Liver Tissue Concentrations Research Articles

Effect of Body Size on Plasma and Tissue Pharmacokinetics of Danofloxacin in Rainbow Trout (Oncorhynchus mykiss)

Danofloxacin is a fluoroquinolone antibiotic approved for use in fish. It can be used for bacterial infections in fish of all body sizes. However, physiological differences in fish depending on size may change the pharmacokinetics of danofloxacin and therefore its therapeutic efficacy. In this study, the change in the pharmacokinetics of danofloxacin in rainbow trout of various body sizes was revealed for the first time. The objective of this investigation was to compare the plasma and tissue pharmacokinetics of danofloxacin in rainbow trout of different body sizes. The study was conducted at 14 ± 0.5 °C in fish of small, medium, and large body size and danofloxacin was administered orally at a dose of 10 mg/kg. Concentrations of this antimicrobial in tissues and plasma were quantified by high performance liquid chromatography with ultraviolet detector. The plasma elimination half-life (t1/2ʎz), volume of distribution (Vdarea/F), total clearance (CL/F), peak concentration (Cmax), and area under the plasma concentration–time curve (AUC0–last) were 27.42 h, 4.65 L/kg, 0.12 L/h/kg, 2.53 µg/mL, and 82.46 h·µg/mL, respectively. Plasma t1/2ʎz, AUC0–last and Cmax increased concomitantly with trout growth, whereas CL/F and Vdarea/F decreased. Concentrations in liver, kidney, and muscle tissues were higher than in plasma. Cmax and AUC0–last were significantly higher in large sizes compared to small and medium sizes in all tissues. The scaling factor in small, medium, and large fish was 1.0 for bacteria with MIC thresholds of 0.57, 0.79, and 1.01 µg/mL, respectively. These results show that therapeutic efficacy increases with body size. However, since increases in danofloxacin concentration in tissues of large fish may affect withdrawal time, attention should be paid to the risk of tissue residue.

Phase Preparation of Xiao-chai-hu Decoction and its Pharmacodynamics of Acute Liver Injury.

Self-emulsifying nano-phase of traditional Chinese medicine are a research hotspot. Xiao-Chai-Hu decoction is a commonly used compound decoction in clinical practice, which is of great research significance. The aim of this study was to isolate and characterize the self-emulsifying nano-phase and other phases of Xiao-Chai-Hu decoction, and to study the effects of each phase on acute liver injury. The liquid medicine was prepared employing centrifugation followed by dialysis. Single- factor investigation methodology was utilized to optimize the preparation parameters for both phases. Characterization of the formulated phase involved analyses such as surface morphology assessment, measurement of nanoparticle size and Zeta potential using an analyzer, observation of the Tyndall effect, conducting diffusion and dilution tests, examination under a microscope, and structural visualization via transmission electron microscopy (TEM). Furthermore, an acute liver injury model was established in rats through intraperitoneal injection of D-Galactosamine (D-Gal- N). To assess hepatic function and oxidative stress status, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content in liver tissue were quantified. The liver coefficients for each group were calculated as an additional parameter. For histopathological evaluation, liver tissue sections from the experimental group were stained with Hematoxylin and Eosin (H&E) and examined microscopically under light conditions. These revisions aim to enhance clarity, correct minor grammatical errors (such as capitalization of "HE" to "H&E"), and ensure a smoother flow of information without altering the scientific content of your original text. Successful establishment and separation of four distinct phases were achieved, including the self-emulsifying nano-phase, precipitation phase, suspension phase, and true solution phase. The self-emulsifying nano-phase was characterized as spherical particles with an average diameter of approximately 100 nm. Pharmacodynamic assessments revealed that both Xiao-Chai-Hu decoction and its self-emulsifying nano-phase significantly reduced liver coefficients and alanine aminotransferase (ALT) levels compared to controls (P<0.05). However, no statistically significant differences were observed in regards to aspartate aminotransferase (AST) concentrations, malondialdehyde (MDA) content, or superoxide dismutase (SOD) activity between the treatment groups and control (P>0.05). These findings indicate that both Xiao-Chai-Hu decoction and its self-emulsifying nano-formulation ameliorated D-GalN-induced acute liver injury, albeit without statistically distinguishable efficacy between them (P>0.05). The presence of a self-emulsifying nano-phase within Xiao-Chai-Hu decoction is confirmed, and this nano-phase emerges as a therapeutically efficacious component in mitigating acute liver injury.

