Úvod: Dutina ústní představuje komplexní systém, kde probíhá vzájemná chemická komunikace mezi tkáněmi, mikrobiotou a složkami sliny a potravy. Tento článek je zaměřen na hormetické efekty a elektrofilní sloučeniny, které mohou hrát roli v obranných mechanismech proti oxidačnímu stresu a zánětlivým procesům. Hormetické efekty, vyvolané subletálními nebo subtoxickými stresory, mohou aktivovat reparační mechanismy a posílit odolnost tkání proti poškození. Metodika: Analýza byla provedena prostřednictvím vyhledávání ve třech elektronických databázích: Web of Science, PubMed a Scopus. V rámci rešerše jsme se soustředili na studie publikované mezi lety 2000 a 2023, které se zabývaly oxidačně-redukčními procesy, zánětlivými stavy a aktivací Nrf2 dráhy v ústní dutině. Vyloučeny byly studie zaměřené na nádorová onemocnění. Závěr: Elektrofilní sloučeniny působí jako jeden z činitelů zasahujících do homeostázy dutiny ústní a mohou tak představovat terapeutický potenciál v zubním lékařství, konkrétně v parodontologii. Zjištění založená na in vitro a preklinických studiích však vyžadují další ověření v klinických podmínkách, přičemž je třeba zvážit i interakce s orální mikrobiotou.
Introduction: The oral cavity is a complex system in which mutual chemical communication occurs between tissues, microbiota, and components of saliva and food. This paper focuses on hormetic effects and electrophilic compounds, which can play a role in defense mechanisms against oxidative stress and inflammatory processes. Hormetic effects, induced by sublethal or subtoxic stressors, can activate repair mechanisms and enhance tissue resistance to damage. Methods: The analysis was conducted through searches in three electronic databases: Web of Science, PubMed, and Scopus. Our research focused on studies published between 2000 and 2023 that dealt with redox processes, inflammatory conditions, and activation of the Nrf2 pathway in the oral cavity. Studies focused on cancerous diseases were excluded. Conclusion: Electrophilic compounds act as one of the agents that interfere with the homeostasis of the oral cavity, and can thus find therapeutic potential in dentistry, specifically in periodontology. However, findings based on in vitro and preclinical studies require further verification under clinical conditions, and also considering interactions with oral microbiota.
X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.
- MeSH
- Androgens * genetics MeSH
- Genome-Wide Association Study * MeSH
- Genetic Predisposition to Disease MeSH
- Polymorphism, Single Nucleotide MeSH
- Kidney MeSH
- Humans MeSH
- Chromosomes, Human, X genetics MeSH
- Response Elements MeSH
- Tetraspanins genetics MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
A limited number of studies are devoted to regulating TRIP6 expression in cancer. Hence, we aimed to unveil the regulation of TRIP6 expression in MCF-7 breast cancer cells (with high TRIP6 expression) and taxane-resistant MCF-7 sublines (manifesting even higher TRIP6 expression). We found that TRIP6 transcription is regulated primarily by the cyclic AMP response element (CRE) in hypomethylated proximal promoters in both taxane-sensitive and taxane-resistant MCF-7 cells. Furthermore, in taxane-resistant MCF-7 sublines, TRIP6 co-amplification with the neighboring ABCB1 gene, as witnessed by fluorescence in situ hybridization (FISH), led to TRIP6 overexpression. Ultimately, we found high TRIP6 mRNA levels in progesterone receptor-positive breast cancer and samples resected from premenopausal women.
