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.

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.

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.

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.

Heart rate reactivity, recovery, and endurance of the incremental shuttle walk test in patients prone to heart failure.

AIMS: Few randomized trials assessed the changes over time in the chronotropic heart rate (HR) reactivity (CHR), HR recovery (HRR) and exercise endurance (EE) in response to the incremental shuttle walk test (ISWT). We addressed this issue by analysing the open HOMAGE (Heart OMics in Aging) trial. METHODS: In HOMAGE, 527 patients prone to heart failure were randomized to usual treatment with or without spironolactone (25-50 mg/day). The current sub-study included 113 controls and 114 patients assigned spironolactone (~70% on beta-blockers), who all completed the ISWT at baseline and at Months 1 and 9. Within-group changes over time (follow-up minus baseline) and between-group differences at each time point (spironolactone minus control) were analysed by repeated measures ANOVA, unadjusted or adjusted for sex, age and body mass index, and additionally for baseline for testing 1 and 9 month data. RESULTS: Irrespective of randomization, the resting HR and CHR did not change from baseline to follow-up, with the exception of a small decrease in the HR immediately post-exercise (-3.11 b.p.m.) in controls at Month 9. In within-group analyses, HR decline over the 5 min post-exercise followed a slightly lower course at the 1 month visit in controls and at the 9 month visits in both groups, but not at the 1 month visit in the spironolactone group. Compared with baseline, EE increased by two to three shuttles at Months 1 and 9 in the spironolactone group but remained unchanged in the control group. In the between-group analyses, irrespective of adjustment, there were no HR differences at any time point from rest up to 5 min post-exercise or in EE. Subgroup analyses by sex or categorized by the medians of age, left ventricular ejection fraction or glomerular filtration rate were confirmatory. Combining baseline and Months 1 and 9 data in both treatment groups, the resting HR, CHR and HRR at 1 and 5 min averaged 61.5, 20.0, 9.07 and 13.8 b.p.m. and EE 48.3 shuttles. CONCLUSIONS: Spironolactone on top of usual treatment compared with usual treatment alone did not change resting HR, CHR, HRR and EE in response to ISWT. Beta-blockade might have concealed the effects of spironolactone. The current findings demonstrate that the ISWT, already used in a wide variety of pathological conditions, is a practical instrument to measure symptom-limited exercise capacity in patients prone to developing heart failure because of coronary heart disease.

Molecular targets of caffeine in the central nervous system.

Caffeine is an alkaloid obtained from plants and is one of the most consumptive drug in the form of chocolate, coffee and beverages. The potential impact of caffeine within CNS can be easily understood by mechanism of action-antagonism of adenosine receptor, calcium influx, inhibits phosphodiesterases. Adenosine a neuromodulator for adenosine receptors, which are abundantly expressed within the central nervous system. Caffeine antagonized the adenosine receptor, hence stimulate expression of dopamine. It plays pivotal role in many metabolic pathways within the brain and nervous system, it reduced the amyloid-ß-peptide (Aß) accumulation, downregulation of tau protein phosphorylation, stimulate cholinergic neurons and inhibits the acetylcholinestrase (AChE). It also possess antioxidant and antiapoptotic activity. Caffeine act as nutraceutical product, improves mental health. It contains antioxidants, vitamins, minerals and dietary supplements, by reducing the risk factor of several neurodegenerations including Alzheimer's disease, migraine, gallstone, cancer, Huntington's disease and sclerosis. This act as a stimulant and have capability to increase the effectiveness of certain pain killer. Beside positive affects, over-consumption of caffeine leads to negative impact: change in sleep pattern, hallucinations, high blood pressure, mineral loss and even heartburn. This chapter highlights pros and cons of caffeine consumption.

[Characteristics of Soil Selenium-cadmium Migration and Accumulation and Its Bioeffectiveness in Typical Geological High Background Area].