Trace elements in liver and muscle tissues from wild waterfowls in Australia: Risk associated with human consumption in a global context

Trace elements in game meats remain a point of concern for both the public and policymakers alike due to the human health implications if levels present are above guideline limits. This study aimed to: (1) determine trace element concentrations (As, Cd, Hg, Pb Cr, Cu, Se, Zn) in edible portions (breast meat and liver) of the four most frequently hunted duck Anatidae species inhabiting wetlands in Victoria, Australia, to identify the risk to human health from consumption; (2) investigate landscape-scale variables that may influence the detected concentrations and; (3) review the studies available (n = 41) in duck liver and muscle tissues from the 1970s to 2024, to contextualise the detected concentrations found on a global scale. Our study shows that ducks in Victoria had trace element concentrations below tolerable daily intake (TDI) guidelines for human health with one exception: notably high Hg in a filter-feeding specialist, the Pink-eared duck (Malacorhynchus membranaceus). Yet, the only trace element concentrations that were influenced by proximity to populated centres, were As and Zn. Compared to international reports, Pb concentrations in livers and muscle of Victorian waterfowl were lower, however, Pink-eared ducks had higher Hg than other duck (Anas spp.) species. Review of the worldwide data indicate that Pb concentrations in liver tissues from all Anas species have declined from the 1970s to 2024. This is the first study to identify this trend at a global scale. International movements towards Pb-shot bans, along with phasing out of Pb in gasoline and paint are the most likely cause of declining concentrations in tissues of wild waterfowl. These findings strongly underscore the importance of legislative efforts to limit trace elements entering the environment.

Effects of perfluoroalkyl sulfonic acids on developmental, physiological, and immunological measures in northern leopard frog tadpoles

The chronic toxicity of short chain perfluoroalkyl sulfonic acids (PFSAs), such as perfluorobutanesulfonic acid (PFBS) and perfluorohexanesulfonic acid (PFHxS), are relatively understudied despite the increasing detection of these compounds in the environment. We investigated the chronic toxicity and bioconcentration of PFBS and PFHxS using northern leopard frog (Rana [Lithobates] pipiens) tadpoles. We exposed Gosner stage (GS) 25 tadpoles to either PFBS or PFHxS at nominal concentrations of 0.1, 1, 10, 100, and 1000 μg/L until metamorphosis (GS42). We then assessed tadpole growth, development, stress, and immune metrics, and measured fatty acid (FA) composition and PFSA concentrations in liver and whole-body tissues. Tadpole growth and development measures were relatively unaffected by PFSA exposure. However, tadpoles exposed to 1000 μg/L PFBS or PFHxS had significantly increased hepatosomatic indexes (HSI) relative to controls. Further, tadpoles from the 1000 μg/L PFHxS treatment had altered FA profiles relative to controls, with increased total FAs, saturated FAs, monounsaturated FAs, and omega-6 polyunsaturated FAs. In addition, tadpoles from the 1000 μg/L PFHxS treatment had a higher probability of waterborne corticosterone detection. These results suggest that PFBS and PFHxS influence the hepatic health of tadpoles, and that PFHxS may alter lipid metabolism in tadpoles. We also observed a higher probability of tadpoles being phenotypically female after exposure to an environmentally relevant concentration (0.1 μg/L) of PFHxS, suggesting that PFHxS may exert endocrine disrupting effects on tadpoles during early development. The measured bioconcentration factors (BCFs) for both compounds were ≤10 L kg−1 wet weight, suggesting low bioconcentration potential for PFBS and PFHxS in tadpoles. Many of the significant effects observed in this study occurred at concentrations several orders of magnitude above those measured in the environment; however, our work shows effects of PFSAs exposure on amphibians and provides essential information for ecological risk assessments of these compounds.

PSXI-16 Increased copper concentrations in liver and duodenum tissues in Rambouillet-crossbred sheep receiving copper supplementation

PSXI-16 Increased copper concentrations in liver and duodenum tissues in Rambouillet-crossbred sheep receiving copper supplementation

Abstract P300: Modulation of Osmolyte Levels by ACE Inhibitors and SGLT-2 Inhibitors in Normotensive Rats

