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Background Objective Materials and methods Results Conclusion Recently, the metabolic pathways involved in energy production and the role of aquaglyceroporins in capacitation‐associated events have been studied in humans and mice. However, little is known about these in ram spermatozoa.The present study investigated bioenergetic and aquaglyceroporin 3 variations during in vitro capacitation of ram spermatozoa. In addition, differences in testosterone levels between males were examined to determine their influence on capacitation‐like changes.Spermatozoa obtained from nine rams (ejaculates = 36) were incubated for 180 min in three different media (control, capacitating, and aquaglyceroporin‐inhibitor media) at 38.5°C. At 0 and 180 min of incubation in each medium, sperm viability, kinetics, chlortetracycline patterns, adenosine triphosphate concentration, lactate excretion (final subproduct of glycolysis), and immunolocalization of aquaporin 3 were evaluated.The increment of the capacitated spermatozoa‐chlortetracycline pattern and the hyperactivated‐like movement characterized by the highest curvilinear velocity and amplitude of lateral head displacement and the lowest linearity was only recorded after 180 min in the capacitating medium. At this time and conditions, adenosine triphosphate content and lactate excretion decreased, whereas the aquaglyceroporin 3 location in the midpiece and principal piece increased compared to 0 min. Such changes were not observed in the control medium over time. Incubation in the aquaglyceroporin‐inhibitor medium for 180 min reduced drastically sperm motility and adenosine triphosphate content compared to the other media. Testosterone analysis revealed a significant individual variability, which was also present in all sperm parameters evaluated. Furthermore, testosterone was negatively correlated with adenosine triphosphate content but positively correlated with lactate excretion levels, sperm viability, motility, capacitated sperm‐chlortetracycline pattern, and aquaglyceroporin 3 immunolabeling in the midpiece and principal piece.Despite individual differences, capacitation of ram spermatozoa increases adenosine triphosphate consumption, energy metabolism, and aquaglyceroporin 3 location in the midpiece and principal piece, which seems to be related to the acquisition of hyperactivated‐like motility. Furthermore, testosterone levels may serve as a valuable tool to select those males with a greater sperm metabolism rate and fertilizing capacity. [ABSTRACT FROM AUTHOR]

Introduction: Deglycosylated azithromycin (Deg-AZM), a newly developed Class I drug with good therapeutic effects on slow transit constipation, is a smallmolecule transgelin agonist that has been approved for clinical trials in 2024. The preclinical pharmacokinetic profile of Deg-AZM was investigated to support further development. Methods: A LC-MS/MS method was established and validated to detected the concentration of Deg-AZM in various biological samples. In vivo tests such as pharmacokinetic studies in rats and dogs, tissue distribution studies in rats, and extraction studies in rats were conducted to investigated the preclinical pharmacokinetic behaviors of Deg-AZM comprehensively. The plasma protein rate of Deg-AZM was determined by rapid equilibrium dialysis method in vitro. The metabolic stability and metabolite profile of Deg-AZM was assessed using pooled mice, rats, dogs, monkeys and humans microsomes in vitro. The PK profiles of Deg-AZM in human was predicted based on physiologically based pharmacokinetic (PBPK) models. Results: The plasma protein binding rates of Deg-AZM were lower in mice and rats, higher in dogs, and moderate in humans. The metabolic process of Deg-AZM was similar in rat and human liver microsomes. From Pharmacokinetic studies in rats and dogs, Deg-AZM was rapidly absorbed into the blood and then quickly eliminated. Plasma exposure of Deg-AZM was dose dependent with no accumulation after continuous gavage administration. In addition, there is no significant gender difference in the pharmacokinetic behavior of Deg-AZM. Deg-AZM was widely distributed in the tissues without obvious accumulation, and mainly excreted from the urinary excretion pathway. Furthermore, the pharmacokinetic profiles of Deg-AZM in humans showed dose dependency. Conclusion: The pharmacokinetic profiles of Deg-AZM was fully explored, these results could provide valuable information to support the first-in-human dosage prediction and phase I clinical design. [ABSTRACT FROM AUTHOR]

Under New Zealand grazing systems, a high proportion of the nitrogen consumed by ruminants is excreted. This experiment examined the effect of feeding morning and afternoon harvested annual ryegrass, fed shortly after harvest, on the timing of nitrogen excretion in one-year-old sheep during winter. Dry matter and water-soluble carbohydrate (WSC) content increased in the afternoon-harvested ryegrass. This resulted in increased protein and WSC intakes and a decrease in nitrogen loss in the sheep fed in the afternoon with afternoon-harvested grass. The pattern of urinary nitrogen excretion was related to feeding time with peak urinary urea excretion in the period 4–8 hours after feeding, with over 60% of the daily urinary urea excreted in the 12 hours after the feed was offered. This study suggests that shifting stock onto new pasture breaks in the afternoon could reduce nitrous oxide production by increasing the efficiency of nitrogen utilisation in animals and reducing the total amount of nitrogen excreted. It may be possible to utilise the potential diurnal differences in pasture composition to reduce nitrogen losses. This practise could also improve animal performance as well as change the timing of nitrogen excretion. [ABSTRACT FROM AUTHOR]

There are several in vitro systems that enable evaluation of the absorption direction, but there are few quantitative systems that enable easy evaluation of the excretion direction. Enteroids, organoids derived from intestine, have been frozen and passaged for various research. But it is not clear how the freezing and passaging affect the expression and function of transporters. We investigated the effects of passage and cryopreservation of enteroids. We focused on P-gp (P-glycoprotein) and compared the transfer rates of rhodamine 123 (Rh123) into the lumen of enteroids with and without a P-gp inhibitor. mRNA expression levels did not change significantly before and after passage and cryopreservation. Accumulation of Rh123 in the lumen of enteroids was observed. With some P-gp inhibitors, excretion of Rh123 into the lumen of enteroids was inhibited and the nonexcreted Rh123 accumulated in enteroids epithelial cells. The transfer rate of Rh123 into the lumen of enteroids with a P-gp inhibitor was significantly decreased compared to that of without a P-gp inhibitor. Before and after passage and cryopreservation, the transfer rate was almost the same as that of primary cultured enteroids. We succeeded in easily evaluating whether a component is a substrate of P-gp using enteroids. [Display omitted] • mRNA expression level of efflux intestinal transporter was not changed before and after passage and number of culture days. • This method allows semi-quantitative evaluation of efflux transporters function regardless of the shapes of enteroids. • Our method enables to easily evaluate whether a component is a substrate of P-gp using enteroids. [ABSTRACT FROM AUTHOR]

Microplastics have become a ubiquitous contaminant, but their fate in food animals is largely unknown. In this study, [14C]-polystyrene microplastic (PS-MP) particles were orally dosed to lactating sheep to evaluate their absorption and disposition. Elimination of the [14C]-PS-MP was predominately through faeces with faecal radioactivity peaking at 24 h post-dosing but continuing to be present throughout the entire 72 h study period. Only a small fraction (≤ 1%) of the dosed [14C]-PS-MP was present in blood, milk, and urine. Pharmacokinetic analysis of blood plasma radioactivity, using non-compartment modeling, indicated rapid absorption (T1/2 0.4 to 3 h) with slow elimination (T1/2 37 to 48 h). Radioactivity in milk and urine had similar elimination patterns with radiocarbon activities peaking 24 h post-dosing with detectable elimination throughout the 72 h study period. No radioactivity was quantifiable in tissues at the 72 h withdrawal period. [ABSTRACT FROM AUTHOR]