The prevalence of selenium-cadmium （Se-Cd） symbiosis in soils of geologically high background areas directly affects the safe utilization of Se-rich land resources. To investigate the migration and accumulation characteristics and bio-effectiveness of Se-Cd in the soil-crop system in typical geological high background areas of Southwest China and to realize the safe use of natural Se-rich land resources in geological high background areas, we collected 84 samples of agricultural crops （maize） and their supporting root systems and analyzed the Se-Cd content and physicochemical properties. Se-Cd accumulation characteristics, influencing factors, and bio-effectiveness of the soil-crop system were evaluated using geostatistics, bioenrichment factors, and geographic detectors. The results showed that the Se-Cd content in the study area was significantly higher than the background value of the soil in the whole country and in Yunnan Province. Influenced by the geological background, secondary enrichment in the process of soil formation, and agricultural activities, the accumulation and enrichment characteristics of Se in the root soil varied from no enrichment to slightly enriched, and the occurrence form was dominated by the residue state. The accumulation index of soil Cd was mainly in the medium pollution level, and the occurrence form was mainly in the residual state and the combined state of iron and manganese. The Se-enrichment rate of crop seeds reached 98.8% （DB 50/T 524-2013 standard）, and the average value of bioconcentration factor was 5.8%. The exceeding rate of Cd content in crop seeds was only 1.19% （GB 2762-2022 standard）, and the average value of Cd bioconcentration factor was 2.11%, so the ecological risk of heavy metal Cd in crop seeds was relatively low. In the Se-Cd symbiosis area under geological background, the weak alkaline environment of the soil could effectively reduce the bioavailability of Cd in crop seeds, and the Se-rich soil could inhibit the uptake of Cd by the crops to a certain extent. Correlation analysis showed that the migration and accumulation of Se and Cd from soil to crop seeds in the soil-crop system were affected by the elemental accumulation pattern and the physical and chemical properties （pH） of the soil, and at the same time, there was a certain synergistic-antagonistic effect between Se and Cd in the soil-crop system. Correlation analysis showed that the migration and accumulation of Se and Cd from soil to crop seeds in the soil-crop system was influenced by the occurrence of elements, soil physicochemical properties （pH）, and other factors, and there was also a certain synergistic-antagonistic interaction between Se and Cd in the soil-crop system.

GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly.

CONTEXT: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. OBJECTIVE: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. DESIGN, PATIENTS, SETTING, INTERVENTIONS: 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. MAIN OUTCOME MEASURE: The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. RESULTS: In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. CONCLUSIONS: Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

Magnesium: A Defense Line to Mitigate Inflammation and Oxidative Stress in Adipose Tissue.

Magnesium (Mg) is involved in essential cellular and physiological processes. Globally, inadequate consumption of Mg is widespread among populations, especially those who consume processed foods, and its homeostasis is impaired in obese individuals and type 2 diabetes patients. Since Mg deficiency triggers oxidative stress and chronic inflammation, common features of several frequent chronic non-communicable diseases, interest in this mineral is growing in clinical medicine as well as in biomedicine. To date, very little is known about the role of Mg deficiency in adipose tissue. In obesity, the increase in fat tissue leads to changes in the release of cytokines, causing low-grade inflammation and macrophage infiltration. Hypomagnesemia in obesity can potentiate the excessive production of reactive oxygen species, mitochondrial dysfunction, and decreased ATP production. Importantly, Mg plays a role in regulating intracellular calcium concentration and is involved in carbohydrate metabolism and insulin receptor activity. This narrative review aims to consolidate existing knowledge, identify research gaps, and raise awareness of the critical role of Mg in supporting adipose tissue metabolism and preventing oxidative stress.

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.

Aflatoxin B1 Control by Various Pseudomonas Isolates.

