Plasma Alanine Aminotransferase Activity Research Articles

Effects of Laurus nobilis essential oil nano-particles on growth performance, antioxidant and immune responses to bacterial infection in Nile tilapia, Oreochromis niloticus

This study was designed to assess the effects of four feeds containing 0 (CTL), 25 mg/kg (LN25), 50 mg/kg (LN50) and 100 mg/kg (LN100) Laurus nobilis (LN) essential oil nano-liposomes (LN-NP) on Nile tilapia, Oreochromis niloticus. After 56 days of feeding with the above diets, growth performance and digestive enzyme activities determined in all treatments. Then, the fish were experimentally infected by Aeromonas hydrophila and their survival, antioxidant capacity, biochemical parameters and immune-related transcripts were measured, before and after the infection. The results showed that the growth rate and intestinal activities of amylase, lipase and protease were significantly higher in the LN50 and LN100 treatments than CTL. Post-infection survivals in the LN50 and LN100 treatments were similar and significantly higher than the CTL and LN25 treatments. Compared to the CTL treatment, the LN50 and LN100 treatments showed improved hepatic antioxidant parameters and lower malondialdehyde levels before and/or after infection. Infection significantly decreased plasma lysozyme and complement activities, but the LN50 and LN100 treatments had significantly higher activities before and after infection. These treatments had lower alanine aminotransferase and aspartate aminotransferase activities in plasma before and after infection, compared to the CTL treatment. The expression of tumor necrosis factor-alpha, interleukin-8 and interleukin-1 beta increased significantly in the LN50 and LN100 treatments, before and after infection, when compared to the CTL treatment. Based on the results, LN-NP at a dosage of 50 mg/kg is suitable for feeding Nile tilapia as it is a growth promoter and immunostimulator and increases the resistance of fish to A. hydrophila.

Suppressive Effects of β-Hydroxybutyrate Administration on Lipopolysaccharide-Induced Inflammation in Broiler Chickens.

This study aimed to evaluate the suppressive effects of β-hydroxybutyrate (BHB) administration on lipopolysaccharide (LPS)-induced inflammation in broiler chickens. Twenty-day-old male broiler chickens were randomly allocated to three groups, each of which was treated with saline (control), intraperitoneal administration of LPS [1.5 mg/kg body weight (BW), Escherichia coli O127:B8], or LPS plus BHB (3 mmol/kg BW). Plasma albumin and total protein concentration were significantly reduced by LPS administration, while BHB co-treatment partially attenuated the effects. The LPS treatment significantly induced plasma aspartate and alanine aminotransferase activities, and interleukin (IL)-6 concentration, with the increases suppressed by BHB co-treatment (p < 0.05). The LPS treatment significantly increased the gene expression levels of IL-1β, IL-6, and IL-18 in the spleen and peripheral blood monocytes (PBMC), while the increases were partially attenuated by BHB in the spleen. Relatively higher levels of BHB dehydrogenase 1 and succinyl-CoA:3-ketoacid CoA transferase were observed in the spleen and skeletal muscle, while these gene levels were lower in PBMC and the liver. The present results suggest that BHB can suppress LPS-induced inflammation, in which ketolytic enzyme expression levels may be involved in broiler chickens.

Diacylglycerol O-acyltransferase 1 inhibitor increases plasma alanine aminotransferase and aspartate aminotransferase activities via a shedding of the intestinal villi and an increase in intestinal permeability in rats

Diacylglycerol O-acyltransferase 1 (DGAT1) is a key enzyme for fat absorption step in the enterocytes. We previously reported that DGAT1 inhibition increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in corn oil-loaded rats via protein kinase C (PKC) activation. In the present study, we investigated the mechanism with respect to the morphology and permeability of the small intestine, focusing on PKC function, and found that shortening of the intestinal villi and a decrease in the number of tdT-mediated dUTP-biotin nick-end labeling-positive cells in the tips of the villi were observed in the jejunum of DGAT1 inhibitor-treated rats loaded with corn oil. These results suggested that the tips of the villi were shed into the intestinal lumen. Next, fluorescein isothiocyanate-dextran, 110 kDa (FD-110) was administered intraduodenally to DGAT1 inhibitor-treated rats loaded with corn oil and we found that plasma FD-110 concentrations increased, indicating that the intestinal permeability to molecules with a molecular weight of approximately 110,000 (e.g., ALT and AST) increased. Taken together, the present results suggested that DGAT1 inhibitor-treatment in combination with corn oil causes ALT and AST to leak from the enterocytes into the blood by shedding the tips of the intestinal villi and increasing intestinal permeability.

The p21+ perinecrotic hepatocytes produce the chemokine CXCL14 after a severe acetaminophen overdose promoting hepatocyte injury and delaying regeneration

Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available single-nuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as CXCL14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, CXCL14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or CXCL14 with a neutralizing antibody. We found that targeting CXCL14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting senescent hepatocytes had no effect. These data support the conclusion that the sustained induction of p21 in hepatocytes with persistent CXCL14 secretion are critical mechanistic events leading to ALF in mice and human patients.