The urinary mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA) and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) are short-term biomarkers of exposure from acrylamide and its metabolite glycidamide, respectively. The medium-term exposure to acrylamide and glycidamide is monitored by the adducts N-(2-carbamoylethyl)-Val (AA-Val) and N-(2-carbamoyl-2-hydroxyethyl)-Val (GA-Val) in hemoglobin (Hb), respectively. Three questions were addressed by application of these biomarkers in two diet studies including 36 omnivores, 36 vegans and 16 strict raw food eaters (abstaining from any warmed or heated food for at least four months): first, what is the internal acrylamide exposure following a vegan or a raw food diet in comparison to that in omnivores? Second, did the exposure change between 2017 and 2021? And third, what is the stability over time of AAMA/GAMA excretion compared to that of AA-Val/GA-Val levels in Hb between both time points? Median urinary AAMA excretion per day in non-smoking omnivores, vegans and raw food eaters were 62.4, 85.4 and 15.4 µg/day, respectively; the corresponding median AA-Val levels were 27.7, 39.7 and 13.3 pmol/g Hb, respectively. Median levels in strict raw food eaters were about 25% (AAMA excretion) and 48% (AA-Val) of those in omnivores. In comparison to 2017, AAMA and GAMA excretion levels were hardly altered in 2021, however, levels of AA-Val and GA-Val in 2021 slightly increased. There was a weak correlation between AAMA excretion levels determined four years apart (rS = 0.30), and a moderate correlation between levels of AA-Val (rS = 0.55) in this timeframe. Our data in strict raw food eaters confirm a significant endogenous formation to acrylamide in a size range, which is—based on the levels of AA-Val—distinctly higher than reported previously based on levels of urinary AAMA excretion. The relatively lower AAMA excretion in raw food eaters likely represents a lower extent of glutathione conjugation due to missing hepatic first-pass metabolism in case of endogenous formation of acrylamide, which leads to a higher systemic exposure. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the effect of the combination of a water‐soluble calcium (Ca) source (CaCl2) with a water‐soluble phosphorus (P) source (NaH2PO4*2H2O, diet soluble, SOL) in comparison to a water‐insoluble P source (CaHPO4*2H2O, diet insoluble, INS) on apparent digestibility and renal excretion of Ca and P in dogs. The Ca intake was 226 mg/kg bodyweight (bw), the Ca/P ratio 1.9/1 in SOL and 2.0/1 in INS. The percentage of Ca from CaCl2 was 60% in SOL and 33% in INS. Eight adult Foxhound‐crossbred dogs FBI, (3–5 years, bw 24–32 kg) were available. Standard digestion trials were carried out (10 days adaptation, 5 days total faecal collection). Spontaneously excreted urine was collected pre‐ and postprandially. In vitro water solubility of P in the mineral premixes was determined. The Ca digestibility was negative in both trials without significant differences between the groups. Apparent P digestibility was increased in group SOL (26% vs. 20% in INS). In both groups, P content in urine was higher pre‐ compared to postprandial, with higher concentrations in group SOL. The same was true for the P/Crea ratio. The water solubility of P in the mineral premixes used in the trials showed considerable differences: The P in premix INS was insoluble in water after 1 and after 90 min. By contrast, the P in the premix SOL was highly soluble (98%) after 1 minute. After 90 min, however, the P solubility decreased to 43%, suggesting the formation of insoluble CaP salts, presumably from CaCl2 and NaH2PO4*2H2O. In conclusion, in the present study, apparent Ca digestibility in dogs was not affected by the solubility of Ca and P, while P digestibility and renal P excretion increased. [ABSTRACT FROM AUTHOR]

Background: Urinary Dickkopf 3 (DKK3) excretion is a recently established biomarker of renal functional development. Its excretion into the peritoneal cavity has not been reported. We here studied DKK3 in peritoneal dialysis. Methods: DKK3 was assessed in serum, urine and dialysate in a prevalent adult peritoneal dialysis cohort and its concentration analyzed in relation to creatinine and clinical characteristics. Results: Highest DKK3 concentrations were found in serum, followed by urine. Dialysate concentrations were significantly lower. Dialysate DKK3 correlated with both other compartments. Serum, dialysate and urine values were stable during three months of follow-up. Continuous ambulatory dialysis (CAPD) but not cycler-assisted peritoneal dialysis (CCPD) volume-dependently increased peritoneal DKK3 in relation to creatinine. RAAS blockade significantly decreased urinary, but not serum or peritoneal DKK3. Conclusion: Our data provide a detailed characterization of DKK3 in peritoneal dialysis. They support the notion that the RAAS system is essential for renal DKK3 handling. [ABSTRACT FROM AUTHOR]

N-lactoyl-phenylalanine (Lac-Phe) is a lactate-derived metabolite that suppresses food intake and body weight. Little is known about the mechanisms that mediate Lac-Phe transport across cell membranes. Here we identify SLC17A1 and SLC17A3, two kidney-restricted plasma membrane-localized solute carriers, as physiologic urine Lac-Phe transporters. In cell culture, SLC17A1/3 exhibit high Lac-Phe efflux activity. In humans, levels of Lac-Phe in urine exhibit a strong genetic association with the SLC17A1-4 locus. Urine Lac-Phe levels are increased following a Wingate sprint test. In mice, genetic ablation of either SLC17A1 or SLC17A3 reduces urine Lac-Phe levels. Despite these differences, both knockout strains have normal blood Lac-Phe and body weights, demonstrating SLC17A1/3-dependent de-coupling of urine and plasma Lac-Phe pools. Together, these data establish SLC17A1/3 family members as the physiologic urine Lac-Phe transporters and uncover a biochemical pathway for the renal excretion of this signaling metabolite. The lactate metabolite N-lactoyl-phenylalanine (Lac-Phe) plays a role in suppressing food intake and body weight. Here, the authors identify kidney transporters responsible for the renal excretion of Lac-Phe. This discovery highlights a pathway for Lac-Phe regulation in mice and humans. [ABSTRACT FROM AUTHOR]

In this paper, we propose a food chain model in which the primary predator moves directly toward areas of high prey density. Simultaneously, the primary predator, which serves as the prey for the secondary predator, indirectly influences the directional movements of the secondary predator through cues such as chemical signals, scents, or excretions. We investigate whether the distinct influences of direct taxis and indirect taxis, as observed in prey–predator dynamics, are also manifested in the proposed food chain model. Our study demonstrates that the model, which incorporates both direct and indirect prey‐taxis, possesses bounded and global solutions up to three‐dimensional space. [ABSTRACT FROM AUTHOR]

Cyproheptadine hydrochloride (CYP) is a typical antihistamine with antiserotonergic, blocking H1 receptor, anticholine, anti‐inflammatory and anti‐allergic effects. To investigate the pharmacokinetics, biodistribution, and excretion, the liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method was established and validated the CYP concentrations in the plasma of beagle dogs and the biological matrix of mice. CYP was quickly absorbed into the bloodstream and widely distributed to various tissues. The area under the curve (AUC)0–t and peak concentration of CYP were increased with the dose after administration. At the equal dose, the bioavailability of intramuscular injection in mice and beagle dogs was 81.1% and 79.1%. The tissue distribution experiments suggested that CYP would not accumulate for a long time in vivo. CYP levels in tissues peaked after 15 min of injection, and the drug concentrations in the kidney and lung were higher than those in other tissues. For excretion, the cumulative urinary excretion of CYP within 156 h after intramuscular injection in mice accounted for (1.2 ± 0.1)% of the total administration dose. The feces excretion of the drug prototype was below the lower limit of quantitation. High sensitivity and strong specificity are observed based on the established method of LC‐MS/MS, which was successfully applied to the pharmacokinetics, tissue distribution, and excretion studies of CYP. [ABSTRACT FROM AUTHOR]

Calcineurin, protein phosphatase 2B (PP2B) or protein phosphatase 3 (PP3), is a calcium‐dependent serine/threonine protein phosphatase. Calcineurin is widely expressed in the kidney and regulates renal Na+ and K+ transport. In the thick ascending limb, calcineurin plays a role in inhibiting NKCC2 function by promoting the dephosphorylation of the cotransporter and an intracellular sorting receptor, called sorting‐related‐receptor‐with‐A‐type repeats (SORLA), is involved in modulating the effect of calcineurin on NKCC2. Calcineurin also participates in regulating thiazide‐sensitive NaCl‐cotransporter (NCC) in the distal convoluted tubule. The mechanisms by which calcineurin regulates NCC include directly dephosphorylation of NCC, regulating Kelch‐like‐3/CUL3 E3 ubiquitin–ligase complex, which is responsible for WNK (with‐no‐lysin‐kinases) ubiquitination, and inhibiting Kir4.1/Kir5.1, which determines NCC expression/activity. Finally, calcineurin is also involved in regulating ROMK (Kir1.1) channels in the cortical collecting duct and Cyp11 2 expression in adrenal zona glomerulosa. In summary, calcineurin is involved in the regulation of NKCC2, NCC, and inwardly rectifying K+ channels in the kidney, and it also plays a role in modulating aldosterone synthesis in adrenal gland, which regulates epithelial‐Na+‐channel expression/activity. Thus, application of calcineurin inhibitors (CNIs) is expected to abrupt calcineurin‐mediated regulation of transepithelial Na+ and K+ transport in the kidney. Consequently, CNIs cause hypertension, compromise renal K+ excretion, and induce hyperkalemia. [ABSTRACT FROM AUTHOR]