The climate-change-coupled fungal burden in crop management and the need to reduce chemical pesticide usage highlight the importance of finding sustainable ways to control Aspergillus flavus. This study examines the effectiveness of 50 Pseudomonas isolates obtained from corn rhizospheres against A. flavus in both solid and liquid co-cultures. The presence and quantity of aflatoxin B1 (AFB1) and AFB1-related compounds were determined using high-performance liquid chromatography-high resolution mass spectrometry analysis. Various enzymatic- or non-enzymatic mechanisms are proposed to interpret the decrease in AFB1 production, accompanied by the accumulation of biosynthetic intermediates (11-hydroxy-O-methylsterigmatocystin, aspertoxin, 11-hydroxyaspertoxin) or degradation products (the compounds C16H10O6, C16H14O5, C18H16O7, and C19H16O8). Our finding implies the upregulation or enhanced activity of fungal oxidoreductases and laccases in response to bacterial bioactive compound(s). Furthermore, non-enzymatic reactions resulted in the formation of additional degradation products due to acid accumulation in the fermented broth. Three isolates completely inhibited AFB1 or any AFB1-related compounds without significantly affecting fungal growth. These bacterial isolates supposedly block the entire pathway for AFB1 production in the fungus during interaction. Apart from identifying effective Pseudomonas isolates as potential biocontrol agents, this work lays the foundation for exploring new bacterial bioactive compounds.

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.

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.

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.

Worse than nothing at all: the inequality of fusions joining autosomes to the PAR and non-PAR portions of sex chromosomes.

Chromosomal fusions play an integral role in genome remodeling and karyotype evolution. Fusions that join a sex chromosome to an autosome are particularly abundant across the tree of life. However, previous models on the establishment of such fusions have not accounted for the physical structure of the chromosomes. We predict a fusion joining an autosome to the pseudoautosomal region (PAR) of a sex chromosome will not remain stable, and the fusion will switch from the X to the Y chromosome each generation due to recombination. We have produced a forward-time population genetic simulation to explore the outcomes of fusions to both the PAR and non-PAR of sex chromosomes. The model can simulate the fusion of an autosome containing a sexually antagonistic locus to either the PAR or non-PAR end of a sex chromosome. Our model is diploid, two-locus, and biallelic. Our results show a clear pattern where fusions to the non-PAR are favored in the presence of sexual antagonism, whereas fusions to the PAR are disfavored in the presence of sexual antagonism.

Expanding the Pseudomonas diversity of the wheat rhizosphere: four novel species antagonizing fungal phytopathogens and with plant-beneficial properties.

Plant-beneficial Pseudomonas bacteria hold the potential to be used as inoculants in agriculture to promote plant growth and health through various mechanisms. The discovery of new strains tailored to specific agricultural needs remains an open area of research. In this study, we report the isolation and characterization of four novel Pseudomonas species associated with the wheat rhizosphere. Comparative genomic analysis with all available Pseudomonas type strains revealed species-level differences, substantiated by both digital DNA-DNA hybridization and average nucleotide identity, underscoring their status as novel species. This was further validated by the phenotypic differences observed when compared to their closest relatives. Three of the novel species belong to the P. fluorescens species complex, with two representing a novel lineage in the Pseudomonas phylogeny. Functional genome annotation revealed the presence of specific features contributing to rhizosphere colonization, including flagella and components for biofilm formation. The novel species have the genetic potential to solubilize nutrients by acidifying the environment, releasing alkaline phosphatases and their metabolism of nitrogen species, indicating potential as biofertilizers. Additionally, the novel species possess traits that may facilitate direct promotion of plant growth through the modulation of the plant hormone balance, including the ACC deaminase enzyme and auxin metabolism. The presence of biosynthetic clusters for toxins such as hydrogen cyanide and non-ribosomal peptides suggests their ability to compete with other microorganisms, including plant pathogens. Direct inoculation of wheat roots significantly enhanced plant growth, with two strains doubling shoot biomass. Three of the strains effectively antagonized fungal phytopathogens (Thielaviopsis basicola, Fusarium oxysporum, and Botrytis cinerea), demonstrating their potential as biocontrol agents. Based on the observed genetic and phenotypic differences from closely related species, we propose the following names for the four novel species: Pseudomonas grandcourensis sp. nov., type strain DGS24T ( = DSM 117501T = CECT 31011T), Pseudomonas purpurea sp. nov., type strain DGS26T ( = DSM 117502T = CECT 31012T), Pseudomonas helvetica sp. nov., type strain DGS28T ( = DSM 117503T = CECT 31013T) and Pseudomonas aestiva sp. nov., type strain DGS32T ( = DSM 117504T = CECT 31014T).

