Significant Increase In Liver Weight Research Articles

Effects of D-allulose on di (2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP)-induced toxicity in rats

Background: Oral exposure to high concentrations of DEHP and DBP causes testicular and hepatotoxicity in rodents. Phthalate metabolites such as mono (2-ethylhexyl) phthalate (MEHP) and mono-n-butyl phthalate (MBP) stimulate peroxisome proliferator-activated receptors and disrupts carbohydrate and lipid metabolism. The oxidative stress generated may be closely related to these toxicities. Method: To clarify the effects of the rare sugar D-allulose, a potent free radical scavenger, on testicular and hepatotoxicity induced by DEHP and DBP, rats were fed DEHP or DBP containing diet and D-allulose water. Result: Dietary exposure to DEHP and DBP induced a significant decrease in testicular weight and significant increase in liver weight. D-allulose treatment significantly inhibited the testicular weight loss. But D-allulose treatment did not significantly suppress the increase in liver weight. Plasma glucose levels were significantly lower in the DEHP- or DBP-only treated groups compared to controls, but were improved by D-allulose treatment. This suggests that D-allulose blocks DEHP- and DBP-induced glycemic suppression. Plasma lipid-related markers such as total cholesterol, high-density lipoprotein cholesterol, and triglycerides were lower than controls in all treatment groups on the DEHP and DBP diets, but showed a slight trend toward improvement with D-allulose. Conclusion: D-allulose reduced DEHP- and DBP-induced testicular toxicity and blood glucose suppression in rats, but did not improve liver hypertrophy. This effect may be due to the strong oxidant scavenging ability of D-allulose.

Effects of dietary zinc oxide nanoparticles supplementation on broiler growth performance, zinc retention, liver health status, and gastrointestinal microbial load

BackgroundZinc (Zn) is an essential trace element for poultry health and biological functions. Inorganic Zn, like Zn oxide and Zn sulfate, was commonly used in poultry feed due to its low cost. However, the bioavailability of inorganic Zn is low, leading to a high level of Zn being added to the feed and resulting in other issues. Zinc oxide nanoparticles (ZnO NPs) have emerged as a promising alternative to their bulkier counterparts, but concerns about their safety persist. Therefore, this study aimed to evaluate the potential benefits and toxicity of dietary ZnO NPs as a feed supplement and antibacterial agent in broiler chickens. Methods180 broiler chicks (Cobb500) were randomly allocated to five dietary treatment groups (36 birds/group). The experimental treatment groups were as follows: (G1) basal diet supplemented with 100 mg kg−1 ZnO (control group), (G2-G5) basal diet supplemented with 10, 40, 70, and 100 mg kg−1 ZnO NPs. The effects of dietary ZnO NPs at different inclusion levels were studied by measuring growth performance (FI, BWG, and FCR), Zn retention, liver enzyme activity, lymphoid organ weight, and gastrointestinal microbial load. ResultsThe results showed that dietary ZnO and different levels of ZnO NPs inclusion had no effect on broiler growth performance (p > 0.05). The birds fed dietary ZnO NPs retained significantly more Zn than the control group (p < 0.05), lowering feces Zn excretion. The supplementation of ZnO NPs did not reduce lymphoid organs weight; in fact, a notable increase in weight was observed in groups supplemented with higher levels of ZnO NPs when compared to the control group. Furthermore, no significant increase in liver weight (p > 0.05) or enzymatic activities (AST and ALT) were observed in birds fed ZnO NPs, indicating no liver damage occurred. ZnO NPs at 100 mg kg−1 in the diet showed antibacterial effects, reducing Enterococcus spp. and E. coli count significantly, without affecting commensal bacteria (lactic acid bacteria) count. ConclusionThe inclusion of ZnO NPs to broiler chicken feed as a Zn source had no negative effects on growth or health. Additionally, it increased Zn absorption and bioavailability, reduced Zn excretion, and exhibited potential antibacterial activity against tested pathogens.

EVALUATION OF HEPATOPROTECTIVE ACTIVITY OF DRACAENA TERNIFLORA ROXB. AGAINST ETHANOL INDUCED HEPATIC INJURY IN WISTAR ALBINO RATS

Objectives: The objectives of the study were to investigate hepatoprotective activity of ethanolic root extract of Dracaena terniflora Roxb. (DTR-E) in alcohol-induced hepatotoxicity in rats. Methods: Hepatotoxicity was induced in albino Wistar rats by oral administration of 40% ethanol (2 mL/100 g body weight). DTR-E root extract was administered at a dose level of 100 mg/kg and 200 mg/kg orally for 21 days. On the 22nd day blood was taken by puncturing retro orbital plexus and used for the estimation of biochemical parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, creatinine, urea, triglycerides, total cholesterol, albumin, and total protein. Animals were sacrificed by cervical dislocation and liver was dissected out and histopathological analysis of liver and kidney was carried out. Results: Obtained results revealed that administration of ethanol caused a significant increase in liver weight, plasma ALT, AST, ALP, bilirubin creatinine, urea, triglycerides,and total cholesterol compared to the control group, while total protein and albumin concentration are significantly declined which were effectively prevented by the DTR-E extract. The histopathological observations supported the biochemical evidence of hepatoprotection. Conclusions: The findings suggest that DTR-E root extract protects the liver cell from ethanol induced liver damages due to its antioxidative effect on hepatocytes. The results of the present investigation indicated that roots of D. terniflora Roxb. possesses significant hepatoprotective activity.

Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets.

ZBED6 (zinc finger BED domain containing protein 6) is a transcription factor unique to placental mammals and its interaction with the IGF2 (insulin-like growth factor 2) locus plays a prominent role in the regulation of postnatal skeletal muscle growth. Here, we generated lean Bama miniature pigs by generating ZBED6-knockout (ZBED6−/−) and investigated the mechanism underlying ZBED6 in growth of muscle and internal organs of placental mammals. ZBED6−/− pigs show markedly higher lean mass, lean mass rate, larger muscle fiber area and heavier internal organs (heart and liver) than wild-type (WT) pigs. The striking phenotypic changes of ZBED6-/- pigs coincided with remarkable upregulation of IGF2 mRNA and protein expression across three tissues (gastrocnemius muscle, longissimus dorsi, heart). Despite a significant increase in liver weight, ZBED6-/- pigs show comparable levels of IGF2 expression to those of WT controls. A mechanistic study revealed that elevated methylation in the liver abrogates ZBED6 binding at the IGF2 locus, explaining the unaltered hepatic IGF2 expression in ZBED6-/- pigs. These results indicate that a ZBED6-IGF2-independent regulatory pathway exists in the liver. Transcriptome analysis and ChIP-PCR revealed new ZBED6 target genes other than IGF2, including cyclin dependent kinase inhibitor 1A (CDKN1A) and tsukushi, small leucine rich proteoglycan (TSKU), that regulates growth of muscle and liver, respectively.

Rutin activates AMPKα to ameliorate liver damage caused by perfluorooctanoic acid in mice

To study the protective effect and mechanism of rutin on perfluorooctanoic acid(PFOA)-induced liver damage in mice. A total of 24 male ICR mice were randomly divided into 3 groups, 8 in each group: control group(ctrl group: ddH_2O), perfluorooctanoic acid group(PFOA group: PFOA 20 mg/(kg·d)), rutin intervention group(rutin+PFOA group: PFOA 20 mg/(kg·d)+rutin 20 mg/(kg·d)), normal diet, oral gavage, daily observation, weighting, and recording. After 14 days of treatment, the liver was quickly stripped and weighted after blood sampling and execution. Part of the liver tissue is fixed in 4% paraformaldehyde for HE staining and PAS staining; glutamic-pyruvic transaminase(GPT) activity in the sera samples and triglyceride(TG), total cholesterol(TC), malondialhyde(MDA) content in hepatic tissue homogenate, as well as the activity of some enzymes were assayed; Using western blot to detect adenylate activated protein kinase α(AMPKα) and phosphorylated adenylate-activated protein kinase α(p-AMPKα) expression levels. PFOA caused a significant decrease in the weight of mice, a significant increase in liver weight and liver relative body weight coefficient(P& lt; 0.05), hepatocyte cord dissociation, hepatocyte swelling, dissolution, and obvious damage, and PAS staining positive result were significantly reduced. The GPT activity of the PFOA group was 204.63±11.26 U/L, which was significantly higher than that of the control group(28.80±4.51 U/L)(P& lt; 0.05); The contents of TG, TC and MDA in the liver tissues of mice were 4.89±0.51 mmol/g prot, 8.06±0.84 mmol/g prot and 315.38±60.79 nmol/mg prot, respectively, which were significantly higher than those of the control group(P& lt; 0.05); The activity of T-SOD was 4175.56±334.96 U/mg prot, which was significantly lower than that of the control group(P& lt; 0.05); After rutin intervention, compared with PFOA exposure group, the weight of the mice did not change significantly(P& gt; 0.05), however, the liver weight and the relative weight coefficient of the liver were significantly reduced(P& lt; 0.05), and the hepatocytes swollen and cell lysis were attenuated, the structure of cell cord changed clear, the positive PAS staining cells were significantly increased, the GPT activity of the rutin intervention group was 168.75±18.32 U/L, which was significantly lower than that of the PFOA group(P& lt; 0.05); The contents of TC and MDA in the liver tissues of mice were 4.25±0.77 mmol/g prot and 211.27±44.44 nmol/mg prot, respectively, which were significantly lower than those in the PFOA group(P& lt; 0.05); The T-SOD activity was 7368.88±673.09 U/mg prot, which was significantly higher than that of the PFOA group(P& lt; 0.05). There was no significant difference in AMPKα protein expression in the liver tissues of the three groups. Compared with the PFOA group, the p-AMPKα protein expression in the PFOA+rutin group was significantly up-regulated. PFOA exposure can cause liver damage and lipid accumulation in mice. Rutin has a certain protective effect on this damage, which may be related to rutin& apos; s activation of AMPKα protein expression to effectively correct TG levels and enhance the activity of antioxidant enzymes.

