A novel approach for the treatment of AML, through GHRH antagonism: MIA-602.

Acute myeloid leukemia (AML) is the most aggressive and prevalent form of leukemia in adults. The gold-standard intervention revolves around the use of chemotherapy, and in some cases hematopoietic stem cell transplantation. Drug resistance is a frequent complication resulting from treatment, as it stands there are limited clinical measures available for refractory AML besides palliative care. The goal of this review is to renew interest in a novel targeted hormone therapy in the treatment of AML utilizing growth hormone-releasing hormone (GHRH) antagonism, given it may provide a potential solution for current barriers to achieving complete remission post-therapy. Recapitulating pre-clinical evidence, GHRH antagonists (GHRH-Ant) have significant anti-cancer activity across experimental human AML cell lines in vitro and in vivo and demonstrate significant inhibition of cancer in drug resistant analogs of leukemic cell lines as well. GHRH-Ant act in manners that are orthogonal to anthracyclines and when administered in combination synergize to produce a more potent anti-neoplastic effect. Considering the adversities associated with standard AML therapies and the developing issue of drug resistance, MIA-602 represents a novel approach worth further investigation.

Ketamine and α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) Receptor Potentiation in the Somatosensory Cortex: A Comprehensive Review.

Ketamine, a dissociative anesthetic primarily recognized for its antagonism of N-methyl-D-aspartate (NMDA) receptors, has gained significant attention for its rapid antidepressant effects and potential in treating mood disorders. However, recent research indicates that ketamine's influence extends beyond NMDA receptor inhibition, affecting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and sensory processing. This review delves into ketamine's role in enhancing AMPA receptor function and its implications for sensory processing within the somatosensory cortex. AMPA receptors, essential for fast excitatory neurotransmission and synaptic plasticity, play a key role in sensory perception and integration. By examining preclinical and clinical studies, this review sheds light on how ketamine's modulation of AMPA receptors may improve sensory processing and contribute to its therapeutic effects. Additionally, the review explores the potential for ketamine-based therapies to treat sensory processing disorders and refine current treatment strategies. A deeper understanding of ketamine's complex effects on AMPA receptors and sensory processing could provide valuable insights for developing targeted interventions and advancing clinical applications.

CYSLTR1 antagonism displays potent anti-tumor effects in uveal melanoma.

Uveal Melanoma (UM) is the most common primary intraocular malignancy in adults. Although rare, it is a deadly tumor, with a long-term prognosis of death occurring in more than 50% of the cases. It is characterized by frequent (∼80%) driver mutations in GNAQ and GNA11 genes, both of which are activated by cysteinyl leukotriene receptors (CYSLTRs). CYSLTR1 is upregulated and participated in the progression of several cancers. In the present study, we sought to determine the expression levels of CYSLTR1 in 31 human UM specimens and cell lines (3 primary and 1 metastatic), and its role in the proliferation and viability of these cells by analyzing cell metabolic activity, cell confluence and apoptosis levels. We show that all analyzed UM specimens and cells expressed CYSLTR1 at high levels. Notably, the pharmacological blockage of this receptor, using the inverse agonist MK571, reduced the growth and metabolic activity, and increased the apoptotic cell death of all analyzed UM cell lines. We provide evidence that CYSLTR1 is expressed in human UM and plays a significant role in UM progression behavior. Our data highlight the potential beneficial effects of targeting CYSLTR1 in the control of UM progression.

Quantitative Monitoring Maximizes Cost-Saving Strategies When Antagonizing Neuromuscular Block With Sugammadex.

