Association of enterolactone with blood pressure and hypertension risk in NHANES.

The gut microbiome may affect overall cardiometabolic health. Enterolactone is an enterolignan reflective of dietary lignan intake and gut microbiota composition and diversity that can be measured in the urine. The purpose of this study was to examine the association between urinary enterolactone concentration as a reflection of gut health and blood pressure/risk of hypertension in a large representative sample from the US population. This analysis was conducted using data from the National Health and Nutrition Examination Survey (NHANES) collected from January 1999 through December 2010. Variables of interest included participant characteristics (including demographic, anthropometric and social/environmental factors), resting blood pressure and hypertension history, and urinary enterolactone concentration. 10,637 participants (45 years (SE = 0.3), 51.7% (SE = 0.6%) were female) were included in analyses. In multivariable models adjusted for demographic, socioeconomic and behavioral/environmental covariates, each one-unit change in log-transformed increase in enterolactone was associated with a 0.738 point (95% CI: -0.946, -0.529; p<0.001) decrease in systolic blood pressure and a 0.407 point (95% CI: -0.575, -0.239; p<0.001) decrease in diastolic blood pressure. Moreover, in fully adjusted models, each one-unit change in log-transformed enterolactone was associated with 8.2% lower odds of hypertension (OR = 0.918; 95% CI: 0.892, 0.944; p<0.001). Urinary enterolactone, an indicator of gut microbiome health, is inversely associated with blood pressure and hypertension risk in a nationally representative sample of U.S. adults.

[Research progress on mechanisms of ligustilide in treatment of nervous system diseases].

Ligustilide is the main active component of the volatile oil from Angelica sinensis and Ligusticum chuanxiong in the Umbelliferae family. It is a phthalein compound with anti-inflammatory, analgesic, antioxidant, anti-tumor, anti-atherosclerosis, neuroprotective, and other pharmacological effects. It can improve the permeability of the blood-brain barrier and has important potential in the treatment of neurodegenerative diseases and other nervous system diseases, such as Alzheimer's disease, ischemic stroke, Parkinson's disease, vascular dementia, and depression. Therefore, the mechanism of ligustilide in the treatment of nervous system diseases was summarized to provide a reference for drug development and clinical application.

Multiple stresses induced by chronic exposure to flupyradifurone affect honey bee physiological states.

Flupyradifurone (FPF) has been reported to have a potential risk to terrestrial and aquatic ecosystems. In the present study, the effects of chronic FPF exposure on bees were systematically investigated at the individual behavioral, tissue, cell, enzyme activity, and the gene expression levels. Chronic exposure (14 d) to FPF led to reduced survival (12 mg/L), body weight gain (4 and 12 mg/L), and food utilization efficiency (4 and 12 mg/L). Additionally, FPF exposure (12 mg/L) impaired sucrose sensitivity and memory of bees. Morphological analysis revealed significant cellular and subcellular changes in brain neurons and midgut epithelial cells, including mitochondrial damage, nuclear disintegration, and apoptosis. FPF exposure (4 and 12 mg/L) led to oxidative stress, as evidenced by increased lipid peroxidation and alterations in antioxidant enzyme activity. Notably, gene expression analysis indicated significant dysregulation of apoptosis, immune, detoxification, sucrose responsiveness and memory-related genes, suggesting the involvement of different pathways in FPF-induced toxicity. The multiple stresses and potential mechanisms described here provide a basis for determining the intrinsic toxicity of FPF.

Lead Optimization of Butyrolactone I as an Orally Bioavailable Antiallergic Agent Targeting FcγRIIB.

Food allergy (FA) poses a growing global food safety concern, yet no effective cure exists in clinics. Previously, we discovered a potent antifood allergy compound, butyrolactone I (BTL-I, 1), from the deep sea. Unfortunately, it has a very low exposure and poor pharmacokinetic (PK) profile in rats. Therefore, a series of structural optimizations toward the metabolic pathways of BTL-I were conducted to provide 18 derives (2-19). Among them, BTL-MK (19) showed superior antiallergic activity and favorable pharmacokinetics compared to BTL-I, being twice as potent with a clearance (CL) rate of only 0.5% that of BTL-I. By oral administration, Cmax and area under the concentration-time curve (AUC0-∞) were 565 and 204 times higher than those of BTL-I, respectively. These findings suggest that butyrolactone methyl ketone (BTL-BK) could serve as a drug candidate for the treatment of FAs and offer valuable insights into optimizing the druggability of lead compounds.

