Liver Concentrations Research Articles

Inhibitory Effects of Alkaloids on OATP1B1 In Vitro and In Vivo: Prediction for Food/Herb-Drug Interactions and Hepatoprotective Effects Based on Structure-Activity Relationships.

Alkaloids, a class of low-molecular-weight nitrogenous compounds, attract a great deal of interest because of their biological activities and therapeutic potential. Yet, surprisingly little is known about their interactions with drug transporters, especially Organic Anion Transporting Polypeptide 1B1 (OATP1B1), a liver-specific uptake transporter, which is closely associated with drug-induced liver injury (DILI). This study aims to investigate the inhibitory effects of 160 alkaloids on OATP1B1, assess the hepatoprotective effects against bosentan-induced liver injury, and elucidate the structure-activity relationships of alkaloids with OATP1B1. Four alkaloids, including dihydroberberine, deacetyltaxol, dihydrocapsaicin, and tetrahydropalmatine, significantly inhibited OATP1B1 transport activity in OATP1B1-HEK293 cells (>50%), which reduced the OATP1B1-mediated uptake of methotrexate and microcystin-LR, and consequently decreased their cell toxicity. In bosentan-induced liver injury models, 4 alkaloids reduced serum total bile acid (TBA) levels and liver concentration of bosentan to different degrees, especially deacetyltaxol, which exhibited the most potent hepatoprotective effect against bosentan. The pharmacophore model suggested that the critical pharmacophores of alkaloid inhibitors are hydrogen bond acceptors and hydrophobic groups. Our findings pave the way for predicting the potential risks of alkaloids-containing food/herb-drug interactions in humans and optimizing the alkaloid structure for alleviating OATP1B1-related DILI.

The role of the hypothalamus-gut microbiota in the pathogenesis of periparturient fatty liver disease in dairy cows.

During the periparturient period, dairy cows experience negative energy balance due to reduced feed intake, leading to adipose tissue breakdown, liver damage, and fat accumulation. This study examined the gut-liver-brain axis to explore the link between fatty liver disease, changes in hypothalamic appetite-related neurons, and microbiome shifts in dairy cows. Thirty cows were monitored, with daily DMI recordings and blood sampling. Postpartum brain, liver, and ileal contents were collected from 10 selected cows, divided into two groups: H-DMI (slight DMI decrease) and L-DMI (severe DMI decrease). The L-DMI group of cows exhibited higher plasma NEFA, BHBA, ALT, and AST levels, along with severe hepatic steatosis and lipid accumulation. Transcriptome sequencing of the hypothalamic arcuate nucleus (ARC) revealed decreased expression of Hypocretin Neuropeptide Precursor (HCRT), orexin-A (OX-A), Orexin Receptor Type 1 (OX1R), and Cannabinoid Receptor 1 (CB1) in the L-DMI group, while Pro-opiomelanocortin (POMC) and Melanocortin 4 Receptor (MC4R) expression increased. Metagenomic analysis of ileal contents showed reduced abundance of Ruminococcus spp. in the L-DMI group, which may be associated with fatty liver disease (FL). Integrated omics analysis showed that increased MC4R expression was correlated with the elevated abundance of bacteria such as Akkermansia glycaniphila, and reduced abundance of species such as Methanobrevubacter thaueri and Ruminococcus spp. Decreased HCRT expression was also linked to Akkermansia glycaniphila. In conclusion, these changes may affect DMI through the OX-A/POMC pathway, with neurological and gut microbiome alterations potentially leading to appetite suppression, negative energy balance, and the development of fatty liver disease.

Wintering loons in South Korea face an ongoing threat from polycyclic aromatic hydrocarbons: Shifting sources and potential DNA damage.

