Abstract The role of adenosine 5′-triphosphate (ATP) as a major intracellular energy source is well-established. In addition, ATP and related nucleotides have widespread extracellular actions via the ...ionotropic P2X (ligand-gated cation channels) and metabotropic P2Y (G protein-coupled) receptors. Numerous experimental techniques, including myography, electrophysiology and biochemical measurement of neurotransmitter release, have been used to show that ATP has several major roles as a neurotransmitter in peripheral nerves. When released from enteric nerves of the gastrointestinal tract it acts as an inhibitory neurotransmitter, mediating descending muscle relaxation during peristalsis. ATP is also an excitatory cotransmitter in autonomic nerves; 1) It is costored with noradrenaline in synaptic vesicles in postganglionic sympathetic nerves innervating smooth muscle preparations, such as the vas deferens and most arteries. When coreleased with noradrenaline, ATP acts at postjunctional P2X1 receptors to evoke depolarisation, Ca 2 + influx, Ca 2 + sensitisation and contraction. 2) ATP is also coreleased with acetylcholine from postganglionic parasympathetic nerves innervating the urinary bladder and again acts at postjunctional P2X1 receptors, and possibly also a P2X1 + 4 heteromer, to elicit smooth muscle contraction. In both cases the neurotransmitter actions of ATP are terminated by dephosphorylation by extracellular, membrane-bound enzymes and soluble nucleotidases released from postganglionic nerves. There are indications of an increased contribution of ATP to control of blood pressure in hypertension, but further research is needed to clarify this possibility. More promising is the upregulation of P2X receptors in dysfunctional bladder, including interstitial cystitis, idiopathic detrusor instability and overactive bladder syndrome. Consequently, these roles of ATP are of great therapeutic interest and are increasingly being targeted by pharmaceutical companies.
Pakistan 1992 Kennedy, Charles H
2019, 1993, 2019-06-04
eBook
203Ever since the creation of Pakistan as an independent Muslim state in 1947, the country has struggled to integrate a diverse population and stabilize its borders. During its short but turbulent ...history, Pakistan has yet to achieve those goals, as political, economic, and social upheavals continue to challenge the world's ninth most populous state.
Despite the importance of Pakistan's status as a regional power and as a pivotal player on the global stage, relatively little timely, detailed analysis is available on the country. This book fills that gap by providing up-to-date analysis and information by leading scholars. The first in a biennial series, this volume interprets current developments in politics, economics, and foreign relations. In addition, special-interest chapters cover the 1990 general election, Islamization, health poiicy, and the intractable Kashmir conflict.
Scholars and general readers alike will find valuable insights and comprehensive coverage in this thoughtful collection of essays. A detailed chronology and glossary provide especially useful reference points.
Klotho: An Elephant in Aging Research Cheikhi, Amin; Barchowsky, Aaron; Sahu, Amrita ...
The journals of gerontology. Series A, Biological sciences and medical sciences,
06/2019, Letnik:
74, Številka:
7
Journal Article
Recenzirano
Odprti dostop
The year 2017 marked the 20th anniversary of the first publication describing Klotho. This single protein was and is remarkable in that its absence in mice conferred an accelerated aging, or ...progeroid, phenotype with a dramatically shortened life span. On the other hand, genetic overexpression extended both health span and life span by an impressive 30%. Not only has Klotho deficiency been linked to a number of debilitating age-related illnesses but many subsequent reports have lent credence to the idea that Klotho can compress the period of morbidity and extend the life span of both model organisms and humans. This suggests that Klotho functions as an integrator of organ systems, making it both a promising tool for advancing our understanding of the biology of aging and an intriguing target for interventional studies. In this review, we highlight advances in our understanding of Klotho as well as key challenges that have somewhat limited our view, and thus translational potential, of this potent protein.
Eight G protein‐coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin‐like GPCRs and contain ...two structurally distinct subfamilies: P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 (principally Gq protein‐coupled P2Y1‐like) and P2Y12–14 (principally Gi protein‐coupled P2Y12‐like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y1, P2Y2, P2Y4, and P2Y6 receptors induce vasodilation, while smooth muscle P2Y2, P2Y4, and P2Y6 receptor activation leads to vasoconstriction. Pancreatic P2Y1 and P2Y6 receptors stimulate while P2Y13 receptors inhibits insulin secretion. Antagonists of P2Y12 receptors, and potentially P2Y1 receptors, are anti‐thrombotic agents, and a P2Y2/P2Y4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro‐inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X‐ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly ...1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15539. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
The growth in size and significance of NGOs and particularly of Grameen Bank and the Bangladesh Rural Advancement Committee (BRAC) in Bangladesh challenges the idealtypical relationship between the ...state, donors and NGOs. Such an ideal envisions a clear demarcation of roles in which NGOs compete with other NGOs for resources from the state and/or donors and one in which NGO activities and programmes are regulated or held accountable by their respective funding sources. The emergence of large multitasking NGOs in a relatively small and weak state such as Bangladesh belies this ideal. Grameen and BRAC compete with government ministries for donor funding; statal institutions designed to regulate the activities of such NGOs are functionally ineffective; and international donors face insuperable hurdles in assessing accountability.