Ligustilide covalently binds to Cys703 in the pre-S1 helix of TRPA1, blocking the opening of channel and relieving pain in rats with acute soft tissue injury.

ETHNOPHARMACOLOGICAL RELEVANCE: The natural anodyne Ligustilide (Lig), derived from Angelica sinensis (Oliv.) Diels and Ligusticum chuanxiong Hort., has been traditionally employed for its analgesic properties in the treatment of dysmenorrhea and migraine, and rheumatoid arthritis pain. Despite the existing reports on the correlation between TRP channels and the analgesic effects of Lig, a comprehensive understanding of their underlying mechanisms of action remains elusive. AIM OF THE STUDY: The objective of this study is to elucidate the mechanism of action of Lig on the analgesic target TRPA1 channel. METHODS: The therapeutic effect of Lig was evaluated in a rat acute soft tissue injury model. The analgesic target was identified through competitive inhibition of TRP channel agonists at the animal level, followed by Fluo-4/Ca2+ imaging on live cells overexpressing TRP proteins. The potential target was verified through in-gel imaging, colocalization using a Lig-derived molecular probe, and a drug affinity response target stability assay. The binding site of Lig was identified through protein spectrometry and further analyzed using molecular docking, site-specific mutation, and multidisciplinary approaches. RESULTS: The administration of Lig effectively ameliorated pain and attenuated oxidative stress and inflammatory responses in rats with soft tissue injuries. Moreover, the analgesic effects of Lig were specifically attributed to TRPA1. Mechanistic studies have revealed that Lig directly activates TRPA1 by interacting with the linker domain in the pre-S1 region of TRPA1. Through metabolic transformation, 6,7-epoxyligustilide (EM-Lig) forms a covalent bond with Cys703 of TRPA1 at high concentrations and prolonged exposure time. This irreversible binding prevents endogenous electrophilic products from entering the cysteine active center of ligand-binding pocket of TRPA1, thereby inhibiting Ca2+ influx through the channel opening and ultimately relieving pain. CONCLUSIONS: Lig selectively modulates the TRPA1 channel in a bimodal manner via non-electrophilic/electrophilic metabolic conversion. The epoxidized metabolic intermediate EM-Lig exerts analgesic effects by irreversibly inhibiting the activation of TRPA1 on sensory neurons. These findings not only highlight the analgesic mechanism of Lig but also offer a novel nucleophilic attack site for the development of TRPA1 antagonists in the pre-S1 region.

Proposal for structure revision of pinofuranoxin A through total syntheses of stereoisomers.

The relative configuration of the epoxide functionality in pinofuranoxin A (1), α-alkylidene-ß-hydroxy-γ-methyl-γ-butyrolactone with trans-epoxy side chain isolated by Evidente et al. in 2021, was revised by DFT-based spectral reinvestigations and stereo-controlled synthesis. The present investigation demonstrates the difficulty of the configurational elucidation of the stereogenic centers on the conformationally flexible acyclic side-chains. Sharpless's enantioselective epoxidations and dihydroxylations were quite effective in the reinvestigations of the configurations. As our syntheses made all diastereomers available, these would be quite effective in the next structure-biological activity relationship studies.

Flupyradifurone negatively affects survival, physical condition and mobility in the two-spotted lady beetle (Adalia bipunctata).