- MeSH
- Adaptor Proteins, Signal Transducing genetics MeSH
- Cyclic AMP MeSH
- Drug Resistance, Neoplasm * genetics MeSH
- In Situ Hybridization, Fluorescence MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Neoplasms * genetics MeSH
- ATP Binding Cassette Transporter, Subfamily B * genetics MeSH
- LIM Domain Proteins * genetics MeSH
- Response Elements MeSH
- Taxoids MeSH
- Transcription Factors genetics MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Background: Oxidative stress is a key factor in the pathophysiology of many diseases. This study aimed to verify the antioxidant activity of selected plant phenolics in cell-based assays and determine their direct or indirect effects. Methods: The cellular antioxidant assay (CAA) assay was employed for direct scavenging assays. In the indirect approach, the influence of each test substance on the gene and protein expression and activity of selected antioxidant enzymes was observed. One assay also dealt with activation of the Nrf2-ARE pathway. The overall effect of each compound was measured using a glucose oxidative stress protection assay. Results: Among the test compounds, acteoside showed the highest direct scavenging activity and no effect on the expression of antioxidant enzymes. It increased only the activity of catalase. Diplacone was less active in direct antioxidant assays but positively affected enzyme expression and catalase activity. Morusin showed no antioxidant activity in the CAA assay. Similarly, pomiferin had only mild antioxidant activity and proved rather cytotoxic. Conclusions: Of the four selected phenolics, only acteoside and diplacone demonstrated antioxidant effects in cell-based assays.
- MeSH
- Antioxidant Response Elements MeSH
- Antioxidants chemistry pharmacology MeSH
- Biomarkers MeSH
- Gene Expression MeSH
- NF-E2-Related Factor 2 genetics metabolism MeSH
- Phenols chemistry pharmacology MeSH
- Glucose MeSH
- Humans MeSH
- Molecular Structure MeSH
- Oxidative Stress MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Plant Extracts chemistry pharmacology MeSH
- Superoxide Dismutase-1 genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
P53, P63, and P73 proteins belong to the P53 family of transcription factors, sharing a common gene organization that, from the P1 and P2 promoters, produces two groups of mRNAs encoding proteins with different N-terminal regions; moreover, alternative splicing events at C-terminus further contribute to the generation of multiple isoforms. P53 family proteins can influence a plethora of cellular pathways mainly through the direct binding to specific DNA sequences known as response elements (REs), and the transactivation of the corresponding target genes. However, the transcriptional activation by P53 family members can be regulated at multiple levels, including the DNA topology at responsive promoters. Here, by using a yeast-based functional assay, we evaluated the influence that a G-quadruplex (G4) prone sequence adjacent to the p53 RE derived from the apoptotic PUMA target gene can exert on the transactivation potential of full-length and N-terminal truncated P53 family α isoforms (wild-type and mutant). Our results show that the presence of a G4 prone sequence upstream or downstream of the P53 RE leads to significant changes in the relative activity of P53 family proteins, emphasizing the potential role of structural DNA features as modifiers of P53 family functions at target promoter sites.
- MeSH
- Apoptosis genetics MeSH
- DNA genetics ultrastructure MeSH
- G-Quadruplexes * MeSH
- Nucleic Acid Conformation MeSH
- Humans MeSH
- Membrane Proteins genetics ultrastructure MeSH
- Tumor Suppressor Protein p53 genetics ultrastructure MeSH
- Promoter Regions, Genetic genetics MeSH
- Tumor Protein p73 genetics ultrastructure MeSH
- Apoptosis Regulatory Proteins genetics MeSH
- Proto-Oncogene Proteins genetics MeSH
- Response Elements genetics MeSH
- Saccharomyces cerevisiae genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Reactive oxygen species are an important element of redox regulation in cells and tissues. During physiological processes, molecules undergo chemical changes caused by reduction and oxidation reactions. Free radicals are involved in interactions with other molecules, leading to oxidative stress. Oxidative stress works two ways depending on the levels of oxidizing agents and products. Excessive action of oxidizing agents damages biomolecules, while a moderate physiological level of oxidative stress (oxidative eustress) is necessary to control life processes through redox signaling required for normal cellular operation. High levels of reactive oxygen species (ROS) mediate pathological changes. Oxidative stress helps to regulate cellular phenotypes in physiological and pathological conditions. Nrf2 (nuclear factor erythroid 2-related factor 