Vitamins and Hormones最新文献

Sonic hedgehog (Shh) is a secreted glycopeptide belonging to the hedgehog family that is essential for morphogenesis during embryonic development. The Shh signal is mediated by two membrane proteins, Patched-1 (Ptch-1) and Smoothened (Smo), following the activation of transcription factors such as Gli. Shh decreases the permeability of the blood-brain barrier (BBB) and plays a key role in its function. In the damaged brain, BBB function is remarkably disrupted. The BBB disruption causes brain edema and neuroinflammation resulting from the extravasation of serum components and the infiltration of inflammatory cells into the cerebral parenchyma. Multiple studies have suggested that astrocyte is a source of Shh and that astrocytic Shh production is increased in the damaged brain. In various experimental animal models of acute brain injury, Shh or Shh signal activators alleviate BBB disruption by increasing tight junction proteins in endothelial cells. Furthermore, activation of astrocytic Shh signaling reduces reactive astrogliosis, neuroinflammation, and increases the production of vascular protective factors, which alleviates BBB disruption in the damaged brain. These findings suggest that astrocytic Shh and Shh signaling protect BBB function in the damaged brain and that target drugs for Shh signaling are expected to be novel therapeutic drugs for acute brain injuries.

Mouse models have been widely used in the study of adrenal gland development and diseases. The X-zone is a unique structure of the mouse adrenal gland and lineage-tracing studies show that the X-zone is a remnant of the fetal adrenal cortex. Although the X-zone is considered analogous to the fetal zone in the human adrenal cortex, the functional significance of the X-zone has remained comparatively more obscure. The X-zone forms during the early postnatal stages of adrenal development and regresses later in a remarkable sexually dimorphic fashion. The formation and regression of the X-zone can be different in mice with different genetic backgrounds. Mouse models with gene mutations, hormone/chemical treatments, and/or gonadectomy can also display an aberrant development of the X-zone or alternatively a dysregulated X-zone regression. These models have shed light on the molecular mechanisms regulating the development and regression of these unique adrenocortical cells. This review paper briefly describes the development of the adrenal gland including the formation and regression processes of the X-zone. It also summarizes and lists mouse models that demonstrate different X-zone phenotypes.

The adrenal gland is composed of two distinctly different endocrine moieties. The interior medulla consists of neuroendocrine chromaffin cells that secrete catecholamines like adrenaline and noradrenaline, while the exterior cortex consists of steroidogenic cortical cells that produce steroid hormones, such as mineralocorticoids (aldosterone), glucocorticoids (cortisone and cortisol) and androgens. Synthesis of steroid hormones in cortical cells requires substantial amounts of cholesterol, which is the common precursor for steroidogenesis. Cortical cells may acquire cholesterol from de novo synthesis and uptake from circulating low- and high-density lipoprotein particles (LDL and HDL). As cholesterol is part of the plasma membrane in all mammalian cells and an important regulator of membrane fluidity, cellular levels of free cholesterol are tightly regulated. To ensure a robust supply of cholesterol for steroidogenesis and to avoid cholesterol toxicity, cortical cells store large amounts of cholesterol as cholesteryl esters in intracellular lipid droplets. Cortical steroidogenesis relies on both mobilization of cholesterol from lipid droplets and constant uptake of circulating cholesterol to replenish lipid droplet stores. This chapter will describe mechanisms involved in cholesterol uptake, cholesteryl ester synthesis, lipid droplet formation, hydrolysis of stored cholesteryl esters, as well as their impact on steroidogenesis. Additionally, animal models and human diseases characterized by altered cortical cholesteryl ester storage, with or without abnormal steroidogenesis, will be discussed.

