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Pharmaceutics Jun 2024Epinephrine autoinjectors (EAIs) are used for the treatment of severe allergic reactions in a community setting; however, their utility is limited by low prescription... (Review)
Review
Epinephrine autoinjectors (EAIs) are used for the treatment of severe allergic reactions in a community setting; however, their utility is limited by low prescription fulfillment rates, failure to carry, and failure to use due to fear of needles. Given that delayed administration of epinephrine is associated with increased morbidity/mortality, there has been a growing interest in developing needle-free, easy-to-use delivery devices. (epinephrine nasal spray) consists of three Food and Drug Administration (FDA)-approved components: epinephrine, Intravail A3 (absorption enhancer), and a Unit Dose Spray (UDS). 's development pathway was established in conjunction with the FDA and the European Medicines Agency and included multiple clinical trials to evaluate pharmacokinetic and pharmacodynamic responses under a variety of conditions, such as self-administration and allergic and infectious rhinitis, as well as an animal anaphylaxis model of severe hypotension, where demonstrated a pharmacokinetic profile that is within the range of approved injection products and a pharmacodynamic response that is as good or better than injections. The increased pulse rate (PR) and blood pressure (BP) observed even one minute following the administration of confirm the activation of α and β adrenergic receptors, which are the key components of epinephrine's mechanism of action. The results suggest that will provide a safe and effective needle-free option for the treatment of severe allergic reactions, including anaphylaxis.
PubMed: 38931932
DOI: 10.3390/pharmaceutics16060811 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances... (Review)
Review
Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances are recognized in commonly reported ingestions. Victims of all ages, otherwise in good health, often present as pale and lethargic to the emergency department (ED) after unintentionally ingesting topical eye medication. While eye drop poisoning cases in childhood include accidents during the play and poisonings in adults mean either suicide attempts or side effects caused by the systemic absorption of the substance, fluid of the ocular surface is a risk to all age groups. With this in mind, this study aimed to summarize data in the literature on tetrahydrozoline and alpha-2 adrenergic receptor agonists as dangerous medications, even when administered in low-bioavailability forms, such as eye drops. With this aim, a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of relevant studies was conducted. A search of PubMed, Scopus, Web of Science, and EBSCOhost yielded nine studies that met the rigorous inclusion criteria. The primary studies were subject to a meta-analysis once a quality appraisal of the studies and a narrative synthesis of the extracted data had been conducted. The author hopes that this information will provide observations that will lead to better designs for over-the-counter eye drops, off-label drug usage policies, and parental attention.
PubMed: 38931425
DOI: 10.3390/ph17060758 -
International Journal of Molecular... Jun 2024G-protein coupled receptors (GPCRs) are transmembrane proteins that transmit signals from the extracellular environment to the inside of the cells. Their ability to...
G-protein coupled receptors (GPCRs) are transmembrane proteins that transmit signals from the extracellular environment to the inside of the cells. Their ability to adopt various conformational states, which influence their function, makes them crucial in pharmacoproteomic studies. While many drugs target specific GPCR states to exert their effects-thereby regulating the protein's activity-unraveling the activation pathway remains challenging due to the multitude of intermediate transformations occurring throughout this process, and intrinsically influencing the dynamics of the receptors. In this context, computational modeling, particularly molecular dynamics (MD) simulations, may offer valuable insights into the dynamics and energetics of GPCR transformations, especially when combined with machine learning (ML) methods and techniques for achieving model interpretability for knowledge generation. The current study builds upon previous work in which the layer relevance propagation (LRP) technique was employed to interpret the predictions in a multi-class classification problem concerning the conformational states of the β2- (β2AR) receptor from MD simulations. Here, we address the challenges posed by class imbalance and extend previous analyses by evaluating the robustness and stability of deep learning (DL)-based predictions under different imbalance mitigation techniques. By meticulously evaluating explainability and imbalance strategies, we aim to produce reliable and robust insights.
Topics: Molecular Dynamics Simulation; Deep Learning; Receptors, Adrenergic, beta-2; Receptors, G-Protein-Coupled; Protein Conformation; Humans
PubMed: 38928278
DOI: 10.3390/ijms25126572 -
International Journal of Molecular... Jun 2024Endometritis is a common disease in animals, leading to disruption of reproductive processes and economic losses. Noradrenergic control of prostaglandin (PG)I2 formation...
