS2R4 in HEK293T cells, and calcium imaging indicated 3 mM PROP is a weak TAS2R4 agonist. In sum, our data are consistent with the second receptor hypothesis and may explain the recovery of the PROP tasting phenotype in some AVI homozygotes; further, this finding may potentially help explain the conflicting results on the diplotype and food intake.
Topics: Humans; Propylthiouracil; Receptors, G-Protein-Coupled; Polymorphism, Single Nucleotide; Female; Taste; Male; Adult; Haplotypes; Homozygote; Young Adult; Taste Threshold
PubMed: 38732607
DOI: 10.3390/nu16091357 -
The Journal of Physical Chemistry. A Mar 2024DNA in living beings is constantly damaged by exogenous and endogenous agents. However, in some cases, DNA photodamage can have interesting applications, as it happens...
DNA in living beings is constantly damaged by exogenous and endogenous agents. However, in some cases, DNA photodamage can have interesting applications, as it happens in photodynamic therapy. In this work, the current knowledge on the photophysics of 4-thiouracil has been extended by further quantum-chemistry studies to improve the agreement between theory and experiments, to better understand the differences with 2-thiouracil, and, last but not least, to verify its usefulness as a photosensitizer for photodynamic therapy. This study has been carried out by determining the most favorable deactivation paths of UV-vis photoexcited 4-thiouracil by means of the photochemical reaction path approach and an efficient combination of the complete-active-space second-order perturbation theory//complete-active-space self-consistent field (CASPT2//CASSCF), (CASPT2//CASPT2), time-dependent density functional theory (TDDFT), and spin-flip TDDFT (SF-TDDFT) methodologies. By comparing the data computed herein for both 4-thiouracil and 2-thiouracil, a rationale is provided on the relatively higher yields of intersystem crossing, triplet lifetime and singlet oxygen production of 4-thiouracil, and the relatively higher yield of phosphorescence of 2-thiouracil.
PubMed: 38504122
DOI: 10.1021/acs.jpca.3c06310 -
European Review For Medical and... Mar 2024Thyroid hormones are essential for regulating metabolism, reproduction, and growth. Hypothyroidism is connected with lower sperm count and motility, leading to male...
OBJECTIVE
Thyroid hormones are essential for regulating metabolism, reproduction, and growth. Hypothyroidism is connected with lower sperm count and motility, leading to male infertility. Oxidative stress is likely to be linked to this interaction. Melatonin, being known as an oxidative scavenger, may offer a feasible treatment method for reproductive dysfunction accompanying hypothyroidism in adult male rats. The purpose of this investigation was to determine the mechanism by which melatonin treatment affected spermatogenic and steroidogenic function in an experimental model-induced hypothyroidism in adult male rats.
MATERIALS AND METHODS
Twenty-one male albino adult rats weighing between 150 and 210 g were used in this experiment. Rats were split into three groups and studied for 11 weeks. The control euthyroid group, in which rats received 0.9% Sodium Chloride (NaCl) solution by intraperitoneal injection [solvent for 6-propyl 2-thouracil (PTU)], 6 days/week for 8 weeks; the PTU-induced hypothyroid group, in which chemical thyroidectomy was induced by intraperitoneal injection of PTU at a dose of 10 mg/kg body weight, 6 days/week for 8 weeks; and the melatonin-treated hypothyroid group, which received 3 mg/kg melatonin intraperitoneally daily for 21 days plasma free Triiodothyronine (T3), free Thyroxin (T4), thyroid stimulating hormone (TSH), free testosterone, Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH) and prolactin were measured. Also, semen analysis, testicular tissue malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α) were accessed.
RESULTS
The results indicated that melatonin significantly increased sperm viability and motility compared to the untreated PTU-induced hypothyroid group (p<0.001). Testicular MDA and TNF-α showed a significant decrease in the melatonin-treated hypothyroid group compared with the PTU-induced hypothyroid group (p<0.05). In addition, plasma testosterone levels were significantly increased, accompanied by a significant reduction of plasma prolactin levels compared to the untreated hypothyroid group (p<0.05 for both).