Hypertension is associated with disturbances in the water-electrolyte balance, leading to changes in osmotic pressure. Osmolytes, such as taurine among other compounds, play a critical role in maintaining cellular integrity under osmotic stress. This study evaluated the effects of ACE inhibitors (ACE-I) and SGLT-2 inhibitors (SGLT2i) on osmolyte homeostasis. Twelve-week-old male Sprague-Dawley (SD, n = 38) rats were divided into five groups: control (water), low and high doses of canagliflozin, and low and high doses of captopril. Metabolic studies were conducted in metabolic cages. Using liquid chromatography coupled with mass spectrometry (LC-MS), we measured osmolyte concentrations in blood, urine, kidney, liver and heart tissues. The obtained results demonstrated significant increases in liver taurine concentrations (13.34 ± 1.39 vs. 10.49 ± 1.45, p=0.029) and urinary taurine excretion (25.08 ± 2.81 vs. 16.54 ± 3.77, p=0.001) in the high-dose canagliflozin group compared to controls. Both treatments enhanced the total urinary excretion of L-alanine, β-alanine, choline, glycine, taurine, and carnitine. Additionally, canagliflozin increased the excretion of betaine and glycerophosphorylcholine (GPC). A reduction in serum β-alanine was noted in the captopril-treated rats. These findings highlight the novel effects of SGLT-2 inhibitors and ACE-I on osmolyte levels in normotensive rats, suggesting potential mechanisms contributing to their cardioprotective effects. Further research is required to elucidate the clinical significance of osmolyte changes in enhancing the protective effects of these drug classes.

Trace Metal Bioaccumulation in Feral Pigeons (Columba livia f. domestica) and Rooks (Corvus frugilegus) Residing in the Urban Environment of Iasi City, Romania.

Nowadays, trace metal contamination within urban atmospheres is a significant and concerning global issue. In the present study, two synanthropic bird species, namely, the feral pigeon (Columba livia f. domestica) and the rook (Corvus frugilegus), were employed as bioindicators to assess the atmospheric trace metal pollution in Iasi City, Romania. The concentrations of Ni, Pb, Cd, Co, Cr, and Cu were determined through high-resolution continuum source graphite furnace atomic absorption spectrometry (HR-CS GF-AAS) of various tissues, including the liver, kidney, lung, heart, muscle, and bone, of feral pigeons and rooks collected in Iasi City. The order of trace metal concentrations in the tissues of feral pigeons and rooks in Iasi City was similar: Cu > Pb > Ni > Cd > Cr > Co. However, trace element values in most tissues were higher in the rook samples than in feral pigeon ones, except for Co, which had elevated levels in feral pigeon renal and cardiac tissues, and Cu, which registered the highest concentrations in feral pigeon liver and kidney tissues. While not statistically significant, Pb concentration values in the PM10 fraction of atmospheric particles positively correlated with Pb concentrations in rook kidney samples (p = 0.05). The concentration levels of Cd, Pb, and Ni in the PM10 fraction of air particles showed a positive correlation with Cd levels in the samples of pigeon heart and rook liver, kidney, and heart, Pb levels in the samples of pigeon kidney, heart, and muscle and rook liver and bone, and Ni levels in the samples of pigeon liver, kidney, and bone and rook liver, muscle, and bone, respectively.

Liver structure and function in yellowtail kingfish, Seriola lalandi, in response to alternative oils in feed

The inclusion of low cholesterol alternatives to fish oil (FO) in aquaculture diets could result in alterations to the biosynthesis and availability of bile acids for the digestions and absorption of dietary lipids. In this study the effects of graded substitution of FO with poultry oil (PO) and the replacement of PO with canola oil (CO) in formulated feeds on Yellowtail Kingfish (1.45 ± 0.12 kg; n = 342) liver function was investigated over 84 days. Dietary FO was replaced with PO at 100%, 75% and 50% inclusion levels (Diets 1, 2 and 3, respectively). The lipid source (PO) was further replaced with CO at 0%, 33.3%, 66.7% and 100% (Diets 2, 4, 5 and 6, respectively). The liver vacuole volume as a proportion of the liver cell volume (VPLC%) was significantly increased (P = 0.008) in fish fed the 100% PO diet (Diet 1) compared to that of fish fed diets with greater levels of FO inclusion (Diets 2 and 3). Regression analyses showed that: 1) liver VPLC% increased as FO decreased (r2 = 0.588; P = 0.016), 2) total bile acid concentration in liver tissue decreased with increasing CO and decreasing PO (r2 = 0.402; P = 0.027), and 3) liver CYP7A1 concentration increased with increasing PO and decreasing FO (r2 = 0.506; P = 0.032). No statistically significant differences were observed in any of the blood biochemistry parameters measured from fish fed diets with decreasing FO and increasing PO nor from fish fed diets formulated with FO and a graded PO and CO blend. Yellowtail Kingfish may be able to be fed a formulated diet containing: 1) ∼25% dietary lipid level (2.12 g 100 g−1 of ƩLC n-3 PUFA) with up to 100% of the FO component replaced by PO; and 2) ∼25% dietary lipid level (2.12 g 100 g−1 of ƩLC n-3 PUFA) with up to 100% of the commercially used alternative lipid source (PO) replaced with CO without an apparent negative impact on any of the parameters measured in this study.