Endometritis is a common disease in animals, leading to disruption of reproductive processes and economic losses. Noradrenergic control of prostaglandin (PG)I2 formation by inflamed endometrium is unknown. We determined the involvement of α1-, α2- and β-adrenoreceptors (ARs) in noradrenaline-influenced PGI synthase (PGIS) protein abundance and PGI2 release from porcine (1) endometrial explants with ()-induced inflammation in vivo, and (2) lipopolysaccharide (LPS)-treated endometrial epithelial cells. Experiment 1. suspension ( group) or saline (CON group) was injected into the uterine horns. In both groups, noradrenaline increased endometrial PGIS abundance and PGI2 release versus the control values, and it was higher in the group than in the CON group. In the CON group, a noradrenaline stimulating effect on both parameters takes place through α1D-, α2C- and β2-ARs. In the group, noradrenaline increased PGIS abundance and PGI2 release via α1A-, α2(B,C)- and β(1,2)-ARs, and PGI2 release also by α2A-ARs. Experiment 2. LPS and noradrenaline augmented the examined parameters in endometrial epithelial cells versus the control value. In LPS-treated cells, β(1,2)-ARs mediate in noradrenaline excitatory action on PGIS protein abundance and PGI2 release. β3-ARs also contribute to PGI2 release. Under inflammatory conditions, noradrenaline via ARs increases PGI2 synthesis and release from the porcine endometrium, including epithelial cells. Our findings suggest that noradrenaline may indirectly affect processes regulated by PGI2 in the inflamed uterus.
Topics: Animals; Female; Norepinephrine; Endometrium; Swine; Epoprostenol; Receptors, Adrenergic; Lipopolysaccharides; Inflammation; Escherichia coli; Endometritis; Epithelial Cells; Intramolecular Oxidoreductases; Cytochrome P-450 Enzyme System
PubMed: 38928020
DOI: 10.3390/ijms25126313 -
Bioengineering (Basel, Switzerland) Jun 2024The purpose of the current study was to elucidate the physiological roles of intraocularly present fatty acid-binding protein 4 (FABP4). Using four representative...
The purpose of the current study was to elucidate the physiological roles of intraocularly present fatty acid-binding protein 4 (FABP4). Using four representative intraocular tissue-derived cell types, including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cells, the intraocular origins of FABP4 were determined by qPCR analysis, and the intracellular functions of FABP4 were investigated by seahorse cellular metabolic measurements and RNA sequencing analysis using a specific inhibitor for FABP4, BMS309403. Among these four different cell types, FABP4 was exclusively expressed in HOCF cells. In HOCF cells, both mitochondrial and glycolytic functions were significantly decreased to trace levels by BMS309403 in a dose-dependent manner. In the RNA sequencing analysis, 67 substantially up-regulated and 94 significantly down-regulated differentially expressed genes (DEGs) were identified in HOCF cells treated with BMS309403 and those not treated with BMS309403. The results of Gene Ontology enrichment analysis and ingenuity pathway analysis (IPA) revealed that the DEGs were most likely involved in G-alpha (i) signaling, cAMP-response element-binding protein (CREB) signaling in neurons, the S100 family signaling pathway, visual phototransduction and adrenergic receptor signaling. Furthermore, upstream analysis using IPA suggested that NKX2-1 (thyroid transcription factor1), HOXA10 (homeobox A10), GATA2 (gata2 protein), and CCAAT enhancer-binding protein A (CEBPA) were upstream regulators and that NKX homeobox-1 (NKX2-1), SFRP1 (Secreted frizzled-related protein 1) and TREM2 (triggering receptor expressed on myeloid cells 2) were causal network master regulators. The findings in this study suggest that intraocularly present FABP4 originates from the ocular choroid and may be a critical regulator for the cellular homeostasis of non-adipocyte HOCF cells.
PubMed: 38927820
DOI: 10.3390/bioengineering11060584 -
Biomedicines May 2024Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients, with estimates of at least 30%...
Single and Combined Effects of Cannabigerol (CBG) and Cannabidiol (CBD) in Mouse Models of Oxaliplatin-Associated Mechanical Sensitivity, Opioid Antinociception, and Naloxone-Precipitated Opioid Withdrawal.
