This chapter thoroughly examines the basic mechanisms, structure, expression patterns, and the cleavage of amyloid plaques. Further, it analyzes the diagnosis and potential treatments for Alzheimer's disease.
Corticotropin-releasing hormone (CRH) is foundational for both resting and stress-induced processes in the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic brain circuits, modulating behavioral and humoral responses to stress through its role as a neuromodulator. A review of cellular components and molecular mechanisms of CRH system signaling through G protein-coupled receptors (GPCRs) CRHR1 and CRHR2 is presented, drawing on current models of GPCR signaling within both plasma membrane and intracellular compartments, establishing the basis of signal resolution in space and time. Neurohormonal function's interplay with CRHR1 signaling, as demonstrated by recent studies in physiologically relevant contexts, discloses novel mechanisms of cAMP production and ERK1/2 activation. A concise overview of the CRH system's pathophysiological role is presented here, emphasizing the requirement for a complete characterization of CRHR signaling pathways to develop novel and targeted therapies for stress-related conditions.
Ligand-dependent transcription factors, nuclear receptors (NRs), regulate a spectrum of cellular functions crucial to reproduction, metabolism, and development and are categorized into seven superfamilies. bioequivalence (BE) In all NRs, the domain structure of A/B, C, D, and E is present, accompanied by distinct and essential functions. NRs, whether monomeric, homodimeric, or heterodimeric, connect with DNA sequences called Hormone Response Elements (HREs). 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 are capable of controlling the expression of their target genes, achieving both activation and repression. Ligand engagement with nuclear receptors (NRs) in positively regulated genes triggers the recruitment of coactivators, thereby activating the expression of the target gene; conversely, unliganded NRs induce transcriptional repression. However, NRs' gene expression repression employs two disparate approaches: (i) ligand-dependent transcriptional suppression and (ii) ligand-independent transcriptional suppression. This chapter will offer a succinct account of NR superfamilies, highlighting their structures, molecular mechanisms, and roles in pathophysiological scenarios. Potential for the discovery of new receptors and their associated ligands, coupled with a deeper understanding of their roles in a myriad of physiological processes, is presented by this prospect. A component of the strategy to control the dysregulation of nuclear receptor signaling will involve the development of therapeutic agonists and antagonists.
Acting as a key excitatory neurotransmitter, the non-essential amino acid glutamate significantly influences the central nervous system. This molecule's binding to ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs) results in the postsynaptic excitation of neurons. The importance of these factors is evident in their role in memory, neural development, communication, and learning processes. Cellular excitation and the modulation of receptor expression on the cell membrane are fundamentally dependent on endocytosis and the receptor's subcellular trafficking. The interplay of receptor type, ligand, agonist, and antagonist determines the efficiency of endocytosis and trafficking for the receptor. This chapter investigates glutamate receptors, encompassing their diverse subtypes and the intricate processes of their internalization and transport. Briefly considering the roles of glutamate receptors in neurological diseases is also pertinent.
Neurotrophins, acting as soluble factors, emanate from neurons and the postsynaptic targets they engage with, crucial for neuronal health and development. The intricate process of neurotrophic signaling governs critical functions such as neurite expansion, neuronal maintenance, and the formation of synapses. The internalization of the ligand-receptor complex, following the binding of neurotrophins to their receptors, tropomyosin receptor tyrosine kinase (Trk), is a key part of the signaling process. This complex is subsequently channeled into the endosomal network, where downstream signaling by Trks is initiated. Endosomal localization, along with the involvement of co-receptors and the expression of adaptor proteins, plays a crucial role in the multifaceted regulatory capacity of Trks. This chapter provides a systematic study of the endocytosis, trafficking, sorting, and signaling of neurotrophic receptors.