Background: Ex vivo normothermic machine perfusion (NMP) is a promising tool for assessing an isolated kidney prior to transplantation. However, there is no consensus on the perfusate's optimal oxygen‐carrying capacity to support renal function. To investigate the association of hemoglobin levels with renal function parameters, a retrospective analysis of isolated, normothermically, perfused porcine kidneys was performed. Methods: Between 2015 and 2021, a total of 228 kidneys underwent 4 h of NMP with perfusates that varied in hemoglobin levels. A generalized linear model was used to determine the association of hemoglobin levels with time‐weighted means of renal function markers, such as fractional sodium excretion (FENa) and creatinine clearance (CrCl). Stratified by baseline hemoglobin level (<4.5, 4.5–6, or >6 mmol/L), these markers were modeled over time using a generalized linear mixed‐effects model. All models were adjusted for potential confounders. Results: Until a hemoglobin level of around 5 mmol/L was reached, increasing hemoglobin levels were associated with superior FENa and CrCl. Thereafter, this association plateaued. When hemoglobin levels were categorized, hemoglobin <4.5 mmol/L was associated with worse renal function. Hemoglobin levels were neither significantly associated with proteinuria during NMP nor with ATP levels at the end of NMP. Hemoglobin levels >6 mmol/L showed no additional benefits in renal function. Conclusion: In conclusion, we found an association between baseline hemoglobin levels and superior renal function parameters, but not injury, during NMP of porcine kidneys. Furthermore, we show that performing a retrospective cohort study of preclinical data is feasible and able to answer additional questions, reducing the potential use of laboratory animals. [ABSTRACT FROM AUTHOR]

Aims: To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BPL-003, a novel intranasal benzoate salt formulation of 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT), in healthy participants. Methods: In all, 44 psychedelic-naïve participants enrolled in the double-blind, placebo-controlled single ascending dose study (1–12 mg BPL-003). Concentrations of 5-MeO-DMT and its pharmacologically active metabolite, bufotenine, were determined in plasma and urine. PD endpoints included subjective drug intensity (SDI) rating, the Mystical Experience Questionnaire (MEQ-30) and the Ego Dissolution Inventory (EDI). Results: BPL-003 was well tolerated at doses up to 12 mg. There were no serious adverse events (AEs), and most AEs were mild; the most common being nasal discomfort, nausea, headache and vomiting. 5-MeO-DMT was rapidly absorbed and eliminated; the median time to peak plasma concentration was approximately 8–10 min and the mean terminal elimination half-life was <27 min. 5-MeO-DMT systemic exposure increased approximately dose-proportionally, while plasma bufotenine concentrations and urinary excretion of 5-MeO-DMT and bufotenine were negligible. The intensity of the SDI ratings was associated with plasma 5-MeO-DMT concentrations. MEQ-30 and EDI scores generally increased with the BPL-003 dose; 60% of participants had a 'complete mystical experience' at 10 and 12 mg doses. Profound and highly emotional consciousness-altering effects were observed with BPL-003, with a rapid onset and short-lasting duration. Conclusion: The novel intranasal formulation of BPL-003 was well tolerated with dose-proportional increases in PK and PD effects. The short duration of action and induction of mystical experiences suggest clinical potential, warranting further trials. Clinical trial registration: NCT05347849. [ABSTRACT FROM AUTHOR]

Glycyrrhizin‐enriched extracts from licorice root are associated with numerous health benefits and are widely used in phytotherapy. There is evidence that ingesting glycyrrhizin beyond threshold concentrations can impact the metabolism of cortisol, inhibiting its conversion to an inactive form, cortisone, via 11‐hydroxysteroid dehydrogenase. A consequence can be a form of hypermineralocorticoidism, with elevated potassium excretion and associated hypertension, as demonstrated in rats and humans. Here, 3 orally dosed concentrations of glycyrrhizin (0.2, 0.4 and 0.6 mg/kg bodyweight/day) were assessed over 28 days in dogs. As the current guidelines reflect a lack of reliable data in this species, our aim was to provide relevant information for doses above the current guidelines. The specific purpose of this study was to demonstrate that an intake of licorice with a known therapeutic benefit to dogs does not cause hypermineralocorticoidism in this species. No changes in blood pressure, nor electrolyte excretion were observed in the dogs given these three glycyrrhizin concentrations. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1) and ochratoxin A (OTA) are highly toxic mycotoxins present in food and feed, posing serious health risks to humans and animals. This study aimed to validate an efficient and cost-effective analytical method for quantifying AFB1 and OTA in rat urine using immunoaffinity column extraction and liquid chromatography with fluorescence detection (IAC-LC-FD). Additionally, the study evaluated the effect of incorporating fermented whey and pumpkin into the feed on the urinary excretion of these mycotoxins. The limits of detection and quantification were determined to be 0.1 µg/kg and 0.3 µg/kg, respectively, for both mycotoxins in feed, and 0.2 ng/mL and 0.6 ng/mL, respectively, in urine. The method demonstrated robust recovery rates ranging from 74% to 119% for both AFB1 and OTA in both matrices. In feed samples, the levels of AFB1 and OTA ranged from 4.3 to 5.2 µg/g and from 5.4 to 8.8 µg/g, respectively. This validated method was successfully applied to analyze 116 urine samples from rats collected during the fourth week of an in vivo trial. The results indicated that the addition of fermented whey and pumpkin to the feed influenced mycotoxin excretion in urine, with variations observed based on the sex of the rats, type of mycotoxin, and exposure dosage. [ABSTRACT FROM AUTHOR]

Climbazole is an antimycotic compound used in cosmetic products as a preservative or as an active ingredient in anti-dandruff (AD) formulations. In this study we provide human toxicokinetic data on climbazole. Using our previously published analytical method, we investigated the urinary excretion of two climbazole metabolites, (OH) 2 -climbazole and cx-OH-climbazole, for 48 h after oral ingestion (n = 5, 49–77 µg/kg bw) and for 72 h after dermal application of either a climbazole-containing rinse-off AD shampoo or a leave-on hair tonic (n = 2×3). In total, 23.9 % (18.0–33.4 %) of the oral dose were excreted as the two abovementioned metabolites over 48 h. In one volunteer, who used an over-the-counter phytopharmaceutical, metabolite excretion was about three times lower and we found influences on diastereoselectivity of (OH) 2 -climbazole formation using a modified analytical method. After dermal application, urinary concentration maxima occurred considerably later than after oral intake. The two different dermal exposure scenarios also revealed a relevance of exposure duration and product formulation on the systemic availability of climbazole. Back-calculated oral-dose-equivalent intakes from the dermal exposures showed a maximum climbazole intake of 18.5 µg/kg bw/d after hair tonic use, or 6.6 µg/kg bw/d after AD shampoo application. • (OH) 2 -climbazole and cx-OH-climbazole identified as suitable exposure biomarkers. • On average 24 % of the dose were recovered in form of the investigated biomarkers within 48 h. • Shifting diastereomeric ratios observed within the investigated excretion period. • Sum parameter recommended as the most robust approach for reverse dosimetry. [ABSTRACT FROM AUTHOR]

AbstractTheaflavins, a major kind of component in black tea, have been reported to show a variety of biological activities and health effects. However, the unstable chemical properties, low bioavailability and unclear metabolism pathways of theaflavins have left much to be desired in terms of its specific efficacy and applications. This paper provides a comprehensive knowledge on the digestion, absorption, metabolism, distribution and excretion of theaflavins. We find that pH-dependent stability, efflux transport proteins are closely related to the low absorption rate and low bioavailability of theaflavins. When pass through the gastrointestinal tract, TFDG, TF2A and TF2B are gradually degraded to TF1, and release gallic acid. Then, the theaflavins skeleton are degraded into small molecular phenolic substances under the action of enzymes and microorganisms. In addition, theaflavins are widely distributed in the human body including brain, lung, heart, kidney, liver, blood tissue in a low content and can be excreted through feces. However, the influence of digestive enzymes barrier and gut microbial barrier on theaflavins are still unclear. Importantly, most findings are reported by in vitro methods and animal experiments, the metabolites and metabolic pathways of theaflavins in human body are not fully understood and need to be further investigated. We hope to lay a theoretical basis for exploring methods to improve the bioavailability of theaflavins and expanding the application of theaflavins in health foods as well as pharmaceuticals. [ABSTRACT FROM AUTHOR]