Diving birds, particularly those sharing coastal habitats with fishing grounds, are at risk from oil pollution. Despite documented cases of bird mortality, the specific role of oil pollution in these death remains unclear. To address this knowledge gap, this study examined polycyclic aromatic hydrocarbon (PAH) contamination, its sources, and its impact on loon health. An analysis of 86 carcasses from three species of loons revealed drowning as the leading cause of death, followed by oil pollution and unknown debilitation. While liver concentrations of 16 PAHs (∑PAHs) showed no significant variation by sex, location, species, or cause of death, it was evident that wintering loons were exposed to PAH pollution along South Korea's eastern coast. The ratio of low (di- and tri-cyclic) to high (tetra-, penta-, and hexa-cyclic) molecular weight PAHs was approximately 3-5 across all three loon species. From 2010 to 2017, the composition of PAHs shifted, with a decline in low molecular weight PAHs (indicative of petrogenic sources) and a concerning increase in high molecular weight PAHs (associated with pyrogenic sources). This trend coincided with a tenfold increase in the toxic equivalency quotient of benzo[a]pyrene (TEQBaP), despite a decrease in overall ∑PAH concentrations. The detection of benzo[a]pyrene diol epoxide (BPDE)-DNA adducts in some loons further suggests potential genotoxic effects from PAH exposure. These findings underscore the persistent PAH contamination affecting wintering loons. Continued research is crucial to understand the evolving threats posed by PAHs and to support the conservation of these migratory birds along the North America-Asia flyway.

Protective effects of dietary protein against nitrite stress in grass carp (Ctenopharyngodon idella): A new perspective

Protein constitutes the predominant essential nutrient in fish feed. Despite extensive research efforts on the dietary protein of fish, limited attention has focused on its potential antistress properties. Therefore, this study sought to examine the impact of dietary protein on the liver structure of grass carp (Ctenopharyngodon idella) and its underlying molecular mechanism after nitrite stress, with the objective of elucidating the role of dietary protein in the stress response of fish. Specifically, various levels of dietary protein (16 %, 19 %, 22 %, 25 %, 28 % and 31 %) were investigated for their effects on liver tissue damage, oxidative stress, endoplasmic reticulum (ER) stress, autophagy and apoptosis in grass carp after exposure to a nitrite solution at a concentration of 10 mg/L for a duration of 96 h.Our study revealed that exposure to nitrite solution resulted in liver structural damage in grass carp. However, 22–25 % dietary protein levels might attenuate the impact of nitrite stress by decreasing liver contents of nitric oxide (NO), peroxynitrite anion (ONOO-), reactive oxygen species (ROS), protein carbonyl (PC), and malondialdehyde (MDA), which is reflected in serum activities of glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT). Histological analysis further supported the protective role of appropriate protein levels (22–28 %) in alleviating nitrite-induced liver tissue damage. Subsequent investigations demonstrated that optimal dietary protein levels decreased ER stress and autophagy in fish by modulating the expression of gene and protein involved in 78 kDa glucose regulated protein (GRP78) pathway and autophagosome formation process, respectively. Meanwhile, appropriate dietary protein levels decreased the activities of caspase-3, caspase-8 and caspase-9 by inhibiting both death receptor pathway and mitochondrial pathway associated with apoptosis. Finally, based on regression analysis of liver ONOO− content, the dietary protein requirement for grass carp (721–1381 g) under nitrite stress was determined to be 25.07 %. Overall, this study provides novel evidence that optimal protein levels can enhance the resistance of grass carp to nitrite stress and mitigate liver tissue damage by reducing oxidative stress cascade damage.

Tissue bioaccumulation and distribution of organic contaminants in Brazilian guitarfish Pseudobatos horkelii reveal a concerning impact of contraceptive hormones and fecal sterols.

The critically endangered Brazilian guitarfish faces significant threats from environmental contamination. Assessing the impacts of such stressor is paramount from a conservational perspective. This study investigated the concentrations, distribution and accumulation patterns of organic contaminants in pregnant Brazilian guitarfish Pseudobatos horkelii. Blood, gill, gonad, liver, and muscle concentrations of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers, fecal sterols, and synthetic hormones used as human contraceptives were assessed. Synthetic hormones, especially D-norgestrel, showed the highest concentrations, mainly in the liver. Together with the results of fecal sterols, this finding suggests that guitarfish are exposed to sewage discharge. OCPs, especially hexachlorobenzene, mirex, endosulfans, and drins, showed considerably high concentrations, indicating the relevance of agricultural inputs. PCBs presented significant concentrations in the muscle, indicating long-term exposure, in contrast with other analytes that were primarily concentrated in the liver. These results have conservational implications, since contaminants analyzed herein have endocrine disruptive effects.