Exploring synergistic and antagonistic interactions in phage-antibiotic combinations against ESKAPE pathogens.

In the era of antimicrobial resistance, phage-antibiotic combinations offer a promising therapeutic option, yet research on their synergy and antagonism is limited. This study aims to assess these interactions, focusing on protein synthesis inhibitors and cell envelope-active agents against multidrug-resistant bacterial strains. We evaluated synergistic and antagonistic interactions in multidrug-resistant Staphylococcus aureus, Enterococcus faecium, and Pseudomonas aeruginosa strains. Phages were combined with protein synthesis inhibitors [linezolid (LZD), minocycline (MIN), gentamicin (GEN), and azithromycin (AZM)] or cell envelope-active agents [daptomycin (DAP), ceftaroline (CPT), and cefepime (FEP)]. Modified checkerboard minimum inhibitory concentration assays and 24-h time-kill analyses were conducted, alongside one-step growth curves to analyze phage growth kinetics. Statistical comparisons used one-way analysis of variance (ANOVA) and the Tukey test (P < 0.05). In the checkerboard and 24-h time-kill analyses (TKA) of S. aureus and E. faecium, phage-LZD and phage-MIN combinations were antagonistic (FIC > 4) while phage-DAP and phage-CPT were synergistic (FIC 0.5) (ANOVA range of mean differences 0.52-2.59 log10 CFU/mL; P < 0.001). For P. aeruginosa, phage-AZM was antagonistic (FIC > 4), phage-GEN was additive (FIC = 1), and phage-FEP was synergistic (ANOVA range of mean differences 1.04-1.95 log10 CFU/mL; P < 0.001). Phage growth kinetics were altered in the presence of LZD and MIN against S. aureus and in the presence of LZD against a single E. faecium strain (HOU503). Our findings indicate that select protein synthesis inhibitors may induce phage-antibiotic antagonism. However, this antagonism may not solely stem from changes in phage growth kinetics, warranting further investigation into the complex interplay among strains, phage attributes, and antibiotic mechanisms affecting bacterial inhibition.IMPORTANCEIn the face of escalating antimicrobial resistance, combining phages with antibiotics offers a promising avenue for treating infections unresponsive to traditional antibiotics. However, while studies have explored synergistic interactions, less attention has been given to potential antagonism and its impact on phage growth kinetics. This research evaluates the interplay between phages and antibiotics, revealing both synergistic and antagonistic patterns across various bacterial strains and shedding light on the complex dynamics that influence treatment efficacy. Understanding these interactions is crucial for optimizing combination therapies and advancing phage therapy as a viable solution for combating antimicrobial resistance.

Insights into the antagonistic effects of calcium on cadmium accumulation in peanuts (Arachis hypogaea L.).