AbstractThe pharmacokinetics, metabolism, excretion, mass balance, and tissue distribution of [14C]aficamten were evaluated following oral administration of an 8 mg/kg dose in Sprague Dawley rats and in a quantitative whole-body autoradiography study in Long Evans rats.[14C]Aficamten accounted for ∼80% and a hydroxylated metabolite (M1) accounted for ∼12% of total radioactivity in plasma over 48-h (AUC0–48). Plasma tmax was 4-h and the t1/2 of total plasma radioactivity was 5.8-h.Tissues showing highest Cmax exposures were myocardium and semitendinosus muscle.Most [14C]aficamten-derived radioactivity was excreted within 48-h post-administration. Mean cumulative recovery in urine and faeces over 168-h was 8.3% and 90.7%, respectively.In urine and bile, unchanged aficamten was detected at <0.1 and <0.2% of dose, respectively; however, based on total radioactivity excreted in urine (8.0%) and bile (51.7%), approximately 60% of dose was absorbed.[14C]Aficamten was metabolised by hydroxylation with subsequent glucuronidation where the most abundant metabolite recovered in bile was M5 (35.2%), the oxygen-linked glucuronide of hydroxylated aficamten (M1a). The major metabolite detected in faeces was a 1,2,4-oxadiazole moiety ring-cleaved metabolite (M18, 35.3%), shown to be formed from the metabolism of M5 in incubations with rat intestinal contents solution.The pharmacokinetics, metabolism, excretion, mass balance, and tissue distribution of [14C]aficamten were evaluated following oral administration of an 8 mg/kg dose in Sprague Dawley rats and in a quantitative whole-body autoradiography study in Long Evans rats.[14C]Aficamten accounted for ∼80% and a hydroxylated metabolite (M1) accounted for ∼12% of total radioactivity in plasma over 48-h (AUC0–48). Plasma tmax was 4-h and the t1/2 of total plasma radioactivity was 5.8-h.Tissues showing highest Cmax exposures were myocardium and semitendinosus muscle.Most [14C]aficamten-derived radioactivity was excreted within 48-h post-administration. Mean cumulative recovery in urine and faeces over 168-h was 8.3% and 90.7%, respectively.In urine and bile, unchanged aficamten was detected at <0.1 and <0.2% of dose, respectively; however, based on total radioactivity excreted in urine (8.0%) and bile (51.7%), approximately 60% of dose was absorbed.[14C]Aficamten was metabolised by hydroxylation with subsequent glucuronidation where the most abundant metabolite recovered in bile was M5 (35.2%), the oxygen-linked glucuronide of hydroxylated aficamten (M1a). The major metabolite detected in faeces was a 1,2,4-oxadiazole moiety ring-cleaved metabolite (M18, 35.3%), shown to be formed from the metabolism of M5 in incubations with rat intestinal contents solution. [ABSTRACT FROM AUTHOR]

Background: While numerous studies have reported associations between low dietary potassium intake and adverse clinical outcomes, methods to estimate potassium intake, mainly self-reported dietary measures and urinary potassium excretion, entail certain limitations. Self-reported measures are subject to underreporting and overreporting. Urinary potassium excretion is affected by multiple factors including renal function. Revealing the degree of bias inherent in these measures would help accurately assess potassium intake and its association with disease risk. We aim to summarize evidence on the strength of the associations between potassium intake estimated from 24-h urinary potassium excretion and potassium intake estimated from self-reported dietary measures or objective quantification methods in populations with different kidney function levels and age groups. We also aim to identify factors that affect the association strength. Methods: We will search for potentially eligible studies that examined associations between self-reported potassium intake, 24-h urinary potassium excretion, and objectively quantified potassium intake, using MEDLINE (PubMed), Embase, Web of Science, and Scopus. Studies on children, adolescents, adults, and the elderly are eligible. Studies of patients on dialysis will be excluded. Collective study results, including a meta-analysis, will be synthesized if an adequate number of studies examining similar dietary potassium intake estimation methods are found. Analyses will be performed separately according to age groups and renal function. For the meta-analysis, fixed-effects or random-effect models will be employed depending on the degree of study heterogeneity to combine across studies the correlation coefficient, ratio, or standardized mean difference for potassium intake, comparing dietary potassium intake based on self-reported or objectively quantified methods and intake based on 24-h urinary potassium excretion. The degree of heterogeneity among included studies will be examined by calculating I2 statistics. To investigate sources of study heterogeneity, random-effects meta-regression analyses will be performed. Discussion: Revealing the strength of the association between dietary and urinary measures in populations with different levels of kidney function and age groups will enhance researchers' and clinicians' ability to interpret studies that utilize these measures and help establish a more solid evidence base for the role of potassium intake in changing chronic disease risk. Identifying factors that modify the associations between these measures may aid in developing predictive models to estimate actual potassium intake. Systematic review registration: PROSPERO CRD42022357847. [ABSTRACT FROM AUTHOR]

Renal hemodynamics, renal transporter expression levels, and urine excretion exhibit circadian variations. Disruption of these diurnal patterns is associated with the pathophysiology of hypertension and chronic kidney disease. Renal hemodynamics determines oxygen delivery, whereas renal transport and metabolism determines oxygen consumption; the balance between them yields renal oxygenation which also demonstrates 24-h periodicity. Another notable modulator of kidney function is sex, which has impacts on renal hemodynamics and transport function that are regulated by as well as independent of the circadian clock. The goal of this study was to investigate the diurnal and sexual variations in renal oxygen consumption and oxygenation. For this purpose, we developed computational models of rat kidney function that represent sexual dimorphism and circadian variation in renal hemodynamics and transporter activities. Model simulations predicted substantial differences in tubular Na+ transport and oxygen consumption among different nephron segments. We also simulated the effect of loop diuretics, which are used in the treatment of renal hypoxia, on medullary oxygen tension. Our model predicted a significantly higher effect of loop diuretics on medullary oxygenation in female rats compared to male rats and when administered during the active phase. [ABSTRACT FROM AUTHOR]

Recently, we compared an interplay of the adenosine system and nitric oxide (NO) in the regulation of renal function between male normoglycaemic (NG) and streptozotocin-induced diabetic rats (DM). Considering the between-sex functional differences, e.g., in the NO status, we present similar studies performed in female rats. We examined if the theophylline effects (non-selective adenosine antagonist) in NG and DM females with or without active NO synthases differed from the earlier findings. In anaesthetised female Sprague Dawley rats, both NG and DM, untreated or after NO synthesis blockade with L-NAME, theophylline effects, on blood pressure, renal hemodynamics and excretion, and renal tissue NO were investigated. Renal artery blood flow (Transonic probe), cortical, outer-, and inner-medullary flows (laser-Doppler technique), and renal tissue NO signal (selective electrode) were measured. In contrast to males, in female NG and DM rats, theophylline induced renal vasodilation. In NO-deficient females, theophylline induced comparable renal vasodilatation, confirming the vasoconstrictor influence of the renal adenosine. In NG and DM females with intact NO synthesis, adenosine inhibition diminished kidney tissue NO, contrasting with an increase reported in males. Lowered baseline renal excretion in DM females suggested stimulation of renal tubular reabsorption due to the prevalence of antinatriuretic over natriuretic tubular action of adenosine receptors. An opposite inter-receptor balance pattern emerged previously from male studies. The study exposed between-sex functional differences in the interrelation of adenosine and NO in rats with normoglycaemia and streptozotocin diabetes. The findings also suggest that in diabetes mellitus, the abundance of individual receptor types can distinctly differ between females and males. [ABSTRACT FROM AUTHOR]