Mechanism of Si Ni San Combined with Astragalus in Treating Hepatic Fibrosis: A Network Pharmacology and Molecular Docking Study.

Si Ni San combined with Astragalus (SNSQ) has demonstrated significant efficacy in the treatment of hepatic fibrosis (HF), as confirmed by clinical practice. However, its pharmacological mechanism remains unclear. This study employs network pharmacology to identify key targets and proteins for molecular docking. Additionally, animal experiments were conducted to validate the network pharmacology results, providing further insights into the mechanism of SNSQ in treating HF. Effective compounds of SNSQ were screened from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Encyclopedia of Traditional Chinese Medicine (ETCM) databases. Molecular formula structures of these effective compounds were obtained from the PubChem database. Partial target proteins with a probability greater than 0.6 were sourced from the SWISS database. Uniprot IDs corresponding to these target proteins were retrieved from the SUPERPRED database. The remaining target proteins of the compounds were obtained from the Uniprot database based on the Uniprot IDs. The drug target proteins were then summarized. Target points related to HF were selected from the GeneCards and OMIM databases. Common target points were identified in the Venn diagram and imported into Cytoscape 3.9.1 software to construct the "SNSQ-effective compound-target pathway-HF" network. AutoDock software was used for molecular docking of compounds and target proteins with high-degree values. The common target points underwent GO function enrichment and KEGG pathway enrichment analysis using the DAVID database. An HF rat model was established, and serum AST and ALT activities were measured. The Hyp assay kit was utilized to detect the Hyp content in liver tissue. To the transcription levels of pro-inflammatory factors (IL-1β, TNF-α, IL-6) and anti-inflammatory factors (IL-10, TGF-β1, IL-4) in rat serum and liver.IL-1β, TNF-α, IL-10, and TGF-β1 were chosen for validation through ELISA. Western blotting and qRT-PCR were used to assess the expression of related proteins, namely NFKB1, NF-κBp65, NF-κBp50, α-SMA, and Col-1 in liver tissue. qRT-PCR was also employed to study the expression of ECM synthesis and proliferation-related genes, including Cyclin D1, TIMP1, COL1A1 in HSC-T6 cells and rat liver tissue, as well as the inhibition of the ECM-related gene MMP13 in HSC-T6 cells and rat liver tissue. A total of 16 valid compounds were predicted, with kaempferol, sitosterol, and isorhamnetin exhibiting high-degree values. KEGG enrichment analysis revealed that the target genes of SNSQ were enriched in multiple pathological pathways, with the NF-Kappa B signaling pathway being predominant. Molecular docking simulations indicated strong affinities between SNSQ's primary components-kaempferol, sitosterol, isorhamnetin-and NFKB1. Experimental results demonstrated significant reductions in AST, ALT, and Hyp levels in the SNSQ group. Pro-inflammatory factors (IL-1β, TNF-ɑ) were markedly reduced, while anti-inflammatory factors (IL-10, TGF-β1) were substantially increased. The protein expression and transcription levels of α-SMA and Col-1 were significantly decreased, whereas those of NFKB1, NF-κBp65, and NF-κBp50 were notably elevated. mRNA expression levels of Cyclin D1, TIMP1, COL1A1 in HSC-T6 cells and rat liver tissue were significantly decreased, whereas MMP13 mRNA expression level was significantly increased. Treatment of HF with SNSQ involves multiple targets and pathways, with a close association with the overexpression of NFKB1 and activation of the NF-Kappa B signaling pathway. Its mechanism is closely linked to the activation of inflammatory responses, HSC activation, and proliferation.