Liver Profile of Artemether-lumefantrine-tinidazole in Healthy and Parasitized Mice

Artemether/lumefantrine/tinidazole (A/L/T) has shown additive antiplasmodial activity; therefore its safety assessment is imperative. This study examined its hepatotoxic effect on healthy and diseased mice. Fifty four Swiss albino mice of n=6 were used. The mice were diseased with Plasmodium berghei ( ) and treated with T (28.6 mg/kg), A/L (2.3/13.7mg/kg) and A/L/T for 4 days, respectively. Healthy mice were treated with T (28.6 mg/kg), A/L (2.3/13.7mg/kg) and A/L/T for 28 days, respectively. After drug treatment; the mice were weighed and anesthetized. Liver samples were excised, weighed and evaluated for oxidative stress indices and histology. Blood samples were assessed for serum liver function indices. Treatment with T, A/L and A/L/T produced no significant (p&gt;0.05) effects on all evaluated parameters in parasitized mice when compared to control. Significant decrease in body weight with significant increase in liver weight occurred in healthy mice treated with A/L (p&lt;0.05) and A/L/T (p&lt;0.01) when compared to control. Impaired liver function characterized by significantly increased serum aminotranferases, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transferase, and bilirubin levels with significantly decreased total protein and albumin levels occurred in healthy mice treated with T (p&lt;0.05), A/L (p&lt;0.01) and A/L/T (p&lt;0.001) when compared to control. Significantly decreased glutathione peroxidase, superoxide dismutase, glutathione, and catalase levels with significantly increased malondialdehyde levels occurred in healthy mice treated with T (p&lt;0.05), A/L (p&lt;0.01) and A/L/T (p&lt;0.001) when compared to control. A/L/T caused hepatocyte necrosis in healthy mice. The use of A/L/T for malaria treatment seems safe on the liver, but may impair liver function with prolonged use.

Importance du temps en médecine traditionnelle : Cas de l’usage de trois plantes de la pharmacopée togolaise

Introduction. The effectiveness of folk medicine has been demonstrated by several studies. However, the chrono-toxicological aspect is barely addressed. Objective. The present study, conducted in the region of Kara in Togo, assessed the importance of the factor "time" in the use of 3 plants commonly used in traditional pharmacopoeia: Sarcocephalus latifolius, Jatropha multifida, and Blighia sapida. Material and methods. The methodology was based on ethnobotanical surveys, semi-structured individual interviews of 36 traditional healers using the three plants. Analysis of these data was based on consensus values (CV), and use values (UV). A chrono-toxicological assessment of their hydro-alcoholic extracts permitted to determine the impact of administration time on liver and kidney of Swiss albinos mice male. Results. The most used organs by traditional healers were roots (UV=0.62) for S. latifolius, bark (UV=0.53) for B. sapida, and leaves (0.66) for J. multifida. Malaria was the most treated disease with S. latifolius (CV=0.44), and J. multifida (CV=0.5). Haemorrhoid was cured with B. sapida (CV=0.28). Plant parts were harvested mainly in the morning (VC≥ 0.55). The most recommended dosing period was morning - evening for S. latifolius (VC=0.70), and B. sapida (VC=0.70), and only in the morning for J. multifida (VC=0.50). The hydro-alcoholic extracts administration of S. latifolius at 12H increased significantly mice liver weight. There was also a significant increase in liver weight in mice treated morning and evening by a hydro-alcoholic extract of J. multifida. Conclusion. Checking account of harvest time, and/or administration of phytomedicines will contribute to improve significantly the effectiveness of traditional medicine.

Thrombospondin-I is a critical modulator in non-alcoholic steatohepatitis (NASH).