Lady beetles play a crucial role in natural ecosystems and agricultural settings. Unfortunately, these insects and more specifically the two-spotted lady beetle (Adalia bipunctata) are currently facing a severe decline in populations due to various stressors, with pesticide exposure being a significant threat. Flupyradifurone is a relatively newly introduced insecticide and as existing research is mainly elucidating its effects on bees there remains a limited understanding of its effects on non-hymenopteran insects, including lady beetles. In this study we investigated the impact of acute orally applied flupyradifurone doses on survival and sublethal parameters such as physical condition and mobility on A. bipunctata. Our findings revealed a significant increase in mortality among individuals subjected to flupyradifurone doses of 19 ng/individual (corresponding to >1.5-2.0 ng active substance (a.s.)/mg body weight (bw). The calculated LD50 of flupyradifurone at 48 h was 2.11 ng a.s./mg bw corresponding to an amount of 26.38 ng/individual. Sublethal consequences were observable immediately after pesticide application. Even at doses as low as 2 ng/individual (corresponding to >0.0-0.5 ng a.s./mg bw), flupyradifurone induced trembling and temporary immobility in treated animals. Furthermore, pesticide intoxication led to hypoactivity, with less distance covered and a decline in straightness of locomotion. In conclusion, our study underscores the harmful effects of flupyradifurone on the two-spotted lady beetle at doses notably lower than those affecting bees. These findings stress the importance of additional research to attain a more holistic understanding of pesticide impacts not only on a broader range of non-target arthropods species, but also on various exposure routes as well as lethal and sublethal effects.

The Development and Evaluation of a Literature-Based Dietary Index for Gut Microbiota.

The aim of the study was to develop and evaluate a novel dietary index for gut microbiota (DI-GM) that captures dietary composition related to gut microbiota profiles. We conducted a literature review of longitudinal studies on the association of diet with gut microbiota in adult populations and extracted those dietary components with evidence of beneficial or unfavorable effects. Dietary recall data from the National Health and Nutrition Examination Survey (NHANES, 2005-2010, n = 3812) were used to compute the DI-GM, and associations with biomarkers of gut microbiota diversity (urinary enterodiol and enterolactone) were examined using linear regression. From a review of 106 articles, 14 foods or nutrients were identified as components of the DI-GM, including fermented dairy, chickpeas, soybean, whole grains, fiber, cranberries, avocados, broccoli, coffee, and green tea as beneficial components, and red meat, processed meat, refined grains, and high-fat diet (≥40% of energy from fat) as unfavorable components. Each component was scored 0 or 1 based on sex-specific median intakes, and scores were summed to develop the overall DI-GM score. In the NHANES, DI-GM scores ranged from 0-13 with a mean of 4.8 (SE = 0.04). Positive associations between DI-GM and urinary enterodiol and enterolactone were observed. The association of the novel DI-GM with markers of gut microbiota diversity demonstrates the potential utility of this index for gut health-related studies.

Effect of Nasal Continuous Positive Airway Pressure on Retinopathy of Prematurity in Preterm Newborns: A Comparative Analysis with Mechanical Ventilation and High-Flow Nasal Cannula Therapy.

BACKGROUND Retinopathy of prematurity (ROP), originally described as retrolental fibroplasia, represents an abnormal growth of blood vessels in the premature retina that can occur in response to oxygen therapy. The association between ROP and invasive mechanical ventilation has been widely studied in the literature; however, the relationships between different types of ventilation and ROP have not been as well documented. This study aimed to compare the association of ROP incidence with mechanical ventilation (MV), nasal continuous positive airway pressure (nCPAP), and high-flow nasal cannula (HFNC) therapies in 130 pre-term infants with gestational ages <32 weeks. MATERIAL AND METHODS The study includes 130 premature newborns, out of which 54 underwent MV therapy, either alone or in combination with nCPAP or HFNC therapy, 63 underwent nCPAP therapy, either alone or in combination with MV or HFNC therapy, and 23 underwent HFNC therapy, either alone or in combination with MV or nCPAP therapy. The relationships between ROP and the 3 types of ventilation were analyzed by univariate followed by multivariate logistic regression. RESULTS When adjusting for covariates, only nCPAP and birth weight were significantly associated with ROP, the former being a strong risk factor, with an adjusted odds ratio (AOR) of 7.264 (95% CI, 2.622-20.120; P<0.001), and the latter being a weak protective factor, with an AOR of 0.998 (95% CI, 0.996-0.999; P<0.05). CONCLUSIONS The results showed nCPAP was a strong ROP risk factor, birth weight was a weak ROP protective factor, and MV and HFNC were not significantly associated with increased ROP risk.

Enzymes with Lactonase Activity against Fungal Quorum Molecules as Effective Antifungals.

