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Endocrinology and Metabolism (Seoul,... Feb 2021Glucagon-like peptide-1 (GLP-1) receptor agonists are efficacious glucose-lowering medications with salient benefits for body weight and cardiovascular events. This... (Review)
Review
Glucagon-like peptide-1 (GLP-1) receptor agonists are efficacious glucose-lowering medications with salient benefits for body weight and cardiovascular events. This class of medications is now recommended as the top priority for patients with established cardiovascular disease or indicators of high risk. Until the advent of oral semaglutide, however, GLP-1 receptor agonists were available only in the form of subcutaneous injections. Aversion to needles, discomfort with self-injection, or skin problems at the injection site are commonly voiced problems in people with diabetes, and thus, attempts for non-invasive delivery strategies have continued. Herein, we review the evolution of GLP-1 therapy from its discovery and the development of currently approved drugs to the unprecedented endeavor to administer GLP-1 receptor agonists via the oral route. We focus on the pharmacokinetic and pharmacodynamic properties of the recently approved oral GLP-1 receptor agonist, oral semaglutide. Small molecule oral GLP-1 receptor agonists are currently in development, and we introduce how these chemicals have addressed the challenge posed by interactions with the large extracellular ligand binding domain of the GLP-1 receptor. We specifically discuss the structure and pharmacological properties of TT-OAD2, LY3502970, and PF-06882961, and envision an era where more patients could benefit from oral GLP-1 receptor agonist therapy.
Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Isoquinolines; Phenylalanine; Pyridines
PubMed: 33677922
DOI: 10.3803/EnM.2021.102 -
Journal of Neuroinflammation May 2023TNF signaling is an essential regulator of cellular homeostasis. Through its two receptors TNFR1 and TNFR2, soluble versus membrane-bound TNF enable cell death or...
TNF signaling is an essential regulator of cellular homeostasis. Through its two receptors TNFR1 and TNFR2, soluble versus membrane-bound TNF enable cell death or survival in a variety of cell types. TNF-TNFRs signaling orchestrates important biological functions such as inflammation, neuronal activity as well as tissue de- and regeneration. TNF-TNFRs signaling is a therapeutic target for neurodegenerative diseases such as multiple sclerosis (MS) and Alzheimer's disease (AD), but animal and clinical studies yielded conflicting findings. Here, we ask whether a sequential modulation of TNFR1 and TNFR2 signaling is beneficial in experimental autoimmune encephalomyelitis (EAE), an experimental mouse model that recapitulates inflammatory and demyelinating aspects of MS. To this end, human TNFR1 antagonist and TNFR2 agonist were administered peripherally at different stages of disease development in TNFR-humanized mice. We found that stimulating TNFR2 before onset of symptoms leads to improved response to anti-TNFR1 therapeutic treatment. This sequential treatment was more effective in decreasing paralysis symptoms and demyelination, when compared to single treatments. Interestingly, the frequency of the different immune cell subsets is unaffected by TNFR modulation. Nevertheless, treatment with only a TNFR1 antagonist increases T-cell infiltration in the central nervous system (CNS) and B-cell cuffing at the perivascular sites, whereas a TNFR2 agonist promotes Treg CNS accumulation. Our findings highlight the complicated nature of TNF signaling which requires a timely balance of selective activation and inhibition of TNFRs in order to exert therapeutic effects in the context of CNS autoimmunity.
Topics: Animals; Humans; Mice; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Multiple Sclerosis; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Tumor Necrosis Factor-alpha
PubMed: 37138340
DOI: 10.1186/s12974-023-02785-y -
Frontiers in Immunology 2023TNFR2 agonists have been investigated as potential therapies for inflammatory diseases due to their ability to activate and expand immunosuppressive CD4+Foxp3+ Treg... (Review)
Review
TNFR2 agonists have been investigated as potential therapies for inflammatory diseases due to their ability to activate and expand immunosuppressive CD4+Foxp3+ Treg cells and myeloid-derived suppressor cells (MDSCs). Despite TNFR2 being predominantly expressed in Treg cells at high levels, activated effector T cells also exhibit a certain degree of TNFR2 expression. Consequently, the role of TNFR2 signaling in coordinating immune or inflammatory responses under different pathological conditions is complex. In this review article, we analyze possible factors that may determine the therapeutic outcomes of TNFR2 agonism, including the levels of TNFR2 expression on different cell types, the biological properties of TNFR2 agonists, and disease status. Based on recent progress in the understanding of TNFR2 biology and the study of TNFR2 agonistic agents, we discuss the future direction of developing TNFR2 agonists as a therapeutic agents.