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by dysregulated lipid metabolism and chronic inflammation ultimately resulting in fibrosis. Untreated, NAFLD may progress to non-alcoholic steatohepatitis (NASH), cirrhosis and death. However, currently there are no FDA approved therapies that treat NAFLD/NASH. Thrombospondin-I (TSP-1) is a large glycoprotein in the extracellular matrix that regulates numerous cellular pathways including transforming growth factor beta 1 (TGF-β1) activation, angiogenesis, inflammation and cellular adhesion. Increased expression of TSP-1 has been reported in various liver diseases; however, its role in NAFLD/NASH is not well understood. We first examined TSP-1 modulation in hepatic stellate cell activation, a critical initiating step in hepatic fibrosis. Knockdown or inhibition of TSP-1 attenuated HSC activation measured by alpha smooth muscle actin (α-SMA) and Collagen I expression. To investigate the impact of TSP-1 modulation in context of NAFLD/NASH, we examined the effect of TSP-1 deficiency in the choline deficient L-amino acid defined high fat diet (CDAHFD) model of NASH in mice by assessing total body and liver weight, serum liver enzyme levels, serum lipid levels, liver steatosis, liver fibrosis and liver gene expression in wild type (WT) and TSP-1 null mice. CDAHFD fed mice, regardless of genotype, developed phenotypes of NASH, including significant increase in liver weight and liver enzymes, steatosis and fibrosis. However, in comparison to WT, CDAHFD-fed TSP-1 deficient mice were protected against numerous NASH phenotypes. TSP-1 null mice exhibited a decrease in serum lipid levels, inflammation markers and hepatic fibrosis. RNA-seq based transcriptomic profiles from the liver of CDAHFD fed mice determined that both WT and TSP-1 null mice exhibited similar gene expression signatures following CDAHFD, similar to biophysical and histological assessment comparison. Comparison of transcriptomic profiles based on genotype suggested that peroxisome proliferator activated receptor alpha (PPARα) pathway and amino acid metabolism pathways are differentially expressed in TSP-1 null mice. Activation of PPARα pathway was supported by observed decrease in serum lipid levels. Our findings provide important insights into the role of TSP-1 in context of NAFLD/NASH and TSP-1 may be a target of interest to develop anti-fibrotic therapeutics for NAFLD/NASH.

NLRP3 inhibitor glibenclamide attenuates high-fat diet and streptozotocin-induced non-alcoholic fatty liver disease in rat: studies on oxidative stress, inflammation, DNA damage and insulin signalling pathway.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is much higher in diabetic and obese individuals. Combined exposure of high-fat diet (HFD) and single low-dose streptozotocin (STZ) was used to induce type II diabetes-associated NAFLD, as it better replicates the human pathology of fatty liver. Glibenclamide (GLB) is a potent NLRP3 inflammasome inhibitor and possesses anti-inflammatory and anti-oxidant properties. So it was pertinent to investigate its hepatoprotective potential against NAFLD in rat. HFD was provided to rat for 17 consecutive weeks and glibenclamide (GLB; 0.5 and 2.5mg/kg/day, orally) was administered for the last 12 consecutive weeks. Establishment of NAFLD was clearly indicated by significant increase in liver weight, glucose, triglyceride, cholesterol, % glycosylated haemoglobin and insulin levels, and GLB intervention reduced the same. GLB restored HFD-induced significant increase in ROS, MDA and decrease in GSH. Histopathological studies revealed the macro- and micro-vascular steatosis and mild degree of inflammation in HFD-fed rat compared with control, and GLB intervention reduced the same. HFD exposure significantly increased the DNA damage and apoptosis compared with control, and GLB intervention reduced the same. Immunohistochemical and immunoblotting findings showed that GLB improved the hepatic expressions of inflammatory markers (NLRP3, ASC, caspase-1, IL-1β, NF-κB), anti-oxidant markers (SOD, catalase) and insulin signalling markers (p-AKT, p-GSK-3β, p-IRS). Hepatoprotective effects of GLB was mediated by decreasing the levels of glucose, triglycerides, cholesterol, DNA damage, apoptosis and inflammatory markers, and by improving the anti-oxidant status and insulin signalling pathway in HFD fed rat.

Hepatoprotective effect of artichoke leaf extracts in comparison with silymarin on acetaminophen-induced hepatotoxicity in mice

ABSTRACTAcetaminophen is a common analgesic-antipyretic agent, which is safe in therapeutic doses but in higher doses can produce hepatic necrosis. The aim of this study is to investigate the hepatoprotective effects of artichoke, silymarin, and both agents in acetaminophen-induced liver damage in mice. Forty male mice were divided into five main groups, (1) control (2) Acetaminophen (APAP) (3) Artichoke leaf extracts (ALE) and APAP (4) silymarin and APAP group (5) ALE, silymarin and APAP groups. Blood samples were collected for the measurement of liver enzymes (ALT, AST, and ALP). The liver was excised, weighed and dissected into two parts, one used for measurement of malondialdehyde (MDA) and glutathione reductase, and the other part used for histopathological examination and assessment of proliferative cell nuclear antigen (PCNA) immunohistochemical expression. APAP group showed a significant increase in liver weight, ALT, AST, ALP, MDA, and PCNA expression with a significant decrease in glutathione reductase in comparison to control group. All these parameters were significantly improved in the three treated groups when compared to APAP group. APAP group showed marked portal inflammation and parenchyma necrosis. Co-administration of ALE and/or silymarin to acetaminophen treated mice showed a significant reduction in PCNA expression compared to APAP group. Both ALE and silymarin co-treatment showed a significant decrease in PCNA percentage to a level near to control group. Artichoke and/or silymarin are suggested to protect against acetaminophen-induced hepatotoxicity in mice by ameliorating liver enzymes, antioxidant effect, decreasing liver damage and proliferation.Abbreviation: ALT, alanine transaminase. AST, aspartate transaminase. ALP, alkaline phosphatase.MDA, malondialdehyde. PCNA, proliferative cell nuclear antigen

Kanechlor 500‐mediated changes in serum and hepatic thyroxine levels primarily occur in a transthyretin‐unrelated manner

