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Thymus Influence on Differentiation and Functional Maturation of T Lymphocytes
Published in Marek P. Dabrowski, Barbara K. Dabrowska-Bernstein, Immunoregulatory Role of Thymus, 2019
Marek P. Dabrowski, Barbara K. Dabrowska-Bernstein
The steroid hormones are bound to intracellular receptors and subsequently are transported to acceptors involved in the regulation of transcription. The thymic hormones are probable candidates to act via this route.198 In addition to these four mechanisms, the regulators of calcium availability and its cellular influx are essential for the activation of lymphocyte proliferation.198,201
Overview of Drug Development
Published in Mark Chang, John Balser, Jim Roach, Robin Bliss, Innovative Strategies, Statistical Solutions and Simulations for Modern Clinical Trials, 2019
Mark Chang, John Balser, Jim Roach, Robin Bliss
For a drug to work, it has to interact with a disease target in the human body. In most situations, it is the proteins or receptors that drug molecules are developed to interact with to provide the therapeutic benefit. The exceptions are in cases such as antisense drugs and gene therapy, where the nucleotides and genes are targeted, respectively. When presented to the target, drug molecules can elicit reactions to switch on or switch off certain biochemical reactions. The main drug targets in the human body can be classified into three categories: enzymes, intracellular receptors, and cell surface receptors. Enzymes are biomolecules that catalyze (i.e. increase the rates of) chemical reactions. Drugs can interact with enzymes to modulate their enzymatic activities. Intracellular receptors are in the cytoplasm or nucleus. Drugs or endogenous ligand molecules have to pass through the cell membrane (a lipid bilayer) to interact with these receptors. The molecules must be hydrophobic or coupled to a hydrophobic carrier to cross the cell membrane. Cell surface receptors are on the cell surface and have an affinity for hydrophilic binding molecules. Signals are transduced from external stimuli to the cytoplasm, and affect cellular pathways via these surface receptors. There are three main superfamilies (groups) of cell surface receptors: G-protein coupled receptors (GPCRs), ion channel receptors, and catalytic receptors using enzymatic activities.
Growth Factor Receptors
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
Endogenous extracellular signaling agents such as hormones, growth factors, regulatory peptides, and neurotransmitters act through their interaction with specific receptors that are capable of discriminating between different types of signaling molecules.5-9 The receptor and its ligand establish interactions that are specific and reversible and can occur with very high affinity. Interactions between growth factors, protein hormones, and regulatory peptides occur on the cell surface, where the receptors for these signaling agents are located. Nonpeptide hormones, such as the steroid and thyroid hormones, interact with intracellular receptors. In general, the interactions between the physiologic ligand and its receptor exhibit a high degree of specificity, but in certain cases one receptor may be activated by a signal designed for another.10 This phenomenon of “specificity spillover” is observed mainly in pathologic conditions, when the hormone or growth factor is present in excess.
Cardioprotective effects of arjunolic acid in LPS-stimulated H9C2 and C2C12 myotubes via the My88-dependent TLR4 signaling pathway
Published in Pharmaceutical Biology, 2023
Md Mahmudul Hasan, Priya Madhavan, Nur Adelina Ahmad Noruddin, Wai Kwan Lau, Qamar Uddin Ahmed, Aditya Arya, Zainul Amiruddin Zakaria
Toll-like receptors (TLRs) (Figure 1) are well-characterized as pattern recognition receptors in the innate immune system (Seneviratne et al. 2012). The mammalian TLRs can be categorized as cell membrane receptors (TLR1, TLR2, TLR4, TLR5, and TLR6) or intracellular receptors (TLR3, TLR7, TLR8, and TLR9). They are type 1 transmembrane proteins with an ectodomain consisting of leucine-rich repeats required to recognize exogenous (Pathogen Associated Molecular Patterns, PAMPs) or endogenous (Damage Associated Molecular Patterns, DAMPs) ligands; a transmembrane domain, which determines cellular localization; and an intracellular domain (TIR) needed for downstream signaling (Takeda and Akira 2005). Downstream signaling starts upon the recognition of DAMPs or PAMPs by TLRs leading to the recruitment of adaptor proteins such as MyD88 and TRIF.
Study of the intracellular delivery mechanism of a pH-sensitive peptide modified with enhanced green fluorescent protein
Published in Journal of Drug Targeting, 2020
Po-Chuan Chiu, Pei-Yu Hsieh, Jyun-Wei Kang, Po-Hsun Chang, Li-Jiuan Shen
Many intracellular receptors and organelles have been considered potential therapeutic targets for cancer treatment [1,2], but the cell membrane serves as a natural defence barrier that prevents macromolecules from entering cells. Endocytosis is considered one of the common cellular uptake pathways for macromolecules. Investigating endocytic mechanisms is important for the delivery of therapeutic drugs [3]. Furthermore, to achieve the effect of tumour targeting, the special characteristics of tumour cells and their surrounding microenvironment are often taken into consideration [4,5]. Rather than going through the tricarboxylic acid (TCA) cycle, cancer cells convert one molecule of glucose into pyruvate and then to lactic acid, producing 2 ATP molecules through the process known as the Warburg effect [6]. On account of the Warburg effect, a great amount of lactic acid and H+ ions are produced and transported out of cells, which acidify the microenvironment around tumour cells [7,8]. The pH difference between tumour cells and normal cells in the microenvironment can be exploited for tumour-targeted delivery. To our knowledge, there has been no study evaluating the endocytic mechanism behind pH-selective protein intracellular delivery to this point.
Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility
Published in Stress, 2018
Julia K Gjerstad, Stafford L Lightman, Francesca Spiga
Glucocorticoids exert their effects through activation of the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) (Reul & de Kloet, 1985). These are intracellular receptors belonging to the nuclear receptor family. After binding to CORT, MR and GR translocate to the nucleus where they regulate gene transcription and subsequent protein synthesis (Pratt et al., 2006; Robertson et al., 1993). Increasing evidence suggests that, in addition to genomic actions, CORT can induce rapid, nongenomic effects occurring within seconds to minutes (Groeneweg et al., 2012; Tasker et al., 2006). MR and GR are expressed in different tissues and therefore exert different physiological functions. GR expression is ubiquitous throughout the body and is involved in mediating CORT-regulated processes such as energy distribution (e.g. glycogenesis, fat and protein metabolism) and immune function. In the brain, GR levels are particularly high in the hippocampus, amygdala, PVN and prefrontal cortex while MR is mainly expressed in limbic areas, with high levels in the hippocampus, and moderate levels in the amygdala and prefrontal cortex (Reul & de Kloet, 1985, 1986). Because of their different affinities for CORT, MR is already occupied when CORT concentrations are low, such as during the hormonal circadian nadir, while GR is only activated when CORT levels are high, such as during the circadian peak and in response to stress (Conway-Campbell et al., 2007; Kitchener et al., 2004; Reul & de Kloet, 1985; Reul et al., 1990; Spencer et al., 1993).