CONCLUSIONS
Based on the study findings, melatonin could mitigate gonadal dysfunction induced by hypothyroidism by improving several components of semen analysis, such as sperm motility and sperm viability, as well as by enhancing testosterone production focusing on oxidative and inflammatory stress as the underlying mechanisms.
Topics: Male; Animals; Rats; Propylthiouracil; Melatonin; Prolactin; Tumor Necrosis Factor-alpha; Semen; Sperm Motility; Hypothyroidism; Testosterone
PubMed: 38497875
DOI: 10.26355/eurrev_202403_35606 -
International Journal of Molecular... Jan 2024Hypothyroidism compromises the testicular redox status and is associated with reduced sperm quality and infertility in men. In this regard, studies have demonstrated the...
Hypothyroidism compromises the testicular redox status and is associated with reduced sperm quality and infertility in men. In this regard, studies have demonstrated the antioxidant potential of kisspeptin in reproductive and metabolic diseases. In this study, we evaluate the effects of kisspeptin-10 (Kp10) on the testicular redox, as well as mediators of the unfolded protein response (UPR) in adult rats with hypothyroidism. Adult male Wistar rats were randomly separated into the Control ( = 15), Hypo ( = 13) and Hypo + Kp10 ( = 14) groups, and hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals received Kp10. Testis samples were collected for enzymatic, immunohistochemical and/or gene evaluation of mediators of oxidative stress (TBARs, lipid hydroperoxides (LOOH), ROS, peroxynitrite, SOD, CAT and GPX), endoplasmic reticulum stress (GRP78, ATF6, PERK, CHOP, HO-1 and sXBP1) and antiapoptocytes (BCL-2). Hypothyroidism increased apoptosis index, TBARS and LOOH concentrations, and reduced testicular gene expression of , and , as well as the expression of , , and . Treatment with Kp10, in turn, reduced testicular apoptosis and the production of peroxynitrite, while increased SOD1 and GPX ½ expression, and enzymatic activity of CAT, but did not affect the lower expression of UPR mediators caused by hypothyroidism. This study demonstrated that hypothyroidism causes oxidative stress and dysregulated the UPR pathway in rat testes and that, although Kp10 does not influence the low expression of UPR mediators, it improves the testicular redox status, configuring it as an important antioxidant factor in situations of thyroid dysfunction.
Topics: Humans; Rats; Male; Animals; Antioxidants; Testis; Kisspeptins; Rats, Wistar; Superoxide Dismutase-1; Endoplasmic Reticulum Chaperone BiP; Peroxynitrous Acid; Thiobarbituric Acid Reactive Substances; Semen; Oxidation-Reduction; Hypothyroidism; Oxidative Stress; Unfolded Protein Response
PubMed: 38338793
DOI: 10.3390/ijms25031514 -
Molecules (Basel, Switzerland) Dec 2023This study demonstrated the capability of two readily available optical spectroscopy tools, namely UV-Vis absorption spectrophotometry and Raman/surface-enhanced Raman...
This study demonstrated the capability of two readily available optical spectroscopy tools, namely UV-Vis absorption spectrophotometry and Raman/surface-enhanced Raman spectroscopy, to select in a rapid and noninvasive manner the most homogenous gold nanoparticle (AuNP) models and to identify their chemical binding mechanism to 2-thiouracil (2-TU). 2-TU is an anticancer drug of great promise in the antiproliferative and photothermal therapies of cancer. The citrate-capped AuNPs emerged as the most stable as well as time- and cost-effective AuNP model out of the three widely used colloidal nanocores (citrate-, borohydride-citrate-, and sodium dodecyl sulfate (SDS)-capped AuNPs) that were examined. 2-TU chemically attached to the relatively monodispersed AuNPs via a chemisorption mechanism. The 2-TU-AuNPs complex formed through the covalent bonding of the S atom of 2-TU to the nanosurface in a vertical orientation. The spectroscopic results were then confirmed with the help of density functional theory (DFT) calculations and other physicochemical characterization tools for nanomaterials such as transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential. Overall, the purified 2-TU-AuNPs were found to be spherical, had an average diameter of 25 ± 2 nm, a narrow size distribution (1-30 nm), a sharp localized surface plasmon resonance (LSPR) peak at 525 nm, and a negative surface charge (-14 mV).
