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Medicinal Research Reviews Jul 2024Adjuvants are of critical value in vaccine development as they act on enhancing immunogenicity of antigen and inducing long-lasting immunity. However, there are only a... (Review)
Review
Adjuvants are of critical value in vaccine development as they act on enhancing immunogenicity of antigen and inducing long-lasting immunity. However, there are only a few adjuvants that have been approved for clinical use, which highlights the need for exploring and developing new adjuvants to meet the growing demand for vaccination. Recently, emerging evidence demonstrates that the cGAS-STING pathway orchestrates innate and adaptive immunity by generating type I interferon responses. Many cGAS-STING pathway agonists have been developed and tested in preclinical research for the treatment of cancer or infectious diseases with promising results. As adjuvants, cGAS-STING agonists have demonstrated their potential to activate robust defense immunity in various diseases, including COVID-19 infection. This review summarized the current developments in the field of cGAS-STING agonists with a special focus on the latest applications of cGAS-STING agonists as adjuvants in vaccination. Potential challenges were also discussed in the hope of sparking future research interests to further the development of cGAS-STING as vaccine adjuvants.
Topics: Humans; Nucleotidyltransferases; Membrane Proteins; Animals; Adjuvants, Vaccine; Signal Transduction; COVID-19; SARS-CoV-2; Immunity, Innate; Adjuvants, Immunologic; COVID-19 Vaccines
PubMed: 38323921
DOI: 10.1002/med.22016 -
Biochemical Pharmacology Oct 2023Development of specific therapies that target and accelerate diabetic wound repair is an urgent need to alleviate pain and suffering and the huge socioeconomic burden of...
Development of specific therapies that target and accelerate diabetic wound repair is an urgent need to alleviate pain and suffering and the huge socioeconomic burden of this debilitating disease. C-X-C Motif Chemokine Ligand 12 (CXCL12) also know an stromal cell-derived factor 1α (SDF-1α) is a chemokine that binds the CXC chemokine receptor type 4 (CXCR4) and activates downstream signaling resulting in recruitment of hematopoietic cells to locations of tissue injury and promotes tissue repair. In diabetes, low expression of CXCL12 correlates with impaired wound healing. Activation of CXCR4 receptor signaling with agonists or positive allosteric modulators (PAMs) provides a potential for small molecule therapeutic discovery and development. We recently reported high throughput screening and identification of the CXCR4 partial agonist UCUF-728, characterization of in vitro activity and reduced wound closure time in diabetic mice at 100 μM as a proof-of-concept study. We report here, the discovery of a second chemical scaffold demonstrating increased agonist potency and represented by thiadiazine derivative, UCUF-965. UCUF-965 is a potent partial agonist of β-arrestin recruitment in CXCR4 receptor overexpressing cell line. Furthermore, UCUF-965 potentiates the CXCL12 maximal response in cAMP signaling pathway, activates CXCL12 stimulated migration in lymphoblast cells and modulates the levels of specific microRNA involved in the complex wound repair process, specifically in mouse fibroblasts. Our results indicate that UCUF-965 acts as a PAM agonist of the CXCR4 receptor. Furthermore, UCUF-965 enhanced angiogenesis markers and reduced wound healing time by 36% at 10.0 μM in diabetic mice models compared to untreated control.
Topics: Animals; Mice; Cell Movement; Chemokine CXCL12; Diabetes Mellitus, Experimental; Hematopoietic Stem Cells; Receptors, CXCR4; Signal Transduction; Wound Healing
PubMed: 37634595
DOI: 10.1016/j.bcp.2023.115764 -
Science Advances Nov 2023Adiponectin receptors, AdipoR1 and AdipoR2 are promising targets for the prevention and treatment of metabolic diseases. In this study, we aimed to establish agonistic...