Comparing Nitric Oxide Generation Pathways using Dietary L-Arginine and Dietary Nitrate: A 15N tracer study in Wistar Rats

Mammals generate nitric oxide (NO) through two main pathways. In the direct production pathway, endogenous nitric oxide synthase (NOS) enzymes catalyze the reaction of L-arginine with oxygen, producing nitric oxide and citrulline. When oxygen accessibility is low, the reductive pathway supplies nitric oxide through the nitrate-nitrite-NO reduction cascade. Additional research is needed to understand whether the two NO generation pathways interact and what effects the two pathways have on the body and each other. We investigated how dietary supplementation of 15N-L-arginine (0.5 g/kg), 15N-nitrate (0.013 g/kg), or a combination of L-arginine and nitrate influences nitrate concentrations in plasma, skeletal muscle, and liver tissue from Wistar rats. We administered treatments via oral gavage. Two hours after treatment administration, we euthanized the rats and collected tissue samples. The nitrate concentrations were measured using chemiluminescence, and future mass spectrometry analysis for 15N/14N ratios will be performed. The calculated concentrations were compared between treatment groups using single factor analysis of variance. Firstly, we observed that nitrate administration significantly increased total nitrate levels in plasma, liver, and muscle tissues compared to the control group. Interestingly, L-arginine alone did not result in a significant rise in total nitrate concentrations. Notably, liver tissue from the L-arginine-treated group had slightly lower concentrations of nitrate than the control group. The combination of L-arginine and nitrate showed no statistically significant difference when compared with the nitrate-treated group in all three tissues. These results suggest that a bolus of L-arginine does not have a substantial short-term effect (within 2 hours after ingestion) on total nitrate concentrations in rat tissues. Future mass spectrometry analysis will indicate how the tissues handle acute ingestion of two different NO sources: L-arginine and nitrate. Further research must be performed for a more detailed understanding of the kinetics of arginine and nitrate, as well as for the effects of these dietary supplements on improving NO homeostasis. This work was supported by intramural NIDDK/NIH grant ZIA DK 025104-15 to Alan N. Schechter. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Changes in Carbon, Nitrogen, and Oxygen Stable Isotope Ratios and Mercury Concentrations in Killer Whales (Orcinus orca) during and after Lactation

The changes in the stable isotope ratios of carbon (δ13C), nitrogen (δ15N), oxygen (δ18O), and mercury (Hg) concentrations in muscle and liver tissues during and after lactation were studied in killer whales stranded along the coast of Hokkaido, in the northern area of Japan (n = 16). Calf muscles displayed δ13C- and δ15N-enriched peaks and a δ18O-depleted peak during lactation. The δ13C- and δ15N-enriched peaks appear to reflect the extensive nursing of 13C- and 15N-enriched milk and the onset of weaning, whereas the δ18O-depleted peak may be attributable to the extensive nursing of 18O-depleted milk and the onset of weaning. The δ13C and δ15N values tended to gradually increase after the weaning, whereas the δ18O values tended to decrease. The δ13C and δ15N levels in calves were similar between liver and muscle samples, whereas those in mature animals were higher in liver than in muscle samples. The isotopic turnover rates of C and N may be similar between the liver and muscle tissues in calves, which are rapidly growing animals. The Hg concentrations in muscle tissues were slightly higher in small calves than in large calves, probably due to the Hg transfer across placenta. The Hg concentrations in liver and muscle samples increased with increasing body length, and those in two liver samples from mature animals exceeded the high-risk threshold for marine mammal health effects (82 μg/wet g).

Acetaminophen overdose causes a breach of the blood-bile barrier in mice but not in rats.

Acetaminophen (APAP) is known to cause a breach of the blood-bile barrier in mice that, via a mechanism called futile bile acid (BA) cycling, increases BA concentrations in hepatocytes above cytotoxic thresholds. Here, we compared this mechanism in mice and rats, because both species differ massively in their susceptibility to APAP and compared the results to available human data. Dose and time-dependent APAP experiments were performed in male C57BL6/N mice and Wistar rats. The time course of BA concentrations in liver tissue and in blood was analyzed by MALDI-MSI and LC-MS/MS. APAP and its derivatives were measured in the blood by LC-MS. APAP-induced liver damage was analyzed by histopathology, immunohistochemistry, and by clinical chemistry. In mice, a transient increase of BA in blood and in peri-central hepatocytes preceded hepatocyte death. The BA increase coincided with oxidative stress in liver tissue and a compromised morphology of bile canaliculi and immunohistochemically visualized tight junction proteins. Rats showed a reduced metabolic activation of APAP compared to mice. However, even at very high doses that caused cell death of hepatocytes, no increase of BA concentrations was observed neither in liver tissue nor in the blood. Correspondingly, no oxidative stress was detectable, and the morphology of bile canaliculi and tight junction proteins remained unaltered. In conclusion, different mechanisms cause cell death in rats and mice, whereby oxidative stress and a breach of the blood-bile barrier are seen only in mice. Since transient cholestasis also occurs in human patients with APAP overdose, mice are a clinically relevant species to study APAP hepatotoxicity but not rats.