Post-translational modification of proteins by Maillard reaction, known as glycation, is thought to be the root cause of different complications, particularly in diabetes mellitus and age-related disorders. Methylglyoxal (MG), a reactive α-oxoaldehyde, increases in diabetic condition and reacts with the proteins to form advanced glycation end products (AGEs) following a Maillard-like reaction. In a time-dependent reaction study of MG with the heme protein myoglobin (Mb), MG was found to induce significant structural alterations of the heme protein, such as heme loss, changes in tryptophan fluorescence, and decrease of α-helicity with increased β-sheet content. These changes were found to occur gradually with increasing period of incubation. Incubation of Mb with MG induced the formation of several AGE adducts, including, carboxyethyllysine at Lys-16, carboxymethyllysine at Lys-87, carboxyethyllysine or pyrraline-carboxymethyllysine at Lys-133, carboxyethyllysine at Lys-42 and hydroimidazolone or argpyrimidine at Arg-31 and Arg-139. MG induced amyloid-like aggregation of Mb was detected at a longer period of incubation. MG-derived AGEs, therefore, appear to have an important role as the precursors of protein aggregation, which, in turn, may be associated with pathophysiological complications.

Beta-caryophyllene is an abundant terpene in cannabis, cinnamon, black pepper, cloves, and citrus fruit, delivering a striking, woody-spicy, like cloves and a sweet fruity aroma. Beta-caryophyllene is a Food and Drug Administration-approved food additive with Generally Recognized as Safe status. Interestingly, several biologic activities have been described for beta-caryophyllene, including anti-inflammatory and analgesic effects, neuroprotection against cerebral ischemia and neuronal injury, protection of neurovascular unit against oxidative damage, glial activation and neuroinflammation and anticonvulsant effects. In this chapter, we intend to review the beneficial effects of beta-caryophyllene in the context of psychiatric and neurological diseases. Also, we will analyze the possibility that the blood-brain-barrier may be a central target underlying the beneficial actions of beta-caryophyllene.

Advanced glycation end products (AGEs) are compounds formed via non-enzymatic reactions between reducing sugars and amino acids or proteins. AGEs can accumulate in various tissues and organs and have been implicated in the development and progression of various diseases, including lung diseases. The receptor of advanced glycation end products (RAGE) is a receptor that can bind to advanced AGEs and induce several cellular processes such as inflammation and oxidative stress. Several studies have shown that both AGEs and RAGE play a role in the pathogenesis of lung diseases, such as chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, and acute lung injury. Moreover, the soluble form of the receptor for advanced glycation end products (sRAGE) has demonstrated its ability to function as a decoy receptor, possessing beneficial characteristics such as anti-inflammatory, antioxidant, and anti-fibrotic properties. These qualities make it an encouraging focus for therapeutic intervention in managing pulmonary disorders. This review highlights the current understanding of the roles of AGEs and (s)RAGE in pulmonary diseases and their potential as biomarkers and therapeutic targets for preventing and treating these pathologies.

The adrenal glands are key components of the mammalian endocrine system, helping maintain physiological homeostasis and the coordinated response to stress. Each adrenal gland has two morphologically and functionally distinct regions, the outer cortex and inner medulla. The cortex is organized into three concentric zones which secrete steroid hormones, including aldosterone and cortisol. Neural crest-derived chromaffin cells in the medulla are innervated by preganglionic sympathetic neurons and secrete catecholamines (epinephrine, norepinephrine) and neuropeptides into the bloodstream, thereby functioning as the neuroendocrine arm of the sympathetic nervous system. In this article we review serotonin (5-HT) and the serotonin transporter (SERT; SLC6A4) in the adrenal gland. In the adrenal cortex, 5-HT, primarily sourced from resident mast cells, acts as a paracrine signal to stimulate aldosterone and cortisol secretion through 5-HT₄/5-HT₇ receptors. Medullary chromaffin cells contain a small amount of 5-HT due to SERT-mediated uptake and express 5-HT_1A receptors which inhibit secretion. The atypical mechanism of the 5-HT_1A receptors and interaction with SERT fine tune this autocrine pathway to control stress-evoked catecholamine secretion. Receptor-independent signaling by SERT/intracellular 5-HT modulates the amount and kinetics of transmitter release from single vesicle fusion events. SERT might also influence stress-evoked upregulation of tyrosine hydroxylase transcription. Transient signaling via 5-HT₃ receptors during embryonic development can limit the number of chromaffin cells found in the mature adrenal gland. Together, this emerging evidence suggests that the adrenal medulla is a peripheral hub for serotonergic control of the sympathoadrenal stress response.