Topics: Immunosuppressive Agents; Myeloid-Derived Suppressor Cells; Receptors, Tumor Necrosis Factor, Type II; Signal Transduction; T-Lymphocytes, Regulatory
PubMed: 37662935
DOI: 10.3389/fimmu.2023.1209188 -
Advanced Drug Delivery Reviews Dec 2021Adjuvant is an essential component in subunit vaccines. Many agonists of pathogen recognition receptors have been developed as potent adjuvants to optimize the... (Review)
Review
Adjuvant is an essential component in subunit vaccines. Many agonists of pathogen recognition receptors have been developed as potent adjuvants to optimize the immunogenicity and efficacy of vaccines. Recently discovered cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has attracted much attention as it is a key mediator for modulating immune responses. Vaccines adjuvanted with STING agonists are found to mediate a robust immune defense against infections and cancer. In this review, we first discuss the mechanisms of STING agonists in the context of vaccination. Next, we present recent progress in novel STING agonist discovery and the delivery strategies. We next highlight recent work in optimizing the efficacy while minimizing toxicity of STING agonist-assisted subunit vaccines for protection against infectious diseases or treatment of cancer. Finally, we share our perspectives of current issues and future directions in further developing STING agonists for adjuvanting subunit vaccines.
Topics: Adjuvants, Immunologic; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dendritic Cells; Humans; Immunity, Humoral; Membrane Proteins; Nucleotidyltransferases; Vaccines, Subunit
PubMed: 34756942
DOI: 10.1016/j.addr.2021.114020 -
The World Allergy Organization Journal May 2020The current COVID-19 pandemic has changed many medical practices in order to provide additional protection to both our patients and healthcare providers. In many cases... (Review)
Review
BACKGROUND
The current COVID-19 pandemic has changed many medical practices in order to provide additional protection to both our patients and healthcare providers. In many cases this includes seeing patients through electronic means such as telehealth or telephone rather than seeing them in person. Asthma exacerbations cannot always be treated in this way.
PROBLEM
Current emergency unit asthma guidelines recommend bronchodilators be administered by metered dose inhaler (MDI) and spacer for mild-moderate asthma and include it as a choice even in severe asthma, but many emergency units continue to prefer nebulised therapy for patients who urgently require beta-agonists. The utilization of nebulised therapy potentially increases the risk of aerosolization of the coronavirus. Since nosocomial transmission of respiratory pathogens is a major threat in the context of the SARS-CoV-2 pandemic, use of nebulised therapy is of even greater concern due to the potential increased risk of infection spread to nearby patients and healthcare workers.
PRACTICAL IMPLICATIONS
We propose a risk stratification plan that aims to avoid nebulised therapy, when possible, by providing an algorithm to help better delineate those who require nebulised therapy. Protocols that include strategies to allow flexibility in using MDIs rather than nebulisers in all but the most severe patients should help mitigate this risk of aerosolised infection transmission to patients and health care providers. Furthermore, expedient treatment of patients with high dose MDI therapy augmented with more rapid initiation of systemic therapy may help ensure patients are less likely to deteriorate to the stage where nebulisers are required.
PubMed: 32411315
DOI: 10.1016/j.waojou.2020.100125 -
The International Journal of... Sep 2023Trace amine-associated receptor-1 (TAAR1) agonists have been proposed as potential antipsychotics, with ulotaront and ralmitaront having reached clinical trials. While...
BACKGROUND
Trace amine-associated receptor-1 (TAAR1) agonists have been proposed as potential antipsychotics, with ulotaront and ralmitaront having reached clinical trials. While ulotaront demonstrated efficacy in a recent Phase II trial, a corresponding study studies of ralmitaront failed to show efficacy as a monotherapy or as an adjunct to atypical antipsychotics. In addition to TAAR1 agonism, ulotaront is a partial agonist at the serotonin 1A receptor (5-HT1AR). However, little is known about ralmitaront.
