{"title":"Interventional functional diagnostics in gastrointestinal endoscopy: Combining diagnostic and therapeutic tools in the endoscopy suite with the functional lumen imaging probe","authors":"Zuzana Vackova , Ian Levenfus , Daniel Pohl","doi":"10.1016/j.coph.2023.102414","DOIUrl":"https://doi.org/10.1016/j.coph.2023.102414","url":null,"abstract":"<div><p>With technical progress of gastrointestinal functional testing, there has been a demand for more comprehensive examination of esophageal physiology and pathophysiology beyond high-resolution manometry. A new interventional technology based on impedance planimetry, the functional lumen imaging probe (FLIP), enables intraluminal measurement of distensibility and compliance of hollow organs. EndoFLIP uses balloon catheters to measure diameter and distension pressure to calculate cross-sectional area and distensibility in different organs (mostly esophagus, stomach, anorectal region) and can be used in wide variety of indications (diagnostics, pre- and post-treatment evaluation) and currently serves as a helpful adjunctive tool in ambiguous clinical cases. EsoFLIP is a therapeutic variation that uses a stiffer balloon catheter allowing for dilation. The trend to simplify the clinical process from diagnosis to treatment tends to a one-session procedure combining diagnostics and therapeutic interventions. In specified conditions like e.g. achalasia or gastroparesis, a combination of EndoFLIP and EsoFLIP procedures may therefore be useful. The aim of this narrative review is to introduce the clinical use of FLIP and its potential benefit in combined diagnostic-therapeutic procedures.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"73 ","pages":"Article 102414"},"PeriodicalIF":4.0,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1471489223000693/pdfft?md5=a85fbc9fb6d7221a1db26a1995fcc341&pid=1-s2.0-S1471489223000693-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138453586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Beining Jin, Naveen Thakur, Anuradha V. Wijesekara, Matthew T. Eddy
{"title":"Illuminating GPCR signaling mechanisms by NMR spectroscopy with stable-isotope labeled receptors","authors":"Beining Jin, Naveen Thakur, Anuradha V. Wijesekara, Matthew T. Eddy","doi":"10.1016/j.coph.2023.102364","DOIUrl":"10.1016/j.coph.2023.102364","url":null,"abstract":"<div><p>G protein-coupled receptors (GPCRs) exhibit remarkable structural plasticity, which underlies their capacity to recognize a wide range of extracellular molecules and interact with intracellular partner proteins. Nuclear magnetic resonance (NMR) spectroscopy is uniquely well-suited to investigate GPCR structural plasticity, enabled by stable-isotope “probes” incorporated into receptors that inform on structure and dynamics. Progress with stable-isotope labeling methods in Eukaryotic expression systems has enabled production of native or nearly-native human receptors with varied and complementary distributions of NMR probes. These advances have opened up new avenues for investigating the roles of conformational dynamics in signaling processes, including by mapping allosteric communication networks, understanding the specificity of GPCR interactions with partner proteins and exploring the impact of membrane environments on GPCR function.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"72 ","pages":"Article 102364"},"PeriodicalIF":4.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pharmacologic treatment of gastroparesis: What is (still) on the horizon?","authors":"D. Schweckendiek, D. Pohl","doi":"10.1016/j.coph.2023.102395","DOIUrl":"10.1016/j.coph.2023.102395","url":null,"abstract":"<div><p>Gastroparesis is a neuromuscular disorder of the upper gastrointestinal tract. Patients typically complain about early satiety, postprandial fullness, nausea and vomiting. Etiology is multifactorial. Treatment strategies include nutritional support, pharmacologic agents or surgery for refractory cases. Metoclopramide is the first and only FDA approved pharmacologic agent for (diabetic) Gastroparesis. A couple of compounds are currently in clinical testing. Some beacons of hope have failed recently, however. Here we present an update on possible future treatment options.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"72 ","pages":"Article 102395"},"PeriodicalIF":4.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Discerning conformational dynamics and binding kinetics of GPCRs by 19F NMR","authors":"R.S. Prosser , Nicholas A. Alonzi","doi":"10.1016/j.coph.2023.102377","DOIUrl":"https://doi.org/10.1016/j.coph.2023.102377","url":null,"abstract":"<div><p><sup>19</sup>F NMR provides a way of monitoring conformational dynamics of G-protein coupled receptors (GPCRs) from the perspective of an ensemble. While X-ray crystallography provides exquisitely resolved high-resolution structures of specific states, it generally does not recapitulate the true ensemble of functional states. Fluorine (<sup>19</sup>F) NMR provides a highly sensitive spectroscopic window into the conformational ensemble, generally permitting the direct quantification of resolvable states. Moreover, straightforward T<sub>1</sub>- and T<sub>2</sub><span>-based relaxation experiments allow for the study of fluctuations within a given state and exchange between states, on timescales spanning nanoseconds to seconds. Conveniently, most biological systems are free of fluorine. Thus, via fluorinated amino acid analogues or thiol-reactive fluorinated tags, F or CF</span><sub>3</sub> reporters can be site specifically incorporated into proteins of interest. In this review, fluorine labeling protocols and <sup>19</sup>F NMR experiments will be presented, from the perspective of small molecule NMR (i.e. drug or small molecule interactions with receptors) or macromolecular NMR (i.e. conformational dynamics of receptors and receptor–G-protein complexes).</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"72 ","pages":"Article 102377"},"PeriodicalIF":4.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50172845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The role of Pannexin-1 channels, ATP, and purinergic receptors in the pathogenesis of HIV and SARS-CoV-2","authors":"Cristian A. Hernandez, Eliseo A. Eugenin","doi":"10.1016/j.coph.2023.102404","DOIUrl":"10.1016/j.coph.2023.102404","url":null,"abstract":"<div><p>Infectious agents such as human immune deficiency virus-1 (HIV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) use host proteins to infect, replicate, and induce inflammation within the host. A critical component of these diseases is the axis between pannexin-1 channels, extracellular ATP, and purinergic receptors. Here, we describe the potential therapeutic role of Pannexin-1/purinergic approaches to prevent or reduce the devastating consequences of these pathogens.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"73 ","pages":"Article 102404"},"PeriodicalIF":4.0,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41177349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charlotte Kayser , Barbora Melkes , Cécile Derieux , Andreas Bock