Topics: Gold; Metal Nanoparticles; Nanostructures; Citrates; Antineoplastic Agents
PubMed: 38202703
DOI: 10.3390/molecules29010121 -
Communications Biology Oct 2023In all domains of life, transfer RNAs (tRNAs) contain post-transcriptionally sulfur-modified nucleosides such as 2- and 4-thiouridine. We have previously reported that a...
In all domains of life, transfer RNAs (tRNAs) contain post-transcriptionally sulfur-modified nucleosides such as 2- and 4-thiouridine. We have previously reported that a recombinant [4Fe-4S] cluster-containing bacterial desulfidase (TudS) from an uncultured bacterium catalyzes the desulfuration of 2- and 4-thiouracil via a [4Fe-5S] cluster intermediate. However, the in vivo function of TudS enzymes has remained unclear and direct evidence for substrate binding to the [4Fe-4S] cluster during catalysis was lacking. Here, we provide kinetic evidence that 4-thiouridine-5'-monophosphate rather than sulfurated tRNA, thiouracil, thiouridine or 4-thiouridine-5'-triphosphate is the preferred substrate of TudS. The occurrence of sulfur- and substrate-bound catalytic intermediates was uncovered from the observed switch of the S = 3/2 spin state of the catalytic [4Fe-4S] cluster to a S = 1/2 spin state upon substrate addition. We show that a putative gene product from Pseudomonas putida KT2440 acts as a TudS desulfidase in vivo and conclude that TudS-like enzymes are widespread desulfidases involved in recycling and detoxifying tRNA-derived 4-thiouridine monophosphate nucleosides for RNA synthesis.
Topics: Thiouridine; RNA, Transfer; Bacteria; Catalysis; Sulfur
PubMed: 37891428
DOI: 10.1038/s42003-023-05450-5 -
Environmental Pollution (Barking, Essex... Jan 2024Mice were exposed to a low dose of the model thyroid hormone disruptor, propylthiouracil. Although this had only a modest effect on maternal thyroid hormones production,...
Mice were exposed to a low dose of the model thyroid hormone disruptor, propylthiouracil. Although this had only a modest effect on maternal thyroid hormones production, postnatal analysis of the pups' plasma by mass spectrometry and the brain striatum by RNA sequencing gave evidence of low lasting changes that could reflect an adverse effect on neurodevelopment. Overall, these methods proved to be sensitive enough to detect minor disruptions of thyroid hormone signalling in vivo.
Topics: Animals; Mice; Transcriptome; Thyroid Hormones; Thyroid Gland; Propylthiouracil; Brain
PubMed: 37866749
DOI: 10.1016/j.envpol.2023.122783 -
Scientific Reports Oct 2023We evaluated whether the administration of kisspeptin-10 (Kp10) is capable of restoring gonadal function in hypothyroid male rats. Hypothyroidism was induced with...
We evaluated whether the administration of kisspeptin-10 (Kp10) is capable of restoring gonadal function in hypothyroid male rats. Hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals were treated with Kp10. Hypothyroidism reduced testicular and sex gland mass, decreased the proliferation of the seminiferous epithelium, and compromised sperm morphology, motility, and vigor. A decrease in plasma LH and testosterone levels and an increase in prolactin secretion were observed in the hypothyroid rats. Hypothyroidism reduced Kiss1 and Kiss1r protein and gene expression and Star and Cyp11a1 mRNA levels in the testis. Furthermore, it reduced Lhb, Prl, and Drd2 and increased Tshb and Gnrhr expression in the pituitary. In the hypothalamus, hypothyroidism increased Pdyn and Kiss1r while reducing Gnrh1. Kp10 treatment in hypothyroid rats restored testicular and seminal vesicle morphology, improved sperm morphology and motility, reversed high prolactin levels, and increased LH and testosterone levels. In addition, Kp10 increased testicular expression of Kiss1, Kiss1r, Fshr, and Nr5a1 and pituitary Kiss1 expression. Our findings describe the inhibitory effects of hypothyroidism on the male gonadal axis and sperm quality and demonstrate that Kp10 treatment reverses high prolactin levels and improves gonadal function and sperm quality in hypothyroid rats.