Introduction Weight-based dosing combined with variable patient weights in pediatric anesthesia can lead to significant medication excess and waste from single-use medication vials packaged for dosing in adults. Medication aliquots have been proposed as a strategy to decrease waste and therefore expense when using high-cost medications such as sugammadex. Appropriate dosing of sugammadex to antagonize neuromuscular block is based on the results of quantitative monitoring, though the use of these monitors is not routine. In this quality improvement project, we demonstrate cost savings from aliquoting sugammadex from large, single-use vials and using quantitative monitoring to guide accurate and appropriate dosing.  Methods After institutional review and approval, patients receiving rocuronium neuromuscular block during their anesthetic care between October 10 and December 9, 2022, were included for analysis. Sugammadex aliquots were prepared under sterile conditions in the operating room pharmacy according to current compounding guidelines. Quantitative neuromuscular monitoring with electromyography-based monitors was used to guide accurate sugammadex dosing. Cost analysis included the actual savings achieved when aliquots were used instead of single-use vials, the potential savings if aliquots had been used as opposed to single-use vials, and the actual savings achieved when quantitative monitoring indicated that adequate spontaneous recovery was reached and sugammadex administration was not needed. Results A total of 200 patients were included in the analysis. In 73 patients, a 200 mg/2 ml vial of sugammadex was utilized, while 86 patients received sugammadex from pre-filled aliquot syringes of 50 mg/0.5 ml. Forty-one patients did not require sugammadex antagonism as they achieved spontaneous recovery to a train-of-four ratio ≥90%. Conclusion Administration of sugammadex from aliquots rather than manufacturer-packaged single-use vials, with dosing guided by quantitative neuromuscular monitoring, produced a net cost savings of approximately $46 per case and projected net annual cost savings of nearly $370,000 in our institution. Forty percent of the net cost savings came from confirmation by quantitative monitoring of adequate spontaneous recovery to a train-of-four ratio ≥90%.

Comparison of three spatial interpolation methods in predicting time-dependent toxicities of single substances and mixtures.

This study aims to optimize the time-dependent toxicity assessments for both single substances, particularly those causing hormesis, and mixtures that exhibit toxicological interactions. To achieve this, three time-dependent toxicity prediction methods were developed using geologic interpolation techniques: Inverse distance weighted (IDW), Kriging, and linear interpolation based on Delaunay triangulation (LDT). The toxicity of 7 single substances and 80 mixtures on Vibrio qinghaiensis sp.-Q67, along with 6 single substances and 19 mixtures on Microcystis aeruginosa, were assessed to evaluate the predictive accuracy of these methods. The coefficient of determination (R2), mean absolute error (MAE), and root-mean-square error (RMSE) were employed as performance metrics during cross-validation. The results showed that IDW underperformed LDT and Kriging in terms of both RMSE and MAE, indicating that LDT and Kriging had superior accuracy compared to IDW. Although LDT and Kriging demonstrated comparable predictive capabilities, LDT was identified as the more practical option for time-dependent toxicity prediction due to its simplicity and no requirement for parameter tuning. Consequently, LDT was presented as a new, efficient, and user-friendly tool for assessing the time-dependent toxicity of both individual chemicals and chemical mixtures. LDT will help to better assess the ecological risks of chemicals.

Interactive Effects of Climate Change and Pathogens on Plant Performance: A Global Meta-Analysis.

Plant health is increasingly threatened by abiotic and biotic stressors linked to anthropogenic global change. These stressors are frequently studied in isolation. However, they might have non-additive (antagonistic or synergistic) interactive effects that affect plant communities in unexpected ways. We conducted a global meta-analysis to summarize existing evidence on the joint effects of climate change (drought and warming) and biotic attack (pathogens) on plant performance. We also investigated the effect of drought and warming on pathogen performance, as this information is crucial for a mechanistic interpretation of potential indirect effects of climate change on plant performance mediated by pathogens. The final databases included 1230 pairwise cases extracted from 117 recently published scientific articles (from 2006) on a global scale. We found that the combined negative effects of drought and pathogens on plant growth were lower than expected based on their main effects, supporting the existence of antagonistic interactions. Thus, the larger the magnitude of the drought, the lower the pathogen capacity to limit plant growth. On the other hand, the combination of warming and pathogens caused larger plant damage than expected, supporting the existence of synergistic interactions. Our results on the effects of drought and warming on pathogens revealed a limitation of their growth rates and abundance in vitro but an improvement under natural conditions, where multiple factors operate across the microbiome. Further research on the impact of climate change on traits explicitly defining the infective ability of pathogens would enhance the assessment of its indirect effects on plants. The evaluated plant and pathogen responses were conditioned by the intensity of drought or warming and by moderator categorical variables defining the pathosystems. Overall, our findings reveal the need to incorporate the joint effect of climatic and biotic components of global change into predictive models of plant performance to identify non-additive interactions.

Slow dissociation kinetics of fentanyls and nitazenes correlates with reduced sensitivity to naloxone reversal at the µ-opioid receptor.

