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JCI Insight Jun 2023Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for...
Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.
Topics: Rats; Mice; Male; Female; Animals; Glucagon-Like Peptide 1; Alcohol Drinking; Alcoholism; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 37192005
DOI: 10.1172/jci.insight.170671 -
Nature Metabolism Feb 2024Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1... (Randomized Controlled Trial)
Randomized Controlled Trial
Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R). AMG 133 (maridebart cafraglutide) is a bispecific molecule engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. In a phase 1, randomized, double-blind, placebo-controlled clinical study in participants with obesity ( NCT04478708 ), AMG 133 had an acceptable safety and tolerability profile along with pronounced dose-dependent weight loss. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133.
Topics: Animals; Humans; Male; Mice; Glucagon-Like Peptide 1; Obesity; Peptides; Weight Loss; Glucagon-Like Peptide-1 Receptor
PubMed: 38316982
DOI: 10.1038/s42255-023-00966-w -
Discovery of ecnoglutide - A novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog.Molecular Metabolism Sep 2023Glucagon-like peptide (GLP)-1 is an incretin hormone that acts after food intake to stimulate insulin production, enhance satiety, and promote weight loss. Here we... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Glucagon-like peptide (GLP)-1 is an incretin hormone that acts after food intake to stimulate insulin production, enhance satiety, and promote weight loss. Here we describe the discovery and characterization of ecnoglutide (XW003), a novel GLP-1 analog.
METHODS
We engineered a series of GLP-1 peptide analogs with an alanine to valine substitution (Ala8Val) and a γGlu-2xAEEA linked C18 diacid fatty acid at various positions. Ecnoglutide was selected and characterized in GLP-1 receptor signaling assays in vitro, as well as in db/db mice and a diet induced obese (DIO) rat model. A Phase 1, double-blind, randomized, placebo-controlled, single (SAD) and multiple ascending dose (MAD) study was conducted to evaluate the safety, tolerability, and pharmacokinetics of subcutaneous ecnoglutide injection in healthy participants. SAD doses ranged from 0.03 to 1.0 mg; MAD doses ranged from 0.2 to 0.6 mg once weekly for 6 weeks (ClinicalTrials.gov Identifier: NCT04389775).
RESULTS
In vitro, ecnoglutide potently induced cAMP (EC = 0.018 nM) but not GLP-1 receptor internalization (EC > 10 μM), suggesting a desirable signaling bias. In rodent models, ecnoglutide significantly reduced blood glucose, promoted insulin induction, and led to more pronounced body weight reduction compared to semaglutide. In a Phase 1 trial, ecnoglutide was generally safe and well tolerated as a once-weekly injection for up to 6 weeks. Adverse events included decreased appetite, nausea, and headache. The half-life at steady state ranged from 124 to 138 h, supporting once-weekly dosing.
CONCLUSIONS
Ecnoglutide showed a favorable potency, pharmacokinetic, and tolerability profile, as well as a simplified manufacturing process. These results support the continued development of ecnoglutide for the treatment of type 2 diabetes and obesity.
Topics: Mice; Rats; Animals; Glucagon-Like Peptide 1; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Body Weight; Obesity; Weight Loss; Insulin
PubMed: 37364710
DOI: 10.1016/j.molmet.2023.101762 -
Gastroenterology & Hepatology Sep 2023Bile acid diarrhea (BAD) is characterized by increased frequency of bowel movements, looser stool consistency, urgency, and need for proximity to toilet facilities owing...
Bile acid diarrhea (BAD) is characterized by increased frequency of bowel movements, looser stool consistency, urgency, and need for proximity to toilet facilities owing to the severity of the diarrhea, when compared with or relative to irritable bowel syndrome with diarrhea. Consequently, BAD leads to decreased quality of life. The condition is often misdiagnosed as irritable bowel syndrome with diarrhea or functional diarrhea. Patients with BAD have accelerated colonic transit, increased intestinal or colonic mucosal permeability, and altered stool microbiome composition associated with reduced dehydroxylation of primary to secondary bile acids. The established diagnostic test, selenium-75 homocholic acid taurine retention, is not available in the United States. Therefore, 48-hour fecal bile acid excretion has been the gold standard for diagnosis. With recent validation of combined measurement of primary bile acids in a single, random stool in addition to fasting serum 7α-hydroxy-4-cholesten-3-one, a practical point-of-care diagnostic test will soon be available. Randomized controlled trials have documented superiority of colesevelam to placebo and, in a separate study, superiority of the glucagon-like peptide 1 agonist liraglutide compared with colesevelam. Novel experimental approaches for BAD include farnesoid X receptor agonists and fibroblast growth factor 19 analogs. This article updates information on the pathophysiology, mechanisms, manifestations, diagnosis, and treatment of BAD.