Topics: Rats; Animals; Male; Kisspeptins; Prolactin; Luteinizing Hormone; Receptors, Kisspeptin-1; Semen; Hypothyroidism; Testis; Testosterone
PubMed: 37798396
DOI: 10.1038/s41598-023-44056-z -
BioRxiv : the Preprint Server For... Sep 2023Cells respond to environmental and developmental stimuli by remodeling their transcriptomes through regulation of both mRNA transcription and mRNA decay. A central goal...
Cells respond to environmental and developmental stimuli by remodeling their transcriptomes through regulation of both mRNA transcription and mRNA decay. A central goal of biology is identifying the global set of regulatory relationships between factors that control mRNA production and degradation and their target transcripts and construct a predictive model of gene expression. Regulatory relationships are typically identified using transcriptome measurements and causal inference algorithms. RNA kinetic parameters are determined experimentally by employing run-on or metabolic labeling (e.g. 4-thiouracil) methods that allow transcription and decay rates to be separately measured. Here, we develop a deep learning model, trained with single-cell RNA-seq data, that both infers causal regulatory relationships and estimates RNA kinetic parameters. The resulting model predicts future gene expression states and can be perturbed to simulate the effect of transcription factor changes. We acquired model training data by sequencing the transcriptomes of 175,000 individual cells that were subject to an external perturbation and continuously sampled over a one hour period. The rate of change for each transcript was calculated on a per-cell basis to estimate RNA velocity. We then trained a deep learning model with transcriptome and RNA velocity data to calculate time-dependent estimates of mRNA production and decay rates. By separating RNA velocity into transcription and decay rates, we show that rapamycin treatment causes existing ribosomal protein transcripts to be rapidly destabilized, while production of new transcripts gradually slows over the course of an hour. The neural network framework we present is designed to explicitly model causal regulatory relationships between transcription factors and their genes, and shows superior performance to existing models on the basis of recovery of known regulatory relationships. We validated the predictive power of the model by perturbing transcription factors and comparing transcriptome-wide effects with experimental data. Our study represents the first step in constructing a complete, predictive, biophysical model of gene expression regulation.
PubMed: 37790443
DOI: 10.1101/2023.09.21.558277 -
Bioorganic Chemistry Dec 2023Lactoperoxidase was previously used as a model enzyme to test the inhibitory activity of selenium analogs of anti-thyroid drugs with...
Lactoperoxidase was previously used as a model enzyme to test the inhibitory activity of selenium analogs of anti-thyroid drugs with 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) as a substrate. Peroxidases oxidize ABTS to a metastable radical ABTS, which is readily reduced by many antioxidants, including thiol-containing compounds, and it has been used for decades to measure antioxidant activity in biological samples. We showed that anti-thyroid drugs 6-n-propyl-2-thiouracil, methimazole, and selenium analogs of methimazole also reduced it rapidly. This reaction may explain the anti-thyroid action of many other compounds, particularly natural antioxidants, which may reduce the oxidized form of iodine and/or tyrosyl radicals generated by thyroid peroxidase thus decreasing the production of thyroid hormones. However, influence of selenium analogs of methimazole on the rate of hydrogen peroxide consumption during oxidation of ABTS by lactoperoxidase was moderate. Direct hydrogen peroxide reduction, proposed before as their mechanism of action, cannot therefore account for the observed inhibitory effects. 1-Methylimidazole-2-selone and its diselenide were oxidized by ABTS to relatively stable seleninic acid, which decomposed slowly to selenite and 1-methylimidazole. In contrast, oxidation of 1,3-dimethylimidazole-2-selone gave selenite and 1,3-dimethylimidazolium cation. Accumulation of the corresponding seleninic acid was not observed.
Topics: Antioxidants; Cations; Hydrogen Peroxide; Lactoperoxidase; Methimazole; Oxidation-Reduction; Selenious Acid; Selenium; Propylthiouracil
PubMed: 37788560
DOI: 10.1016/j.bioorg.2023.106891