2, NFE2L2) transcription factor functions as a target nuclear receptor against oxidative stress and is a key factor in redox regulation in hypertension and cardiovascular disease. Nrf2 mediates transcriptional regulation of a variety of target genes. The Keap1-Nrf2-ARE system regulates many detoxification and antioxidant enzymes in cells after the exposure to reactive oxygen species and electrophiles. Activation of Nrf2/ARE signaling is differentially regulated during acute and chronic stress. Keap1 normally maintains Nrf2 in the cytosol and stimulates its degradation through ubiquitination. During acute oxidative stress, oxidized molecules modify the interaction of Nrf2 and Keap1, when Nrf2 is released from the cytoplasm into the nucleus where it binds to the antioxidant response element (ARE). This triggers the expression of antioxidant and detoxification genes. The consequence of long-term chronic oxidative stress is activation of glycogen synthase kinase 3beta (GSK-3beta) inhibiting Nrf2 activity and function. PPARgamma (peroxisome proliferator-activated receptor gamma) is a nuclear receptor playing an important role in the management of cardiovascular diseases, hypertension and metabolic syndrome. PPARgamma targeting of genes with peroxisome proliferator response element (PPRE) has led to the identification of several genes involved in lipid metabolism or oxidative stress. PPARgamma stimulation is triggered by endogenous and exogenous ligands - agonists and it is involved in the activation of several cellular signaling pathways involved in oxidative stress response, such as the PI3K/Akt/NOS pathway. Nrf2 and PPARgamma are linked together with their several activators and Nrf2/ARE and PPARgamma/PPRE pathways can control several types of diseases.
- MeSH
- Antioxidant Response Elements MeSH
- NF-E2-Related Factor 2 metabolism MeSH
- Hypertension metabolism physiopathology MeSH
- Cardiovascular Diseases metabolism physiopathology MeSH
- Kelch-Like ECH-Associated Protein 1 metabolism MeSH
- Blood Pressure * MeSH
- Humans MeSH
- Oxidative Stress * MeSH
- PPAR gamma metabolism MeSH
- Reactive Oxygen Species metabolism MeSH
- Signal Transduction MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
p53 is one of the most studied tumor suppressor proteins that plays an important role in basic biological processes including cell cycle, DNA damage response, apoptosis, and senescence. The human TP53 gene contains alternative promoters that produce N-terminally truncated proteins and can produce several isoforms due to alternative splicing. p53 function is realized by binding to a specific DNA response element (RE), resulting in the transactivation of target genes. Here, we evaluated the influence of quadruplex DNA structure on the transactivation potential of full-length and N-terminal truncated p53α isoforms in a panel of S. cerevisiae luciferase reporter strains. Our results show that a G-quadruplex prone sequence is not sufficient for transcription activation by p53α isoforms, but the presence of this feature in proximity to a p53 RE leads to a significant reduction of transcriptional activity and changes the dynamics between co-expressed p53α isoforms.
- MeSH
- G-Quadruplexes * MeSH
- Humans MeSH
- Tumor Suppressor Protein p53 genetics metabolism MeSH
- Promoter Regions, Genetic genetics MeSH
- Protein Isoforms genetics metabolism MeSH
- Apoptosis Regulatory Proteins genetics metabolism MeSH
- Proto-Oncogene Proteins genetics metabolism MeSH
- Response Elements genetics MeSH
- Protein Binding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Transcription factors (TFs) fine-tune the host defense transcriptome in response to pathogen invasions. No information is available on Zingiber zerumbet (Zz) TFs involved in defense response against Pythium myriotylum. Here, we provide a global identification, characterization, and temporal expression profiling of Zz TFs following an incompatible interaction with P. myriotylum using a transcriptome sequencing approach. We identified a total of 903 TFs belonging to 96 families based on their conserved domains. Evolutionary analysis clustered the Zz TFs according to their phylogenetic affinity, providing glimpses of their functional diversities. High throughput expression array analysis highlighted a complex interplay between activating and repressing transcription factors in fine-tuning Zz defense response against P. myriotylum. The high differential modulation of TFs involved in cell wall fortification, lignin biosynthesis, and SA/JA hormone crosstalk allows us to envisage that this mechanism plays a central role in restricting P. myriotylum proliferation in Zz. This study lays a solid foundation and provides valuable resources for the investigation of the evolutionary history and biological functions of Zz TF genes involved in defense response.