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients, with estimates of at least 30% of patients experiencing persistent neuropathy for months or years after treatment cessation. An emerging potential intervention for the treatment of CIPN is cannabinoid-based pharmacotherapies. We have previously demonstrated that treatment with the psychoactive CB1/CB2 cannabinoid receptor agonist Δ-tetrahydrocannabinol (Δ-THC) or the non-psychoactive, minor phytocannabinoid cannabidiol (CBD) can attenuate paclitaxel-induced mechanical sensitivity in a mouse model of CIPN. We then showed that the two compounds acted synergically when co-administered in the model, giving credence to the so-called entourage effect. We and others have also demonstrated that CBD can attenuate several opioid-associated behaviors. Most recently, it was reported that another minor cannabinoid, cannabigerol (CBG), attenuated cisplatin-associated mechanical sensitivity in mice. Therefore, the goals of the present set of experiments were to determine the single and combined effects of cannabigerol (CBG) and cannabidiol (CBD) in oxaliplatin-associated mechanical sensitivity, naloxone-precipitated morphine withdrawal, and acute morphine antinociception in male C57BL/6 mice. Results demonstrated that CBG reversed oxaliplatin-associated mechanical sensitivity only under select dosing conditions, and interactive effects with CBD were sub-additive or synergistic depending upon dosing conditions too. Pretreatment with a selective α2-adrenergic, CB1, or CB2 receptor selective antagonist significantly attenuated the effect of CBG. CBG and CBD decreased naloxone-precipitated jumping behavior alone and acted synergistically in combination, while CBG attenuated the acute antinociceptive effects of morphine and CBD. Taken together, CBG may have therapeutic effects like CBD as demonstrated in rodent models, and its interactive effects with opioids or other phytocannabinoids should continue to be characterized.
PubMed: 38927352
DOI: 10.3390/biomedicines12061145 -
Insects May 2024Resistance against amitraz in mite populations has become a subject of interest in recent years due to the increasing reports of the reduced field efficacy of amitraz...
Resistance against amitraz in mite populations has become a subject of interest in recent years due to the increasing reports of the reduced field efficacy of amitraz treatments, especially from some beekeepers in France and the United States. The loss of amitraz as a reliable tool to effectively reduce mite infestation in the field could severely worsen the position of beekeepers in the fight to keep infestation rates in their colonies at low levels. In this publication, we present data from French apiaries, collected in the years 2020 and 2021. These data include the field efficacy of an authorized amitraz-based treatment (Apivar ,Véto-pharma, France) and the results of laboratory sensitivity assays of mites exposed to the reference LC concentration of amitraz. In addition, a total of 240 mites from Eastern, Central, and Southern regions in France that were previously classified as either "sensitive" or "resistant" to amitraz in a laboratory sensitivity assay were genotyped. The genetic analyses of mite samples are focused on the β-adrenergic-like octopamine receptor, which is considered as the main target site for amitraz in mites. Special attention was paid to a single-nucleotide polymorphism (SNP) at position 260 of the gene that was previously associated to amitraz resistance in French mites, . Our findings confirm that amitraz resistance occurs in patches or "islands of resistance", with a less severe reduction in treatment efficacy compared to pyrethroid resistance or coumaphos resistance in mites. The results of our genetic analyses of mites call into question the hypothesis of the SNP at position 260 of the gene being directly responsible for amitraz resistance development.
PubMed: 38921105
DOI: 10.3390/insects15060390 -
BioRxiv : the Preprint Server For... Jun 2024The receptor tyrosine kinase EphA2 drives cancer malignancy by facilitating metastasis. EphA2 can be found in different self-assembly states: as a monomer, dimer, and...
The receptor tyrosine kinase EphA2 drives cancer malignancy by facilitating metastasis. EphA2 can be found in different self-assembly states: as a monomer, dimer, and oligomer. However, our understanding remains limited regarding which EphA2 state is responsible for driving pro-metastatic signaling. To address this limitation, we have developed SiMPull-POP, a single-molecule method for accurate quantification of membrane protein self-assembly. Our experiments revealed that a reduction of plasma membrane cholesterol strongly promoted EphA2 self-assembly. Indeed, low cholesterol caused a similar effect to the EphA2 ligand ephrinA1-Fc. These results indicate that cholesterol inhibits EphA2 assembly. Phosphorylation studies in different cell lines revealed that low cholesterol increased phospho-serine levels, the signature of oncogenic signaling. Investigation of the mechanism that cholesterol uses to inhibit the assembly and activity of EphA2 indicate an in-trans effect, where EphA2 is phosphorylated by protein kinase A downstream of beta-adrenergic receptor activity, which cholesterol also inhibits. Our study not only provides new mechanistic insights on EphA2 oncogenic function, but also suggests that cholesterol acts as a molecular safeguard mechanism that prevents uncontrolled self-assembly and activation of EphA2.