Background and Objective: Ginseng has been regarded as a precious medicinal herb with miraculous effects in Eastern culture. The primary chemical constituents of ginseng are saponins, and the physiological activities of ginsenosides determine their edible and medicinal value. The aim of this study is to comprehensively and systematically investigate the kinetic processes of 20(S)--protopanaxadiol (PPD) in rats and dogs, in order to promote the rational combination of ginseng as a drug and dietary ingredient. Methods: PPD was administered, and drug concentration in different biological samples were detected by liquid chromatography tandem mass spectrometry (LC/MS/MS) and radioactive tracer methods. Pharmacokinetic parameters such as absorption, bioavailability, tissue distribution, plasma protein binding rate, excretion rate, and cumulative excretion were calculated, along with inference of major metabolites. Results: This study systematically investigated the absorption, distribution, metabolism, excretion (ADME) of PPD in rats and dogs for the first time. The bioavailabilities of PPD were relatively low, with oral absorption nearly complete, and the majority underwent first-pass metabolism. PPD had a high plasma protein binding rate and was relatively evenly distributed in the body. Following oral administration, PPD underwent extensive metabolism, potentially involving one structural transformation and three hydroxylation reactions. The metabolites were primarily excreted through feces and urine, indicating the presence of enterohepatic circulation. The pharmacokinetic processes of PPD following intravenous administration aligned well with a three-compartment model. In contrast, after gastric administration, it fitted better with a two-compartment model, conforming to linear pharmacokinetics and proportional elimination. There were evident interspecies differences between rats and dogs regarding PPD, but individual variations of this drug were minimal within the same species. Conclusion: This study systematically studied the kinetic process of PPD in rats and also investigated the kinetic characteristics of PPD in dogs for the first time. These findings lay the foundation for further research on the dietary nutrition and pharmacological effects of PPD. [ABSTRACT FROM AUTHOR]

Raisins are a nutrient-dense food known for their high content of dietary fiber, antioxidants, and bioactive compounds, including quercetin, which exists predominantly in the form of quercetin glycosides, enhancing their potential health benefits. This study investigates the impact of dietary matrix on quercetin bioavailability by analyzing urinary excretion following consumption of raisins. Employing advanced LC/MS techniques, the study quantified quercetin and its metabolites to evaluate how whole foods influence the absorption and metabolic processing of dietary polyphenols. Initial results indicated a significant increase in urinary quercetin excretion, with concentrations ranging from 21.8 μg/ml to 238.8 μg/ml among participants after consuming raisins. The study showed the role of the food matrix in enhancing quercetin bioavailability, suggesting that the complex interactions within whole foods like raisins could significantly influence the solubility, stability, and absorption of quercetin. [ABSTRACT FROM AUTHOR]

Exposure of firefighting instructors to polycyclic aromatic hydrocarbons (PAHs) such as naphthalene is unavoidable during live fire training. The study aimed to investigate naphthalene uptake by measuring the urinary excretion of the naphthalene metabolite 1,2-dihydroxynaphthalene (DHN), to describe the DHN elimination kinetics and to evaluate the results by comparison to further biomarkers of PAH exposure. N = 6 male non-smoking firefighting instructors completed five training sessions each in a residential fire simulation unit under respiratory protection. All participants provided two urine samples before and another seven samples within an 18-h-interval after each session. DHN was detected by gas chromatography/tandem mass spectrometry (GC–MS/MS) in all samples (n = 237) with median concentrations ranging from 3.3 µg/g crea. (range 0.9–10.2) before exposure to 134.2 µg/g crea. (43.4–380.4) post exposure. Maximum elimination found 3.3 h (median) after onset of exposure decreased with a mean half-life of 6.6 h to 27.1 µg/g crea. (15.7–139.5) 18 h after training. DHN sensitively indicated a presumed dermal naphthalene intake during training, showing similar elimination kinetics like other naphthalene metabolites. Internal exposure of the participants transiently exceeded exposures determined for non-smokers in the general population, but was lower than at other workplaces with PAH exposure. Despite limited uptake, accumulation is possible with daily exposure. [ABSTRACT FROM AUTHOR]

Tilmicosin, a macrolide antibiotic, has the potential to treat bacterial infections in donkeys. However, the pharmacokinetics of tilmicosin in donkeys have not been reported. The aim of this study was to investigate the pharmacokinetics of tilmicosin in donkey plasma, urine, and feces after a single intragastric administration to determine the suitability of tilmicosin for donkeys. A total of 5 healthy male donkeys with similar body weights were selected. The donkeys were administered a single dose of 10 mg · kg−1 body weight (BW) tilmicosin by gavage. The concentrations of tilmicosin in plasma, urine, and feces were determined. The results showed that after a single intragastric administration of 10 mg · kg−1 body weight, tilmicosin in donkey plasma reached a maximum concentration of 11.23 ± 5.37 mg · L−1 at 0.80 ± 0.10 h, with a half‐life of 14.49 ± 7.13 h, a mean residence time of 28.05 ± 3.05 h, a Cl/F of 0.48 ± 0.18 L · kg−1 · h−1, and a Vd/F of 9.28 ± 2.63 Lkg−1. The percentage of tilmicosin excreted through the urine of donkeys is 2.47%, and the percentage excreted through the feces is 66.43%. Our study provides data to inform the use of tilmicosin in donkeys. [ABSTRACT FROM AUTHOR]

Artificial Intelligence (AI) is poised or has already begun to influence absorption, distribution, metabolism and excretion (ADME) science. It is not in the area expected – that of superior modelling of ADME data to increase its predictive power. It is influencing traditional exhaustive and careful literature research by providing almost perfect summaries of existing information. This will highly influence how people study, graduate and progress in the ADME sciences. The literature contains many flaws (protein binding influence on unbound drug concentration is one of the examples cited) and without direction AI may help to popularise them. ADME science has a relatively small number of key assays and values, but these are produced under widely varying conditions so large data sets, the best substrate for artificial intelligence, are not readily available to produce new more predictive systems. The use of AI to enrich the databases may be a near term goal. AI is already contributing in other areas such as technical skill assimilation, maintenance of complex instruments (combined with virtual reality) and the processing of pharmacovigilance. [ABSTRACT FROM AUTHOR]

Background: The development of autism spectrum disorder (ASD) may stem from exposure to environmental pollutants such as heavy metals. The primary objective of this study is to determine the role of heavy metals of concern such as manganese (Mn), cadmium (Cd), lead (Pb), arsenic (As), and essential trace element selenium (Se) among ASD children in Kuala Lumpur, Malaysia. Method: A total of 155 preschoolers in Kuala Lumpur between the ages 3 to 6 participated in an unmatched case-control study, comprising ASD children (n = 81) recruited from an early intervention program for autism, and 74 children without autism who were recruited from public preschools. Urine samples were collected at home, delivered to the study site, and transported to the environmental lab within 24 hours. Inductively coupled plasma mass spectrometry (ICP-MS) was applied to measure the concentration of heavy metals in the samples. Data were analysed using bivariate statistical tests (Chi-square and T-test) and logistic regression models. Result: This study demonstrated that Cd, Pb, and As urine levels were significantly greater in children without autism relative to those affected with ASD (p < 0.05). No significant difference was in the levels of Se (p = 0.659) and Mn (p = 0.875) between children with ASD and the control group. The majority of children in both groups have urine As, Pb, and Cd values lower than 15.1 µg/dL, 1.0 µg/dL, and 1.0 µg/dL, respectively which are the minimal risk values for noncarcinogenic detrimental human health effect due to the heavy metal's exposure. Factors associated with having an ASD child included being a firstborn, male, and higher parental education levels (adjusted odds ratios (aOR) > 1, p < 0.05). Conclusion: Preschoolers in this study demonstrated low levels of heavy metals in their urine samples, which was relatively lower in ASD children compared to the healthy matched controls. These findings may arise from the diminished capacity to excrete heavy metals, especially among ASD children, thereby causing further accumulation of heavy metals in the body. These findings, including the factors associated with having an ASD child, may be considered by healthcare professionals involved in child development care, for early ASD detection. Further assessment of heavy metals among ASD children in the country and interventional studies to develop effective methods of addressing exposure to heavy metals will be beneficial for future reference. [ABSTRACT FROM AUTHOR]

Objective The present study aimed to measure fecal and urinary phosphorus (P) excretion from pigs and to develop prediction models for P excretion of pigs. Methods A total of 96 values for P excretions were obtained from pigs of 15 to 93 kg body weight (BW) fed 12 diets in four experiments and were used to develop the prediction models. All experimental diets contained exogenous phytase at 500 phytase units per kg. Body weight of pigs and dietary P concentrations were used as independent variables in the prediction models. Results The BW, feed intake, and P intake were positively correlated with total (fecal plus urinary) P excretions (r = 0.80, 0.91, and 0.94, respectively; p