Adiponectin receptors, AdipoR1 and AdipoR2 are promising targets for the prevention and treatment of metabolic diseases. In this study, we aimed to establish agonistic antibodies against AdipoR1 and AdipoR2 with a long enough half-life to provide a means of improving poor medication adherence associated with preclinical small-molecule AdipoR agonists or existing antidiabetic drugs. Monoclonal antibodies were obtained by immunizing AdipoR knockout mice with human AdipoR-expressing cells. Of the antibodies shown to bind to both, an agonist antibody was obtained, which exhibited adenosine 5'-monophosphate-activated protein kinase-activating properties such as adiponectin and was named AdipoR-activating monoclonal antibody (AdipoRaMab). AdipoRaMab ameliorated glucose intolerance in high-fat diet-fed mice, which was not observed in AdipoR1·AdipoR2 double knockout mice. AdipoRaMab exhibited anti-inflammatory and antifibrotic effects in the nonalcoholic steatohepatitis (NASH) model, indicating its therapeutic potential in diabetes and in NASH. In addition, the results of this study indicated that AdipoRaMab may exert therapeutic effects even in a once-monthly dosing regimen through its humanization.
Topics: Humans; Mice; Animals; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Antibodies, Monoclonal; Glucose Intolerance; Mice, Knockout
PubMed: 37948516
DOI: 10.1126/sciadv.adg4216 -
British Journal of Pharmacology Apr 2024The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available... (Review)
Review
The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and glucagon. There are several approved single or dual incretin agonists which can be administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and other experimental dual or triple incretin agonists. Analogues of amylin, peptide YY and oxyntomodulin, as well as the combination of a GLP1R agonist and GIPR antagonist also are in development. Oral semaglutide (administered daily) is approved for type 2 diabetes mellitus and is on track for regulatory review for obesity. The review includes specifically perspectives on the effects of these mechanisms and pharmacological agents on gastric emptying, which contribute to satiation and weight loss, in addition to the established evidence on effects on central mechanisms controlling appetite. In the future, it is anticipated that small molecule GLP-1 receptor agonists (e.g., oral danuglipron) will be developed for treating obesity. These pharmacological agents are having significant impact on glycaemic control and obesity and on their co-morbidities.
Topics: Humans; Incretins; Diabetes Mellitus, Type 2; Obesity; Glucagon-Like Peptide 1; Gastric Inhibitory Polypeptide; Hypoglycemic Agents; Glucagon-Like Peptide-1 Receptor
PubMed: 37917871
DOI: 10.1111/bph.16278 -
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 -
Revue Medicale Suisse Mar 2024The management of obesity is changing dramatically with the emergence of new drug treatments. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for this... (Review)
Review
The management of obesity is changing dramatically with the emergence of new drug treatments. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for this indication in Switzerland, and approval is currently being sought for a GLP-1 and glucose-dependent insulinotropic polypetide (GIP) co-agonist. Reimbursement conditions are restrictive, and patients are given only one opportunity to achieve the weight loss required for continued reimbursement. The popularity of these treatments has led to worldwide stock-outs for several months now, and it is essential that prescribers respect the indications so as not to prejudice obese patients. This article provides a review of the treatments available and the conditions under which they are reimbursed, as well as those that should be reimbursed soon.
Topics: Humans; Blood Glucose; Gastric Inhibitory Polypeptide; Obesity; Glucagon-Like Peptide 1; Glucose; Glucagon-Like Peptide-1 Receptor; Diabetes Mellitus, Type 2
PubMed: 38506456
DOI: 10.53738/REVMED.2024.20.866.570 -
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 -
Bioorganic & Medicinal Chemistry Letters Jan 2024Screening a library of >100,000 compounds identified the substituted tetrazole compound 1 as a selective TRPML1 agonist. Both enantiomers of compound 1 were separated...