Relative bioavailability of selenium yeast, selenomethionine, hydroxyl-selenomethionine and nano-selenium for broilers.

Selenium (Se) is an essential trace element for humans and animals. Development and application of new forms of Se sources with lower toxicity and higher bioavailability has been attracting more attention. However, the bioavailabilities of Se from several new Se sources for broilers remain unclear. Therefore, the aim of this study was to assess the relative bioavailabilities of Se from Se yeast (SY), selenomethionine (SM), hydroxyl-selenomethionine (SO) and nano-Se (NS) relative to sodium selenite (SS) for broilers fed a conventional corn-soybean meal diet. A total of 576 one-day-old Arbor Acres commercial male broilers were randomly assigned to 16 treatments with 6 replicate cages per treatment in a completely randomized design involving a 5 (Se sources: SY, SM, SO, NS and SS) × 3 (added Se levels: 0.15, 0.30 and 0.45 mg Se/kg) factorial design of treatments plus 1 (a Se-unsupplemented control) for 21 d. The relative bioavailabilities of Se sources were estimated based on plasma or tissue Se concentrations as well as selenoprotein mRNA expressions and activities in broilers. The results showed that the Se concentrations and glutathione peroxidase (GPX) activities in plasma, liver, breast muscle, pancreas and kidney as well as Se concentration in erythrocytes of broilers, and Gpx1 and Selenop mRNA expressions in pancreas increased linearly (p < 0.03) as added Se level increased. Furthermore, the differences (p < 0.05) among different Se sources were detected for the Se concentrations in liver, breast muscle, pancreas and erythrocytes, GPX activities in pancreas and kidney. Based on slope ratios from the multiple linear regressions of the above indices, the Se bioavailabilities of SY, SM, SO, NS relative to SS (100%) were 78 to 367%, 67.8 to 471%, 57 to 372%, and 45 to 92%, respectively. The results from this study indicated that the Se from SM, SY and SO are more available to broilers than the Se from SS in enhancing the Se concentrations in liver, breast muscle, pancreas and erythrocytes and GPX activity in pancreas, and the Se from SM had the highest while the Se from NS had the lowest relative bioavailability.

Cadmium content in commercial fishes of the Barents Sea (based on long-term data)

The aim: to study the amount of cadmium found in muscle tissue and liver of the main commercial fish species of the Barents Sea.Research material was comprised of fish samples collected during the expeditions of N.M. Knipovich «PINRO» in the Barents Sea in 2009–2021. The study was based on muscle and liver samples taken from cod, haddock, long rough dab, Greenland halibut, plaice and spotted catfish. Over 1500 samples were analyzed.Novelty: for the first time a comparative analysis of Cd concentration in six commercial fish species of the Barents Sea was run and background readings were provided using such a big amount of data.Methods used: the content of Cd in fish samples was measured using Shimadzu (Japan) Atomic Absorption Spectrophotometer (AAS). Statistical data processing and charting were done using MS Excel and application software package of Statistica 13.The results show that the average content of Cd in muscle and liver of the examined fish did not exceed the established sanitary standard for the maximal concentrations of 0.2 and 0.7 mg/kg of wet weight, respectively. No evidence of anthropogenic contamination of the studied species by cadmium was found. The cadmium concentrations in liver was 11–17 times higher than in muscle. The total content of Cd in muscle and liver demonstrated a high variability (dispersion). The main reason for this variability is differences in the diet and feeding habits of the fishes. The cadmium content in muscle tissues is species-specific. The liver is capable of removing Cd from the body actively. The study also found other factors influencing the cadmium concentrations, such as taxonomic affiliation and regional peculiarities (particularly, habitats and fishing areas).Practical significance: the acquired results were used to determine whether the commercial fishes meet the sanitary standards used in Russia.