The effects of Kanechlor-500 (KC500) on the levels of serum total thyroxine (T4 ) and hepatic T4 in wild-type C57BL/6 (WT) and its transthyretin (TTR)-deficient (TTR-null) mice were comparatively examined. Four days after a single intraperitoneal injection with KC500 (100mg/kg body weight), serum total T4 levels were significantly decreased in both WT and TTR-null mice. The KC500 pretreatment also promoted serum [125 I]T4 clearance in both strains of mice administrated with [125 I]T4 , and the promotion of serum [125 I]T4 clearance in WT mice occurred without inhibition of the [125 I]T4 -TTR complex formation. Furthermore, the KC500 pretreatment led to significant increases in liver weight, steady-state distribution volume of [125 I]T4 , hepatic accumulation level of [125 I]T4 , and concentration ratio of the liver to serum in both strains of mice. The present findings indicate that the KC500-mediated decrease in serum T4 level occurs in a TTR-unrelated manner and further suggest that KC500-promoted T4 accumulation in the liver occurs through the development of liver hypertrophy and the promotion of T4 transportation from serum to liver.

Xian-Ling-Gu-Bao induced inflammatory stress rat liver injury: Inflammatory and oxidative stress playing important roles

Ethnopharmacological relevanceXian-Ling-Gu-Bao (XLGB) Fufang is an herbal formula that has been used in clinical settings to treat osteoporosis, osteoarthritis, aseptic bone necrosis, and climacteric syndrome. Despite its uses, XLGB treatment has been linked to potential liver injury. To date, there is a lack of clear demonstration of such toxicity in animal models. Aim of the studyAs animal models fail to reproduce the XLGB hepatotoxicity reported in humans, because human hepatocytes are clearly more sensitive to XLGB, this study was designed to investigate a more reliable animal model of such toxicity. Materials and methodsWe randomized rats into five groups, as follows: CON (control), XLGB, lipopolysaccharide (LPS), L-XLGB/LPS (XLGB, 0.125 g/kg; LPS, 0.1 mg/kg), and XLGB/LPS (XLGB, 1.25 g/kg; LPS, 0.1 mg/kg). These groups were treated with 0.5% sodium carboxymethyl cellulose (CMC-Na), XLGB suspension, normal saline, or LPS. The first administration of XLGB [0.125 g/kg or 1.25 g/kg, by mouth (PO)] or its solvent (0.5% CMC-Na) was delivered, and then food was removed. Twelve hours after the first administration of XLGB, rats received LPS [0.1 mg/kg, intravenously (IV)] or saline control. After 30 min, a second administration of XLGB (0.125 g/kg or 1.25 g/kg, PO) or solvent was administered. The rats were anesthetized at 12 h or 24 h following the second administration of XLGB. Liver function was evaluated by measuring liver weight, liver microscopy, serum biochemistry and plasma microRNA-122 (miR-122). The plasma levels of 27 cytokines were measured to evaluate inflammation. Moreover, the expression of cytochrome P450 2E1 (CYP2E1), nicotinic adenine dinucleotide phosphate (NADPH) oxidase and inducible nitric oxide synthase (iNOS) at protein levels were observed; immunofluorescence and immunohistochemistry were used to confirmed the hepatotoxicity of XLGB. ResultsHepatotoxicity in male rats with moderate inflammation induced by XLGB was indicated by liver histopathology, serum biochemical analysis, serum miR-122 levels, and immunofluorescent assessments. We observed significant increases in liver weight and liver indexes in male rats with moderate inflammation in response to XLGB. Histopathological assessment further showed that extensive hepatocellular necrosis and inflammatory infiltration were evident in rats co-treated with XLGB/LPS. The levels of serum transaminases [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT)], total bilirubin (TBIL) and triglyceride (TG), which are markers of liver function, were also significantly increased by XLGB/LPS treatment. Similarly, miR-122 was significantly elevated in XLGB/LPS treated rats relative to other groups. An immunofluorescent assessment showed extensive apoptosis in hepatocytes from these co-treated rats. What is more, XLGB can dose-dependently induce liver injury in male rats with moderate inflammation.Hepatic CYP2E1, neutrophil chemotactic factor (NCF-1), iNOS, and NOX-2 (an NADPH oxidase subunit) levels were increased in response to XLGB treatment, and staining for DMPO nitrone adducts further showed elevated oxidative stress level in XLGB/LPS-treated rats relative to the other experimental groups. ConclusionLPS and XLGB co-treatment in rats led to marked hepatotoxicity. This toxicity was associated with disrupted lipid metabolism, extensive liver necrosis and inflammatory infiltration, apoptosis, and expression of oxidative stress-related proteins. These results demonstrate a valuable model for the study of iDILI in the context of XLGB treatment, and further provide insights into the potential mechanisms by which XLGB may induce hepatotoxicity in humans.