METHODS
We compared ulotaront and ralmitaront at TAAR1, 5-HT1AR, and dopamine D2 using luciferase complementation-based G protein recruitment, cAMP accumulation, and G protein-coupled inward rectifier potassium channel activation assays.
RESULTS
Ralmitaront showed lower efficacy at TAAR1 in G protein recruitment, cAMP accumulation, and GIRK activation assays. Moreover, ralmitaront lacked detectable activity at 5-HT1AR and dopamine D2.
CONCLUSIONS
Compared with ulotaront, ralmitaront shows lower efficacy and slower kinetics at TAAR1 and lacks efficacy at 5-HT1AR. These data may be relevant to understanding differences in clinical profiles of these 2 compounds.
Topics: Dopamine; Antipsychotic Agents; Receptors, G-Protein-Coupled; Pyrans
PubMed: 37549917
DOI: 10.1093/ijnp/pyad049 -
Journal of Experimental & Clinical... Jun 2023Osteosarcoma (OS) is the most common primary bone tumor in children and adolescent. Surgery and multidrug chemotherapy are the standard of treatment achieving 60-70% of...
BACKGROUND
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescent. Surgery and multidrug chemotherapy are the standard of treatment achieving 60-70% of event-free survival for localized disease at diagnosis. However, for metastatic disease, the prognosis is dismal. Exploiting immune system activation in the setting of such unfavorable mesenchymal tumors represents a new therapeutic challenge.
METHODS
In immune competent OS mouse models bearing two contralateral lesions, we tested the efficacy of intralesional administration of a TLR9 agonist against the treated and not treated contralateral lesion evaluating abscopal effect. Multiparametric flow cytometry was used to evaluate changes of the tumor immune microenviroment. Experiments in immune-deficient mice allowed the investigation of the role of adaptive T cells in TLR9 agonist effects, while T cell receptor sequencing was used to assess the expansion of specific T cell clones.
RESULTS
TLR9 agonist strongly impaired the growth of locally-treated tumors and its therapeutic effect also extended to the contralateral, untreated lesion. Multiparametric flow cytometry showed conspicuous changes in the immune landscape of the OS immune microenvironment upon TLR9 engagement, involving a reduction in M2-like macrophages, paralleled by increased infiltration of dendritic cells and activated CD8 T cells in both lesions. Remarkably, CD8 T cells were needed for the induction of the abscopal effect, whereas they were not strictly necessary for halting the growth of the treated lesion. T cell receptor (TCR) sequencing of tumor infiltrating CD8 T cells showed the expansion of specific TCR clones in the treated tumors and, remarkably, their selected representation in the contralateral untreated lesions, providing the first evidence of the rewiring of tumor-associated T cell clonal architectures.
CONCLUSIONS
Overall these data indicate that the TLR9 agonist acts as an in situ anti-tumor vaccine, activating an innate immune response sufficient to suppress local tumor growth while inducing a systemic adaptive immunity with selective expansion of CD8 T cell clones, which are needed for the abscopal effect.
Topics: Animals; Mice; Toll-Like Receptor 9; CD8-Positive T-Lymphocytes; Adaptive Immunity; Osteosarcoma; Bone Neoplasms; Tumor Microenvironment
PubMed: 37365634
DOI: 10.1186/s13046-023-02731-z -
Nature Communications Jan 2023The M2 muscarinic receptor (M2R) is a prototypical G-protein-coupled receptor (GPCR) that serves as a model system for understanding GPCR regulation by both orthosteric...
The M2 muscarinic receptor (M2R) is a prototypical G-protein-coupled receptor (GPCR) that serves as a model system for understanding GPCR regulation by both orthosteric and allosteric ligands. Here, we investigate the mechanisms governing M2R signaling versatility using cryo-electron microscopy (cryo-EM) and NMR spectroscopy, focusing on the physiological agonist acetylcholine and a supra-physiological agonist iperoxo, as well as a positive allosteric modulator LY2119620. These studies reveal that acetylcholine stabilizes a more heterogeneous M2R-G-protein complex than iperoxo, where two conformers with distinctive G-protein orientations were determined. We find that LY2119620 increases the affinity for both agonists, but differentially modulates agonists efficacy in G-protein and β-arrestin pathways. Structural and spectroscopic analysis suggest that LY211620 stabilizes distinct intracellular conformational ensembles from agonist-bound M2R, which may enhance β-arrestin recruitment while impairing G-protein activation. These results highlight the role of conformational dynamics in the complex signaling behavior of GPCRs, and could facilitate design of better drugs.