Since the growing number of fungi resistant to the fungicides used is becoming a serious threat to human health, animals, and crops, there is a need to find other effective approaches in the eco-friendly suppression of fungal growth. One of the main mechanisms of the development of resistance in fungi, as well as in bacteria, to antimicrobial agents is quorum sensing (QS), in which various lactone-containing compounds participate as signaling molecules. This work aimed to study the effectiveness of action of enzymes exhibiting lactonase activity against fungal signaling molecules. For this, the molecular docking method was used to estimate the interactions between these enzymes and different lactone-containing QS molecules of fungi. The catalytic characteristics of enzymes such as lactonase AiiA, metallo-ß-lactamase NDM-1, and organophosphate hydrolase His6-OPH, selected for wet experiments based on the results of computational modeling, were investigated. QS lactone-containing molecules (butyrolactone I and γ-heptalactone) were involved in the experiments as substrates. Further, the antifungal activity of the enzymes was evaluated against various fungal and yeast cells using bioluminescent ATP-metry. The efficient hydrolysis of γ-heptalactone by all three enzymes and butyrolactone I by His6-OPH was demonstrated for the first time. The high antifungal efficacy of action of AiiA and NDM-1 against most of the tested fungal cells was revealed.

Engineering quorum quenching acylases with improved kinetic and biochemical properties.

Many Gram-negative bacteria use N-acyl-L-homoserine lactone (AHL) signals to coordinate phenotypes such as biofilm formation and virulence factor production. Quorum-quenching enzymes, such as AHL acylases, chemically degrade these molecules which prevents signal reception by bacteria and inhibits undesirable biofilm-related traits. These capabilities make acylases appealing candidates for controlling microbes, yet candidates with high activity levels and substrate specificity and that are capable of being formulated into materials are needed. In this work, we undertook engineering efforts against two AHL acylases, PvdQ and MacQ, to generate these improved properties using the Protein One-Stop Shop Server. The engineering of acylases is complicated by low-throughput enzymatic assays. Alleviating this challenge, we report a time-course kinetic assay for AHL acylases that monitors the real-time production of homoserine lactone. Using the assay, we identified variants of PvdQ that were significantly stabilized, with melting point increases of up to 13.2°C, which translated into high resistance against organic solvents and increased compatibility with material coatings. While the MacQ mutants were unexpectedly destabilized, they had considerably improved kinetic properties, with >10-fold increases against N-butyryl-L-homoserine lactone and N-hexanoyl-L-homoserine lactone. Accordingly, these changes resulted in increased quenching abilities using a biosensor model and greater inhibition of virulence factor production of Pseudomonas aeruginosa PA14. While the crystal structure of one of the MacQ variants, M1, did not reveal obvious structural determinants explaining the observed changes in kinetics, it allowed for the capture of an acyl-enzyme intermediate that confirms a previously hypothesized catalytic mechanism of AHL acylases.

Effects of exogenous N-acyl homoserine lactones (AHLs) on methanogenic activities and microbial community differences during anaerobic digestion.

N-acyl homoserine lactones (AHLs) function as signaling molecules influencing microbial community dynamics. This study investigates the impact of exogenously applied AHLs on methane production during waste-activated sludge (WAS) anaerobic digestion (AD). Nine AHL types, ranging from 10-4 to 10 µg/g VSS, were applied, comparing microbial community composition under optimal AHL concentrations. Firmicutes, Bacteroidetes, Chloroflexi, and Proteobacteria were identified in anaerobic digesters with C4-HSL, C6-HSL, and C8-HSL. Compared to the control, Halobacterota increased by 19.25%, 20.87%, and 9.33% with C7-HSL, C10-HSL, and C12-HSL. Exogenous C7-HSL enhanced the relative abundance of Methanosarcina, Romboutsia, Sedimentibacter, Proteiniclasticum, Christensenellaceae_R-7_group. C10-HSL increased Methanosarcina abundance. C4-HSL, C6-HSL, C8-HSL, C10-HSL, and C12-HSL showed potential to increase unclassified_Firmicutes. Functional Annotation of Prokaryotic Taxa (FAPROTAX) predicted AHLs' impact on related functional genes, providing insights into their role in AD methanogenesis regulation. This study aimed to enhance the understanding of the influence of different types of exogenous AHLs on AD and provide technical support for regulating the methanogenesis efficiency of AD by exogenous AHLs.