BACKGROUND AND PURPOSE: Fentanyls and nitazenes are µ-opioid receptor agonists responsible for a large number of opioid overdose deaths. Here, we determined the potency, dissociation kinetics and antagonism by naloxone at the µ receptor of several fentanyl and nitazene analogues, compared to morphine and DAMGO. EXPERIMENTAL APPROACH: In vitro assays of G protein activation and signalling and arrestin recruitment were performed. AtT20 cells expressing µ receptors were loaded with a membrane potential dye and changes in fluorescence used to determine agonist potency, dissociation kinetics and susceptibility to antagonism by naloxone. BRET experiments were undertaken in HEK293T cells expressing µ receptors to assess Gi protein activation and ß-arrestin 2 recruitment. KEY RESULTS: The apparent rate of agonist dissociation from the µ receptor varied: morphine, DAMGO, alfentanil and fentanyl dissociated rapidly, whereas isotonitazene, etonitazene, ohmefentanyl and carfentanil dissociated slowly. Slowly dissociating agonists were more resistant to antagonism by naloxone. For carfentanil, the slow apparent rate of dissociation was not because of G protein receptor kinase-mediated arrestin recruitment as its apparent rate of dissociation was not increased by inhibition of G protein-coupled receptor kinases (GRKs) with Compound 101. The in vitro relative potencies of fentanyls and nitazenes compared to morphine were much lower than that previously observed in in vivo experiments. CONCLUSIONS AND IMPLICATIONS: With fentanyls and nitazenes that slowly dissociate from the µ receptor, antagonism by naloxone is pseudo-competitive. In overdoses involving fentanyls and nitazenes, higher doses of naloxone may be required for reversal than those normally used to reverse heroin overdose.

Toxicity of selected pharmaceuticals and their mixtures to the aquatic indicators Daphnia magna and Aliivibrio fischeri.

Despite the benefits derived from the use of pharmaceuticals, these compounds are currently considered contaminants of emerging concern because of their presence and persistence in the environment. This study aimed to determine the toxicity of 27 pharmaceuticals and the interaction effects of binary mixtures of selected compounds towards two model organisms: the microcrustacean Daphnia magna and the bacterium Aliivibrio fischeri (Microtox test). Six compounds, namely polymyxin B, polymyxin E, fluoxetine, diphenhydramine, clenbuterol and ketoprofen exhibited moderate toxicity towards D. magna. Additionally, three compounds (cefotaxime, polymyxin B, polymyxin E) also showed a moderate toxic effect on A. fischeri. The comparison of such results with model estimations showed inaccuracy in the predicted data, highlighting the relevance of experimental ecotoxicological assays. The assayed mixtures contained four selected drugs of high-hazard according to their reported concentrations in wastewater and surface water (diphenhydramine, trimethoprim, ketoprofen, and fluoxetine); data revealed interactions only in the fluoxetine-containing mixtures for D. magna, while all mixtures showed interactions (mostly synergistic) for Microtox. Chronic effects on the reproduction of D. magna were observed after exposure to fluoxetine and diphenhydramine, although higher sensitivity was determined for the latter, while the mixture of these compounds (which showed acute synergy in both models) also affected the reproduction patterns. Nonetheless, all the effects described at the acute or chronic level (for individual compounds or mixtures) were determined at concentrations higher than commonly reported at environmental levels. This work provides valuable ecotoxicological information for the risk assessment of pharmaceuticals and their mixtures in the environment.

An Experimental Study to Optimize Neuromuscular Blockade Protocols in Cynomolgus Macaques: Monitoring, Doses, and Antagonism.