PubMed: 38915729
DOI: 10.1101/2024.06.10.598255 -
BioRxiv : the Preprint Server For... Jun 2024Our previous studies have indicated that insulin resistance, hyperglycemia, and hypertension in aged wild-type (WT) mice can be reversed in mice lacking chromogranin-A...
Our previous studies have indicated that insulin resistance, hyperglycemia, and hypertension in aged wild-type (WT) mice can be reversed in mice lacking chromogranin-A (CgA-KO mice). These health conditions are associated with a higher risk of Alzheimer's disease (AD). CgA, a neuroendocrine secretory protein has been detected in protein aggregates in the brains of AD patients. Here, we determined the role of CgA in tauopathies, including AD (secondary tauopathy) and corticobasal degeneration (CBD, primary tauopathy). We found elevated levels of CgA in both AD and CBD brains, which were positively correlated with increased phosphorylated tau in the frontal cortex. Furthermore, CgA ablation in a human P301S tau (hTau) transgenic mice (CgA-KO/hTau) exhibited reduced tau aggregation, resistance to tau spreading, and an extended lifespan, coupled with improved cognitive function. Transcriptomic analysis of mice cortices highlighted altered levels of alpha-adrenergic receptors (Adra) in hTau mice compared to WT mice, akin to AD patients. Since CgA regulates the release of the Adra ligands epinephrine (EPI) and norepinephrine (NE), we determined their levels and found elevated EPI levels in the cortices of hTau mice, AD and CBD patients. CgA-KO/hTau mice exhibited reversal of EPI levels in the cortex and the expression of several affected genes, including Adra1 and 2, nearly returning them to WT levels. Treatment of hippocampal slice cultures with EPI or an Adra1 agonist intensified, while an Adra1 antagonist inhibited, tau hyperphosphorylation and aggregation. These findings reveal a critical role of CgA in regulation of tau pathogenesis via the EPI-Adra signaling axis.
PubMed: 38915622
DOI: 10.1101/2024.06.11.598548 -
Frontiers in Cardiovascular Medicine 2024There have been conflicting reports about the proarrhythmic risk of -synephrine (SYN). To address this, human induced pluripotent stem cell-derived cardiomyocytes...
Non-invasive assessment of proarrhythmic risks associated with isoprenaline and the dietary supplement ingredient synephrine using human induced pluripotent stem cell-derived cardiomyocytes.
BACKGROUND
There have been conflicting reports about the proarrhythmic risk of -synephrine (SYN). To address this, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with the microelectrode array (MEA) system have been utilized to assess arrhythmia risks, particularly in the context of adrenomimetic drugs.
AIM
This study aims to determine whether MEA recordings from hiPSC-CMs could predict the proarrhythmic risk of adrenomimetic drugs and to investigate the cardiovascular effects and mechanisms of SYN.
MATERIALS AND METHODS
We employed MEA recordings to assess the electrophysiological properties of hiPSC-CMs and conducted concentration-response analyses to evaluate the effects of SYN and Isoprenaline (ISO) on beating rate and contractility. A risk scoring system for proarrhythmic risks was established based on hiPSC-CMs in this study. ISO, a classic beta-adrenergic drug, was also evaluated. Furthermore, the study evaluated the risk of SYN and recorded the concentration-response of beating rate, contractility and the change in the presence or absence of selective β1, β2 and β3 adrenergic blockers.
RESULTS
Our results suggested that ISO carries a high risk of inducing arrhythmias, aligning with existing literature. SYN caused a 30% prolongation of the field potential duration (FPD) at a concentration of 206.326 μM, a change significantly different from baseline measurements and control treatments. The half maximal effective concentration (EC50) of SYN (3.31 μM) to affect hiPSC-CM beating rate is much higher than that of ISO (18.00 nM). The effect of SYN at an EC50 of 3.31 μM is about ten times more potent in hiPSC-CMs compared to neonatal rat cardiomyocytes (34.12 μM). SYN increased the contractility of cardiomyocytes by 29.97 ± 11.65%, compared to ISO's increase of 50.56 ± 24.15%. β1 receptor blockers almost eliminated the beating rate increase induced by both ISO and SYN, while neither β2 nor β3 blockers had a complete inhibitory effect.
CONCLUSION
The MEA and hiPSC-CM system could effectively predict the risk of adrenomimetic drugs. The study concludes that the proarrhythmia risk of SYN at conventional doses is low. SYN is more sensitive in increasing beating rate and contractility in human cardiomyocytes compared to rats, primarily activating β1 receptor.
PubMed: 38911513
DOI: 10.3389/fcvm.2024.1407138