Obesity-associated inflammatory macrophage polarization is inhibited by capsaicin and phytolignans.

Obesity is often accompanied by increased adipose tissue inflammation, a process that is partially driven by adipose tissue-resident macrophages. In this study, we explored the potential for plant-derived dietary compounds to exert anti-inflammatory effects in macrophages that alleviate obesity-associated adipocyte dysfunction. Capsaicin (CAP), schisandrin A (SA), enterodiol (END), and enterolactone (ENL) treatment polarized J774 macrophages to an "M2" or anti-inflammatory phenotype and inhibited responses to stimulation with lipopolysaccharide (LPS). Furthermore, these compounds blocked inflammasome activation when administered just before ATP-induced NLRP3 activation, as evidenced by the abrogation of IL-1ß release in mouse macrophages and human peripheral blood monocytes. The addition of CAP, SA, or ENL during the differentiation of bone marrow-derived macrophages was also sufficient to inhibit LPS-induced IL-6 and TNFα production. Finally, CAP, END, and ENL treatment during differentiation of 3T3-L1 adipocytes induced an adiponectin-high phenotype accompanied by increases in thermogenic gene expression, and conditioned media from these adipocytes inhibited LPS-induced production of IL-1ß, IL-6, and TNFα from J774 macrophages. These polarizing effects were partially mediated by the elevated adiponectin and decreased syndecan-4 in the adipocyte-conditioned media. These results implicate the contribution of plant-derived dietary components to the modulation of macrophages and adipocytes in obesity.NEW & NOTEWORTHY The utility of food-based products to prevent or alleviate chronic conditions such as obesity and its associated comorbidities is an attractive approach. Capsaicin, schisandrin A, enterodiol, and enterolactone, phytochemicals present in traditional medicinal food, decreased proinflammatory cytokine production from macrophages that, in turn, reduced obesity-associated adipocyte dysfunction. These results implicate the contribution of plant-derived dietary components to the modulation of macrophages and adipocytes in obesity.

Overexpression of CYP6CX4 contributing to field-evolved resistance to flupyradifurone, one novel butenolide insecticide, in Bemisia tabaci from China.

Bemisia tabaci is a formidable insect pest worldwide, and exhibits significant resistance to various insecticides. Flupyradifurone is one novel butenolide insecticide and has emerged as a new weapon against B. tabaci, but field-evolved resistance to this insecticide has become a widespread concern. To unravel the mechanisms of field-evolved flupyradifurone resistance, we conducted a comprehensive investigation into susceptibility of twenty-one field populations within the Beijing-Tianjin-Hebei Region of China. Alarmingly, thirteen of these populations displayed varying degrees of resistance, ranging from low to medium levels, and building upon our prior findings, we meticulously cloned and characterized the CYP6CX4 gene in B. tabaci. Our investigations unequivocally confirmed the association between CYP6CX4 overexpression and flupyradifurone resistance in three of the thirteen resistant strains via RNA interference. To further validate our findings, we introduced CYP6CX4 overexpression into a transgenic Drosophila melanogaster line, resulting in a significant development of resistance to flupyradifurone in D. melanogaster. Additionally, homology modeling and molecular docking analyses showed the stable binding of flupyradifurone to CYP6CX4, with binding free energy of -6.72 kcal mol-1. Collectively, our findings indicate that the induction of CYP6CX4 exerts one important role in detoxification of flupyradifurone, thereby promoting development of resistance in B. tabaci.

Single and combined exposure to 'bee safe' pesticides alter behaviour and offspring production in a ground-nesting solitary bee (Xenoglossa pruinosa).

