Vitamins and Hormones最新文献

The Estrogen Receptor (ER) is a well-established regulator of the biologic behavior of breast cancer and a biomarker of response to endocrine treatments. Other steroid and non-steroid nuclear receptors, including Progesterone Receptor (PR), Androgen Receptor (AR), Vitamin D Receptor (VDR) and Thyroid Receptors (TRs), are often co-expressed with ER in breast cancers and modulate its biologic effects. In addition these receptors are also expressed in sub-sets of ER negative breast cancers and act as alternative transcription factors with cancer associated effects. The isotypes of TRs, TRα, TRβ, and other receptors of hormones of the thyroid axis such as the surface thyroid receptor, αvβ3 integrin and the receptor for TSH, TSH-R expressed in sub-sets of breast cancers, have both pro-carcinogenic and anti-carcinogenic functions that depend on the specific cancer cell environment. For TRs, co-expression of ER is important for their respective transcriptional output as these nuclear receptors interact at the chromatin level. The surface αvβ3 integrin receptor, on the other hand, activates signal transduction pathways that may affect ER function and its ability to execute its transcriptional program. Based on the role of the thyroid axis in breast cancer tissues, therapeutic opportunities from the manipulation of the axis in breast cancer arise, and initial studies have been performed with intriguing results. A biomarker based approach taking into consideration the breast cancer sub-types, including expression of other nuclear receptors and the expression of nuclear and surface thyroid receptors in breast cancer cells, could provide therapeutic opportunities, in a personalized manner.

Light is the most reliable environmental cue allowing animals to breed successfully when conditions are optimal. In seasonal breeders, photoperiod (length of daylight) information is sensed by the eyes and transmitted to the suprachiasmatic nucleus, the master clock region located in the hypothalamus. This structure has a 24-h firing rhythm involving a cycle of clock protein synthesis and degradation, and provides the timing to synchronize the synthesis and release of melatonin, the chemical signal that transduces the photoperiod information. The enzyme arylalkylamine N-acetyltransferase, responsible for melatonin synthesis in the pineal gland, is modulated by environmental light. Melatonin is secreted during the dark hours of the night to blood circulation and cerebrospinal fluid conveying photoperiod information to other tissues. Melatonin exerts its action by binding to specific membrane receptors MT1 and MT2, and can modulate several pathways including neurotransmitters, and hormones like kisspeptin, the gonadotropin-inhibitory hormone, and thyroid hormones, all of them impacting on gonadotropin-releasing hormone (GnRH) secretion. Then, GnRH will modulate in turn the reproductive axis. In conclusion, acting as a transducer of photoperiod information, this hormone exerts precisely timed activation of different pathways that modulate seasonal breeding ensuring optimal conditions for reproduction.

Glucose transporters (GLUTs) belong to a membrane-protein family that essentially participates in easing the transportation and absorption of glucose molecules throughout the cellular membranes. From the brain to the eyes, each section delves into the intricate mechanisms of glucose uptake and utilization, shedding light on the unique adaptations and regulatory pathways in different anatomical structures. Beginning with the brain, known for its high energy demands, the chapter explicates the specialized GLUT expression patterns crucial for neuronal function and synaptic transmission. Moving to metabolic powerhouses like the liver, muscles, and adipose tissue, it elucidates the dynamic interplay of GLUT isoforms in energy storage, mobilization, and insulin responsiveness. Furthermore, the chapter navigates through the kidneys, lungs, skin, and reproductive organs, unveiling the diverse roles of GLUTs in renal glucose reabsorption, pulmonary-epithelial transportation, skin barrier associated functions, and gonadal development. It also explores the significance of placental GLUTs in fatal nutrient supply and the implications of cardiac GLUTs in myocardial energy metabolism. Additionally, it examines the intricate regulation of GLUTs at key barriers like the BBB (Blood-Brain Barrier) and placenta, as well as in endocrine glands such as the pancreas, adrenal medulla and thyroid. Moreover, it further elucidates the less-explored territories of GLUT expression in the bones, gastrointestinal tract, and ocular tissues like the retina, unraveling their implications in immune function, bone metabolism, intestinal glucose-sensing, and retinal physiology.