Perfluoroalkyl sulfonamides (FASAs) and other FASA‐based per‐ and polyfluoroalkyl substances (PFASs) can transform into recalcitrant perfluoroalkyl sulfonates in vivo. We conducted high‐resolution mass spectrometry suspect screening of urine and tissues (kidney and liver) from mice dosed with an electrochemically fluorinated aqueous film‐forming foam (AFFF) to better understand the biological fate of AFFF‐associated precursors. The B6C3F1 mice were dosed at five levels (0, 0.05, 0.5, 1, and 5 mg kg−1 day−1) based on perfluorooctane sulfonate and perfluorooctanoate content of the AFFF mixture. Dosing continued for 10 days followed by a 6‐day depuration. Total oxidizable precursor assay of the AFFF suggested significant contributions from precursors with three to six perfluorinated carbons. We identified C4 to C6 FASAs and N‐glucuronidated FASAs (FASA‐N‐glus) excreted in urine collected throughout dosing and depuration. Based on normalized relative abundance, FASA‐N‐glus accounted for up to 33% of the total excreted FASAs in mouse urine, highlighting the importance of phase II metabolic conjugation as a route of excretion. High‐resolution mass spectrometry screening of liver and kidney tissue revealed accumulation of longer‐chain (C7 and C8) FASAs not detected in urine. Chain‐length–dependent conjugation of FASAs was also observed by incubating FASAs with mouse liver S9 fractions. Shorter‐chain (C4) FASAs conjugated to a much greater extent over a 120‐min incubation than longer‐chain (C8) FASAs. Overall, this study highlights the significance of N‐glucuronidation as an excretion mechanism for short‐chain FASAs and suggests that monitoring urine for FASA‐N‐glus could contribute to a better understanding of PFAS exposure, as FASAs and their conjugates are often overlooked by traditional biomonitoring studies. Environ Toxicol Chem 2024;00:1–11. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Canine urinary excretion of chloramphenicol was evaluated to optimize a dosing protocol for treating urinary tract infections. Seven healthy male intact purpose‐bred Beagles and six healthy client‐owned dogs of various breeds each received a single oral 50 mg/kg dose of chloramphenicol. Urine was collected at baseline, and 6, 8, 12, and 24 h after chloramphenicol. Chloramphenicol urine concentrations were measured and compared to the epidemiological cutoff value for E. coli (16 mcg/mL). At 8 h, mean chloramphenicol concentration from all dogs was 266.9 mcg/mL (90% CI 136.2–397.7 mcg/mL) but was lower in Beagles than client‐owned dogs. At 12 h, mean chloramphenicol concentration from all dogs was 111.0 mcg/mL (90% CI 36.9–185.0 mcg/mL) and was lower in Beagles (10.6 mcg/mL, 90% CI 1.4–19.8 mcg/mL) than client‐owned dogs (228.0 mcg/mL, 90% CI 103.0–353.1 mcg/mL). Urine half‐life was similar for all dogs (1.8–3.8 h). This justifies dosing chloramphenicol 50 mg/kg PO q 8 h. All client‐owned dogs additionally maintained concentrations well above 16 mcg/mL, for 12 h, suggesting that q 12‐h dosing might be appropriate for non‐Beagle dogs with susceptible lower urinary tract infections. A clinical trial in dogs with urinary tract infections is needed as well as further investigation into potential breed differences. [ABSTRACT FROM AUTHOR]

The purpose of this research was to examine the potential effects of bentonite (BN) supplemented diets on growth, feed utilization, blood biochemistry, and histomorphology of Dicentrarchus labrax. Six treatments in triplicate were tested: B0, B0.5, B1.0, B1.5, B3.0, and B4.5, which represented fish groups fed diets supplemented with 0, 0.5, 1, 1.5, 3, and 4.5% BN, respectively. For 84 days, juveniles' seabass (initial weight = 32.73 g) were fed diets containing 46% protein, three times daily at 3% of body weight. With a 5% daily water exchange, underground seawater (32 ppt) was used. Findings revealed significant improvements in water quality (TAN and NH3), growth (FW, WG and SGR) and feed utilization (FCR, PER and PPV) in fish fed BN-supplemented diets, with the best values in favor of the B1.5 group. Additional enhancements in kidney function indicators (urea and uric acid) and liver enzymes were observed in fish of the BN-treated groups along with a decrease in cholesterol level in the B1.5 group. Further improvements in fish innate immunity (hemoglobin, red blood cells, glucose, total protein, globulin, and immunoglobulin IgM), antioxidant activity (total antioxidative capacity and catalase), and decreased cortisol levels in fish of the BN-treated groups. Histological examinations of the anterior and posterior intestines and liver in groups B1.5 and B3 revealed the healthiest organs. This study recommends BN at a concentration of 1.5% as a feed additive in the Dicentrarchus labrax diet. [ABSTRACT FROM AUTHOR]

Simple Summary: Ningxiang pigs are popular for their high meat quality and unique flavor, but they contain a low lean percentage. Long-term excessive intake of pork with high fat content and its products might be associated with dyslipidemia. Lactobacillus delbrueckii has been proven to regulate lipid metabolism and improve blood lipids in our previous studies; however, the underlying mechanism remains unclear. In the present study, we investigated the effects of L. delbrueckii on gut microbiota and body lipid metabolism and found that L. delbrueckii regulated hepatic and tissular fat metabolism via gut microbiota modulation and fecal TBA excretion to reduce blood lipid levels in Ningxiang pigs. Lactobacillus delbrueckii intervention can regulate body lipid metabolism, but the underlying mechanism remains unclear. Our study investigated the effects of L. delbrueckii on serum lipid levels, tissular fat metabolism and deposition, bile acid metabolism, and gut microbiota in Ningxiang pigs. Ninety-six pigs were divided into two groups and fed basal diets containing either 0 (CON) or 0.1% L. delbrueckii (LD) for 60 days. Dietary L. delbrueckii promoted fecal total bile acid (TBA) excretion and increased hepatic enzyme activities related to cholesterol and bile synthesis but decreased hepatic and serum lipid concentrations. L. delbrueckii downregulated gene expression associated with fatty acid synthesis but upregulated gene expression related to lipolysis and β-fatty acid oxidation in liver and subcutaneous fat. L. delbrueckii elevated gut Lactobacillus abundance and colonic short-chain fatty acid (SCFA)-producing bacteria but declined the abundance of some pathogenic bacteria. These findings demonstrated that L. delbrueckii modulated intestinal microbiota composition and facilitated fecal TBA excretion to regulate hepatic fat metabolism, which resulted in less lipid deposition in the liver and reduced levels of serum lipids. [ABSTRACT FROM AUTHOR]

Background: The potential influence of hyperuricemia on the genesis and progression of chronic kidney disease (CKD) remains controversial. In general, the correlation between blood levels of uric acid (UA) and the rate of progression of CKD is considered to be modest, if any, and the results of relevant trials oriented to disclose the effect of urate-lowering therapies on this outcome have been disappointing. Urinary excretion rates of UA could reflect more accurately the potential consequences of urate-related kidney injury. Method: Using a cross-sectional design, we investigated the correlation between different estimators of the rates of urinary excretion of UA (total 24-hour excretion, mean urinary concentration, renal clearance and fractional excretion)(main study variables), on one side, and urinary levels of selected biomarkers of kidney injury and CKD progression (DKK3, KIM1, NGAL, interleukin 1b and MCP)(main outcome variables), in 120 patients with advanced CKD (mean glomerular filtration rate 21.5 mL/minute). We took into consideration essential demographic, clinical and analytic variables with a potential confounding effect on the explored correlations (control variables). Spearman's rho correlation and nonlinear generalized additive regression models (GAM) with p-splines smoothers were used for statistical analysis. Main results: Multivariate analysis disclosed independent correlations between urinary UA concentrations, clearances and fractional excretion rates (but not plasma UA or total 24-hour excretion rates of UA), on one side, and the scrutinized markers. These correlations were more consistent for DKK3 and NGAL than for the other biomarkers. Glomerular filtration rate, proteinuria and treatment with statins or RAA axis antagonists were other independent correlates of the main outcome variables. Conclusions: Our results support the hypothesis that urinary excretion rates of UA may represent a more accurate marker of UA-related kidney injury than plasma levels of this metabolite, in patients with advanced stages of CKD. Further, longitudinal studies will be necessary, to disclose the clinical significance of these findings. [ABSTRACT FROM AUTHOR]