Mounting evidence supporting the negative impacts of exposure to neonicotinoids on bees has prompted the registration of novel 'bee-friendly' insecticides for agricultural use. Flupyradifurone (FPF) is a butenolide insecticide that shares the same mode of action as neonicotinoids and has been assessed to be 'practically non-toxic to adult honeybees' using current risk assessment procedures. However, these assessments overlook some routes of exposure specific to wild bees, such as contact with residues in soil for ground-nesters. Co-exposure with other pesticides may also lead to detrimental synergistic effects. In a fully crossed experiment, we assessed the possible lethal and sublethal effects of chronic exposure to two pesticides used on Cucurbita crops, the insecticide Sivanto Prime (FPF) and the fungicide Quadris Top (azoxystrobin and difenoconazole), alone or combined, on solitary ground-nesting squash bees (Xenoglossa pruinosa). Squash bees exposed to Quadris Top collected less pollen per flower visit, while Sivanto-exposed bees produced larger offspring. Pesticide co-exposure induced hyperactivity in female squash bees relative to both the control and single pesticide exposure, and reduced the number of emerging offspring per nest compared to individual pesticide treatments. This study demonstrates that 'low-toxicity' pesticides can adversely affect squash bees under field-realistic exposure, alone or in combination.

Residual renal volume as a long-term independent predictive factor of developing chronic kidney disease after donor nephrectomy.

To assess the long-term association between the residual renal volume and the progression of chronic kidney disease (CKD) in kidney donors following open or laparoscopic donor nephrectomy. A retrospective observational study involving 452 individuals who underwent open or laparoscopic donor nephrectomy at Ramathibodi Hospital, Bangkok, Thailand. The study spanned over a comprehensive 60-month monitoring period. Residual renal volume was determined through Computer Tomography. Patient characteristics, surgical techniques, donated kidney side, and estimated glomerular filtration rate (eGFR) were collected and analysed. In a multivariate analysis, a residual renal volume exceeding 50% of original volume is associated with an increased likelihood of developing CKD, with a hazard ratio (HR) of 1.675 (P < 0.05), and male gender has a hazard ratio (HR) of 4.013 (P < 0.001). Additionally, age is identified as a minor risk factor for developing CKD, with hazard ratio (HR) of 1.107 (P < 0.001). Higher residual renal volume, male gender, and older age were identified as independent risk factors for the development of CKD following open or laparoscopic donor nephrectomy during long-term follow-up.

Molecular and functional characterization of heat-shock protein 70 in Aphis gossypii under thermal and xenobiotic stresses.

Aphis gossypii, a globally distributed and economically significant pest of several crops, is known to infest a wide range of host plants. Heat shock proteins (Hsps), acting as molecular chaperones, are essential for the insect's environmental stress responses. The present study investigated the molecular characteristics and expression patterns of AgHsp70, a heat shock protein gene, in Aphis gossypii. Our phylogenetic analysis revealed that AgHsp70 shared high similarity with homologs from other insects, suggesting a conserved function across species. The developmental expression profiles of AgHsp70 in A. gossypii showed that the highest transcript levels were observed in the fourth instar nymphs, while the lowest levels were detected in the third instar nymphs. Heat stress and exposure to four different xenobiotics (2-tridecanone, tannic acid, gossypol, and flupyradifurone (4-[(2,2-difluoroethyl)amino]-2(5H)-furanone)) significantly up-regulated AgHsp70 expression. Knockdown of AgHsp70 using RNAi obviously increased the susceptibility of cotton aphids to 2-tridecanone, gossypol and flupyradifurone. Dual-luciferase reporter assays revealed that gossypol and flupyradifurone significantly enhanced the promoter activity of AgHsp70 at a concentration of 10 mg/L. Furthermore, we identified the transcription factor heat shock factor (HSF) as a regulator of AgHsp70, as silencing AgHSF reduced AgHsp70 expression. Our results shed light on the role of AgHsp70 in xenobiotic adaptation and thermo-tolerance.

Pancreatic adenocarcinoma treated with surgical resection, toceranib phosphate and firocoxib in a dog: a case report.

Exocrine pancreatic carcinomas are rarely reported in dogs. A ductal pancreatic adenocarcinoma in a 10-year-old intact beagle is described in this report. The diagnosis was made based on clinical signs, imaging (abdominal ultrasound and CT scan) and histopathology. Treatment consisted of partial right lobe pancreatectomy followed by adjuvant therapy with toceranib phosphate (Palladia®) and firocoxib (Previcox®) for six months. The treatment was well tolerated, and the survival time was 445 days. To our knowledge, this is the longest survival reported in the literature for a dog diagnosed with exocrine pancreatic adenocarcinoma. The results described here may contribute to provide a better understanding about this neoplasia and potential treatment options.