Seasonal shift in energy allocation from somatic growth to lipid storage and the link between pre-winter condition and overwintering potential in juvenile Pacific cod

Abstract Warming temperatures in the Gulf of Alaska have been linked to recruitment failure in Pacific cod (Gadus macrocephalus), but the mechanisms and timing of mortality events for juveniles are unclear. To date, limited research has focused on overwintering success, and the knowledge of juvenile ecology and physiology is based entirely on summer observations. Here, we investigate the changes in body condition, diet composition, and tissue-specific fatty acid (FA) storage for age-0 Pacific cod in Kodiak, Alaska, from February to December during 2018 and 2020. We observed protracted nearshore residency from June to December. Cod body condition (Kdry) and predicted weight at length were lowest in October, November, and December. Although not different interannually, diet composition varied seasonally, which corresponded to an increase in cod length. A range of condition metrics (HSIwet, FA concentration in liver tissue, and the % of whole body FAs stored in the liver) began to increase in September. Cod prioritized growth during the summer, while in the autumn and pre-winter they allocated more energy into lipid storage. We conclude that seasonal changes in tissue-specific FA storage and pre-winter fish conditions are important factors to consider for understanding overwintering potential of juvenile Pacific cod.

Chitosan and Grifola Frondosa nanoparticles insulate liver dysfunction in EAC-bearing mice.

Ehrlich ascites carcinoma (EAC) is a rapidly growing and undifferentiated tumor that can prompt oxidative stress and liver toxicity, whereas chitosan and Grifola Frondosa have widely recognized biological qualities. Therefore, our study designed to assess the potential ameliorative ability of chitosan nanoparticles (CS NPs) and Grifola Frondosa nanoparticles (GF-loaded casein NPs) on EAC-induced hepatic injury in mice. A total of 60 female albino mice were segregated into 6 groups (10 mice each), G1, control group; G2, CS NPs group; G3, GF-loaded casein NPs group; G4, EAC group; G5, EAC treated with CS NPs; G6, EAC treated with GF-loaded casein NPs. According to the findings, EAC considerably increased serum activities of ALT, AST, ALP as well as LDL, cholesterol, and triglycerides levels coincided with marked decrease in albumin and total protein content in liver tissue. At the same time, it drastically lowered GSH levels and catalase activity while significantly elevating MDA levels. In addition, EAC caused DNA damage and apoptosis by decreasing Bcl-2 while increasing p53 expressions. However, either CS NPs or GF-loaded casein NPs therapy improved liver architecture and functioning, increased antioxidant parameters, and prevented hepatocyte death in EAC mice. Our findings concluded that CS NPs and GF-loaded casein NPs have insulating functions against EAC-induced hepatic damage in mice.

Proteomic study of gamma-oryzanol preventive effect on a diet-induced non-alcoholic fatty liver disease model

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with obesity and diabetes prevalence. The use of natural compounds has become an attractive approach to prevent NAFLD and its progression. Gamma-oryzanol (Orz) is a natural compound whose beneficial effects on chronic metabolic diseases have been reported. Therefore, we aimed to investigate the preventive effect of Orz on the hepatic proteome in a diet induced NAFLD model. Wistar rats were randomly distributed into three experimental groups (n=6/group) according to the diet received for 30 weeks: Control group, high sugar-fat (HSF) group, and HSF+Orz group. The isolated Orz was added to the chow at the dose of 0.5% (w/w). We evaluated the nutritional profile, characterized the presence of steatosis through histological analysis, triglyceride content in liver tissue and hepatic inflammation. Next, we performed label-free quantitative proteomics of hepatic tissue. Network analysis was performed to describe involved protein pathways. NAFLD induction was characterized by the presence of hepatic steatosis. Orz prevented lipid accumulation. The compound prevented alterations of the hepatic proteome, highlighted by the modulation of lipid metabolism, inflammation, oxidative stress, xenobiotic metabolism, and the sirtuin signaling pathway. It was possible to identify key altered pathways of NAFLD pathophysiology modulated by Orz which may provide insights into NAFLD treatment targets.