BACKGROUND: Neuromuscular blocking agents (NMBAs) are a crucial component of anesthesia and intensive care through the relaxation of skeletal muscles. They can lead to adverse reactions such as postoperative residual neuromuscular block. Only one agent is capable of an instant block reversal in deep block situations, but is restricted to aminosteroid agents. Among animal models, non-human primates are an essential model for a great diversity of human disease models. The main objective of this study was to establish a model for NMBA monitoring with current available drugs before testing new reversal agents. METHODS: Seven healthy male cynomolgus macaques were randomly assigned to this study. Experiments using macaques were approved by the local ethical committee (CEtEA #44). All animals were anesthetized according to institutional guidelines, with ketamine and medetomidine, allowing IV line placement and tracheal intubation. Anesthesia was maintained with isoflurane. Either rocuronium bromine (with or without sugammadex reversal) or atracurium besylate was evaluated. Monitoring was performed with two devices, TOF-Watch and ToFscan, measuring the T4/T1 and the T4/Tref ratios, respectively. Nonparametric Mann-Whitney statistical analyses were done when indicated. RESULTS: NMBA monitoring required adaptation compared to humans, such as stimulus intensity and electrode placement, to be efficient and valid in cynomolgus macaques. When administered, both NMBAs induced deep and persistent neuro-muscular block at equivalent doses to clinical doses in humans. The rocuronium-induced profound neuromuscular block could be reversed using the cyclodextrin sugammadex as a reversal agent. We report no adverse effects in these models by clinical observation, blood chemistry, or complete blood count. CONCLUSION: These results support the use of non-human primate models for neuromuscular block monitoring. This represented the first step before the forthcoming testing of new NMBA-reversal agents.

Molecular interaction mechanisms on (-)-epigallocatechin-3-gallate improving activities of inhibited acetylcholinesterase by selected organophosphorus pesticides in vitro & vivo.

(-)-Epigallocatechin-3-gallate (EGCG) is reported to have benefits for the treatment of Alzheimer's disease by binding with acetylcholinesterase (AChE) to enhance the cholinergic neurotransmission. Organophosphorus pesticides (OPs) inhibited AChE and damaged the nervous system. This study investigated the combined effects of EGCG and OPs on AChE activities in vitro & vivo. The results indicated that EGCG significantly reversed the inhibition of AChE caused by OPs. In vitro, EGCG reactived AChE in three group tubes incubated for 110 min, and in vivo, it increased the relative activities of AChE from less than 20% to over 70% in brain and vertebral of zebrafish during the exposure of 34 h. The study also proposed the molecular interaction mechanisms through the reactive kinetics and computational analyses of density functional theory, molecular docking, and dynamic modeling. These analyses suggested that EGCG occupied the key residues, preventing OPs from binding to the catalytic center of AChE, and interfering with the initial affinity of OPs to the central active site. Hydrogen bonding, conjugation, and steric interactions were identified as playing important roles in the molecular interactions. The work suggests that EGCG antagonized the inhibitions of OPs on AChE activities and potentially offered the neuroprotection against the induced damage.

Nonadditive Cytotoxicity in Select Disinfection Byproducts and Disinfected Secondary Effluents.

Toxicity studies of water disinfection byproducts (DBPs) typically assume additive interactions. Coupling results from both the bottom-up cytotoxicity interaction approach by selecting six common DBPs and the top-down cytotoxicity fractionating the disinfected secondary effluent containing a much broader DBP selection, we demonstrated a novel effect of clear, nonadditive cytotoxicity at low chemical concentrations regardless of the number of DBP types involved. We revealed that the cytotoxicity interactions were influenced by the chemical's type, concentration factor, and mixing ratio. For the bottom-up approach, the average combination indices (CIs) were 1.61 (chloracetamide + chloroacetonitrile, antagonism), 1.03 (bromoacetamide+bromoacetonitrile, near additivity), and 0.69 (iodoacetamide + iodoacetonitrile, synergism) across the DBPs' concentration range of 10-4-10-7 M. These cytotoxicity interactions also varied with the components' mixing ratios. For the top-down approach, we obtained two fractions of DBP mixtures from the disinfected secondary effluent using solvents of different polarities. The effect of the concentration on CI values was significant, with a maximum 43.1% relative deviation in CI from LC5 to LC95. The average CI values across the sample concentration range of 1-50 × (concentration factor) varied from 1.68 (antagonism) to 0.89 (slight synergism) as the ratio of mixture A increased. These results call for further research in prioritizing the forcing DBPs in mixtures.

Maternal effects and its importance in the genetic evaluations of preweaning live weight traits of beef cattle. A review.