Topics: Acetylcholine; Cryoelectron Microscopy; Allosteric Regulation; Receptors, Muscarinic; Receptor, Muscarinic M2; Receptors, G-Protein-Coupled; GTP-Binding Proteins; Ligands; beta-Arrestins
PubMed: 36690613
DOI: 10.1038/s41467-022-35726-z -
Molecules (Basel, Switzerland) Oct 2021Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated...
Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are selective δ opioid receptor agonists, and their p.o. administration exhibits antinociceptive effects. Although the potency and effect of rubiscolins as G-protein-biased molecules are partially confirmed, their in vitro profiles remain unclear. We, therefore, evaluated the properties of rubiscolins, in detail, through several analyses, including the CellKey assay, cADDis cAMP assay, and PathHunter β-arrestin recruitment assay, using cells stably expressing µ, δ, κ, or µ/δ heteromer opioid receptors. In the CellKey assay, rubiscolins showed selective agonistic effects for δ opioid receptor and little agonistic or antagonistic effects for µ and κ opioid receptors. Furthermore, rubiscolins were found to be G-protein-biased δ opioid receptor agonists based on the results obtained in cADDis cAMP and PathHunter β-arrestin recruitment assays. Finally, we found, for the first time, that they are also partially agonistic for the µ/δ dimers. In conclusion, rubiscolins could serve as attractive seeds, as δ opioid receptor-specific agonists, for the development of novel opioid analgesics with reduced side effects.
Topics: GTP-Binding Proteins; Gene Expression Regulation; HEK293 Cells; Humans; Molecular Structure; Opioid Peptides; Peptide Fragments; Receptors, Opioid, delta; Receptors, Opioid, mu; Ribulose-Bisphosphate Carboxylase; Signal Transduction; Spinacia oleracea; beta-Arrestins
PubMed: 34641621
DOI: 10.3390/molecules26196079 -
Reviews in the Neurosciences Aug 2020In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal... (Review)
Review
In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal and mesolimbic system was systematically assessed after pharmacological challenge with GABAA receptor (R) and and N-methyl d-aspartate (NMDA)R agonists and antagonists. In these studies, [123I]iodobenzamide binding to the D2/3R was mesured in nucleus accumbens (NAC), caudateputamen (CP), substantia nigra/ventral tegmental area (SN/VTA), frontal (FC), motor (MC) and parietal cortex (PC) as well as anterior (aHIPP) and posterior hippocampus (pHIPP) with small animal SPECT in baseline and after injection of either the GABAAR agonist muscimol (1 mg/kg), the GABAAR antagonist bicuculline (1 mg/kg), the NMDAR agonist d-cycloserine (20 mg/kg) or the NMDAR antagonist amantadine (40 mg/kg). Muscimol reduced D2/3R binding in NAC, CP, SN/VTA, THAL and pHIPP, while, after amantadine, decreases were confined to NAC, CP and THAL. In contrast, d-cycloserine elevated D2/3R binding in NAC, SN/VTA, THAL, frontal cortex, motor cortex, PC, aHIPP and pHIPP, while, after bicuculline, increases were confined to CP and THAL. Taken together, similar actions on regional dopamine levels were exterted by the GABAAR agonist and the NMDAR antagonist on the one side and by the GABAAR antagonist and the NMDAR agonist on the other, with agonistic action, however, affecting more brain regions. Thereby, network analysis suggests different roles of GABAARs and NMDARs in the mediation of nigrostriatal, nigrothalamocortical and mesolimbocortical dopamine function.
Topics: Animals; Bicuculline; Dopamine; Humans; Muscimol; Nucleus Accumbens; Rats; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate
PubMed: 32619197
DOI: 10.1515/revneuro-2019-0112