Glucose is the primary energy substrate and an essential precursor for cellular metabolism. Maintaining glucose homeostasis necessitates the presence of glucose transporters, as the hydrophilic nature of glucose prevents its passage across the cell membrane. The GLUT family is a crucial group of glucose transporters that facilitate glucose diffusion along the transmembrane glucose concentration gradient. Dysfunction in GLUTs is associated with diseases, such as GLUT1 deficiency syndrome, Fanconi-Bickel syndrome, and type 2 diabetes. Furthermore, elevated expression of GLUTs fuels aerobic glycolysis, known as the Warburg effect, in various types of cancers, making GLUT isoforms possible targets for antineoplastic therapies. To date, 30 GLUT and homolog structures have been released on the Protein Data Bank (PDB), showcasing multiple conformational and ligand-binding states. These structures elucidate the molecular mechanisms underlying substrate recognition, the alternating access cycle, and transport inhibition. Here, we summarize the current knowledge of human GLUTs and their role in cancer, highlighting recent advances in the structural characterization of GLUTs. We also compare the inhibition mechanisms of exofacial and endofacial GLUT inhibitors, providing insights into the design and optimization of GLUT inhibitors for therapeutic applications.

Vitamin C is a crucial water-soluble antioxidant and an essential cofactor for enzymes like proline and lysine hydroxylases, playing a vital role in cellular physiology. While sodium-dependent ascorbate co-transporters (SVCT1 and SVCT2) are pivotal for vitamin C absorption and bioavailability, dehydroascorbic acid transporters within the facilitative glucose transporter (GLUT) family complement these functions and are relevant in various cellular, tissue-specific, or pathological contexts. This review focuses on comparing the structural and functional characteristics of GLUTs involved in glucose, dehydroascorbic acid and other substrate transport. It also presents evidence of the physiological and pathophysiological roles of dehydroascorbic acid transporters. Improved understanding of these transporters has the potential to advance strategies for preventing, diagnosing, and treating prevalent diseases such as cancer.

Prediagnostic serum concentrations of dehydroepiandrosterone (DHEA) and its sulfated form (DS) are generally increased in breast cancer patients; serum cortisol concentrations are predictably increased as well. The association of increased adrenal steroids with breast cancer may indicate a causal role. However, administration of DHEA to rats and mice has shown a beneficial effect of DHEA in preventing or suppressing breast cancer in numerous studies. DHEA treatment inhibits the development of spontaneous virally induced mammary cancers and suppresses carcinogen-induced as well as radiation-induced mammary tumors. DHEA also antagonizes the effect of estrogen on growth of human breast cancer xenografts in nude mice. DHEA is effective in suppressing cancer development in other organ systems as well including lung, liver, colon, prostate, lymphatic, and skin cancers. We hypothesize that the increase of DHEA in breast fluid and serum is the result of stress-induced adrenal activation and that the glucocorticoid component is the detrimental component rather than DHEA or DS. The mechanisms by which DHEA suppresses tumor growth includes the non-competitive inhibition of glucose-6-phosphate dehydrogenase, inhibition of cholesterol biosynthesis, immune suppression of virally induced breast cancer, enhancement of natural killer cell cytotoxicity by both DHEA and DS, suppression of IL-6, and promotion of estrogen receptor beta expression. The evidence supports the use of DHEA or its derivatives for suppression of cancers regardless of the mechanism by which the cancer arises.

