Management of Asthma in Older Adults
Jonathan A. Bernstein, Mark L. Levy in Clinical Asthma, 2014
Regardless of age, short-acting beta2-adrenergic agonists (SABAs) such as albuterol are considered an essential, life-saving component of asthma management by allowing for rapid bronchodilation during acute asthma exacerbations. Long-acting beta2-adrenergic agonists (LABAs), including salmeterol and formoterol, also play an important role together with ICS controller therapy for individuals who require Step three or higher care.22 It is important to be aware of the potential for age-related differences in responses to beta2-agonists.26 The activity of the sympathetic nervous system increases by about 10%–15% per decade of life. In addition, age-related changes in beta2-receptor density, affinity, and signaling have been suggested. Data regarding the relationship between the density of beta2-receptors and age are complex; however, the administration of corticosteroids to older individuals is known to induce an increased response to beta2-agonists due to an increase in the density of beta2-receptors. In addition, the percentage of high-affinity beta-receptors on target tissues declines with age.30–32 Age-related abnormalities in cyclic adenosine monophosphate (cAMP) levels and activity, which is important for beta-receptor signaling, have also been identified.33
Alcohol Pharmacology and Pharmacotherapy of Alcoholism
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
Dopaminergic D1 receptors coupled to Gs and Golf are activated by alcohol which causes downstream signaling events through activating adenylyl cyclase (AC) and protein kinase A. Conversely, inhibition of several AC isoforms due to activation of D2 receptors coupled to Gi/o can occur. Protein kinase C, especially γ isoform is important and lack of this isoform causes reduced effects of alcohol measured behaviorally (Harris et al., 1995). Tyrosine kinases, mitogen-activated protein kinase (MAPK), and neurotrophic factor receptors are intracellular signal transduction cascades which are also affected by ethanol. Translocation of protein kinase C and A (PKC and PKA) between subcellular partitions also are sensitive to alcohol. Ethanol increases the activities of several isoforms of adenylyl cyclase, with AC7 existing as the most sensitive (Tabakoff and Hoffman, 1998). This causes amplified release of cyclic adenosine monophosphate (AMP) and thus enhanced activity of PKA. Activation of Gs, promotion of the interaction between Gs and adenylyl cyclase—these activities are facilitated by ethanol’s action.
Current and future oral small molecules
M. Alan Menter, Caitriona Ryan in Psoriasis, 2017
Phosphodiesterase inhibitors—of which 11 families are known—increase the level of intracellular cyclic adenosine monophosphate (cAMP) by inhibiting its degradation and inactivation. Cyclic AMP converts protein kinase A from its inactive form into its active form. Protein kinase A is a key regulator of cytokine gene transcription. Increased cAMP levels in leukocytes decrease the expression of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and IL-12, as well as proinflammatory leukotrienes, and increase the level of anti-inflammatory cytokines such as IL-10. Certain phosphodiesterases are tissue specific. PDE4 has four subtypes (A, B, C, D) and is ubiquitously expressed in various cell types, including immune cells, such as T cells, dendritic cells, macrophages, and monocytes. It is also present in different cutaneous cells, including keratinocytes. PDE4 is considered a crucial checkpoint of inflammatory cell functions. In particular, PDE4 promotes a proinflammatory state by decreasing cAMP levels, which is a unique property of PDE4. Other PDEs regulate different functions and pathways, e.g., PDE5, which inactivates cGMP and is targeted by the group of PDE5 inhibitors for the treatment of erectile dysfunction.
Current and emerging treatment options to prevent renal failure due to autosomal dominant polycystic kidney disease
Published in Expert Opinion on Orphan Drugs, 2020
Gopala K. Rangan, Aarya Raghubanshi, Alissa Chaitarvornkit, Ashley N. Chandra, Robert Gardos, Alexandra Munt, Mark N. Read, Sayanthooran Saravanabavan, Jennifer Q.J. Zhang, Annette T.Y. Wong
PKD1 and PKD2 encode polycystin-1 and polycystin-2 respectively which are members of the transient receptor potential channel protein family [29,43]. Both are membrane proteins and exist as a hetero-oligomeric complex (PKD1:PKD2; 1:3 ratio) on the shaft and basal body of the primary cilia and other subcellular locations (e.g. polycystin-2 is expressed on the endoplasmic reticulum where it acts as a nonselective calcium channel) [44]. The functions of the PKD1/PKD2 complex are not fully clear but evidence to date shows that it is a homeostatic suppressor of multiple signal transduction pathways (TORC1, c-myc-sirtuin, Wnt, Jak-Stat) in response to ciliary bending with fluid flow during quiescence [45]. Intracellular cyclic adenosine monophosphate (cAMP) and calcium are critical intermediate molecules involved in mediating these signaling pathways [45]. Thus, in ADPKD, the reduction of polycystin-1 below a critical threshold produces an abnormal cell characterized by: (i) increased intracellular cAMP and reduced calcium; (ii) an increased utilization of aerobic glycolysis (‘Warburg effect’) [46]; and (iii) increased rate in proliferation, loss of differentiation and a more elastic basement membrane [46].