Protective effects of resveratrol and naringenin against nonylphenol-induced oxidative stress in rats

Nonylphenol (NP) is a ubiquitous environmental endocrine disrupting chemical and oxidative stress inducer in biological systems. Resveratrol (RES) and Naringenin (NG) are phytochemicals possessing antioxidant properties and estrogenic activity. This study was conducted to investigate the toxicity of NP and the mitigating effects of RES and NG on NP toxicity in rats. Thirty male rats were classified into 5 groups as follows: 1- Normal control (NC), 2- Dimethyl sulfoxide (DMSO) group, 3- NP group, 4- NP + RES and 5- NP + NG. Results revealed that NP treatment significantly decreased the activities of superoxide dismutase, Catalase, Glutathione peroxidase and Glutathione content in blood, liver and kidney compared to NC and DMSO groups. Conversely, activity of Glutathione-s-transferase was significantly elevated in blood and decreased in liver and kidney. Moreover, significant escalation was observed in the levels of Malondialdehyde. Also, NP treatment led to a significant decrease in serum total testosterone and testis weight, accompanied with concurrent elevation in estradiol level compared to NC and DMSO groups. All the recorded effects induced by NP treatment were effectively countered by co-treatment with RES or NG. In addition, molecular docking studies were carried out to reveal the interactions between NP, RES, NG and estrogen receptor beta which provide a possible mechanism for their potential estrogenic activity. Overall, our study gives a deeper understanding of the toxic effect of NP on antioxidant capacity and endocrine functions as well as the potential therapeutic utility of RES and NG in alleviating these adverse effects.

The Real and the Speculative: Gentrification and Literary Form in Tom Mccarthy’s Remainder

ABSTRACT This article investigates the city novel's relationship to the idea of everyday life through an analysis of Tom McCarthy's Remainder (2005). Remainder is emblematic of a broader shift from realism's preoccupation with the “real”, to the “speculative”- models of prediction and anticipation that attempt to incorporate the flux of everyday life into new forms of social control. McCarthy's novel self-consciously explores how twentieth century attempts to celebrate the contingency of everyday life in the metropolis in fact anticipate forms of metropolitan control based not on the imposition of models of normative behaviour, but on the capacity to respond in real time to the discrete permutations of everyday urban life. Ultimately, McCarthy's novel is sensitive to the inherent violence of the speculative, revealing how ideals of spontaneity and contingency are no longer exclusive to the privileged domain of the quotidian, but are the very foundations of financialised and gentrified urbanization.

Brodifacoum causes coagulopathy, hemorrhages, and mortality in rainbow trout (Oncorhynchus mykiss) at environmentally relevant hepatic residue concentrations.

Widely used second-generation anticoagulant rodenticides like brodifacoum are classified as persistent, bioaccumulative, and toxic. Widespread exposure of terrestrial and avian non-target species is well-known and recently hepatic anticoagulant rodenticide residues have been detected in wild fish. However, no sufficient data exist to interpret the effects of these findings on fish health. In order to assess the potential impact of rodenticide residues on fish, we exposed rainbow trout (Oncorhynchus mykiss) to brodifacoum-spiked feed. In a first experiment, individually kept trout (body weight ca. 200 g) were exposed to a single dose of brodifacoum and observed for 15 days. In a second experiment, fish (body weight ca. 330 g) were kept in groups and fed every 7 or 8 days with brodifacoum-spiked feed for up to 60 days. Sampling of trout every 15 days over the 60 days period allowed monitoring of brodifacoum concentrations in serum, liver, and muscle tissue, as well as occurring effects over the course of the experiment. In both experiments, brodifacoum doses of ≥ 75 µg/kg body weight caused prolonged or non-measurable blood coagulation times. Disturbed hemostasis led to hemorrhages and anemia with significantly decreased albumin levels. In the 60 days-experiment, brodifacoum doses ≥ 100 µg/kg body weight caused additionally discoloration, apathy, and anorexia, resulting in reduced weight gain, and ultimately mortality. The delay until the onset of overt symptoms (14-17 days) highlights the importance of test duration while investigating effects of anticoagulant rodenticides in fish. The lowest hepatic brodifacoum concentration associated with effects in trout was on average 122.6 ng/g liver wet weight, which is in the range of previously reported brodifacoum residues in wild fish. These findings illustrate the risks associated with the use of anticoagulant rodenticides for freshwater fish and reinforce the need to stipulate all available and appropriate risk mitigation measures to prevent emissions at source.