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Extracellular purine and pyrimidine nucleotides produce their pharmacological effects through P2 receptors. These were first named by Geoff Burnstock in an extensive review in 1978. ...They were then subdivided into P2X and P2Y purinoceptors by Burnstock and Kennedy in 1985, based on applying pharmacological criteria to data generated by functional studies in smooth muscle tissues. Several other P2 subtypes, P2T, P2Z, P2U and P2D were subsequently identified in the following years, again using pharmacological criteria. The number and identity of subtypes were clarified and simplified by the cloning of seven ATP-sensitive ligand-gated ion channel subunits and eight adenine and/or uracil nucleotide-sensitive G protein-coupled receptors from 1993 onwards. The former were all classified as members of the P2X receptor family and the latter as members of the P2Y receptor family. More recently, high resolution imaging of the tertiary and quaternary structures of several P2X and P2Y receptor subtypes has provided a much greater understanding of how and where agonists and antagonists bind to the receptors and how this leads to changes in receptor conformation and activity. In addition, medicinal chemistry has produced a variety of subtype-selective agonists and antagonists, some of which are now in clinical use. This progress and success is a testimony to the foresight, intelligence, enthusiasm and drive of Geoff Burnstock, who led the field forward throughout his scientific life.
Highlights • The impact of meropenem resistance in patients with Pseudomonas aeruginosa infections was assessed. • Meropenem resistance resulted in a 2.89-fold increase in mortality in hospitalized ...patients. • Resistance to meropenem was independently associated with increased total hospital cost. • A 3-tiered patient care cleaning program was effective at reducing the incidence of multidrug-resistant organisms.
There have been many advances in our knowledge about different aspects of P2Y receptor signaling since the last review published by our International Union of Pharmacology subcommittee. More receptor ...subtypes have been cloned and characterized and most orphan receptors de-orphanized, so that it is now possible to provide a basis for a future subdivision of P2Y receptor subtypes. More is known about the functional elements of the P2Y receptor molecules and the signaling pathways involved, including interactions with ion channels. There have been substantial developments in the design of selective agonists and antagonists to some of the P2Y receptor subtypes. There are new findings about the mechanisms underlying nucleotide release and ectoenzymatic nucleotide breakdown. Interactions between P2Y receptors and receptors to other signaling molecules have been explored as well as P2Y-mediated control of gene transcription. The distribution and roles of P2Y receptor subtypes in many different cell types are better understood and P2Y receptor-related compounds are being explored for therapeutic purposes. These and other advances are discussed in the present review.
Geoff Burnstock created an outstanding scientific legacy that includes identification of adenosine 5′-triphosphate (ATP) as an inhibitory neurotransmitter in the gut, the discovery and ...characterisation of a large family of purine and uridine nucleotide-sensitive ionotropic P2X and metabotropic P2Y receptors and the demonstration that ATP is as an excitatory cotransmitter in autonomic nerves. The evidence for cotransmission includes that: 1) ATP is costored with noradrenaline in synaptic vesicles in postganglionic sympathetic nerves innervating smooth muscle tissues, including the vas deferens and most arteries. 2) When coreleased with noradrenaline, ATP acts at postjunctional P2X1 receptors to elicit depolarisation, Ca2+ influx, Ca2+ sensitisation and contraction. 3) ATP is also coreleased with acetylcholine from postganglionic parasympathetic nerves innervating the urinary bladder, where it stimulates postjunctional P2X1 receptors, and a second, as yet unidentified site to evoke contraction of detrusor smooth muscle. In both systems membrane-bound ecto-enzymes and soluble nucleotidases released from postganglionic nerves dephosphorylate ATP and so terminate its neurotransmitter actions. Currently, the most promising potential area of therapeutic application relating to cotransmission is treatment of dysfunctional urinary bladder. This family of disorders is associated with the appearance of a purinergic component of neurogenic contractions. This component is an attractive target for drug development and targeting it may be a rewarding area of research.
•ATP is an excitatory cotransmitter in sympathetic nerves of smooth muscle tissues.•ATP is an excitatory parasympathetic cotransmitter in the urinary bladder.•ATP acts at postjunctional P2X1 receptors to elicit smooth muscle contraction.•ATP may also elicit contraction of urinary bladder via a second, as yet unidentified, site.•Ecto- nucleotidases and coreleased soluble nucleotidases terminate ATP's actions.
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