Maternal effects in cattle genetics are defined as the causal influence of the phenotype or maternal genotype on the offspring's phenotype by effects occurring when the genetic and environmental characteristics of the mother influence the phenotype of the offspring beyond the direct inheritance of genes. Its relevance has been strongly described in genetic models focused on the genetic improvement of preweaning traits in cow-calf beef cattle production systems. Here, basic concepts and the importance of maternal effects when using linear and animal model procedures for genetic evaluations of growth and live-weight traits in beef cattle are reviewed and discussed. A brief history of estimation methods from classical studies to recent studies used for the development of animal models for studying maternal effects is also provided. Some important biometric concepts for maternal effect estimation are described, and the antagonism between direct genetic effects and maternal effects, its biological basis, and sources of error in the estimation of direct genetic and maternal covariance are discussed. Finally, some genomic perspectives are presented.

Bacteriocin Antagonistic Potentials of Lactococcus cremoris and Lactococcus lactis Isolates from Different Habitats.

It has not been extensively examined if the ecological role of lactic acid bacterial bacteriocins may affect their distribution in different habitats and thereby impact screenings for novel variants. Further, the functionality of such variants requires additional investigation. This study investigated the distribution of bacteriocin biosynthetic gene clusters (BGCs) and bacteriocinogenic activity of Lactococcus cremoris and Lactococcus lactis from a range of different environments. Whole genome sequencing and phylogenetic analysis of fifty L. cremoris and L. lactis strains showed distinct species clustering without significant genome size differences between species or sources. Genomic screening with AntiSMASH and BAGEL4 identified several BGCs, with variation based on species but not on habitat. Deferred inhibition assays revealed pronounced activity only in strains possessing nisin or lactococcin B BGCs and not in strains with other BGCs. Several hitherto undescribed types of lactococcin BGCs appeared to be incomplete regarding genes encoding secretion and immunity. In conclusion, this study indicates that habitats did not appear to affect distribution of BGCs. Further, the antagonistic functionality of several BGCs was unclear indicating that improving applications of lactococcal bacteriocins may depend as much or more on research on increasing efficacy of well-known bacteriocins than searching for novel variants.

Nicotine's Effects on Schizophrenia-like Symptoms in a Mice Model: Time Matters.

Tobacco consumption in schizophrenia (SCHZ) patients is highly prevalent. Data support the occurrence of sequential events during comorbidity establishment, and both smoking first, SCHZ second and SCHZ first, smoking second sequences have been proposed. To investigate whether these two possibilities lead to distinct outcomes of comorbidity, we used a phencyclidine-induced SCHZ model and nicotine exposure as a surrogate of smoking. C57Bl/6 mice were submitted to a protocol that either began with 4 days of phencyclidine exposure or 4 days of nicotine exposure. This period was followed by 5 days of combined phencyclidine + nicotine exposure. Locomotor sensitization and pre-pulse inhibition (PPI) were assessed due to their well-known associations with SCHZ as opposed to rearing, an unrelated behavior. Nicotine priming potentiated phencyclidine-evoked sensitization. However, nicotine exposure after SCHZ modeling did not interfere with phencyclidine's effects. In the PPI test, nicotine after SCHZ modeling worsened the phencyclidine-evoked deficiency in males. In contrast, nicotine priming had no effects. Regarding rearing, nicotine priming failed to interfere with phencyclidine-mediated inhibition. Similarly, phencyclidine priming did not modify nicotine-mediated inhibition. The present results indicate that the sequence, either SCHZ-first or nicotine-first, differentially impacts comorbidity outcomes, a finding that is relevant for the identification of mechanisms of nicotine interference in the neurobiology of SCHZ.

Biofilm Formation by Lactobacillus Strains of Modern Probiotics and Their Antagonistic Activity against Opportunistic Bacteria.

The species identity of the studied lactobacillus strains was confirmed by matrix-activated laser desorption/ionization with time-of-flight ion separation (MALDI-TOF mass spectrometry). Lactobacillus strains differed in the dynamics of lactic acid accumulation and changes in the pH of the culture medium. The culture medium affected adhesion ability of lactobacilli. The ability to adhere does not affect the formation of biofilms by lactobacillus strains except for the L. acidophilus La5 strain, which has low adhesion ability and fewer microbial cells detected after mechanical destruction of the biofilm. The metabiotics of the lactobacillus culture medium have an antagonistic effect on conditionally pathogenic microorganisms. Adhesion, biofilm formation, and antagonistic activity of probiotic lactobacillus strains are strain-specific properties.

Disease-Inspired Design of Biomimetic Tannic Acid-Based Hybrid Nanocarriers for Enhancing the Treatment of Bacterial-Induced Sepsis.