Surgical Treatment of Hepatocellular Carcinoma Arising from Fontan-associated Liver Disease: A Report of Three Cases

We herein report three patients with Fontan-associated liver disease (FALD) who developed hepatocellular carcinoma (HCC). All three patients had very high serum alpha-fetoprotein (AFP) concentrations, and their HCCs were located in the peripheral areas of the liver. To identify the characteristics of FALD-HCC, we reviewed previously published case reports that included descriptions of imaging. This review revealed that FALD-HCC is generally located in the peripheral areas of the liver and AFP concentrations are usually high. Thus, it is important that follow-up of patients with FALD include repeated AFP concentrations and abdominal imaging.

A New Strain of Preponderant Amphitriploid Carassius Clone Juvenile With Integrated Genomes Partly From White Crucian Carp (C. auratus cuvieri) Requires Low Dietary Protein.

This study was carried out to search for the protein requirement of a new strain of preponderant amphitriploid Carassius clone, which integrated genomes partly from white crucian carp (C. auratus cuvieri). Seven groups of fish (body weight: 9.73 ± 0.03 g) were fed with seven isolipidic and isocarbohydrate diets containing 21.38%, 25.82%, 27.94%, 31.36%, 34.23%, 37.87%, and 40.70% crude protein (P21, P24, P27, P30, P33, P36, and P39), respectively. After 8-week feeding, weight gain rate (WGR) and specific growth rate (SGR) were lower in the P30 group than those in the P39 group, but no difference was found in final body weight (FBW), survival, condition factor (CF), or hepatosomatic index (HSI) between different groups. Increased dietary protein decreased feeding rate (FR) and viscerosomatic index (VSI) while improved feed efficiency (FE). Decreased protein retention efficiency (PRE) and improved activity of liver alanine aminotransferase (ALT) and content of plasma ammonia suggested intensified fish amino acid catabolism in high dietary protein groups. The dietary protein requirement of the new Carassius clone was as low as 21.38% for growth. The optimal dietary protein for high FE was 39.62% and should be less than 30.56% to maintain the maximum protein retention. High dietary protein might be harmful to the fish due to the increased contents of liver malondialdehyde (MDA) and plasma cortisol. Dietary protein level altered fish body and muscle flavor substance composition. Low dietary protein could obtain high muscle fatty acid, free amino acid, and lipid accumulation, including whole body and muscle crude lipid, plasma total triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c). Therefore, the recommended dietary protein for this new Carassius clone juvenile should be 21.38%-30.56%.

The effects of Aronia melanocarpa (AM) dietary supplementation on production performance, meat and egg quality, yolk volatile substances and antioxidant capacity of laying hens

ABSTRACT The effects of Aronia melanocarpa (AM) dietary supplementation on production performance, meat and egg quality, yolk volatile substances and antioxidant capacity of laying hens. A total of 480 Roman brown laying hens aged 25 wks were randomly divided into control, LAM, MAM and HAM groups and fed 0%, 1%, 4% and 7% AM, respectively. The results showed that AM dietary supplementation significantly increased the eggshell strength, significantly reduced 24 h dripping loss of breast and thigh muscles, and increased pH and 48 h dripping loss of breast and thigh muscles. Cooking loss was significantly lower only in the HAM group for breast muscle. The MAM group was able to significantly increase albumen height and Haugh units. Esters gradually decreased with the increase in AM content, and the addition of AM led to a decrease in alcoholic compounds but increased the contents of alkenes, alkanes, ketones, and acids. The dietary AM supplementation significantly reduces the MDA content of serum, liver, ovary, chest muscle, thigh muscle and yolk and increases the activities of GSH-Px, T-SOD and T-AOC. In summary, dietary AM supplementation could improve antioxidant capacity and expression of related genes, thereby improving meat and egg quality.

Iron and Copper Liver Concentrations in Wilson Disease.