Induction of hepatic miR-34a by perfluorooctanoic acid regulates metabolism-related genes in mice

Perfluorooctanoic acid (PFOA) is a widespread organic pollutant with various toxicological impacts on the liver. Members of the miR-34 family are P53-targeted growth suppressors. We found that PFOA exposure (5 mg/kg/d PFOA for 28 d) resulted in a significant increase of miR-34a in the livers of mice but had no effect on either miR-34b or miR-34c. We knocked out miR-34a in mice to explore the role of elevated miR-34a in PFOA-induced liver toxicity. Compared with the corresponding untreated control, significant increases in liver weight as well as serum alanine transaminase, aspartate aminotransferase, and cholinesterase levels were observed in miR-34a−/− and wild-type mice after PFOA exposure. Hepatic cells showed similar swelling in both miR-34a−/− and wild-type mice after PFOA treatment. Hepatic RNA-sequencing (RNA-seq) showed that PFOA led to significant alteration in lipid metabolism genes, especially those involved in the peroxisome proliferator-activated receptor pathway, in both wild-type and miR-34a null mice. With or without PFOA treatment, relatively fewer genes were altered in miR-34a−/− livers compared to wild-type livers. Among the changed genes by miR-34a, the most dominant were metabolism-related genes, such as Fabp3, Cyp7a1, and Apoa4. Our in vivo study indicated that miR-34a mainly exerts a metabolic regulation role, rather than the pro-apoptosis and cell cycle arrest role reported previously by many in vitro studies. In addition, although hepatic P53 was unchanged, the active type of P53 (acetylated P53 (acetyl-p53, Lys379)) was markedly altered under PFOA treatment. Therefore, the increase in acetylated P53 may have activated the transcription of miR-34a in mouse livers after PFOA treatment.

EFFECTS OF FEEDING GENETICALLY MODIFIED (GM) MAIZE ON OXIDATIVE STRESS PARAMETERS IN NEW ZEALAND RABBIT

In this study, we investigated the effects of Genetically Modified (GM) Maize on liver and kidney tissue weights, malondialdehyde (MDA) and glutathione (GSH) levels of liver and kidney tissues in New Zealand Rabbits. For this purpose, rabbits were divided into three groups: parental, first-generation and second-generation. Each group was divided into two sub-groups i.e. control group and the treatment group. Rabbits on the control group were fed with conventional maize (non-GM), whereas rabbits which are in the treatment groups were fed with GM maize. Six females and six male New Zealand rabbits were used per group. At the end of the experimental period, tissue samples were taken and tissue weights, MDA and GSH levels were determined. Overall, as the generations progressed, a statistically significant increase in liver weights and a decrease in kidney weights were observed. There was no statistically significant change as regards MDA and GSH levels of liver and kidney tissues of groups without GM maize inclusion in the diet. However in all three-generation of GM maize treated groups, there was a significant decrease in GSH levels and a significant increase in MDA levels were observed.

THE EFFECT OF MORINGA OLEIFERA LEAVES AS A FEED ADDITIVE ON GROWTH PERFORMANCE, CARCASS CHARACTERISTICS, BLOOD PARAMETERS AND ECONOMICAL EFFICIENCY IN MULARD DUCKS

A total number of 150 unsexed seven day old Mulard ducks were randomly classified into three equal groups of 5 replicates (10 ducklings each). The 1st group received the basal diet and served as control group (G1). The other two groups (G2 and G3) received the basal diet supplemented with Moringa oleifera as feed additive at the level of 1 and 2%, respectively till age 10 wks. The results showed that dietary Moringa oleifera leaves (MOL)at 1% significantly increased the final body weight by 9.5%, the daily body weight gain by 9.4% and the daily feed intake by 6.14%, respectively compared to the control group. Moringa oleifera at 2% significantly decreased the final body weight by 6.7%, the body weight gain by 7.0% and the feed conversion ratio by 7.9%, while showed significant increase in liver weight by 1.6%, the gizzard weight by 13.2%, the giblet weight by 7.5%, the edible parts by 6.4% and the non edible parts by 13.3%, respectively compared to the control group. Feeding MOLat 1% significantly increased the total protein by 13.7%, the albumin by 20.5% and the globulin by 7.4% respectively, compared to the control group. Dietary MOLat 1 and 2% MOL significantly decreased the cholesterol level by 39 and 25%, the triglycerides by 41.3 and 16%, the total lipids by 23.5 and 19.6% as well as decreased the alkaline phosphatase activity by 64.2 and 28.1%, the AST by 31.3 and 41.5% and the renal creatinine by 23.5 and 19.6% respectively, compared to the control group as well as the ALT significantly (P<0.05) decreased by 35.8 with 1% MOL while increased by 18.2% with 2% MOL. It could be concluded that 1% of MOL levels was better results than 2% level.

