Vitamins and Hormones最新文献

Endometriosis is a term referring to a condition whereby the endometrial tissue is found outside the uterine cavity. This progressive and debilitating condition affects up to 15% of women of reproductive age. Due to the fact that endometriosis cells may express estrogen receptors (ERα, Erβ, GPER) and progesterone (P4) receptors (PR-A, PR-B), their growth, cyclic proliferation, and breakdown are similar to the processes occurring in the endometrium. The underlying etiology and pathogenesis of endometriosis are still not fully explained. The retrograde transport of viable menstrual endometrial cells with the retained ability to attach within the pelvic cavity, proliferate, differentiate and invade into the surrounding tissue explains the most widely accepted implantation theory. Endometrial stromal cells (EnSCs) with clonogenic potential constitute the most abundant population of cells within endometrium that resemble the properties of mesenchymal stem cells (MSCs). Accordingly, formation of the endometriotic foci in endometriosis may be due to a kind of EnSCs dysfunction. Increasing evidence indicates the underestimated role of epigenetic mechanisms in the pathogenesis of endometriosis. Hormone-mediated epigenetic modifications of the genome in EnSCs or even MSCs were attributed an important role in the etiopathogenesis of endometriosis. The roles of excess estrogen exposure and P4 resistance were also found to be crucial in the development of epigenetic homeostasis failure. Therefore, the aim of this review was to consolidate the current knowledge regarding the epigenetic background of EnSCs and MSCs and the changed properties due to estrogen/P4 imbalances in the context of the etiopathogenesis of endometriosis.

Many studies implicate mitochondrial dysfunction in the development and progression of numerous chronic diseases. Mitochondria are responsible for most cellular energy production, and unlike other cytoplasmic organelles, mitochondria contain their own genome. Most research to date, through investigating mitochondrial DNA copy number, has focused on larger structural changes or alterations to the entire mitochondrial genome and their role in human disease. Using these methods, mitochondrial dysfunction has been linked to cancers, cardiovascular disease, and metabolic health. However, like the nuclear genome, the mitochondrial genome may experience epigenetic alterations, including DNA methylation that may partially explain some of the health effects of various exposures. Recently, there has been a movement to understand human health and disease within the context of the exposome, which aims to describe and quantify the entirety of all exposures people encounter throughout their lives. These include, among others, environmental pollutants, occupational exposures, heavy metals, and lifestyle and behavioral factors. In this chapter, we summarize the current research on mitochondria and human health, provide an overview of the current knowledge on mitochondrial epigenetics, and describe the experimental and epidemiologic studies that have investigated particular exposures and their relationships with mitochondrial epigenetic modifications. We conclude the chapter with suggestions for future directions in epidemiologic and experimental research that is needed to advance the growing field of mitochondrial epigenetics.

Elucidating how insulin and the related insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) bind to their cellular receptors (IR and IGF-1R) and how the receptors are activated has been the holy grail for generations of scientists. However, deciphering the 3D structure of tyrosine kinase receptors and their hormone-bound complexes has been complicated by the flexible and dimeric nature of the receptors and the dynamic nature of their interaction with hormones. Therefore, mutagenesis of hormones and kinetic studies first became an important tool for studying receptor interactions. It was suggested that hormones could bind to receptors through two binding sites on the hormone surface called site 1 and site 2. A breakthrough in knowledge came with the solution of cryoelectron microscopy (cryoEM) structures of hormone-receptor complexes. In this chapter, we document in detail the mutagenesis of insulin, IGF-1, and IGF-2 with emphasis on modifications of the hypothetical binding site 2 in the hormones, and we discuss the results of structure-activity studies in light of recent cryoEM structures of hormone complexes with IR and IGF-1R.

Liver X receptors α and β are members of the nuclear receptor family, which comprise a flexible N-terminal domain, a DNA binding domain, a hinge linker, and a ligand binding domain. Liver X receptors are important regulators of cholesterol and lipid homeostasis by controlling the transcription of numerous genes. Key to their transcriptional role is synergetic interaction among the domains. DNA binding domain binds on DNA; ligand binding domain is a crucial switch to control the transcription activity through conformational change caused by ligand binding. The Liver X receptors form heterodimers with retinoid X receptor and then the liganded heterodimer may recruit other necessary transcription components to form an active transcription complex.

Prostate cancer (PCa) is one of the major health burdens among all cancer types in men globally. Early diagnosis and efficacious treatment options are highly warranted as far as the incidence of PCa is concerned. Androgen-dependent transcriptional activation of androgen receptor (AR) is central to the prostate tumorigenesis and therefore hormonal ablation therapy remains the first line of treatment for PCa in the clinics. However, the molecular signaling engaged in AR-dependent PCa initiation and progression is infrequent and diverse. Moreover, apart from the genomic changes, non-genomic changes such as epigenetic modifications have also been suggested as critical regulator of PCa development. Among the non-genomic mechanisms, various epigenetic changes such as histones modifications, chromatin methylation and noncoding RNAs regulations etc. play decisive role in the prostate tumorigenesis. Given that epigenetic modifications are reversible using pharmacological modifiers, various promising therapeutic approaches have been designed for the better management of PCa. In this chapter, we discuss the epigenetic control of tumor promoting AR signaling that underlies the mechanism of prostate tumorigenesis and progression. In addition, we have discussed the approaches and opportunities to develop novel epigenetic modifications based therapeutic strategies for targeting PCa including castrate resistant prostate cancer (CRPC).