Wilson disease (WD) results in the defective incorporation of copper into ceruloplasmin as well as decreased biliary copper excretion. Secondary iron overload has also been associated with WD; however, the prevalence is currently unknown. This study aims to determine the prevalence of potential secondary iron overload in patients suspected to have WD. The secondary aim was to determine whether common laboratory tests were associated with liver copper concentrations or the need for liver transplantation in a subset of patients with confirmed WD. Using our institution's laboratory information system, 197 patients with liver copper concentrations > 250 mcg/g were identified who also had a concurrent liver iron concentration available. Correlations between copper, iron, and hepatic iron index were performed by log-transforming the data and then using the Pearson method. Furthermore, in a subpopulation of ten patients clinically confirmed to have WD, various laboratory test values were evaluated to determine associations with liver copper concentration or liver transplantation. There was no significant association between copper and iron liver tissue concentrations (p=0.84). However, 13 (8%) patients aged 13 or older had a hepatic iron index >1.0 which may indicate secondary iron overload. Furthermore, in clinically confirmed WD patients, hemoglobin and hematocrit were inversely associated with liver copper concentrations (p=0.036). Iron overload can be detected in liver tissues with elevated copper concentrations characteristic of WD Furthermore, in WD, low hemoglobin and hematocrit values were associated with elevated liver copper concentration. Clinicians should consider the possibility of secondary iron overload and/or anemia in patients with WD.

Impact of a trace mineral injection at weaning on growth, behavior, and inflammatory, antioxidant, and immune responses of beef calves

Abstract Two experiments evaluated the effects of an injectable trace mineral (ITM) solution at weaning on trace mineral (TM) status, inflammatory and antioxidant responses, grazing behavior, response to vaccination, and growth of beef calves. Exp. 1 used 86 Nellore calves [40 females and 46 males; body weight (BW) = 198 ± 30.8 kg; 8 ± 1 mo of age] weaned (d 0) and assigned into 1 of 2 treatments: Saline (0.9% NaCl) or ITM (60 mg of Zn/mL, 15 mg of Cu/mL, 5 mg of Se/mL and 10 mg of Mn/mL). Saline and ITM were administered subcutaneously at a dose of 1 mL/45 kg of BW. On d 0, calves were vaccinated against infectious bovine rhinotracheitis (IBR), parainfluenza-3 (PI3), bovine viral diarrhea virus type 1 and 2 (BVDV-1 and 2) and bovine respiratory syncytial virus (BRSV). Blood samples and BW were collected on d 0, 3, 8, 15, 51, and 100, and grazing behavior was evaluated on d 1, 2, 4, 5, 6, 7, and 9. The ITM did not affect (P ≥ 0.56) serum mineral concentrations of Zn and Cu, but decreased (P ≤ 0.02) plasma concentrations of cortisol on d 3 and 8 and haptoglobin on d 3. The ITM increased (P &amp;lt; 0.01) plasma concentration of superoxide dismutase on d 8, 15, and 51 and tended to decrease (P = 0.08) plasma concentration of glutathione peroxidase on d 3. Furthermore, there were no effects of treatment (P ≥ 0.14) on most of the behavior variables evaluated, ITM reduced (P = 0.01) the seeking time on d 0 and 4. Furthermore, ITM tended to increase (P = 0.10) the serum titer concentration against IBR on d 15 and 51 but did not affect (P ≥ 0.12) titer concentration against PI3, BVDV-1, and 2, and growth. Exp. 2 used 50 Brangus male calves (BW = 264 ± 34.1 kg; 8 ± 1 mo of age] weaned on d 0, vaccinated against respiratory diseases, stratified by BW, and randomly assigned to Saline or ITM as described in Exp. 1. Liver samples were collected on d 0, 14 and 197, blood samples on d 0, 14 and BW on d 0, 14, 44, 78, 122, 162 and 197. The ITM increased (P ≤ 0.03) the liver concentration of Cu and Se on d 14 but did not affect (P ≥ 0.17) the liver concentration of Zn and Mn. In addition, ITM increased (P = 0.05) the serum titer concentration against BVDV-2 but did not affect (P ≥ 0.20) the titer concentrations against IBR, PI3, BVDV-1, and BRSV, and did not affect (P ≥ 0.29) the growth. In conclusion, ITM application at weaning improved Cu and Se status, enhanced antioxidant and immune responses, and reduced stress and inflammation in calves, though it did not affect growth.

4-Pyridone-3-carboxamide-1-β-D-ribonucleoside Reduces Cyclophosphamide Effects and Induces Endothelial Inflammation in Murine Breast Cancer Model.