The Protective Efficacy of Ethanolic Leaves Extract of Citronella Gras (Cymbopogon nardus) on Glucose Metabolism Alteration Induced By Mercury in Rats

The present study was undertaken to investigate the protective effect of ethanolic citronella grass (C. nardus) leaves extract against mercury (Hg) induced glucose metabolism alteration in rats. Four groups of rats were selected, with 6 rats for each group. Animals of group I was received a 1 ppm of Hg only. Animals of groups II, III, and IV received a combination of 1 ppm Hg and plant extract in different dose (1650, 2520, and 3360 mg/ml). The experiment lasted for 4 weeks. The various parameters studied included liver weight, liver glucose, glycogen, and malondialdehyde (MDA) level in all groups after treatment. The results of this present studies showed that the Hg-induced glucose metabolism alteration in rats which can be seen from the increase of liver glucose and the decreasing of liver glycogen levels. The results also showed that the Hginduced glucose metabolism alteration through its activities in the trigger the liver cells damage which can be seen from the decreasing of liver weight and the increase of liver MDA level. The ethanolic of C. nardus leaves extract shows a protective effect to maintain all parameters into a better a condition which can be seen from the significant increase in liver weight and liver glycogen level, and the significant decrease in liver glucose and MDA levels. The present study indicated that the ethanolic C. nardus leaves extract showed a potential protective effect on glucose metabolism alteration induced by Hg

Comprehensive growth performance, immune function, plasma biochemistry, gene expressions and cell death morphology responses to a daily corticosterone injection course in broiler chickens.

The massive meat production of broiler chickens make them continuously exposed to potential stressors that stimulate releasing of stress-related hormones like corticosterone (CORT) which is responsible for specific pathways in biological mechanisms and physiological activities. Therefore, this research was conducted to evaluate a wide range of responses related to broiler performance, immune function, plasma biochemistry, related gene expressions and cell death morphology during and after a 7-day course of CORT injection. A total number of 200 one-day-old commercial Cobb broiler chicks were used in this study. From 21 to 28 d of age, broilers were randomly assigned to one of 2 groups with 5 replicates of 20 birds each; the first group received a daily intramuscular injection of 5 mg/kg BW corticosterone dissolved in 0.5 ml ethanol:saline solution (CORT group), while the second group received a daily intramuscular injection of 0.5 ml ethanol:saline only (CONT group). Growth performance, including body weight (BW), daily weight gain (DG), feed intake (FI) and feed conversion ratio (FC), were calculated at 0, 3 and 7 d after the start of the CORT injections. At the same times, blood samples were collected in each group for hematological (TWBC’s and H/L ratio), T- and B-lymphocytes proliferation and plasma biochemical assays (total protein, TP; free triiodothyronine hormone, fT3; aspartate amino transaminase, AST; and alanine amino transaminase, ALT). The liver, thymus, bursa of Fabricius and spleen were dissected and weighed, and the mRNA expression of insulin-like growth factor 1 gene (IGF-1) in liver and cell-death-program gene (caspase-9) in bursa were analyzed for each group and time; while the apoptotic/necrotic cells were morphologically detected in the spleen. From 28 to 35 d of age, broilers were kept for recovery period without CORT injection and the same sampling and parameters were repeated at the end (at 14 d after initiation of the CORT injection). In general, all parameters of broiler performance were negatively affected by the CORT injection. In addition, CORT treatment decreased the plasma concentration of fT3 and the mRNA expression of hepatic IGF-1. A significant increase in liver weight accompanied by an increase in plasma TP, AST and ALT was observed with CORT treatment, indicating an incidence of liver malfunction by CORT. Moreover, the relative weights of thymus, bursa and spleen decreased by the CORT treatment with low counts of TWBC’s and low stimulation of T & B cells while the H/L ratio increased; indicating immunosuppressive effect for CORT treatment. Furthermore, high expression of caspase-9 gene occurred in the bursa of CORT-treated chickens, however, it was associated with a high necrotic vs. low apoptotic cell death pathway in the spleen. Seven days after termination of the CORT treatment in broilers, most of these aspects remained negatively affected by CORT and did not recover to its normal status. The current study provides a comprehensive view of different physiological modulations in broiler chickens by CORT treatment and may set the potential means to mount a successful defense against stress in broilers and other animals as well.

Methyl isobutyl ketone-induced hepatocellular carcinogenesis in B6C3F1 mice: A constitutive androstane receptor (CAR)-mediated mode of action