Although several recent studies have shown that vitamin D supplementation beneficially decreases oxidative stress parameters, there is no consensus on this subject in humans. Thus the role of vitamin D supplementation has recently become a controversial topic because large intervention studies in humans have not shown significant benefits. These studies have indicated that supplementation with precursor forms of active vitamin D has no effect on all-cause mortality, cannot reduce the fracture risk of the elderly, cannot reduce the incidence of cancer or cardiovascular disease in the elderly, and cannot significantly reduce the incidence risk of diabetes in the elderly. However, a link between several age-related diseases and enhanced oxidative stress has been found in mice with insufficient or deficient 1,25-dihydroxyvitamin D (1,25(OH)₂D), the active form of vitamin D, which indicates that reduced active vitamin D accelerates aging and age-related diseases by increasing oxidative stress. Furthermore, supplementation of exogenous 1,25(OH)₂D₃, or antioxidants, could dramatically postpone aging, prevent osteoporosis and spontaneous tumor development induced by 1,25(OH)₂D insufficiency or deficiency, by inhibiting oxidative stress. Mechanistically, the antioxidative effects of 1,25(OH)₂D₃ are carried out via the vitamin D receptor (VDR) by activation of the Nrf2 oxidative stress response pathway though transcriptional or posttranscriptional activation of Nrf2 or transcriptional upregulation of Sirt1 and Bmi1 expression. Whether discrepancies between studies in humans and in mice reflect the different forms of vitamin D examined remains to be determined.

The liver performs various biochemical and molecular functions. Its location as a portal to blood arriving from the intestines makes it susceptible to several insults, leading to diverse pathologies, including alcoholic liver disease, viral infections, nonalcoholic steatohepatitis, and hepatocellular carcinoma, which are causes of death worldwide. Illuminating the molecular mechanism underlying hepatic injury will provide targets to develop new therapeutic strategies to fight liver maladies. In this regard, reactive oxygen species (ROS) are well-recognized mediators of liver damage. ROS induce nuclear factor-κB and the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 inflammasome, which are the main proinflammatory signaling pathways that upregulate several proinflammatory and profibrogenic mediators. Additionally, oxygen-derived free radicals induce hepatic stellate cell activation to produce exacerbated quantities of extracellular matrix proteins, leading to fibrosis, cirrhosis and eventually hepatocellular carcinoma. Exogenous and endogenous antioxidants counteract the harmful effects of ROS, preventing liver necroinflammation and fibrogenesis. Therefore, several researchers have demonstrated that the administration of antioxidants, mainly derived from plants, affords beneficial effects on the liver. Notably, nuclear factor-E2-related factor-2 (Nrf2) is a major factor against oxidative stress in the liver. Increasing evidence has demonstrated that Nrf2 plays an important role in liver necroinflammation and fibrogenesis via the induction of antioxidant response element genes. The use of Nrf2 inducers seems to be an interesting approach to prevent/attenuate hepatic disorders, particularly under conditions where ROS play a causative role.

The excessive accumulation of reactive oxygen species (ROS)/free radicals can lead to abnormal oxidation of biomolecules such as proteins, lipids, fats, carbohydrates and nucleic acids in human organisms. Accordingly, endogenous oxidative stress induces the progressive development of various chronic diseases like rheumatoid arthritis, cancers, cardiovascular risks, diabetes, digestive ulcers, hypertension, obesity, neurological disorders, and age-related complications. Therefore, anti-oxidant defense mechanisms are needed to control/prevent the unbalanced molecular oxidative damage. Indeed, the oxidative stress arises from both endogenous and exogenous factors such as smoking, alcohol, medications, air pollution, sunlight, lifestyle disorders, and metabolic processes. Therefore, consumption of fruits, vegetables, grains, beverages, and leafy vegetables rich in antioxidants may inhibit or treat oxidative damage accompanying diseases. From this aspect, dietary foods are rich in various antioxidant metabolites such as flavonoids, vitamin A, C, E, phenolic acids, curcumin, stilbenes, anthocyanins, etc., which promote healthy life and nutritional benefits. Additionally, various studies have also proven that foods rich in antioxidants interact with reactive species to prevent cell damage(s) or therapeutic pathways for diseases. Although, there are various myths about the antioxidant mechanism(s), the optimal dosage of antioxidants can show beneficial pharmacological activities against various molecular oxidation paths.

Reduced glutathione (GSH) is an essential non-enzymatic antioxidant in mammalian cells. GSH can act directly as an antioxidant to protect cells against free radicals and pro-oxidants, and as a cofactor for antioxidant and detoxification enzymes such as glutathione peroxidases, glutathione S-transferases, and glyoxalases. Glutathione peroxidases detoxify peroxides by a reaction that is coupled to GSH oxidation to glutathione disulfide (GSSG). GSSG is converted back to GSH by glutathione reductase and cofactor NADPH. GSH can regenerate vitamin E following detoxification reactions of vitamin E with lipid peroxyl radicals (LOO). GSH is a cofactor for GST during detoxification of electrophilic substances and xenobiotics. Dicarbonyl stress induced by methylglyoxal and glyoxal is alleviated by glyoxalase enzymes and GSH. GSH regulates redox signaling through reversible oxidation of critical protein cysteine residues by S-glutathionylation. GSH is involved in other cellular processes such as protein folding, protecting protein thiols from oxidation and crosslinking, degradation of proteins with disulfide bonds, cell cycle regulation and proliferation, ascorbate metabolism, apoptosis and ferroptosis.