Kisspeptin (KISS1), originally catalogued as metastin because of its capacity as a metastasis suppressor in human melanoma and breast cancer, is now recognized as the major puberty gatekeeper and gonadotropin-releasing hormone (GnRH) neuroendocrine system modulator. It is a member of the family of RFamide-related peptides that also includes the neuropeptide FF group, the gonadotropin-inhibitory hormone, the prolactin-releasing peptide, and the 26RFa peptides. The KISS1 precursor peptide is processed into a family of peptides known as kisspeptins. Its expression has been described in the hypothalamus as well as in the whole reproductive axis and several extra reproductive tissues of mammals as well as fish and amphibians, but not in birds. KISS1 plays an essential role as a regulator of the reproductive axis by inducing the synthesis and release of GnRH, acting through specific receptors. The study of the kisspeptin system and its relation with reproduction in wild and non-classical laboratory species is extremely useful to understand and become aware of the role of KISS1 in the wide variety of possible different reproductive strategies. In this chapter, KISS1 involvement in non-classical laboratory rodents, fishes, and birds is discussed.

The hypothalamus, in addition to controlling the main body's vital functions, is also involved in aging regulation. The aging process in the hypothalamus is accompanied by disturbed intracellular pathways, including Ca²⁺ signaling and neuronal excitability in the brain. Intrinsic electrophysiological properties of individual neurons and synaptic transmission between cells is disrupted in the central nervous system of old animals. However, changes in neuronal excitability and excitation/inhibition balance with aging are specific to the type of neurons, brain region, and species. Glia-neuron interactions play a significant role in the brain and undergo remodeling accompanied by advanced loss of function with aging. In the current review, I have summarized the current understanding of the changes in the brain and especially in the hypothalamus with aging.

The hypothalamus plays a central role in regulating energy expenditure and maintaining energy homeostasis, crucial for an organism's survival. Located in the ventral diencephalon, it is a dynamic and adaptable brain region capable of rapid responses to environmental changes, exhibiting high anatomical and cellular plasticity and integrates a myriad of sensory information, internal physiological cues, and humoral factors to accurately interpret the nutritional state and adjust food intake, thermogenesis, and energy homeostasis. Key hypothalamic nuclei contain distinct neuron populations that respond to hormonal, nutrient, and neural inputs and communicate extensively with peripheral organs like the gastrointestinal tract, liver, pancreas, and adipose tissues to regulate energy production, storage, mobilization, and utilization. The hypothalamus has evolved to enhance energy storage for survival in famine and scarce environments but contribute to obesity in modern contexts of caloric abundance. It acts as a master regulator of whole-body energy homeostasis, rapidly adapting to ensure energy supplies for cellular functions. Understanding hypothalamic function, pertaining to energy expenditure, is crucial for developing targeted interventions to address metabolic disorders, offering new insights into the neural control of metabolic states and potential therapeutic strategies.

The discovery of Kisspeptin (Kiss) has opened a new direction in research on neuroendocrine control of reproduction in vertebrates. Belonging to the RF amide family of peptides, Kiss and its cognate receptor Gpr54 (Kissr) have a long and complex evolutionary history. Multiple forms of Kiss and Kissr are identified in non-mammalian vertebrates, with the exception of birds, and monotreme mammals. However, only a single form of the ligand (KISS1/Kiss1) and receptor (KISS1R/Kiss1r) is retained in higher mammals. Kiss1 is distributed in the hypothalamus-pituitary-gonadal (HPG) axis and its primary function is to stimulate gonadotropin-releasing hormone (GnRH) secretion. Kiss1 neurons are distributed in the rostral periventricular area of the third ventricle (RP3V) and arcuate/infundibular nucleus (ARN/IFN). The ARN/IFN is considered the GnRH pulse generator controlled by steroid negative feedback, and the RP3V neurons is concerned with GnRH surge induced by steroid positive feedback in females. The Kiss1-Kiss1r signaling is important in all aspects of reproduction: puberty onset, maintenance of adult gonadal functions and reproductive aging, and hence assumes therapeutic potentials in the treatment of reproductive dysfunctions and induction of artificial reproduction. This chapter reviews involvement of Kiss1 in the control of the HPG axis functions in female mammals.