Voltage-gated ion channels (VGICs) respond to changes in membrane potential (Vm) and typically exhibit fast kinetic properties. They play an important role in signal detection and propagation in excitable tissues. In contrast, the role of VGICs in non-excitable tissues like epithelia is less studied and less clear. Studies in epithelia of vertebrates and invertebrates demonstrate wide expression of VGICs in epithelia of animals. Recently, VGICs have emerged as regulators of ion transport in the Malpighian tubules (MTs) and other osmoregulatory organs of insects. This mini-review aims to concisely summarize which VGICs have been implicated in the regulation of ion transport in the osmoregulatory epithelia of insects to date, and highlight select groups for further study. We have also speculated on the roles VGICs may potentially play in regulating processes connected directly to ion transport in insects (e.g., acid-base balance, desiccation, thermal tolerance). This review is not meant to be exhaustive but should rather serve as a thought-provoking collection of select existing highlights on VGICs, and to emphasize how understudied this mechanism of ion transport regulation is in insect epithelia. [ABSTRACT FROM AUTHOR]

Understanding how fecal glucocorticoid (GC) concentration is associated with reproduction in wild animals allows us to associate physiological stress with the costs of reproduction. Glucocorticoids are among the main stress-related hormones, and their secretion is strongly associated with reproductive seasonality. Using non-invasive methods (thereby avoiding causing stress), we used fecal GC metabolites (FGC) to test the hypothesis that the reproductive phase (mating, non-mating, gestation, and lactation) influences stress levels of the seasonally reproductive Pampas Deer (Ozotoceros bezoarticus). Furthermore, we compared FGC between sexes and between males of different antler statuses (velvet, hard, cast). During 1 year, in the Pantanal of Brazil, we collected 621 fresh fecal samples (327 from females, 294 from males) from which we estimated FGC using enzyme immunoassay (EIA). FGC concentrations varied by reproductive phase and antler status. Agonistic and courtship interactions associated with mating (i.e., fights between males, attempts to mount females), suggest that they influence FGC concentrations most strongly in both sexes. Females also had greater FGC concentrations during lactation, suggesting that this phase and parental care are also associated with increased physiological stress. In males, the association of FGC concentrations with antler status may be, in part, associated with photoperiod and testosterone secretion, both of which can trigger reproductive and agonistic behaviors. Finally, reproductive synchrony of the sexes causes similar FGC over time and suggests that environmental factors contribute as well. We show that non-invasive monitoring of glucocorticoid metabolites levels is an effective tool for detecting changes in the physiological stress response in Pampas Deer, suggesting that this tool will be useful for detecting changes in physiological stress caused by human disturbance, such as cattle ranching in Pantanal and similar disturbances elsewhere. [ABSTRACT FROM AUTHOR]

Insecticides prevent or reduce insect crop damage, maintaining crop quality and quantity. Physiological traits, such as an insect's feeding behavior, influence the way insecticides are absorbed and processed in the body (toxicokinetics), which can be exploited to improve species selectivity. To fully understand the uptake of insecticides, it is essential to study their total uptake and toxicokinetics independent of their toxic effects on insects. We studied the toxicokinetics (TK) of insecticidally inactive test compounds incorporating agro-like structural motifs in larvae of the Egyptian cotton leafworm (Spodoptera littoralis, Lepidoptera), and their distribution across all biological matrices, using laboratory experiments and modeling. We measured Spodoptera larval behavior and temporal changes of whole-body concentrations of test compounds during feeding on treated soybean leaf disks and throughout a subsequent depuration period. Differences in the distribution of the total quantities of compounds were found between the biological matrices leaf, larva, and feces. Rate constants for uptake and elimination of test compounds were derived by calibrating a toxicokinetic model to the whole-body concentrations. Uptake and elimination rate constants depended on the physicochemical properties of the test compounds. Increasing hydrophobicity increased the bioaccumulation potential of test compounds. Incomplete quantities in larval matrices indicated that some compounds may undergo biotransformation. As fecal excretion was a major elimination pathway, the variable time of release and number of feces pellets led to a high variability in the body burden. We provide quantitative models to predict the toxicokinetics and bioaccumulation potential of inactive insecticide analogs (parent compounds) in Spodoptera. [ABSTRACT FROM AUTHOR]

BACKGROUND: Methanotrophs play an important role in mitigating methane (CH4) emissions in ecosystems. They closely interact with other microorganisms forming communities where the cross‐feeding of metabolites, presumably methanol (MeOH), is essential for the growth and activity of non‐methanotrophs. The experiments in this study were focused on investigating the effect of adding the supernatant from a methanotrophic consortium to pure cultures of Methylomonas methanica. RESULTS: Methanol dehydrogenase inhibition caused the accumulation of MeOH, which resulted in a significant production after 3 h, with 1.99 mmol L−1 CH3OH. The addition of the supernatant was associated with the excretion of MeOH by M. methanica and enhancement of the CH4 consumption rate, despite a reduction in growth. The maximum MeOH concentrations were between 0.7 and 1.5 mmol L−1 CH3OH. CONCLUSION: These findings indicate that MeOH excretion may indeed be linked to a metabolic imbalance, which could potentially be compensated through the cross‐feeding of metabolites within the methanotrophic community. © 2024 The Authors. Journal of Chemical Technology and Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry (SCI). [ABSTRACT FROM AUTHOR]

Background. Tumor necrosis factor receptor 1 (TNFR1) and 2 (TNFR2) can be cleaved from the cell surface and circulate alone or in combination with tumor necrosis factor alpha (TNF-a). These soluble receptors may play a key role in regulating the inflammatory response. Objectives. The study aimed to evaluate the role of TNFRs in regulating the inflammatory response in immunoglobulin A nephropathy (IgAN). Materials and methods: The study included 26 patients with newly diagnosed and biopsy-confirmed IgAN and 20 healthy controls. Study material included blood and fresh urine collected the morning before kidney biopsy and therapy. The serum concentrations of TNFR1 (STNFR1) and TNFR2 (STNFR2) and urinary excretion of TNFR1 (UTNFR1) and TNFR2 (UTNFR2) were determined with immunoassay. Subsequently, the data were evaluated statistically. Results: The STNFR1 and STNFR2 levels were higher in IgAN patients than in healthy subjects (4747.87 pg/mL and 2817.62 pg/mL compared to 2755.68 pg/mL (95% CI: from -2948.41 to -1035.97; p = 0.001) and 1437.83 pg/mL (95% CI: from -1958.50 to -419.60; p = 0.001). The power of the test was 98.5% for STNFR1 and 96% for STNFR2. Urinary concentrations only increased for TNFR1 (3551.29 compared to 2338.95 pg/mg of creatinine (Cr) (95% CI: from -2247.03 to -177.66; p = 0.023). The STNFR1 marker was characterized by a sensitivity of 73.08% and a specificity of 90.00% (p < 0.001). Conclusions. Our results suggest that TNFR1 and TNFR2 are good markers of TNF-a pathway activation in IgAN patients. [ABSTRACT FROM AUTHOR]

Compound 7–16 was designed and synthesized in our previous study and was identified as a more potential selective 5-HT2A receptor antagonist and inverse agonist for treating Parkinson's disease psychosis (PDP). Then, the metabolism, disposition, and excretion properties of 7–16 and its potential inhibition on transporters were investigated in this study to highlight advancements in the understanding of its therapeutic mechanisms. The results indicate that a total of 10 metabolites of 7–16/[14C]7–16 were identified and determined in five species of liver microsomes and in rats using UPLC-Q Exactive high-resolution mass spectrometry combined with radioanalysis. Metabolites formed in human liver microsomes could be covered by animal species. 7–16 is mainly metabolized through mono-oxidation (M470-2) and N-demethylation (M440), and the CYP3A4 isozyme was responsible for both metabolic reactions. Based on the excretion data in bile and urine, the absorption rate of 7–16 was at least 74.7%. 7–16 had weak inhibition on P-glycoprotein and no effect on the transport activity of OATP1B1, OATP1B3, OAT1, OAT3, and OCT2 transporters. The comprehensive pharmacokinetic properties indicate that 7–16 deserves further development as a new treatment drug for PDP. [ABSTRACT FROM AUTHOR]