{"title":"Spatiotemporal GPCR signaling illuminated by genetically encoded fluorescent biosensors","authors":"Charlotte Kayser , Barbora Melkes , Cécile Derieux , Andreas Bock","doi":"10.1016/j.coph.2023.102384","DOIUrl":"10.1016/j.coph.2023.102384","url":null,"abstract":"<div><p><span>G protein-coupled receptors (GPCRs) are ligand-activated cell membrane proteins and represent the most important class of drug targets. GPCRs adopt several active conformations that stimulate different intracellular </span>G proteins<span> (and other transducers) and thereby modulate second messenger levels, eventually resulting in receptor-specific cell responses. It is increasingly accepted that not only the type of active signaling protein but also the duration of its stimulation and the subcellular location from where receptors signal distinctly contribute to the overall cell response. However, the molecular principles governing such spatiotemporal GPCR signaling and their role in disease are incompletely understood. Genetically encoded, fluorescent biosensors—in particular for the GPCR/cAMP signaling axis—have been pivotal to the discovery and molecular understanding of novel concepts in spatiotemporal GPCR signaling. These include GPCR priming, location bias, and receptor-associated independent cAMP nanodomains. Here, we review such technologies that we believe will illuminate the spatiotemporal organization of other GPCR signaling pathways that define the complex signaling architecture of the cell.</span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"71 ","pages":"Article 102384"},"PeriodicalIF":4.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9920447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Miguel Ruiz-Cruz , Carmen Torres-Granados , Manuel Tena-Sempere , Juan Roa
{"title":"Central and peripheral mechanisms involved in the control of GnRH neuronal function by metabolic factors","authors":"Miguel Ruiz-Cruz , Carmen Torres-Granados , Manuel Tena-Sempere , Juan Roa","doi":"10.1016/j.coph.2023.102382","DOIUrl":"10.1016/j.coph.2023.102382","url":null,"abstract":"<div><p>Gonadotropin-releasing hormone (GnRH) neurons are the final output pathway for the brain control of reproduction. The activity of this neuronal population, mainly located at the preoptic area of the hypothalamus, is controlled by a plethora of metabolic signals. However, it has been documented that most of these signal impact on GnRH neurons through indirect neuronal circuits, Kiss1, proopiomelanocortin, and neuropeptide Y/agouti-related peptide neurons being some of the most prominent mediators. In this context, compelling evidence has been gathered in recent years on the role of a large range of neuropeptides and energy sensors in the regulation of GnRH neuronal activity through both direct and indirect mechanisms. The present review summarizes some of the most prominent recent advances in our understanding of the peripheral factors and central mechanisms involved in the metabolic control of GnRH neurons.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"71 ","pages":"Article 102382"},"PeriodicalIF":4.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9971557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting cAMP signaling compartments in iPSC-derived models of cardiovascular disease","authors":"Tiannan Liu , Enno Klussmann","doi":"10.1016/j.coph.2023.102392","DOIUrl":"10.1016/j.coph.2023.102392","url":null,"abstract":"<div><p>Adenosine 3′,5′-cyclic monophosphate (cAMP) acts as a second messenger that is involved in the regulation of a plethora of processes. The activation of cAMP signaling in defined compartments is critical for cells to respond to an extracellular stimulus in a specific manner. Rapid advances in the field of human induced pluripotent stem cells (iPSCs) reflect their great potential for cardiovascular disease modeling, drug screening, regenerative and precision medicine. This review discusses cAMP signaling in iPSC-derived cardiovascular disease models, and the prospects of using such systems to elucidate disease mechanisms, drug actions and to identify novel drug targets for the treatment of cardiovascular diseases with unmet medical need, such as hypertension and heart failure.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"71 ","pages":"Article 102392"},"PeriodicalIF":4.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9918379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caterina Marchioretti , Roberta Andreotti , Emanuela Zuccaro , Andrew P. Lieberman , Manuela Basso , Maria Pennuto
{"title":"Spinal and bulbar muscular atrophy: From molecular pathogenesis to pharmacological intervention targeting skeletal muscle","authors":"Caterina Marchioretti , Roberta Andreotti , Emanuela Zuccaro , Andrew P. Lieberman , Manuela Basso , Maria Pennuto","doi":"10.1016/j.coph.2023.102394","DOIUrl":"10.1016/j.coph.2023.102394","url":null,"abstract":"<div><p>The clinical characteristics of SBMA, also known as Kennedy's disease (OMIM 313200), were initially documented by Dr. H Kawahara in the 18th century and a hundred years later by Dr. W. Kennedy. SBMA is a neuromuscular disease caused by expansions of a CAG microsatellite tandem repeat in exon 1 of the androgen receptor (<em>AR</em>) gene located on the X chromosome. These expansions result in the production of AR with an aberrantly expanded polyglutamine (polyQ) tract. In this review, we explore recent advancements in the significance of gene expression changes in skeletal muscle and discuss how pharmacological interventions targeting this aspect of disease pathogenesis can potentially be translated into therapies for SBMA patients.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"71 ","pages":"Article 102394"},"PeriodicalIF":4.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9909288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}