Assessment of mercury concentrations in fur, liver, and brain tissue from necropsied southern sea otters (Enhydra lutris nereis)

AbstractSouthern sea otters (Enhydra lutris nereis) are a federally listed threatened keystone species of the California kelp forest ecosystem and a sentinel species, indicating environmental health. Mercury (Hg) is a bioaccumulative neurotoxin that poses a threat to high trophic‐level species such as marine mammals. We quantified total Hg (THg) concentrations in fur, brain, and liver tissues of necropsied southern sea otters (n = 44) that stranded along the California coast from 2010 to 2019. THg concentrations differed significantly between fur and brain, and between liver and brain. Tissue type explained 64%, and sex explained only 3.3% of overall THg variability (0.48–46.1 μg/g dry weight). All individuals had liver Hg concentrations measuring well under the proposed lower‐limit low risk guideline for harp seals, Pagophilus groenlandicus. However, six sea otters exceeded the liver THg moderate risk threshold for terrestrial furbearers to which sea otters are closely related. These data represent baseline THg concentrations in fur, brain, and liver of the southern sea otter and build upon previous studies in various sea otter subspecies. Research on sea otter Hg tolerance and continued monitoring are needed to clarify potential health risks associated with the tissue concentrations observed in this study.

The association between trace metals in both cancerous and non-cancerous tissues with the risk of liver and gastric cancer progression in northwest China

Liver cancer and gastric cancer have extremely high morbidity and mortality rates worldwide. It is well known that an increase or decrease in trace metals may be associated with the formation and development of a variety of diseases, including cancer. Therefore, this study aimed to evaluate the contents of aluminium (Al), arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), lead (Pb), selenium (Se), and zinc (Zn) in cancerous liver and gastric tissues, compared to adjacent healthy tissues, and to investigate the relationship between trace metals and cancer progression. During surgery, multiple samples were taken from the cancerous and adjacent healthy tissues of patients with liver and gastric cancer, and trace metal levels within these samples were analysed using inductively coupled plasma mass spectrometry (ICP-MS). We found that concentrations of As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Se, and Zn in tissues from patients with liver cancer were significantly lower than those in healthy controls (P < 0.05). Similarly, patients with gastric cancer also showed lower levels of Cd, Co, Cr, Mn, Ni, and Zn—but higher levels of Cu and Se—compared to the controls (P < 0.05). In addition, patients with liver and gastric cancers who had poorly differentiated tumours and positive lymph node metastases showed lower levels of trace metals (P < 0.05), although no significant changes in their concentrations were observed to correlate with sex, age, or body mass index (BMI). Logistic regression, principal component analysis (PCA), Bayesian kernel regression (BKMR), weighted quantile sum (WQS) regression, and quantile-based g computing (qgcomp) models were used to analyse the relationships between trace metal concentrations in liver and gastric cancer tissues and the progression of these cancers. We found that single or mixed trace metal levels were negatively associated with poor differentiation and lymph node metastasis in both liver and gastric cancer, and the posterior inclusion probability (PIP) of each metal showed that Cd contributed the most to poor differentiation and lymph node metastasis in both liver and gastric cancer (all PIP = 1.000). These data help to clarify the relationship between changes in trace metal levels in cancerous liver and gastric tissues and the progression of these cancers. Further research is warranted, however, to fully elucidate the mechanisms and causations underlying these findings.

Effects of Extracellular Calcium Concentration on Hepatic Ischemia-Reperfusion Injury in a Rat Model.

Hypocalcemia is frequently identified during liver transplant. However, supplementation of extracellular calcium could induce increased intracellular calcium concentration, as a potential factor for injury to the liver graft. We evaluated the effects of regulating extracellular calcium concentrations on hepatic ischemia-reperfusion injury. We randomly divided 24 Sprague-Dawley rats into 3 groups: group C received normal saline (n = 8), group L received citrate to induce hypocalcemia (n = 8), and group L-Co received citrate followed by calcium gluconate to ameliorate hypocalcemia (n = 8). Liver enzyme levels and extracellular calcium were measured before surgery, 1 hour after ischemia, and 2 hours after reperfusion. The primary outcome was liver enzyme levels measured 2 hours after reperfusion. In addition, we evaluated intracellular calcium levels, lactate dehydrogenase activity, and histopathological results in liver tissue. Three groups demonstrated significant differences in extracellular calcium concentrations, but intracellular calcium concentrations in liver tissue were not significantly different. Group L showed significantly lower mean arterial pressure than other groups at 1 hour after ischemia (93.6 ± 20.8 vs 69.4 ± 14.2 vs 86.6 ± 10.4 mmHg; P = .02, for group C vs L vs L-Co, respectively). At 2 hours after reperfusion, group L showed significantly higher liver enzymes than other groups (aspartate aminotransferase 443.0 ± 353.2 vs 952.3 ± 94.8 vs 502.4 ± 327.3 U/L, P = .01; and alanine aminotransferase 407.9 ± 406.5 vs 860.6 ± 210.9 vs 333.9 ± 304.2 U/L, P = .02; for group C vs L vs L-Co, respectively). However, no significant difference was shown in lactate dehydrogenase and histological liver injury grade. Administering calcium to rats with hypocalcemia did not increase intracellular calcium accumulation but instead resulted in less hepatic injury compared with rats with low extracellular calcium concentrations in this rat model study.

