The chapter spotlights basic mechanisms, structures, and expression patterns in amyloid plaque cleavage, and discusses the diagnostic methods and possible treatments for Alzheimer's disease.
The hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic brain circuits rely on corticotropin-releasing hormone (CRH) for fundamental basal and stress-driven reactions; CRH functions as a neuromodulator, organizing behavioral and humoral responses to stress. Cellular components and molecular mechanisms of CRH system signaling through G protein-coupled receptors (GPCRs) CRHR1 and CRHR2 are reviewed and described, encompassing the current model of GPCR signaling from the plasma membrane and intracellular compartments, which serve as the foundation for understanding spatiotemporal signal resolution. Studies examining CRHR1 signaling in physiologically meaningful neurohormonal settings unveiled new mechanistic details concerning cAMP production and ERK1/2 activation. To better understand stress-related conditions, we also briefly discuss the pathophysiological function of the CRH system, highlighting the significance of a comprehensive characterization of CRHR signaling for designing novel and precise therapies.
Reproduction, metabolism, and development are examples of critical cellular processes regulated by nuclear receptors (NRs), ligand-dependent transcription factors. T-DXd clinical trial A common structural theme (A/B, C, D, and E) is shared by all NRs, each segment embodying unique essential functions. Hormone Response Elements (HREs) serve as binding sites for NRs, which exist as monomers, homodimers, or heterodimers. Moreover, the effectiveness of nuclear receptor binding is contingent upon slight variations in the HRE sequences, the spacing between the half-sites, and the surrounding DNA sequence of the response elements. NRs regulate their target genes through a dual mechanism, enabling both activation and repression. Ligand-bound nuclear receptors (NRs) in positively regulated genes enlist coactivators for the activation of the target gene; unliganded NRs, conversely, prompt transcriptional repression. In another view, nuclear receptors (NRs) regulate gene expression in a dual manner, encompassing: (i) ligand-dependent transcriptional repression and (ii) ligand-independent transcriptional repression. A summary of NR superfamilies, their structural features, the molecular mechanisms they utilize, and their involvement in pathophysiological conditions, will be presented in this chapter. The discovery of novel receptors and their ligands, as well as an understanding of their roles in various physiological processes, is potentially achievable through this method. The development of therapeutic agonists and antagonists to control the dysregulation of nuclear receptor signaling is anticipated.
The central nervous system (CNS) is deeply affected by glutamate, a non-essential amino acid functioning as a major excitatory neurotransmitter. Ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs) are engaged by this substance, initiating postsynaptic neuronal excitation. Neural development, communication, memory, and learning are all enhanced by these key elements. Essential for controlling receptor expression on the cell membrane and cellular excitation are the processes of endocytosis and the subcellular trafficking of the receptor. The endocytic and trafficking processes of a receptor are contingent upon the receptor's specific type, along with the nature of ligands, agonists, and antagonists present. The mechanisms of glutamate receptor internalization and trafficking, along with their various subtypes, are explored in detail within this chapter. The roles of glutamate receptors in neurological diseases are also given a brief examination.
Soluble neurotrophins are secreted by neurons themselves as well as the postsynaptic cells they target, which are critical for the sustained life and function of neurons. Neurite elongation, neuronal sustenance, and synapse development are among the various processes governed by neurotrophic signaling. Neurotrophins, through their interaction with tropomyosin receptor tyrosine kinase (Trk) receptors, trigger internalization of the ligand-receptor complex in order to signal. This complex is subsequently directed to the endosomal system, where Trk-mediated downstream signaling begins. Co-receptors, endosomal localization, and the expression profiles of adaptor proteins all contribute to Trks' regulation of a wide array of mechanisms. This chapter presents an overview of neurotrophic receptor endocytosis, trafficking, sorting, and signaling processes.