This study explored the development of novel biomimetic tannic acid-based hybrid nanocarriers (HNs) for targeted delivery of ciprofloxacin (CIP-loaded TAH-NPs) against bacterial-induced sepsis. The prepared CIP-loaded TAH-NPs exhibited appropriate physicochemical characteristics and demonstrated biocompatibility and nonhemolytic properties. Computational simulations and microscale thermophoresis studies validated the strong binding affinity of tannic acid (TA) and its nanoformulation to human Toll-like receptor 4, surpassing that of the natural substrate lipopolysaccharide (LPS), suggesting a potential competitive inhibition against LPS-induced inflammatory responses. CIP released from TAH-NPs displayed a sustained release profile over 72 h. The in vitro antibacterial activity studies revealed that CIP-loaded TAH-NPs exhibited enhanced antibacterial efficacy and efflux pump inhibitory activity. Specifically, they showed a 3-fold increase in biofilm eradication activity against MRSA and a 2-fold increase against P. aeruginosa compared to bare CIP. Time-killing assays demonstrated complete bacterial clearance within 8 h of treatment with CIP-loaded TAH-NPs. In vitro DPPH scavenging and anti-inflammatory investigations confirmed the ability of the prepared hybrid nanosystem to neutralize reactive oxygen species (ROS) and modulate LPS-induced inflammatory responses. Collectively, these results suggest that CIP-loaded TAH-NPs may serve as an innovative nanocarrier for the effective and targeted delivery of antibiotics against bacterial-induced sepsis.

Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistant Acinetobacter spp.

Cefiderocol, a siderophore-cephalosporine conjugate antibiotic, shows promise as a therapeutic option for carbapenem-resistant (CR) Acinetobacter infections. While resistance has already been reported in A. baumannii, combination therapies with avibactam or sulbactam reduce MICs of cefiderocol, extending its efficacy. However, careful consideration is necessary when using these combinations. In our experiments, exposure of A. baumannii and A. lwoffii to cefiderocol and sulbactam or avibactam led to the selection of cefiderocol-resistant strains. Three of those were subjected to whole genome sequencing and transcriptomic analysis. The strains all possessed synonymous and non-synonymous substitutions and short deletions. The most significant mutations affected efflux pumps, transcriptional regulators, and iron homeostasis genes. Transcriptomics showed significant alterations in expression levels of outer membrane proteins, iron homeostasis, and ß-lactamases, suggesting adaptive responses to selective pressure. This study underscores the importance of carefully assessing drug synergies, as they may inadvertently foster the selection of resistant variants and complicate the management of CR Acinetobacter infections.IMPORTANCEThe emergence of carbapenem-resistant Acinetobacter strains as a serious global health threat underscores the urgent need for effective treatment options. Although few drugs show promise against CR Acinetobacter infections, resistance to both drugs has been reported. In this study, the molecular characterization of spontaneous cefiderocol-resistant variants, a CR A. baumannii strain with antagonism to sulbactam, and an A. lwoffii strain with antagonism to avibactam, provides valuable insights into the mechanisms of resistance to cefiderocol. Some mechanisms observed are associated with mutations affecting efflux pumps, regulators, and iron homeostasis genes. These findings highlight the importance of understanding resistance mechanisms to optimize treatment options. They also emphasize the importance of early evaluation of drug synergies to address the challenges of antimicrobial resistance in Acinetobacter infections.

Unexpected antagonism of deoxynivalenol and enniatins in intestinal toxicity through the Ras/PI3K/AKT signaling pathway.

Deoxynivalenol (DON) is a kind of widespread traditional Fusarium mycotoxins in the environment, and its intestinal toxicity has received considerable attention. Recently, the emerging Fusarium mycotoxin enniatins (ENNs) have also been shown to frequently coexist with DON in animal feed and food with large consumption. However, the mechanism of intestinal damage caused by the two mycotoxins co-exposure remains unclear. In this study, Caco-2 cell line was used to investigate the combined toxicity and potential mechanisms of four representative ENNs (ENA, ENA1, ENB, and ENB1) and DON. The results showed that almost all mixed groups showed antagonistic effects, particularly ENB at 1/4 IC50 (CI = 6.488). Co-incubation of ENNs mitigated the levels of signaling molecule levels disrupted by DON, including reactive oxygen species (ROS), calcium mobilization (Ca2+), adenosine triphosphate (ATP). The differentially expressed genes (DEGs) between the mixed and ENB groups were significantly enriched in the Ras/PI3K/Akt signaling pathway, including 28 up-regulated genes and 40 down-regulated genes. Quantitative real-time PCR further confirmed the lower expression of apoptotic gene in the mixed group, thereby reducing the cytotoxic effects caused by DON exposure. This study emphasizes that co-exposure of ENNs and DON reduces cytotoxicity by regulating the Ras/PI3K/Akt signaling pathway. Our results provide the first comprehensive evidence about the antagonistic toxicity of ENNs and DON on Caco-2 cells, and new insights into mechanisms investigated by transcriptomics.