Different factors are essential in increasing the vulnerability to psychiatric disorders, such as genetics. Among these factors, early life stress (ELS), including sexual, physical, emotional abuse, and emotional and physical neglect, enhances the odds of having menial conditions throughout life. Exhaustive research has shown that ELS leads to physiological changes, such as alteration in the HPA axis. During the most critical development period (childhood and adolescence), these changes increase the risk of having child-onset psychiatric disorders. Furthermore, research has suggested a relationship between early life stress and depression, particularly more prolonged episodes of depression with treatment-resistant outcomes. Molecular studies indicate that, in general, the hereditary character of psychiatric disorders is polygenic, multifactorial and highly complex, with innumerable low-effect genetic variants interacting with each other. However, whether there are independent effects among subtypes of ELS remains unclear. This article provides an overview of the interplay of epigenetics, the HPA axis, early life stress and the development of depression. Advances in our knowledge of epigenetics in the context of early life stress and depression provide a new understanding of the genetic influence on psychopathology. Furthermore, they could lead to identifying new targets for clinical intervention.

In mammals, male germ cell development starts during fetal life and is carried out in postnatal life with the formation of sperms. Spermatogenesis is the complex and highly orderly process during which a group of germ stem cells is set at birth, starts to differentiate at puberty. It proceeds through several stages: proliferation, differentiation, and morphogenesis and it is strictly regulated by a complex network of hormonal, autocrine and paracrine factors and it is associated with a unique epigenetic program. Altered epigenetic mechanisms or inability to respond to these factors can impair the correct process of germ development leading to reproductive disorders and/or testicular germ cell cancer. Among factors regulating spermatogenesis an emerging role is played by the endocannabinoid system (ECS). ECS is a complex system comprising endogenous cannabinoids (eCBs), their synthetic and degrading enzymes, and cannabinoid receptors. Mammalian male germ cells have a complete and active ECS which is modulated during spermatogenesis and that crucially regulates processes such as germ cell differentiation and sperm functions. Recently, cannabinoid receptor signaling has been reported to induce epigenetic modifications such as DNA methylation, histone modifications and miRNA expression. Epigenetic modifications may also affect the expression and function of ECS elements, highlighting the establishment of a complex mutual interaction. Here, we describe the developmental origin and differentiation of male germ cells and testicular germ cell tumors (TGCTs) focusing on the interplay between ECS and epigenetic mechanisms involved in these processes.

The term "scavengome" refers to the chemical space of all the metabolites that may be formed from an antioxidant upon scavenging reactive oxygen or nitrogen species (ROS/RNS). This chemical space covers a wide variety of free radical metabolites with drug discovery potential. It is very rich in structures representing an increased chemical complexity as compared to the parent antioxidant: a wide range of unusual heterocyclic structures, new CC bonds, etc. may be formed. Further, in a biological environment, this increased chemical complexity is directly translated from the localized conditions of oxidative stress that determines the amounts and types of ROS/RNS present. Biomimetic oxidative chemistry provides an excellent tool to model chemical reactions between antioxidants and ROS/RNS. In this chapter, we provide an overview on the known metabolites obtained by biomimetic oxidation of a few selected natural antioxidants, i.e., a stilbene (resveratrol), a pair of hydroxycinnamates (caffeic acid and methyl caffeate), and a flavonol (quercetin), and discuss the drug discovery perspectives of the related chemical space.