Current Opinion in Pharmacology

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...

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...

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...

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.

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 (AR) 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...

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...

Increasing evidence demonstrated the relevance of adenosine system in the onset and development of cardiovascular diseases, such as hypertension, myocardial infarct, ischemia, hypertension, heart failure, and atherosclerosis. In this regard, intense research efforts are being focused on the characterization of the pathophysiological significance of adenosine, acting at its membrane receptors named A1 , A2A , A2B , and A3 receptors, in cardiovascular diseases. The present review article provides an integrated and comprehensive overview about current clinical and pre-clinical evidence about the role of adenosine in the pathophysiology of cardiovascular diseases...

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 G proteins (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...

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...

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DNA repair targeted therapeutics is a promising precision medicine strategy in cancer. The development and clinical use of PARP inhibitors has transformed lives for many patients with BRCA germline deficient breast and ovarian cancer as well as platinum sensitive epithelial ovarian cancers. However, lessons learnt from the clinical use of PARP inhibitors also confirm that not all patients respond either due to intrinsic or acquired resistance. Therefore, the search for additional synthetic lethality approaches is an active area of translational and clinical research...

Purinergic signaling is a key molecular pathway in the maintenance of bone health and regeneration. P1 receptor signaling, which is activated by extracellular adenosine, has emerged as a key metabolic pathway that regulates bone tissue formation, function, and homeostasis. Extracellular adenosine is mainly produced by ectonucleotidases, and alterations in the function of these enzymes or compromised adenosine generation can result in bone disorders, such as osteoporosis and impaired fracture healing. This mini review discusses the key role played by adenosine in bone health and how its alterations contribute to bone diseases, as well as potential therapeutic applications of exogenous adenosine to combat bone diseases like osteoporosis and injury...

The alternative lengthening of telomeres (ALT) pathway is a telomere elongation mechanism found in a small but often aggressive subset of cancers. Dependent on break-induced replication, telomere extension in ALT-positive cells relies on a baseline level of DNA replication stress to initiate elongation events. This results in an elevated level of DNA damage and presents a possible vulnerability to be exploited in the development of ALT-targeted cancer therapies. Currently, there are no treatment options that target the ALT mechanism or that are specific for ALT-positive tumors...

19 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 (19 F) NMR provides a highly sensitive spectroscopic window into the conformational ensemble, generally permitting the direct quantification of resolvable states. Moreover, straightforward T1 - and T2 -based relaxation experiments allow for the study of fluctuations within a given state and exchange between states, on timescales spanning nanoseconds to seconds...

Pannexin channels play fundamental roles in regulating inflammation and have been implicated in many diseases including hypertension, stroke, and neuropathic pain. Thus, the ability to pharmacologically block these channels is a vital component of several therapeutic approaches. Pharmacologic interrogation of model systems also provides a means to discover new roles for pannexins in cell physiology. Here, we review the state of the art for agents that can be used to block pannexin channels, with a focus on chemical pharmaceuticals and peptide mimetics that act on pannexin 1...

Human Immunodeficiency Virus Type 1 (HIV-1) causes a chronic, incurable infection associated with chronic inflammation despite virologic suppression on antiretroviral therapy (ART). This chronic inflammation underlies significant comorbidities, including cardiovascular disease, neurocognition decline, and malignancies. The mechanisms of chronic inflammation have been attributed, in part, to the role of extracellular ATP and P2X-type purinergic receptors that sense damaged or dying cells and undergo signaling responses to activate inflammation and immunomodulation...

Peptides form the largest group of ligands that modulate the activity of more than 120 different GPCRs. Among which linear disordered peptide ligands usually undergo significant conformational changes upon binding that is essential for receptor recognition and activation. Conformational selection and induced fit are the extreme mechanisms of coupled folding and binding that can be distinguished by analysis of binding pathways by methods that include NMR. However, the large size of GPCRs in membrane-mimetic environments limits NMR applications...

Primary liver cancer is the third most common cause of cancer-related death worldwide and hepatocellular carcinoma (HCC) accounts for approximately 80%-90% of all primary liver malignancies. Until 2007, there was no effective treatment option available for patients diagnosed with advanced HCC, whereas today, both multireceptor tyrosine kinase inhibitors as well as immunotherapy combinations have entered clinical practice. The choice between the different options is a tailor-made decision to match the efficacy and safety data of the clinical trials with the specific patient and disease profile...

Substantial efforts have been made to understand the immune response during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, in order to identify and characterize risk factors, immune mechanisms responsible for the induction of tissue injury and potential therapeutic targets. Purinergic signaling pathway has shown to modulate the inflammatory processes in the course of several infectious diseases, but its role in the coronavirus disease 2019 (COVID-19) has not been clearly defined. Inflammation is usually associated to the release of ATP from different cell types, starting a cascade of events through the activation of a set of different purinergic receptors...

Duodenal micro-inflammation and microbial dysregulation are increasingly recognized to play an important role in functional dyspepsia (FD) pathophysiology, previously regarded as a purely functional disorder. With current therapeutic options contested through insufficient efficacy or unfavorable adverse effects profiles, novel treatments directed to duodenal alterations could result in superior symptom control in at least a subset of patients. Indeed, recent advances in FD research provided evidence for anti-inflammatory therapies to relieve gastroduodenal symptoms by reducing duodenal eosinophils or mast cells...