Hypercholesterolemia-associated oxidative stress increases the formation of oxidized low-density lipoprotein (oxLDL), which can affect endothelial cell function and potentially contribute to renal dysfunction, as reflected by changes in urinary protein excretion. This study aimed to investigate the impact of exogenous oxLDL on urinary excretion of albumin and nephrin. LDL was isolated from a patient with familial hypercholesterolemia (FH) undergoing lipoprotein apheresis (LA) and was oxidized in vitro with Cu (II) ions. Biochemical markers of LDL oxidation, such as TBARS, conjugated dienes, and free ε-amino groups, were measured. Wistar rats were treated with a single intraperitoneal injection of PBS, LDL, or oxLDL (4 mg of protein/kg b.w.). Urine was collected one day before and two days after the injection. We measured blood lipid profiles, urinary protein excretion (specifically albumin and nephrin), and markers of systemic oxidative stress (8-OHdG and 8-iso-PGF2α). The results showed that injection of oxLDL increased urinary albumin excretion by approximately 28% (310 ± 27 μg/24 h vs. 396 ± 26 μg/24 h, p = 0.0003) but had no effect on nephrin excretion. Neither PBS nor LDL had any effect on urinary albumin or nephrin excretion. Additionally, oxLDL did not affect systemic oxidative stress. In conclusion, hypercholesterolemia may adversely affect renal function through oxidatively modified LDL, which interferes with the renal handling of albumin and leads to the development of albuminuria. [ABSTRACT FROM AUTHOR]

Introduction: Prostate-specific membrane antigen (PSMA) is present in high amounts in salivary glands, but it is unclear whether labeled binders of PSMA are excreted in the saliva. Methods: Ten patients with prostate cancer underwent whole-body [18F]DCFPyL PET/CT (NCT03181867), and saliva samples were collected between 0-120 minutes post-injection. [18F]DCFPyL salivary excretion was measured over 120 minutes and expressed as %ID/g. Protein-associated binding was estimated by the percentage of [18F]DCFPyL versus parent radiotracer. Results: All PET scans of 10 patients (69 ± 8 years) with histologically confirmed prostate cancer (PSA= 2.4 ± 2.4, and Gleason Grade = 6-9) showed high uptake of [18F]-DCFPyL in salivary glands while 8 patients demonstrated high uptake in the saliva at 45 minutes. The intact [18F]-DCFPyL (98%) was also confirmed in the saliva samples at 120 min with increasing salivary radioactivity between 30-120 min. Conclusion: Systemically injected [18F]DCFPyL shows salivary gland uptake, an increasing amount of which is secreted in saliva over time and is not maximized by 120 minutes post-injection. Although probably insignificant for diagnostic studies, patients undergoing PSMA-targeted therapies should be aware of radioactivity in saliva. [ABSTRACT FROM AUTHOR]

The hepatitis E virus is a serious health concern worldwide, with 20 million cases each year. Growing numbers of autochthonous HEV infections in industrialized nations are brought on via the zoonotic transmission of HEV genotypes 3 and 4. Pigs and wild boars are the main animal reservoirs of HEV and play the primary role in HEV transmission. Consumption of raw or undercooked pork meat and close contact with infected animals are the most common causes of hepatitis E infection in industrialized countries. However, during the past few years, mounting data describing HEV distribution has led experts to believe that additional animals, particularly domestic ruminant species (cow, goat, sheep, deer, buffalo, and yak), may also play a role in the spreading of HEV. Up to now, there have not been enough studies focused on HEV infections associated with animal milk and the impact that they could have on the epidemiology of HEV. This critical analysis discusses the role of domestic ruminants in zoonotic HEV transmissions. More specifically, we focus on concerns related to milk safety, the role of mixed farming in cross-species HEV infections, and what potential consequences these may have on public health. [ABSTRACT FROM AUTHOR]

The canine urinary excretion of florfenicol was evaluated to explore its potential for treating urinary tract infections. Nine healthy male intact purpose‐bred Beagles and four healthy client‐owned dogs each received a single oral dose of florfenicol 20 mg/kg (300 mg/mL parenteral solution) with food. All voluntary urinations were collected for 12 h. Although florfenicol is reportedly bitter tasting, 7/9 Beagles and 4/4 client‐owned dogs completely ingested the florfenicol and were enrolled; salivation (n = 1) and headshaking (n = 3) were observed. The last measured urine florfenicol concentrations were variable: Beagles (0.23–3.19 mcg/mL), Pug (3.01 mcg/mL) English Setter (21.29 mcg/mL), Greyhound (32.68 mcg/mL), and Standard Poodle (13.00 mcg/mL). Urine half‐life was similar for the Beagles and the Pug, 0.75–1.39 h, whereas the half‐life was 1.70–1.82 h for the English Setter, Greyhound, and Standard Poodle. Larger breed dogs exceeded 8 mcg/mL florfenicol (wild‐type cutoff) in their urine at 12 h, whereas the Beagles and Pug had <8 mcg/mL; it is unclear if this is an individual, breed, or size difference. These data suggest oral florfenicol may need to be administered q6‐12h for canine urinary tract infections, but further data are needed (more enrolled dogs, multiple‐dose regimens) before considering clinical trials or breed‐specific differences. [ABSTRACT FROM AUTHOR]

Background Primary membranous nephropathy (pMN) is one of the most common types of glomerulonephritis, with a third of patients progressing to renal insufficiency. Various prognostic factors have been reported, of which urinary protein and renal function are the most critical parameters. Fractional excretion of total protein (FETP) indicates protein leakage that accounts for creatinine kinetics and serum protein levels. In this study, we investigated the association between FETP and renal prognosis in pMN. Methods We retrospectively identified 150 patients with pMN. FETP was calculated as follows: (serum creatinine × urine protein)/(serum protein × urine creatinine) %. We divided the patients into three groups according to FETP values and compared the clinicopathological findings. The primary outcome was an estimated glomerular filtration rate (eGFR) decrease of ≥30% from the baseline level. Results FETP was associated with urinary protein and renal function, Ehrenreich and Churg stage, and global glomerulosclerosis. The primary outcome was observed in 38 patients (25.3%), and the frequency of the primary outcome was higher in the high FETP group (P  = .001). FETP is higher than protein–creatinine ratio (PCR) in the area under the curve. In the multivariate analysis adjusted for age, eGFR, PCR and treatment, FETP was significantly associated with primary outcome (adjusted hazard ratio, 8.19; P  = .019). Conclusions FETP is a valuable indicator that can reflect the pathophysiology and is more useful than PCR as a predictor of renal prognosis in patients with Japanese pMN. [ABSTRACT FROM AUTHOR]

Exposure to ultraviolet radiation (UVR) leads to skin DNA damage, specifically in the form of cyclobutane pyrimidine dimers, with thymidine dimers being the most common. Quantifying these dimers can indicate the extent of DNA damage resulting from UVR exposure. Here, a new liquid chromatography-mass spectrometry (LC–MS) method was used to quantify thymidine dimers in the urine after a temporary increase in real-life UVR exposure. Healthy Danish volunteers (n = 27) experienced increased UVR exposure during a winter vacation. Individual exposure, assessed via personally worn electronic UVR dosimeters, revealed a mean exposure level of 32.9 standard erythema doses (SEDs) during the last week of vacation. Morning urine thymidine dimer concentrations were markedly elevated both 1 and 2 days post-vacation, and individual thymidine dimer levels correlated with UVR exposure during the last week of the vacation. The strongest correlation with erythema-weighted personal UVR exposure (Power model, r2 = 0.64, p < 0.001) was observed when both morning urine samples were combined to measure 48-h thymidine dimer excretion, whereas 24-h excretion based on a single sample provided a weaker correlation (Power model, r2 = 0.55, p < 0.001). Sex, age, and skin phototype had no significant effect on these correlations. For the first time, urinary thymidine dimer excretion was quantified by LC–MS to evaluate the effect of a temporary increase in personal UVR exposure in a real-life setting. The high sensitivity to elevated UVR exposure and correlation between urinary excretion and measured SED suggest that this approach may be used to quantify DNA damage and repair and to evaluate photoprevention strategies. [ABSTRACT FROM AUTHOR]