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Journal of Controlled Release :... Jun 2024Therapeutically manipulating the stimulator of interferon genes (STING) pathway has promising potential for enhancing antitumor immunity. Agonists of this pathway (STING...
Therapeutically manipulating the stimulator of interferon genes (STING) pathway has promising potential for enhancing antitumor immunity. Agonists of this pathway (STING agonists) are being evaluated in clinical trials. Loading the STING agonists into lipid nanoparticles (LNPs) increases their safety and efficacy. We previously developed STING agonists loaded LNPs consisting of the ionizable lipid YSK12-C4 (YSK12-LNPs), which showed significant antitumor effects. However, it is largely unclear how the in vivo fate of STING agonists loaded LNPs affects the antitumor immune responses. In this study, we compared the YSK12-LNPs with LNPs composed of DLin-MC3-DMA (MC3-LNPs) showing different in vivo fates. Biodistribution and flow cytometry analyses of mouse tissues revealed that the MC3-LNPs delivered higher amounts of STING agonists to the liver than the YSK12-LNPs. Additionally, significantly more liver leukocytes internalized the MC3-LNPs than the YSK12-LNPs. In contrast, the YSK12-LNPs delivered higher amounts of STING agonists to the liver leukocytes than the MC3-LNPs, leading to the effective induction of innate immunity and inflammation in the tumors. However, the antitumor effects in the B16-F10 lung metastasis and CT26 tumor models were comparable. Interestingly, flow cytometry analyses suggested that the YSK12-LNPs were more likely to activate natural killer cells and M1 macrophages, while the MC3-LNPs were more likely to activate CD8 T cells. Our data suggest that different antitumor immune response mechanisms may operate depending on the characteristics and distribution of the LNPs.
PubMed: 38942082
DOI: 10.1016/j.jconrel.2024.06.064 -
Diabetes & Metabolism Jun 2024GLP-1 (glucagon-like peptide-1) receptor agonists are a class of anti-diabetic agents that act by inducing insulin secretion and inhibiting glucagon release in a...
GLP-1 (glucagon-like peptide-1) receptor agonists are a class of anti-diabetic agents that act by inducing insulin secretion and inhibiting glucagon release in a glucose-dependent manner. They are particularly promising because of their long duration of action, reduced risk of hypoglycaemia and the added benefit of weight loss. Trulicity ® dulaglutide is a GLP-1 receptor agonist approved for type II diabetes and chronic weight management in obese adults. A few rare cases of hypersensitivity reactions have been reported in patients taking the GLP-1 receptor agonists dulaglutide and liraglutide. Here we present a new case of cutaneous hypersensitivity reactions in a man taking dulaglutide for type II diabetes. A 52-year-old man who had been taking dulaglutide for 5 weeks developed a rash on the abdomen when the dose was increased for 3 months. The patient experienced resolution of symptoms within days of stopping dulaglutide.
PubMed: 38942076
DOI: 10.1016/j.diabet.2024.101552 -
Journal of Molecular and Cellular... Jun 2024Cardiac arrhythmia treatment is a clinical challenge necessitating safer and more effective therapies. Recent studies have highlighted the role of the perinexus, an...
Cardiac arrhythmia treatment is a clinical challenge necessitating safer and more effective therapies. Recent studies have highlighted the role of the perinexus, an intercalated disc nanodomain enriched in voltage-gated sodium channels including both Na1.5 and β1 subunits, adjacent to gap junctions. These findings offer insights into action potential conduction in the heart. A 19-amino acid SCN1B (β1/β1B) mimetic peptide, βadp1, disrupts VGSC beta subunit-mediated adhesion in cardiac perinexii, inducing arrhythmogenic changes. We aimed to explore βadp1's mechanism and develop novel SCN1B mimetic peptides affecting β1-mediated adhesion. Using patch clamp assays in neonatal rat cardiomyocytes and electric cell substrate impedance sensing (ECIS) in β1-expressing cells, we observed βadp1 maintained inhibitory effects for up to 5 h. A shorter peptide (LQLEED) based on the carboxyl-terminus of βadp1 mimicked this inhibitory effect, while dimeric peptides containing repeated LQLEED sequences paradoxically promoted intercellular adhesion over longer time courses. Moreover, we found a link between these peptides and β1-regulated intramembrane proteolysis (RIP) - a signaling pathway effecting gene transcription including that of VGSC subunits. βadp1 increased RIP continuously over 48 h, while dimeric agonists acutely boosted RIP for up to 6 h. In the presence of DAPT, an RIP inhibitor, βadp1's effects on ECIS-measured intercellular adhesion was reduced, suggesting a relationship between RIP and the peptide's inhibitory action. In conclusion, novel SCN1B (β1/β1B) mimetic peptides are reported with the potential to modulate intercellular VGSC β1-mediated adhesion, potentially through β1 RIP. These findings suggest a path towards the development of anti-arrhythmic drugs targeting the perinexus.