Efficacy and Safety of Naldemedine for Opioid-Induced Constipation in Children.

Background: Naldemedine, a peripherally acting opioid µ receptor antagonist, is effective for prevention of opioid-induced constipation (OIC); however, evidence on its use in children is limited. Objective: To evaluate the efficacy and safety of naldemedine in pediatric patients with OIC. Design, Setting/Subjects: Retrospective analysis of 32 pediatric patients with OIC treated with naldemedine in a single institution in Japan from June 2017 to March 2021. Measurements: Efficacy was evaluated in 13 evaluable patients with bowel movement (BM) response, defined as those with at least three BMs in the first 7 days after naldemedine initiation and an increase of at least one BM from baseline. Safety was evaluated by examining adverse events (AEs) based on the Common Terminology Criteria for AEs (v5.0). Results: BM response was recorded in 11 of the 13 patients (85%), and the number BMs per day significantly increased from 0.43 before naldemedine to 1.00 after naldemedine (p = 0.025). The most common AE was diarrhea, observed in 16 of the 32 patients (50%), and all instances were grade 1 or 2. In three of the 16 patients, naldemedine was discontinued owing to worsening diarrhea. Conclusions: In pediatric patients, naldemedine resulted in a high rate of BM response and increased the BM frequency, indicating its efficacy. In some patients, grade 2 diarrhea required naldemedine discontinuation, suggesting that it should be used with caution in pediatric patients. Further studies are warranted to determine the optimal naldemedine dose in pediatric patients.

Isolation of the Endophytic Fungus Aspergillus terreus from a Halophyte (Tetraena qatarensis) and Assessment of Its Potential in Tomato Seedling Protection.

Living in diverse environmentally harsh conditions, the plant exhibits a unique survival mechanism. As a result, the endophytes residing within the plant produce specific compounds that promote the plant's growth and defend it against pathogens. Plants and algae symbiotically harbor endophytes, i.e., microbes and microorganisms living within them. The objective of this study is to isolate endophytic fungi, specifically strains of Aspergillus terreus, from the leaves of the salt-tolerant plant Tetraena qatarensis and to explore the salt tolerance, antagonistic activity, and growth promotion properties. Strain C A. terreus (ON117337.1) was screened for salt tolerance and antagonistic effects. Regarding salt tolerance, the isolate demonstrated the ability to thrive in a concentration of up to 10% NaCl. A. terreus showed inhibitory activity against four fungal phytopathogens, namely Fusarium oxysporum, Alternaria alternata, Colletotrichum gloeosporioides, and Botrytis cinerea. The GC-MS investigation of the fungal (strain C Aspergillus terreus) extract showed the presence of about 66 compounds (secondary metabolites). Secondary metabolites (SMs) are produced, like Hexadecanoic acid, which aids in controlling phytopathogens. Also produced is lovastatin, which is used to treat hypercholesterolemia. Strain C, which showed salinity tolerance and the highest inhibitory activity, was further analyzed for its effect on tomato seed germination under pathogen stress from Fusarium oxysporum. The greenhouse experiment indicated that the fungi increased the length of tomato seedlings and the plant biomass. Therefore, the selected endophytes derived from Tetraena qatarensis were scrutinized for their potential as biocontrol agents, aiming to thwart fungal pathogens and stimulate plant growth. The in vitro and in vivo assessments of strain C (Aspergillus terreus) against Fusarium oxysporum in this investigation indicate the promising role of endophytes as effective biological control agents. Investigating novel bio-products offers a sustainable approach to agriculture, gradually reducing dependence on chemical fungicides.