Screening a library of >100,000 compounds identified the substituted tetrazole compound 1 as a selective TRPML1 agonist. Both enantiomers of compound 1 were separated and profiled in vitro and in vivo. Their selectivity, ready availability and CNS penetration should enable them to serve as the tool compounds of choice in future TRPML1 channel activation studies. SAR studies on conformationally locked macrocyclic analogs further improved the TRPML1 agonist potency while retaining the selectivity.
Topics: Transient Receptor Potential Channels; Structure-Activity Relationship; Tetrazoles
PubMed: 38141860
DOI: 10.1016/j.bmcl.2023.129595 -
The Annals of Pharmacotherapy Apr 2024This is a narrative review of incretin analogs and their effect on weight management in adult without diabetes. (Review)
Review
OBJECTIVE
This is a narrative review of incretin analogs and their effect on weight management in adult without diabetes.
DATA SOURCES
Randomized controlled trials were identified by English language. PubMed/MEDLINE, Scopus, and Embase databases were searched from inception through June 2023 to identify all pertinent trials reporting outcomes on efficacy and safety search using the terms: tirzepatide, semaglutide, liraglutide, and obesity.
STUDY SELECTION AND DATA EXTRACTION
Selected studies were included if the study population was composed of adults without diabetes being treated by glucagon-like peptide 1 (GLP-1) receptor agonists or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agonists for weight management, and weight loss was assessed as a primary outcome.
DATA SYNTHESIS
Fifteen studies involving 3 pharmacotherapies (liraglutide, semaglutide, and tirzepatide) were identified. Efficacy data supporting the use of these agents for weight management were promising when compared to placebo and/or other behavioral therapies. Percent weight loss ranged from 5.7% to 11.8%, 14.9% to 17.4%, and 15% to 20.9% for liraglutide, semaglutide, and tirzepatide, respectively. Safety data were relatively similar across all trials and identified gastrointestinal adverse effects as most common.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Glucagon-like peptide 1 agonists are preferred for overweight or obese patients by the American Gastroenterological Association. Future guidelines may address tirzepatides' place in therapy as new evidence comes forth. Providers should consider patient-specific factors such as cost, adverse effects, drug interactions, and comorbidities when prescribing these agents and provide education regarding the need for concurrent diet and exercise modifications.
CONCLUSIONS
All incretin analogs in this review are superior to placebo when used for weight management in adults without diabetes.
Topics: Adult; Humans; Incretins; Liraglutide; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Obesity; Weight Loss; Glucagon-Like Peptide-1 Receptor
PubMed: 37522468
DOI: 10.1177/10600280231190089 -
Journal of Cellular Biochemistry Aug 2023As a master transcription factor, c-Myc plays an important role in promoting tumor immune escape. In addition, PPARγ (peroxisome proliferator-activated receptor γ)...
As a master transcription factor, c-Myc plays an important role in promoting tumor immune escape. In addition, PPARγ (peroxisome proliferator-activated receptor γ) regulates cell metabolism, inflammation, and tumor progression, while the effect of PPARγ on c-Myc-mediated tumor immune escape is still unclear. Here we found that cells treated with PPARγ agonist pioglitazone (PIOG) reduced c-Myc protein expression in a PPARγ-dependent manner. qPCR analysis showed that PIOG had no significant effect on c-Myc gene levels. Further analysis showed that PIOG decreased c-Myc protein half-life. Moreover, PIOG increased the binding of c-Myc to PPARγ, and induced c-Myc ubiquitination and degradation. Importantly, c-Myc increased PD-L1 and CD47 immune checkpoint protein expression and promoted tumor immune escape, while PIOG inhibited this event. These findings suggest that PPARγ agonist inhibited c-Myc-mediated tumor immune escape by inducing its ubiquitination and degradation.
Topics: Humans; Colorectal Neoplasms; Gene Expression Regulation; Pioglitazone; PPAR gamma; Thiazolidinediones; Tumor Escape; Proto-Oncogene Proteins c-myc
PubMed: 37393598
DOI: 10.1002/jcb.30437