PubMed: 38942073
DOI: 10.1016/j.yjmcc.2024.06.008 -
Biomedicine & Pharmacotherapy =... Jun 2024As a broad-spectrum anticancer drug, cisplatin is widely used in the treatment of tumors in various systems. Unfortunately, several serious side effects of cisplatin...
As a broad-spectrum anticancer drug, cisplatin is widely used in the treatment of tumors in various systems. Unfortunately, several serious side effects of cisplatin limit its clinical application, the most common of which are nephrotoxicity and ototoxicity. Studies have shown that cochlear hair cell degeneration is the main cause of cisplatin-induced hearing loss. However, the mechanism of cisplatin-induced hair cell death remains unclear. The present study aimed to explore the potential role of activating transcription factor 6 (ATF6), an endoplasmic reticulum (ER)-localized protein, on cisplatin-induced ototoxicity in vivo and in vitro. In this study, we observed that cisplatin exposure induced apoptosis of mouse auditory OC-1 cells, accompanied by a significant increase in the expression of ATF6 and C/EBP homologous protein (CHOP). In cell or cochlear culture models, treatment with an ATF6 agonist, an ER homeostasis regulator, significantly ameliorated cisplatin-induced cytotoxicity. Further, our in vivo experiments showed that subcutaneous injection of an ATF6 agonist almost completely prevented outer hair cell loss and significantly alleviated cisplatin-induced auditory brainstem response (ABR) threshold elevation in mice. Collectively, our results revealed the underlying mechanism by which activation of ATF6 significantly improved cisplatin-induced hair cell apoptosis, at least in part by inhibiting apoptosis signal-regulating kinase 1 expression, and demonstrated that pharmacological activation of ATF6-mediated unfolded protein response is a potential treatment for cisplatin-induced ototoxicity.
PubMed: 38941893
DOI: 10.1016/j.biopha.2024.117025 -
Biomedicine & Pharmacotherapy =... Jun 2024Xelaglifam, developed as a GPR40/FFAR1 agonist, induces glucose-dependent insulin secretion and reduces circulating glucose levels for Type 2 diabetes treatment. This...
Xelaglifam, developed as a GPR40/FFAR1 agonist, induces glucose-dependent insulin secretion and reduces circulating glucose levels for Type 2 diabetes treatment. This study investigated the effects of Xelaglifam in comparison with Fasiglifam on the in vitro/in vivo anti-diabetic efficacy and selectivity, and the mechanistic basis. In vitro studies on downstream targets of Xelaglifam were performed in GPR40-expressing cells. Xelaglifam treatment exhibited dose-dependent effects, increasing inositol phosphate-1, Ca mobilization, and β-arrestin recruitment (EC50: 0.76 nM, 20 nM, 68 nM), supporting its role in Gq protein-dependent and G-protein-independent mechanisms. Despite a lack of change in the cAMP pathway, the Xelaglifam-treated group demonstrated increased insulin secretion compared to Fasiglifam in HIT-T15 β cells under high glucose conditions. High doses of Xelaglifam (<30 mg/kg) did not induce hypoglycemia in Sprague-Dawley rats. In addition, Xelaglifam lowered glucose and increased insulin levels in diabetic rat models (GK, ZDF, OLETF). In GK rats, 1 mg/kg of Xelaglifam improved glucose tolerance (33.4 % and 15.6 % for the 1 and 5 h) after consecutive glucose challenges. Moreover, repeated dosing in ZDF and OLETF rats resulted in superior glucose tolerance (34 % and 35.1 % in ZDF and OLETF), reducing fasting hyperglycemia (18.3 % and 30 % in ZDF and OLETF) at lower doses; Xelaglifam demonstrated a longer-lasting effect with a greater effect on β-cells including 3.8-fold enhanced insulin secretion. Co-treatment of Xelaglifam with SGLT-2 inhibitors showed additive or synergistic effects. Collectively, these results demonstrate the therapeutic efficacy and selectivity of Xelaglifam on GPR40, supportive of its potential for the treatment of Type 2 diabetes.
PubMed: 38941892
DOI: 10.1016/j.biopha.2024.117044 -
Bioorganic & Medicinal Chemistry Jun 2024This study explored the potential of perfumery compounds as sources of transient receptor potential ankyrin 1 (TRPA1) inhibitors that could be formulated for effective...
This study explored the potential of perfumery compounds as sources of transient receptor potential ankyrin 1 (TRPA1) inhibitors that could be formulated for effective delivery to the skin and airways. A highly potent, small, and selective TRPA1 inhibitor, 2-methyl-4-phenyl-1-pentanol (1), was discovered in perfumery compounds. Compound 1 demonstrated promising inhibitory activity against a broad range of TRPA1 agonists. A single stereoisomer of 1 was identified as the most effective TRPA1 inhibitor, indicating the potential for stereoselective synthesis to enhance its potency. Additionally, the structure-activity relationship of 1 was evaluated to elucidate the structural features of TRPA1 inhibitors within the fragrance-like compounds. Notably, the topical application of 1 alleviated sensory irritation in individuals with sensitive skin, while the inhalation of 1 resulted in a significant reduction in ammonia irritation, underscoring its efficacy in both skin and airway applications.