Peanut (Arachis hypogaea L.) plant has a high requirement for calcium (Ca) during its growth and development, and possesses the ability to accumulate cadmium (Cd) from soil. However, the precise mechanisms underlying the antagonistic effects between Ca and Cd remain unclear. This study aimed to explore the dynamic changes in Cd accumulation in peanut seedlings by varying the Ca-to-Cd concentration ratio (CRCa/Cd) from 250 to 3500. Additionally, the influence of ion channel competition and cell wall fixation in the root on Cd accumulation in peanuts was explored by analyzing Cd chemical forms, subcellular distribution, pectin content, and Cd2+ fluxes using a non-invasive micro-test technique (NMT). The findings revealed that Cd accumulation in peanut seedlings was significantly lower when the CRCa/Cd was higher than 2000. In the Ca-pretreated seedlings (cell wall fixation treatment), Cd content in the shoots and roots decreased by 18.9% and 25.0%, respectively, compared with the simultaneous exposure to Ca and Cd (ion channel competition treatment). Cd2+ influx in peanut roots decreased by 55.8% in the Ca-pretreated group. However, increasing the competitive strength of Ca2+ and Cd2+ did not affect Cd2+ influx under normal Ca conditions (>2 mM Ca). Meanwhile, Ca pretreatment significantly increased Cd distribution in the root cell wall, pectate, and protein-binding forms, while significantly reducing Cd distribution in root soluble components and inorganic Cd forms. The pectin content in the roots increased by 128% and 226% in the Ca and Cd simultaneous exposure treatment and Ca pretreatment, respectively. These results suggest that Ca pretreatment enhanced Cd retention in the root cell wall. Overall, exogenous Ca effectively mitigated Cd accumulation in peanut plants when the CRCa/Cd was below 2000, and Ca2+ channels partially facilitate the entry of Cd2+ into peanut roots. Under normal Ca supply conditions, exogenous Ca reduced Cd accumulation in peanuts primarily through root cell wall fixation rather than ion channel competition. Our findings provide insights into the mechanism by which Ca alleviates the uptake and transfer of Cd in peanuts.

Contrasting toxicity response to a mixture of azithromycin and ivermectin between a freshwater and a euryhaline rotifer.

Organisms are usually exposed to mixtures of emerging pollutants in aquatic environments. Due to their widespread use and environmental relevance, the individual and combined effects of the drugs azithromycin (AZT) and ivermectin (IVM) on the freshwater rotifer Lecane papuana and the euryhaline rotifer Proales similis were investigated. Rotifers showed greater sensitivity to IVM compared to AZT. The LC50 values of IVM and AZT for L. papuana and P. similis were 0.163 and 0.172 mg/L, and 13.52 and 20.00 mg/L, respectively. Population growth rates, assessed in chronic toxicity assays, responded negatively to increasing concentrations of both toxicants, either individually or in combination. Our results revealed two distinct combined toxicity responses: a strong synergistic effect in the freshwater rotifer and a marked antagonistic impact of the AZT-IVM mixtures in the euryhaline rotifer.

New morpholine-containing pyrimidinones act on α-adrenoceptors.

Drugs that act on α-adrenoceptors may contain morpholine and pyrimidinone heterocycles. The aim of this study was to synthesize a series of pyrimidinones (S6a-e and S8) and characterize their α-adrenoceptor activity. Cytotoxicity assays (MTT and LDH) were performed in A7r5 and HUVECs. Concentration-effect curves to phenylephrine (Phe) were performed in rat aortic rings in the presence of compounds S6a-e and S8 or vehicle. Nitric oxide (NO) production and NO stable metabolic products, nitrite and nitrate, expressed as total nitrogen oxides (NOx) were assessed in HUVECs by confocal microscopy with the DAF-2DA probe and by the Griess reaction, respectively. Molecular docking simulations were performed using the 6a compound and α2A-adrenoceptor. In the evaluated conditions, the percentage of viable cells and the release of LDH were similar between control cells and cells exposed to the tested pyrimidinones. S6d, S6e, S8, and the positive control prazosin (but not S6a, S6b, and S6c) decreased Phe-induced contractions in endothelium-denuded aortic rings. S6a, S6b, and S6c decreased Phe-induced contractions in endothelium-intact aortic rings. The effect of S6a was abolished by L-NAME. NO production and NOx levels were inhibited in the presence of the α2 receptor antagonist yohimbine and the NOS inhibitor L-NAME. The 6a docking simulation estimated that the mean binding free energy of the compound was lower than the estimated value for yohimbine. These data suggest that S6d, S6e, and S8 may be α1-adrenoceptor antagonists while S6a acts as an agonist of α2-adrenoceptors.