PubMed: 37771793
DOI: No ID Found -
Gut and Liver Mar 2024Current treatment of chronic hepatitis B virus (HBV) infection, pegylated interferon-α (pegIFN-α) and nucleos(t)ide analogue (NA), can suppress HBV replication,... (Review)
Review
Current treatment of chronic hepatitis B virus (HBV) infection, pegylated interferon-α (pegIFN-α) and nucleos(t)ide analogue (NA), can suppress HBV replication, reverse liver inflammation and fibrosis, and decrease risks of cirrhosis and hepatocellular carcinoma, but hepatitis B surface antigen (HBsAg) loss is rare. Functional HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy. This requires suppression of HBV replication and viral protein production as well as restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. In parallel, immune modulatory therapies to stimulate HBV-specific immune response and to remove immune blockade are being tested. Clinical trials of direct-acting antivirals alone or immune modulatory therapies alone have not been successful in achieving HBV cure. Recent combinations of direct-acting antivirals and immune modulatory therapies have shown promising results particularly with combinations that included pegIFN-α. These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.
PubMed: 38533651
DOI: 10.5009/gnl240023 -
Cancer Biology & Therapy Dec 2023Cholangiocarcinoma (CCA) is an aggressive biliary epithelial tumor with limited therapeutic options and poor prognosis. Curcumin is a promising active natural compound...
Cholangiocarcinoma (CCA) is an aggressive biliary epithelial tumor with limited therapeutic options and poor prognosis. Curcumin is a promising active natural compound with several anti-cancer properties, though its clinical uses remain hindered due to its poor bioavailability. We recently synthesized curcumin analogs with multifunctional pharmacological and bioactivities with enhanced bioavailability. Among these novel curcumin analogs, WZ26 is a representative molecule. However, the anti-tumor effect of WZ26 against CCA is unclear. In this study, we evaluated the anti-tumor effect of WZ26 in both CCA cells and CCA xenograft mouse model. The underlying molecular anti-cancer mechanism of WZ26 was also studied. Our results show that WZ26 significantly inhibited cell growth and induced mitochondrial apoptosis in CCA cell lines, leading to significant inhibition of tumor growth in xenograft tumor mouse model. Treatment of WZ26 increased reactive oxygen species (ROS) generation, subsequently decreased mitochondrial membrane potential and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby inducing G2/M cell cycle arrest and cell apoptosis. Pretreatment of N-acetyl cysteine (NAC), an antioxidant agent, could fully reverse the WZ26-induced ROS-mediated changes in CCA cells. Our findings provide experimental evidence that curcumin analog WZ26 could be a potential candidate against CCA via enhancing ROS induction and inhibition of STAT3 activation.
Topics: Humans; Animals; Mice; Curcumin; Antineoplastic Agents; Reactive Oxygen Species; STAT3 Transcription Factor; Cell Line, Tumor; Cell Death; Apoptosis; Cholangiocarcinoma; Cell Proliferation; G2 Phase Cell Cycle Checkpoints; Bile Ducts, Intrahepatic; Bile Duct Neoplasms
PubMed: 36647192
DOI: 10.1080/15384047.2022.2162807 -
ACS Chemical Neuroscience Jan 2024Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor...
Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT) but differ in their 5-HT-mediated effects . In particular, psilocin produces centrally mediated psychedelic effects , whereas norpsilocin, differing only by the loss of an -methyl group, is devoid of psychedelic-like effects. These observations suggest that the secondary methylamine group in norpsilocin impacts its central nervous system (CNS) bioavailability but not its receptor pharmacodynamics. To test this hypothesis, eight norpsilocin derivatives were synthesized with varied secondary alkyl-, allyl-, and benzylamine groups, primarily aiming to increase their lipophilicity and brain permeability. Structure-activity relationships for the norpsilocin analogues were evaluated using the mouse head-twitch response (HTR) as a proxy for CNS-mediated psychedelic-like effects. HTR studies revealed that extending the -methyl group of norpsilocin by a single methyl group, to give the corresponding secondary -ethyl analogue (4-HO-NET), was sufficient to produce psilocin-like activity (median effective dose or ED = 1.4 mg/kg). Notably, -allyl, -propyl, -isopropyl, and -benzyl derivatives also induced psilocin-like HTR activity (ED = 1.1-3.2 mg/kg), with variable maximum effects (26-77 total HTR events). By contrast, adding bulkier -butyl or cyclohexyl groups in the same position did not elicit psilocin-like HTRs. Pharmacological assessments of the tryptamine series demonstrated interactions with multiple serotonin receptor subtypes, including 5-HT, and other CNS signaling proteins (e.g., sigma receptors). Overall, our data highlight key structural requirements for CNS-mediated psychedelic-like effects of norpsilocin analogues.