THE PROTECTIVE EFFECT OF DEXMEDETOMIDINE ON THE LIVER INJURY IN SEPSIS THROUGH INHIBITION OF NECROPTOSIS.

Background: Sepsis-induced liver injury leads to extensive necroptosis in hepatocytes, which is the main factor of liver dysfunction. This study aims to investigate the protective effect of dexmedetomidine (DEX) on septic liver and to explore whether its molecular mechanism is related to the modulation of necroptosis. Methods: The model of septic liver injury was induced by cecal ligation and puncture (CLP) in rats. DEX and necrostatin-1(Nec-1), a specific antagonist of necroptosis, were administered 1 h before CLP. The levels of arterial blood gas, serum aspartate aminotransferase, and alanine aminotransferase were measured at 6, 12 and 24 h after CLP. The survival rate was observed 24 h after CLP. Liver pathological changes and apoptosis, the contents of IL-6 and TNF-α in liver tissue homogenates, the ROS content in liver tissue, and the expression levels of RIP1, RIP3, MLKL, and HMGB1 were detected. Results: At 6, 12, and 24 h after CLP, the levels of aspartate aminotransferase, and alanine aminotransferase levels increased, and liver enzyme levels gradually increased with the progression of sepsis. In arterial blood gas analysis, P a O 2 gradually decreased and lactic acid concentration gradually increased during these three periods. The morphological impairment of liver tissues, increased apoptosis, elevated inflammatory factors (IL-6 and TNF-α), increased ROS level, and necroptosis components (RIP1, RIP3, MLKL, and HMGB1) were all observed in sepsis rats. However, these injuries can be ameliorated by pretreatment with DEX. Meanwhile, Nec-1 pretreatment also reduced the expression of RIP1, RIP3, MLKL, HMGB1, and ROS level. Conclusion: Our study suggests that DEX alleviates septic liver injury, and the mechanism is associated with the inhibition of necroptosis.

Effects of temperature acclimation on the upper thermal tolerance of two Arctic fishes.

The thermally dynamic nearshore Beaufort Sea, Alaska, is experiencing climate change-driven temperature increases. Measuring thermal tolerance of broad whitefish (Coregonus nasus) and saffron cod (Eleginus gracilis), both important species in the Arctic ecosystem, will enhance understanding of species-specific thermal tolerances. The objectives of this study were to determine the extent that acclimating broad whitefish and saffron cod to 5°C and 15°C changed their critical thermal maximum (CTmax) and HSP70 protein and mRNA expression in brain, muscle and liver tissues. After acclimation to 5°C and 15°C, the species were exposed to a thermal ramping rate of 3.4°C · h-1 before quantifying the CTmax and HSP70 protein and transcript concentrations. Broad whitefish and saffron cod acclimated to 15°C had a significantly higher mean CTmax (27.3°C and 25.9°C, respectively) than 5°C-acclimated fish (23.7°C and 23.2°C, respectively), which is consistent with trends in CTmax between higher and lower acclimation temperatures. There were species-specific differences in thermal tolerance with 15°C-acclimated broad whitefish having higher CTmax and HSP70 protein concentrations in liver and muscle tissues than saffron cod at both acclimation temperatures. Tissue-specific differences were quantified, with brain and muscle tissues having the highest and lowest HSP70 protein concentrations, respectively, for both species and acclimation temperatures. The differences in broad whitefish CTmax between the two acclimation temperatures could be explained with brain and liver tissues from 15°C acclimation having higher HSP70a-201 and HSP70b-201 transcript concentrations than control fish that remained in lab-acclimation conditions of 8°C. The shift in CTmax and HSP70 protein and paralogous transcripts demonstrate the physiological plasticity that both species possess in responding to two different acclimation temperatures. This response is imperative to understand as aquatic temperatures continue to elevate.