4-pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR) is a nicotinamide derivative, considered a new oncometabolite. 4PYR formation induced a cytotoxic effect on the endothelium. Elevated blood 4PYR concentration was observed in patients with cancer. Still, little is known about the metabolic and functional effects of 4PYR in this pathology. The study aimed to investigate whether this toxic accumulation of 4PYR may affect the activity of anticancer therapy with cyclophosphamide in the orthotropic model of breast cancer. Female Balb/c mice were injected with 4T1 breast cancer cells and assigned into three groups: treated with PBS (Control), cyclophosphamide-treated (+CP), 4PYR-treated (+4PYR), and mice treated with both 4PYR and CP(+4PYR+CP) for 28 days. Afterward, blood and serum samples, liver, muscle, spleen, heart, lungs, aortas, and tumor tissue were collected for analysis of concentrations of nucleotides, nicotinamide metabolites, and 4PYR with its metabolites, as well as the liver level of cytochrome P450 enzymes. 4PYR treatment caused elevation of blood 4PYR, its monophosphate and a nicotinamide adenine dinucleotide (NAD+) analog-4PYRAD. Blood 4PYRAD concentration in the +4PYR+CP was reduced in comparison to +4PYR. Tumor growth and final tumor mass were significantly decreased in +CP and did not differ in +4PYR in comparison to Control. However, we observed a substantial increase in these parameters in +4PYR+CP as compared to +CP. The extracellular adenosine deamination rate was measured to assess vascular inflammation, and it was higher in +4PYR than the Control. Treatment with 4PYR and CP caused the highest vascular ATP hydrolysis and adenosine deamination rate. 4PYR administration caused significant elevation of CYP2C9 and reduction in CYP3A4 liver concentrations in both +4PYR and +4PYR+CP as compared to Control and +CP. In additional experiments, we compared healthy mice without cancer, treated with 4PYR (4PYR w/o cancer) and PBS (Control w/o cancer), where 4PYR treatment caused an increase in the serum proinflammatory cytokine expression as compared to Control w/o cancer. 4PYR accumulation in the blood interferes with cyclophosphamide anticancer activity and induces a pro-inflammatory shift of endothelial extracellular enzymes, probably by affecting its metabolism by cytochrome P450 enzymes. This observation may have crucial implications for the activity of various anticancer drugs metabolized by cytochrome P450.

Comparative analysis of PFASs concentrations in fur, muscle, and liver of wild roe deer as biomonitoring matrices

BackgroundRecently, environmental pollution has become a significant concern for human, animal, and environmental health, fitting within the “One Health” framework. Among the various environmental contaminants, per- and polyfluoroalkyl substances (PFASs) have gathered substantial attention due to their persistence, bioaccumulation, and adverse health effects. This study aimed to compare the levels of 12 PFASs in the fur, liver, and muscle of wild roe deer to evaluate the feasibility of using fur as a non-invasive biomonitoring matrix.MethodsA total of 20 male and 20 female roe deer aged between 12 and 24 months were randomly sampled from a hunting area in Northern Italy. Samples of fur, muscle, and liver were collected post-mortem, and PFAS concentrations were measured using a validated UHPLC-HRMS method.Results and discussionThe results indicated significant differences in PFAS concentrations among the three matrices. Fur, although easier to sample and store, showed highly variable PFAS levels, with different detection frequencies compared to the muscle and liver. PFASs such as PFHxA were more frequently detected in fur than in the liver and muscle, while compounds such as PFBA, PFPeA, PFHpA, PFDA, PFHxS, 6-2 FTS, and 8-2 FTS were less frequently detected in fur. In conclusion, while fur presents many practical advantages for biomonitoring, such as non-invasive sampling and stability, its use is complicated by varying detection frequencies and concentration levels. These aspects, together with the use of a single sampling technique, can be considered a limitation of the study. Notably, compounds such as PFOA, PFNA, and PFOS showed partially similar detection frequencies across the matrices, suggesting potential interest for further research. This study offers new perspectives on the use of fur for environmental monitoring, highlighting the need for more extensive research to understand the relationship between PFAS concentrations in fur and other biological matrices. Future studies should focus on methodological improvements in extraction and quantification techniques for PFASs in fur to enhance their reliability as a biomonitoring tool.