PubMed: 38941887
DOI: 10.1016/j.bmc.2024.117812 -
General Hospital Psychiatry Jun 2024Several medications are associated with delirium; however, studies with adequate statistical power are limited, and it is difficult to determine the effects of the...
OBJECTIVE
Several medications are associated with delirium; however, studies with adequate statistical power are limited, and it is difficult to determine the effects of the various concomitant medications used in clinical practice. Therefore, in this study, we aimed to comprehensively evaluate the safety signals of delirium-associated drugs using a spontaneous adverse event reporting system.
METHOD
The JAPIC AERS (Food and Drug Administration Adverse Event Reporting System pre-processed by the Japan Pharmaceutical Information Center) was used for the analysis in this pharmacovigilance study. The reporting odds ratio (ROR) for delirium was adjusted for using multivariate logistic regression analysis with sex, age, indication, and melatonin receptor agonist use, and 22 drug categories were targeted as covariates.
RESULTS
After excluding patients with missing information, 7,527,568 patients were included in the study. Delirium signals were detected even after adjusting for covariates in 17 drug categories, including benzodiazepines (adjusted ROR, 1.76; 95% confidence interval [CI], 1.64-1.89), opioids (adjusted ROR, 4.42; 95% CI, 4.21-4.64), and tricyclic antidepressants (adjusted ROR, 2.44; 95% CI, 2.20-2.71).
CONCLUSIONS
These findings suggest that many drug classes, such as benzodiazepines, are independent risk factors for delirium and strengthen the evidence of an association between delirium and medications.
PubMed: 38941744
DOI: 10.1016/j.genhosppsych.2024.06.012 -
The Journal of Surgical Research Jun 2024Glucagon-like peptide-1 receptor agonist (GLP-1A) medications are gaining widespread popularity for the treatment of obesity. The optimal use of these drugs in pediatric...
INTRODUCTION
Glucagon-like peptide-1 receptor agonist (GLP-1A) medications are gaining widespread popularity for the treatment of obesity. The optimal use of these drugs in pediatric bariatric populations, and especially in those considering metabolic and bariatric surgery (MBS), is yet to be established. We sought to characterize current practice patterns of GLP-1A use at major pediatric bariatric centers across the United States.
MATERIALS AND METHODS
We administered an online survey to a purposive sample of 46 surgeons who perform MBS on children and adolescents. Survey questions explored practices prescribing GLP-1As in patients considering MBS, holding them prior to elective operations, and restarting them postoperatively following MBS. Responses were summarized with descriptive statistics and inductive content analysis.
RESULTS
There were 22 responses (48% response rate) representing 19 institutions. Most (86%) respondents do sometimes prescribe GLP-1As for patients considering MBS, but the specific indications vary. Practices for holding GLP-1As preoperatively also vary, from not at all to holding for 2 wk. Over half (55%) of respondents sometimes restart GLP-1As after MBS. Free-response themes included still-evolving preoperative utilization patterns, difficulty with access and insurance coverage, and a lack of data informing GLP-1A use in the pre and postoperative periods.
CONCLUSIONS
Given the increasing use of these medications for weight loss purposes, this substantial variation in practice highlights a need for further research to examine the safest and most effective use of GLP-1As in the pre and postoperative periods and for practice guidelines to standardize care pathways in pediatric bariatric contexts.
PubMed: 38941713
DOI: 10.1016/j.jss.2024.05.045 -
Science Advances Jun 2024Declined memory is a hallmark of Alzheimer's disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a...
Declined memory is a hallmark of Alzheimer's disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, but the underlying mechanisms are unknown. Here, we investigate the role of 5-HT 2C receptor (5-HTR) in regulating memory. Transgenic mice expressing a humanized mutation exhibit impaired plasticity of hippocampal ventral CA1 (vCA1) neurons and reduced memory. Further, 5-HT neurons project to and synapse onto vCA1 neurons. Disruption of 5-HT synthesis in vCA1-projecting neurons or deletion of 5-HTRs in the vCA1 impairs neural plasticity and memory. We show that a selective 5-HTR agonist, lorcaserin, improves synaptic plasticity and memory in an AD mouse model. Cumulatively, we demonstrate that hippocampal 5-HTR signaling regulates memory, which may inform the use of 5-HTR agonists in the treatment of dementia.
Topics: Animals; Humans; Receptor, Serotonin, 5-HT2C; Memory; Mice; Mice, Transgenic; Neuronal Plasticity; Alzheimer Disease; Hippocampus; Serotonin; Disease Models, Animal; CA1 Region, Hippocampal; Neurons; Serotonin 5-HT2 Receptor Agonists
PubMed: 38941473
DOI: 10.1126/sciadv.adl2675 -
The Journal of Clinical Investigation Jun 2024STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential...
STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation.
Topics: Animals; Glioblastoma; Tumor Microenvironment; Mice; Membrane Proteins; Humans; Cell Line, Tumor; Brain Neoplasms
PubMed: 38941297
DOI: 10.1172/JCI175033