Roles of gender and smoking in the associations between urinary phytoestrogens and asthma/wheeze and lung function: evidence from a cross-sectional study.

BACKGROUND: The role of phytoestrogens in asthma/wheeze and lung function remains controversial. Thus, we aimed to examine whether phytoestrogens have beneficial effects on asthma/wheeze, lung function for subgroups and mortality. METHODS: Participants in this study were individuals aged 20 years or older from the National Health and Nutrition Examination Survey. Multivariate logistic regression models were fitted to examine the associations of urinary phytoestrogens with the risk of asthma/wheeze and lung function in individuals with and without asthma/wheeze. Cox proportional hazards regression was used to examine the relationship between urinary phytoestrogens and all-cause mortality. Stratified analyses were conducted based on gender and smoking status. RESULTS: We included 2465 individuals in this study. Enterolactone levels in the highest quartile were associated with a lower risk of asthma than those in the lowest quartile. As compared with the lowest quartile, the highest quartile of enterodiol and enterolactone was associated with a lower risk of wheeze. Significant associations were observed between subtypes of phytoestrogens (equol and enterolactone) and lung function (forced vital capacity (FVC) and forced expiratory volume in 1 s). Besides, FVC was higher in individuals with higher levels of enterodiol. The results were consistent in subpopulations without asthma/wheeze, while the significant difference was not observed in individuals with asthma/wheeze. The stratified analyses revealed that the associations between phytoestrogens and lung function differed by gender and smoking status among subgroups. No significant association was found between urinary phytoestrogens and all-cause mortality. CONCLUSION: In summary, subtypes of phytoestrogens were associated with lower risk of asthma/wheeze and beneficial for lung function improvement in individuals without asthma/wheeze. Furthermore, gender and smoking may interact in the relationship between phytoestrogens and asthma/wheeze, and lung function. Further researches are needed to confirm these associations and explain the results of stratified analyses.

SINGLE-DOSE, MULTIPLE-DOSE, AND THERAPEUTIC DRUG MONITORING PHARMACOKINETICS OF FIROCOXIB IN ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

Firocoxib is a COX-2-selective nonsteroidal anti-inflammatory drug (NSAID) with limited effects on COX-1, which means it likely has fewer side effects than typically associated with other NSAIDs. This study determined possible doses of firocoxib based on single- and multidose pharmacokinetic trials conducted in 10 Asian elephants (Elephas maximus). Initially, two single oral dose trials (0.01 and 0.1 mg/kg) of a commercially available tablet (n = 6) and paste (n = 4) formulation were used to determine a preferred dose. The 0.1 mg/kg dose was further evaluated via IV single dose (n = 3) and oral multidose trials (tablets n = 6; paste n = 4). Serum peak and trough firocoxib concentrations were also evaluated in Asian elephants (n = 4) that had been being treated for a minimum of 90 consecutive days. Key pharmacokinetic parameters for the 0.1 mg/kg single-dose trials included mean peak serum concentrations of 49 ± 3.3 ng/ml for tablets and 62 ± 14.8 ng/ml for paste, area under the curve (AUC) of 1,332 ± 878 h*mg/ml for tablets and 1,455 ± 634 h*mg/ml for paste, and half-life (T1/2) of 34.3 ± 30.3 h for tablets and 19.9 ± 12.8 h for paste. After 8 d of dosing at 0.1 mg/kg every 24 h, pharmacokinetic parameters stabilized to an AUC of 6,341 ± 3,003 h*mg/ml for tablets and 5,613 ± 2,262 for paste, and T1/2 of 84.4 ± 32.2 h for tablets and 62.9 ± 2.3 h for paste. Serum COX inhibition was evaluated in vitro and ex vivo in untreated elephant plasma, where firocoxib demonstrated preferential inhibition of COX-2. No adverse effects from firocoxib administration were identified in this study. Results suggest administering firocoxib to Asian elephants at a dose of 0.1 mg/kg orally, using either tablet or paste formulations, every 24 h.