Topics: Mice; Animals; Hallucinogens; Serotonin; Receptors, Serotonin; Brain; Receptor, Serotonin, 5-HT2A
PubMed: 38189238
DOI: 10.1021/acschemneuro.3c00610 -
Cureus Oct 2023Obesity is a major public health concern linked to health risks such as hypertension, hyperlipidemia, type 2 diabetes mellitus (T2DM), stroke, metabolic syndrome,... (Review)
Review
Obesity is a major public health concern linked to health risks such as hypertension, hyperlipidemia, type 2 diabetes mellitus (T2DM), stroke, metabolic syndrome, asthma, and cancer. It is among the leading causes of morbidity and mortality worldwide caused by an unhealthy diet and lack of physical activity, but genetic or hormonal factors may also contribute. Over a third of adults in the United States are obese. Pharmacological agents have been designed to reduce weight gain caused by excessive calorie intake and low physical activity. They work by inhibiting the absorption of dietary fat or stimulating the secretion of satiety hormones. These drugs include lipase inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. However, the current weight-loss strategies do not effectively treat genetic-related diseases, such as generalized lipodystrophy, Bardet-Biedl syndrome, and proopiomelanocortin (POMC) deficiency. Emerging therapies for these gene mutations have been developed targeting leptin and melanocortin-4 receptors (MC4Rs), restoring the normal function of leptin or melanocortin-4 receptors regulating energy balance and appetite. Leptin analogs and MC4R agonists are novel therapies that target genetic or hormonal causes of obesity. This article provides a comprehensive review of anti-obesity medications (AOMs). In this review, we discuss the clinical trials, efficacy, United States FDA-approved indication, contraindications, and serious side effects of different classes of drugs, including lipase inhibitors, GLP-1 agonists, leptin analogs, and MC4R agonists.
PubMed: 37937009
DOI: 10.7759/cureus.46623 -
Proceedings of the National Academy of... Aug 2023Trehalose plays a crucial role in the survival and virulence of the deadly human pathogen (). The type I ATP-binding cassette (ABC) transporter LpqY-SugABC is the sole...
Trehalose plays a crucial role in the survival and virulence of the deadly human pathogen (). The type I ATP-binding cassette (ABC) transporter LpqY-SugABC is the sole pathway for trehalose to enter . The substrate-binding protein, LpqY, which forms a stable complex with the translocator SugABC, recognizes and captures trehalose and its analogues in the periplasmic space, but the precise molecular mechanism for this process is still not well understood. This study reports a 3.02-Å cryoelectron microscopy structure of trehalose-bound LpqY-SugABC in the pretranslocation state, a crystal structure of LpqY in a closed form with trehalose bound and five crystal structures of LpqY in complex with different trehalose analogues. These structures, accompanied by substrate-stimulated ATPase activity data, reveal how LpqY recognizes and binds trehalose and its analogues, and highlight the flexibility in the substrate binding pocket of LpqY. These data provide critical insights into the design of trehalose analogues that could serve as potential molecular probe tools or as anti-TB drugs.
Topics: Humans; Cryoelectron Microscopy; Mycobacterium tuberculosis; Trehalose; ATP-Binding Cassette Transporters; Molecular Probes
PubMed: 37603751
DOI: 10.1073/pnas.2307625120 -
Neural Regeneration Research Sep 2024Somatostatin, a naturally produced neuroprotective peptide, depresses excitatory neurotransmission and exerts anti-proliferative and anti-inflammatory effects on the...
Somatostatin, a naturally produced neuroprotective peptide, depresses excitatory neurotransmission and exerts anti-proliferative and anti-inflammatory effects on the retina. In this review, we summarize the progress of somatostatin treatment of diabetic retinopathy through analysis of relevant studies published from February 2019 to February 2023 extracted from the PubMed and Google Scholar databases. Insufficient neuroprotection, which occurs as a consequence of declined expression or dysregulation of retinal somatostatin in the very early stages of diabetic retinopathy, triggers retinal neurovascular unit impairment and microvascular damage. Somatostatin replacement is a promising treatment for retinal neurodegeneration in diabetic retinopathy. Numerous pre-clinical and clinical trials of somatostatin analog treatment for early diabetic retinopathy have been initiated. In one such trial (EUROCONDOR), topical administration of somatostatin was found to exert neuroprotective effects in patients with pre-existing retinal neurodysfunction, but had no impact on the onset of diabetic retinopathy. Overall, we concluded that somatostatin restoration may be especially beneficial for the growing population of patients with early-stage retinopathy. In order to achieve early prevention of diabetic retinopathy initiation, and thereby salvage visual function before the appearance of moderate non-proliferative diabetic retinopathy, several issues need to be addressed. These include the needs to: a) update and standardize the retinal screening scheme to incorporate the detection of early neurodegeneration, b) identify patient subgroups who would benefit from somatostatin analog supplementation, c) elucidate the interactions of somatostatin, particularly exogenously-delivered somatostatin analogs, with other retinal peptides in the context of hyperglycemia, and d) design safe, feasible, low cost, and effective administration routes.
PubMed: 38227526
DOI: 10.4103/1673-5374.390955