In a National Toxicology Program (NTP) chronic inhalation study with methyl isobutyl ketone (MIBK), increases in hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were observed in male and female B6C3F1 mice at 1800 ppm. A DNA reactive Mode-of-Action (MOA) for this liver tumor response is not supported by the evidence as MIBK and its major metabolites lack genotoxicity in both in vitro and in vivo studies. Constitutive androstane receptor (CAR) nuclear receptor-mediated activation has been hypothesized as the MOA for MIBK-induced mouse liver tumorigenesis. To further investigate the MOA for MIBK-induced murine liver tumors, male and female B6C3F1, C57BL/6, and CAR/PXR Knockout (KO) mice were exposed to either 0 or 1800 ppm MIBK for 6 h/day, 5 days/week for a total of 10 days. On day 1, mice were implanted with osmotic mini-pumps containing 5-Bromo-2-deoxyuridine (BrdU) 1 h following exposure and humanely euthanized 1–3 h following the final exposure. B6C3F1 and C57BL/6 mice had statistically significant increases in liver weights compared to controls that corresponded with hepatocellular hypertrophy and increased mitotic figures. Hepatocellular proliferation data indicated induction of S-phase DNA synthesis in B6C3F1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to control, and no increase was observed in MIBK exposed CAR/PXR KO mice. Liver gene expression changes indicated a maximally-induced Cyp2b10 (CAR-associated) transcript and a slight increase in Cyp3a11(PXR-associated) transcript in B6C3F1 and C57BL/6 mice exposed to 1800 ppm MIBK compared to controls, but not in Cyp1a1 (AhR-associated) or Cyp4a10 (PPAR-α-associated) transcripts. CAR/PXR KO mice exposed to 1800 ppm MIBK showed no evidence of activation of AhR, CAR, PXR or PPAR-α nuclear receptors via their associated transcripts. MIBK induced hepatic effects are consistent with a phenobarbital-like MOA where the initiating events are activation of the CAR and PXR nuclear receptors and resultant hepatocellular proliferation leading to rodent liver tumors.

Sub-acute and chronic toxicity profiles of Markhamia tomentosa ethanolic leaf extract in rats

Ethnopharmacological relevanceMarkhamia tomentosa (Benth.) K. Schum Ex Engl. (Bignoniaceae) is used in traditional African medicine for the treatment of diarrhoea, oedema, pain and malaria. The leaf extract was reported to show no visible sign of toxicity on acute exposure. This present study investigates the sub-acute and chronic toxicity effects of Markhamia tomentosa in rats. Materials and methodsThe animals (n=6/group) were treated daily with the extract at doses of 40, 200 and 1000mg/kg orally for 28 and 90 days. Control rats received distilled water and all animals were weighed at 7 days interval. The haematological, biochemical and histological parameters were determined. ResultsThe extract showed non-significant changes in body weight gain of treated compared to control rats in both studies. Extract significantly decreased red blood cell (RBC), mean cell haemoglobin concentration and increased mean corpuscular volume (MCV) parameters after the 28 day study. In the 90 day study, a significant increase in white blood cell, RBC, platelets and decrease in MCV and mean cell haemoglobin (MCH) parameters were observed. Biochemical parameters were significantly changed in both studies; triglycerides, total protein, alanine transaminase, aspartate transaminase and albumin showed significant increase while creatinine, blood urea nitrogen and uric acid levels showed significant decrease. Significant increase in liver weight with no treatment-related histological changes was observed in all harvested vital organs. ConclusionMarkhamia tomentosa extract elicited non-toxic effect in the liver and kidney function parameters in rats. Thus, the extract is safe when administered orally.

Intrahepatic Size Regulation in a Surgical Model: Liver Resection-Induced Liver Regeneration Counteracts the Local Atrophy following Simultaneous Portal Vein Ligation

Background/Aim: Liver size regulation is based on the balance between hepatic regeneration and atrophy. To achieve a better understanding of intrahepatic size regulation, we explored the size regulation of a portally deprived liver lobe on a liver subjected to concurrent portal vein ligation (PVL) and partial hepatectomy (PHx). Materials and Methods: Using a surgical rat model consisting of right PVL (rPVL) plus 70% PHx, we evaluated the size regulation of liver lobes 1, 2, 3, and 7 days after the operation in terms of liver weight and hepatocyte proliferation. Portal hyperperfusion was confirmed by measuring portal flow. The portal vascular tree was visualized by injection of a contrast agent followed by CT imaging of explanted livers. Control groups consisted of 70% PHx, rPVL, and sham operation. Results: The size of the ligated right lobe increased to 1.4-fold on postoperative day 7 when subjected to rPVL + 70% PHx. The right lobe increased to 3-fold when subjected to 70% PHx alone and decreased to 0.3-fold when subjected to rPVL only. The small but significant increase in liver weight after the combined procedure was accompanied by a low proliferative response. In contrast, hepatocyte proliferation was undetectable in the right lobe undergoing atrophy after PVL only. The caudate lobe in the rPVL + 70% PHx group increased to 4.6-fold, which is significantly more than in the other groups. This increase in liver weight was paralleled by persisting portal hyperperfusion and a prolonged proliferative phase of 3 days. Conclusions: A discontinued portal blood supply does not always result in atrophy of the ligated lobe. The concurrent regenerative stimulus induced by 70% PHx seemed to counteract the local atrophy after a simultaneously performed rPVL, leading to a low but prolonged regenerative response of the portally deprived liver lobe. This observation supports the conclusion that portal flow is not necessary for liver regeneration. The persisting portal hyperperfusion may be crucial for the specific kinetics of prolonged liver regeneration after rPVL + 70% PHx in the portally supplied caudate lobe. Both observations deserve more attention regarding the underlying mechanism in further studies.