Degrowth and Form: Reflections on Education’s Lateral Possibilities

In this paper, it is argued that degrowth cannot be discussed in vacuo. Rather, it must be read through its relationship with form. Form and the formative prompt us to engage with learning and growth. Like growth and degrowth, learning and unlearning leave us with more questions than answers. The linearity imposed on learning by a logic of growth needs to be contested. An effective, albeit lateral critique of the logic of growth in learning is found in the pedagogies of unlearning and indirectness, both of which suggest a particular focus on the contingencies of life, which, understood in their aporetic nature, reveal that which can only be embraced through the unforeseen. Discussing the work of Latouche, Unamuno, Rancière, Saeverot, and Torgersen amongst other, this paper concludes with a discussion of degrowth in Ivan Illich’s parable of the snail, and D’Arcy Thompson’s discussion of growth and form.

Dietary Vitamin C Fortification Enhances the Growth Performance, Hematological Status, Defensive Antioxidant Enzymes, and Resistance Against Aeromonas Hydrophila Infection for Bullseye Snakehead (Channa marulius)

To evaluate the impact of increased dietary Vitamin C (VC) levels on the survival, growth performance, hematological serum biochemistry, immune system response, antioxidant enzyme activity, stress parameters, and susceptibility of bullseye snakehead (Channa marulius) to Aeromonas hydrophila infection, a 90-day feeding trial was conducted. Four (40% crude protein) isonitrogenous diets with 0 (basal diet), 75, 150, and 300 mg/kg of targeted diet VC were prepared, having analysed VC contents of 4.6, 67.3, 142.5, and 275.8 mg/kg, respectively. At the end of the trial, results showed significant improvements in weight gain % (104.33±6.0 g fish−1), lowest feed conversion ratio (1.67±0.04), and specific growth rate %/day (1.93±0.06) with added VC. Hematological parameters improved dose-dependently, with significant increases in total cholesterol, total protein, and triglycerides, and alanine phosphatase activity at 275.8 mg/kg of VC. Alanine aminotransferase and aspartate aminotransferase activities decreased, suggesting improved liver integrity. Serum electrolyte levels and antioxidant enzymes rose with higher VC incorporation, while serum cortisol and glucose levels dropped, suggesting reduced stress. Liver VC content also increased dose-dependently. Fish on VC fortified diets showed higher survival rates against A. hydrophila challenge. The ideal VC requirement for liver content and weight gain (%) is estimated between 230 and 273 mg/kg based on third-order polynomial (cubic) regression analysis.

Preclinical and Clinical Pharmacokinetics of JNJ-75220795, an siRNA Therapeutic Targeting PNPLA3, for Metabolic Dysfunction-Associated Steatohepatitis.

JNJ-75220795 or ARO-PNPLA3 is an investigational small interfering ribonucleic acid agent conjugated with N-acetyl-d-galactosamine that targets the PNPLA3 gene, currently being developed for metabolic dysfunction-associated steatohepatitis (MASH). This study evaluated the pharmacokinetics (PK) profile of single subcutaneous doses of JNJ-75220795 in preclinical species as well as in human subjects with homozygous or heterozygous PNPLA3 I148M mutation in two phase 1 studies-a first-in-human study in the United States and a first-in-Japanese study in Japan. Preclinical PK in rats and non-human primates (NHP) showed a rapid systemic absorption and elimination following single subcutaneous doses. JNJ-75220795 was predominantly distributed to the liver with peak liver concentrations reached at 4 h and still detectable at 672 and 336 h in rats and NHPs, respectively, with an apparent liver-to-plasma area under the curve (AUC) ratio of 2800 in rats. Consistent with the preclinical findings, clinical PK showed rapid systemic absorption and clearance in humans with median peak concentrations at 3.0-9.0 h and mean short half-life of 3.4-6.2 h. Plasma PK exposure parameters including Cmax and AUC increased approximately dose proportionally. Kidney had the second highest tissue exposure following the liver in rats. Renal excretion was a significant but minor elimination pathway as approximately 15%-25% of the administered dose was recovered in urine. Based on the overall data, JNJ-75220795 was primarily localized to the liver and exhibited sustained hepatic exposures, which confer prolonged pharmacodynamic effects in the target organ. The favorable PK profiles of single subcutaneous doses observed in the phase 1 studies support continued clinical development of JNJ-75220795 for the treatment of MASH.