- MeSH
- Stress, Physiological MeSH
- Plant Immunity * MeSH
- Evolution, Molecular MeSH
- Pythium pathogenicity MeSH
- Response Elements MeSH
- Plant Proteins genetics metabolism MeSH
- Transcription Factors genetics metabolism MeSH
- Transcriptome * MeSH
- Zingiberaceae genetics immunology microbiology MeSH
- Publication type
- Journal Article MeSH
The limited information available on the structure of complexes involving transcription factors and cognate DNA response elements represents a major obstacle in the quest to understand their mechanism of action at the molecular level. We implemented a concerted structural proteomics approach, which combined hydrogen-deuterium exchange (HDX), quantitative protein-protein and protein-nucleic acid cross-linking (XL), and homology analysis, to model the structure of the complex between the full-length DNA binding domain (DBD) of Forkhead box protein O4 (FOXO4) and its DNA binding element (DBE). The results confirmed that FOXO4-DBD assumes the characteristic forkhead topology shared by these types of transcription factors, but its binding mode differs significantly from those of other members of the family. The results showed that the binding interaction stabilized regions that were rather flexible and disordered in the unbound form. Surprisingly, the conformational effects were not limited only to the interface between bound components, but extended also to distal regions that may be essential to recruiting additional factors to the transcription machinery. In addition to providing valuable new insights into the binding mechanism, this project provided an excellent evaluation of the merits of structural proteomics approaches in the investigation of systems that are not directly amenable to traditional high-resolution techniques.
- MeSH
- DNA-Binding Proteins chemistry metabolism MeSH
- DNA chemistry metabolism MeSH
- Mass Spectrometry MeSH
- Molecular Structure MeSH
- Response Elements MeSH
- Transcription Factors chemistry metabolism MeSH
- Deuterium Exchange Measurement MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
The stilbenoids, a group of naturally occurring phenolic compounds, are found in a variety of plants, including some berries that are used as food or for medicinal purposes. They are known to be beneficial for human health as anti-inflammatory, chemopreventive, and antioxidative agents. We have investigated a group of 19 stilbenoid substances in vitro using a cellular model of THP-1 macrophage-like cells and pyocyanin-induced oxidative stress to evaluate their antioxidant or pro-oxidant properties. Then we have determined any effects that they might have on the expression of the enzymes catalase, glutathione peroxidase, and heme oxygenase-1, and their effects on the activation of Nrf2. The experimental results showed that these stilbenoids could affect the formation of reactive oxygen species in a cellular model, producing either an antioxidative or pro-oxidative effect, depending on the structure pinostilbene (2) worked as a pro-oxidant and also decreased expression of catalase in the cell culture. Piceatannol (4) had shown reactive oxygen species (ROS) scavenging activity, whereas isorhapontigenin (18) had a mild direct antioxidant effect and activated Nrf2-antioxidant response element (ARE) system and elevated expression of Nrf2 and catalase. Their effects shown on cells in vitro warrant their further study in vivo.
- MeSH
- Antioxidant Response Elements drug effects MeSH
- Antioxidants chemistry pharmacology MeSH
- Hep G2 Cells MeSH
- NF-E2-Related Factor 2 genetics MeSH
- Humans MeSH
- Lipid Peroxidation drug effects MeSH
- Pyocyanine chemistry MeSH
- Stilbenes chemistry pharmacology MeSH
- Thiobarbiturates chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