The principal neurotransmitter, GABA (gamma-aminobutyric acid), plays a key role in chemical synapses by suppressing neuronal activity. Deeply embedded within the central nervous system (CNS), it actively maintains a balance between excitatory impulses (controlled by another neurotransmitter, glutamate) and inhibitory impulses. The action of GABA, upon being released into the postsynaptic nerve terminal, involves binding to its particular receptors GABAA and GABAB. The receptors are responsible for regulating the speed of neurotransmission inhibition, with one for fast inhibition and the other for slow. The ionopore GABAA receptor, activated by ligands, opens chloride ion channels, reducing the membrane's resting potential, which results in synapse inhibition. Alternatively, GABAB receptors, functioning as metabotropic receptors, elevate potassium ion levels, impede calcium ion release, and consequently inhibit the discharge of other neurotransmitters at the presynaptic membrane. The internalization and subsequent trafficking of these receptors utilize different pathways and mechanisms, elaborated upon in the chapter. Without the proper GABA levels, maintaining a healthy balance of psychological and neurological states in the brain becomes difficult. Neurodegenerative diseases and disorders like anxiety, mood disorders, fear, schizophrenia, Huntington's chorea, seizures, and epilepsy, share a common thread of low GABA levels. The potency of GABA receptor allosteric sites as drug targets for calming pathological conditions in brain disorders has been scientifically established. Further investigation into the subtypes of GABA receptors and their intricate mechanisms is crucial for identifying novel drug targets and therapeutic strategies to effectively manage GABA-related neurological disorders.
Serotonin, also identified as 5-hydroxytryptamine (5-HT), plays a pivotal role in a wide array of physiological and pathological processes within the human body, encompassing psychoemotional states, sensory perception, blood flow regulation, dietary habits, autonomic function, memory consolidation, sleep cycles, and pain perception, among other crucial functions. G protein subunits' interaction with diverse effectors triggers a range of responses, encompassing the inhibition of adenyl cyclase and the modulation of Ca++ and K+ ion channel activity. selleck inhibitor Activated protein kinase C (PKC) (a second messenger), resulting from signaling cascades, promotes the dissociation of G-protein-linked receptor signaling, leading to the internalization of 5-HT1A. Following internalization, the 5-HT1A receptor engages with the Ras-ERK1/2 pathway. For degradation, the receptor is ultimately directed to the lysosome. Lysosomal compartmental trafficking is avoided by the receptor, which then dephosphorylates. The dephosphorylated receptors are now being transported back to the cell membrane. Within this chapter, the process of 5-HT1A receptor internalization, trafficking, and signaling has been explored.
GPCRs, the largest family of plasma membrane-bound receptor proteins, participate in a wide range of cellular and physiological functions. These receptors are activated by a variety of extracellular stimuli, including hormones, lipids, and chemokines. Human diseases, notably cancer and cardiovascular disease, often exhibit aberrant GPCR expression coupled with genetic alterations. The therapeutic potential of GPCRs is showcased by the substantial number of drugs either approved by the FDA or in clinical trial phases. GPCR research, updated in this chapter, highlights its significant promise as a therapeutic target.
A lead ion-imprinted sorbent, Pb-ATCS, was formed using the ion-imprinting method with an amino-thiol chitosan derivative as the starting material. A crucial step involved amidizing the chitosan with the 3-nitro-4-sulfanylbenzoic acid (NSB) moiety, then selectively reducing the resultant -NO2 moieties to -NH2 groups. Epichlorohydrin-mediated cross-linking of the amino-thiol chitosan polymer ligand (ATCS) with Pb(II) ions, followed by the removal of the lead ions, achieved the imprinting process. The investigation of the synthetic steps, via nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR), culminated in testing the sorbent's ability to selectively bind Pb(II) ions. The Pb-ATCS sorbent's maximum adsorption capacity, approximately 300 milligrams per gram, indicated a higher preference for lead (II) ions, compared to the control NI-ATCS sorbent particle. carbonate porous-media A consistency was observed between the pseudo-second-order equation and the sorbent's adsorption kinetics, which exhibited considerable speed. The coordination of metal ions with introduced amino-thiol moieties on the solid surfaces of Pb-ATCS and NI-ATCS demonstrated chemo-adsorption.
Starch, a naturally occurring biopolymer, is exceptionally well-suited for encapsulating nutraceuticals, owing to its diverse sources, adaptability, and high degree of biocompatibility. This review highlights recent progress toward the development of more efficient starch-based drug delivery systems. We begin by exploring the structure and functionality of starch in the processes of encapsulating and delivering bioactive ingredients. Enhancing the functionalities and expanding the applications of starch in novel delivery systems is achieved through structural modification.