Current and emerging gluconeogenesis inhibitors for the treatment of Type 2 diabetes
Published in Expert Opinion on Pharmacotherapy, 2021
Marc S. Rendell
Glucagon is secreted by α cells in the pancreas. Hypoglycemia results in low intracellular ATP levels that close ATP-sensitive potassium channels (K-ATP-channels) causing a depolarization of the cell membrane, which, in turn, opens voltage-dependent Ca2+ channels [16–19]. This increases intracellular Ca2+ levels, triggering exocytosis of glucagon granules from the alpha cells. Glucagon binds to a G protein coupled receptor with significant expression in the liver and also the kidney. There are two major pathways of subsequent activity [20]. Adenylyl cyclase stimulation produces cyclic adenosine monophosphate (cAMP) that activates protein kinase A (PKA). The activated PKA activates transcription factors like cAMP response element-binding protein (CREB) through phosphorylation. The transcription factors promote expression of the gluconeogenic enzymes. A second prominent pathway is by activation of phospholipase C resulting in an increase in inositol 1,4,5-triphosphate (IP3) which stimulates Ca2+ release and has a large number of target activators [21,22]. Glucagon rapidly activates hepatic conversion of glycogen to glucose (glycogenolysis), stimulates de novo glucose synthesis (gluconeogenesis), and inhibits glucose breakdown (glycolysis) and glycogen formation (glycogenesis). Glucagon promotes break-down of fatty acids to acetyl-coenzyme A and upregulates enzymes that implement gluconeogenesis from amino acids. Additionally, glucagon redirects hepatic fat metabolism to increase pyruvate and ATP production that promotes gluconeogenesis [22].
PLD1 knockdown reduces metastasis and inflammation of fibroblast-like synoviocytes in rheumatoid arthritis by modulating NF-κB and Wnt/β-catenin pathways
Published in Autoimmunity, 2021
Zhengyu Zhang, Xi Chen, Bo Gao, Guomin Sun, Yan Wang, Junke Wang, Ting Zhang, Hao Qian, Yu Zhang, Jun Huang, Rurong Sun, Jiabiao Wu, Lei Zhou
Similar to malignant cells, the proliferation of RA-FLSs leads to the increase of intracellular inflammatory factors [4,18]. Inflammatory transmitters, such as IL-1, IL-6 and tumour necrosis factor-α (TNF-α), could be detected in the synovium of RA patients [19]. PLD can be activated by a variety of inflammatory mediators to dehydrolyze PC, which is related to cell proliferation, cell division, calcium mobilisation, as well as specific protein kinase activation [4]. It has been reported that the mechanism of some anti-inflammatory drugs may be partly associated with the inhibition of PLD. In addition, drugs that increase cellular cyclic adenosine monophosphate levels were reported to inhibit cellular PLD activity . These studies are also consistent with our speculation that elevated PLD1 expression in RA might be associated with the inflammatory symptoms experienced by RA patients. In this study, we confirmed that inhibition of PLD1 expression reduced the levels of inflammatory factors by ELISA, such as L-1β, TNF-α, IL-6, IFN-γ, and MCP-1 in RA-FLSs, which in turn reduced the degree of inflammation.
Related Knowledge Centers
- Adenosine Monophosphate
- Adenylyl Cyclase
- Phosphodiesterase
- Second Messenger System
- Signal Transduction
- Adenosine Triphosphate
- Camp-Dependent Pathway
- Gs Alpha Subunit
- Gi Alpha Subunit
- Hormone