Chemical synapses rely on GABA, the key neurotransmitter (gamma-aminobutyric acid), for its inhibitory action. Located predominantly in the central nervous system (CNS), it sustains a balance between excitatory impulses (driven by another neurotransmitter, glutamate) and inhibitory impulses. GABA's action involves binding to its designated receptors, GABAA and GABAB, when it is discharged into the postsynaptic nerve terminal. These receptors are respectively associated with the fast and slow forms of neurotransmission inhibition. The ionopore GABAA receptor, activated by ligands, opens chloride ion channels, reducing the membrane's resting potential, which results in synapse inhibition. In opposition to the former, the GABAB receptor, a metabotropic kind, increases potassium ion levels, obstructing calcium ion release and therefore hindering the release of additional neurotransmitters from the presynaptic membrane. Through distinct pathways and mechanisms, these receptors undergo internalization and trafficking, processes discussed in detail within the chapter. Insufficient GABA levels disrupt the delicate psychological and neurological balance within the brain. A correlation has been observed between low GABA levels and various neurodegenerative diseases and disorders, including anxiety, mood disorders, fear, schizophrenia, Huntington's chorea, seizures, and epilepsy. The efficacy of allosteric sites on GABA receptors as drug targets in mitigating the pathological states of related brain disorders is well-documented. Comprehensive studies exploring the diverse subtypes of GABA receptors and their intricate mechanisms are needed to discover new therapeutic approaches and drug targets for managing GABA-related neurological conditions.
Crucial to bodily function, serotonin (5-hydroxytryptamine, or 5-HT) governs a diverse spectrum of processes, including psychological states, sensation interpretation, blood flow management, hunger control, autonomic responses, memory consolidation, sleep, and pain responses. By binding to different effectors, G protein subunits induce a range of responses, such as the inhibition of the adenyl cyclase enzyme and the modulation of calcium and potassium ion channel activity. Barometer-based biosensors By activating protein kinase C (PKC), a second messenger, signaling cascades initiate a sequence of events. This includes the detachment of G-protein-coupled receptor signaling and the subsequent cellular uptake of 5-HT1A receptors. Internalization of the 5-HT1A receptor leads to its attachment to the Ras-ERK1/2 pathway. For degradation, the receptor is ultimately directed to the lysosome. The receptor bypasses the lysosomal pathway, undergoing dephosphorylation instead. The cell membrane now receives the dephosphorylated receptors, part of a recycling process. The 5-HT1A receptor's internalization, trafficking, and signaling are the subject of this chapter's investigation.
G-protein coupled receptors (GPCRs), being the largest family of plasma membrane-bound receptor proteins, are essential to the multitude of cellular and physiological functions. These receptors are activated by the presence of extracellular substances such as hormones, lipids, and chemokines. Expression abnormalities and genetic modifications in GPCRs are linked to a range of human diseases, including cancer and cardiovascular disease. GPCRs, emerging as potential therapeutic targets, have seen numerous drugs either FDA-approved or in clinical trials. Regarding GPCR research, this chapter offers an update, emphasizing its potential as a significant therapeutic target.
An amino-thiol chitosan derivative (Pb-ATCS) served as the precursor for a lead ion-imprinted sorbent, produced using the ion-imprinting technique. 3-Nitro-4-sulfanylbenzoic acid (NSB) was used to amidate chitosan, and afterward, the -NO2 residues were selectively reduced to -NH2 groups. Employing epichlorohydrin, the amino-thiol chitosan polymer ligand (ATCS) was cross-linked with Pb(II) ions. The removal of these ions from the formed polymeric complex successfully accomplished the imprinting process. Nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR) were employed to scrutinize the synthetic steps, and the sorbent's capacity for selective Pb(II) ion binding was subsequently assessed. The Pb-ATCS sorbent, upon production, possessed a maximum adsorption capacity of roughly 300 milligrams per gram, showcasing a more significant attraction towards lead (II) ions compared to the control NI-ATCS sorbent. microbiome stability The sorbent's adsorption kinetics, which were quite rapid, were further confirmed by their alignment with the pseudo-second-order equation. Coordination with the introduced amino-thiol moieties resulted in the chemo-adsorption of metal ions onto the surfaces of Pb-ATCS and NI-ATCS solids, as demonstrated.
As a biopolymer, starch is exceptionally well-suited to be an encapsulating material for nutraceuticals, stemming from its readily available sources, versatility, and high compatibility with biological systems. A recent overview of advancements in starch-based delivery systems is presented in this review. A foundational examination of starch's structural and functional roles in the encapsulation and delivery of bioactive ingredients is presented initially. Modifying starch's structure results in improved functionality and expanded application possibilities within novel delivery systems.