Risk factors and implications associated with ultrasound-diagnosed nephrocalcinosis in cats with chronic kidney disease.

Microscopic nephrocalcinosis is a common pathological feature of chronic kidney disease (CKD) in cats. Detection of macroscopic nephrocalcinosis using ultrasonography and its implications remain unexplored. Identify risk factors associated with ultrasound-diagnosed nephrocalcinosis and evaluate the influence of nephrocalcinosis on CKD progression. Thirty-six euthyroid client-owned cats with CKD. Prospective cohort study. Cats with CKD with and without ionized hypercalcemia were enrolled for renal ultrasonography. Cats were categorized according to the presence or absence of ultrasound-diagnosed nephrocalcinosis. Binary logistic regression was performed to identify nephrocalcinosis risk factors. The influence of nephrocalcinosis on CKD progression was assessed using linear mixed models. Ultrasound-diagnosed nephrocalcinosis was evident in 61% of CKD cats overall, with increased prevalence (81%) in those with hypercalcemia. At enrollment, higher blood ionized calcium concentration (odds ratio [OR], 1.27 per 0.1 mg/dL; P = .01), plasma phosphate concentration (OR, 1.16 per 0.1 mg/dL; P = .05), plasma creatinine concentration (OR, 1.29 per 0.1 mg/dL; P = .02) and alanine aminotransferase activity (OR, 2.08 per 10 U/L; P = .04) were independent nephrocalcinosis risk factors. The rate of change in log-transformed fibroblast growth factor-23 differed significantly between groups (P = .04). Cats with CKD and nephrocalcinosis had increasing plasma creatinine concentrations (.03 ± .01 mg/dL/month; P = .04) and phosphate concentrations (.06 ± .02 mg/dL/month; P < .001) and decreasing body weight (.02 ± .01 kg/month; P < .001) over time. Nephrocalcinosis is prevalent in cats with CKD, especially in those with hypercalcemia. This pathological feature appears to be associated with CKD progression in cats.

Influence of 19-Nortestosterone on the Content of Steroid Hormones, Hematological Indicators and Individual Links of Metabolism in Tissues of Carp (Cyprinus carpio)

The influence of different concentrations of the synthetic steroid 19-nortestosterone on the body mass and indexes of internal organs, hematological parameters, testosterone, progesterone and cortisol content, certain links of metabolic processes and enzymatic activity in the tissues of carp (&lt;i&gt;Cyprinus carpio&lt;/i&gt; L.) was studied. Under the short-term impact of 50 &amp;mu;g/dm&lt;sup&gt;3&lt;/sup&gt;, 19-nortestosterone increased the total protein and albumins content, creatine phosphokinase and aspartate aminotransferase activity, decreased the inorganic phosphorus and iron content, alkaline phosphatase and alanine aminotransferase activity in the blood plasma and did not affect the respiratory rate, external body features, the mass of hepatopancreas and spleen and their indexes, hematological indicators, the steroid hormones concentration in blood plasma and hepatopancreas, content of glucose, triglycerides, creatinine, calcium, inorganic phosphorus in blood plasma. Under 200 &amp;mu;g/dm&lt;sup&gt;3&lt;/sup&gt;, the respiratory rate and ESR increased, as well as the cortisol and testosterone content in blood plasma and hepatopancreas, whereas progesterone in blood plasma decreased and in hepatopancreas increased. High concentration of 19-nortestosterone caused elevated protein and albumin content, creatine phosphokinase and aspartate aminotransferase in the blood plasma activity, whereas glucose, inorganic phosphorus, iron, alkaline phosphatase activity was lower. The 19-nortestosterone did not affect the mass and index of hepatopancreas and spleen, hemoglobin concentration, the erythrocytes, leukocytes and lymphocytes number and ratio of eosinophils, neutrophils, lymphocytes and monocytes, as well as triglycerides, creatinine, calcium content, lactate dehydrogenase and alanine aminotransferase activity in blood plasma. The conclusion was made about the carp's ability to adapt to low concentrations of the synthetic steroid 19-nortestosterone under its short-term impact by modification of the certain links of metabolism and enzymatic activity. High concentration of 19-nortestosterone significantly affected the hormonal status and metabolism of carp.

Hippocampal acetylcholinesterase activation induced by streptozotocin in mice is protected by an organotellurium compound without evidence of toxicity.

The cognitive deficit, which is like Alzheimer's disease and is associated with oxidative damage, may be induced by exposure to streptozotocin. This study aimed to evaluate if the tellurium-containing organocompound, 3j, 5'-arylchalcogeno-3-aminothymidine derivative, interferes with the effects of streptozotocin, as well as to investigate its toxicity in adult mice. Cognitive deficit was induced by two doses of streptozotocin (2.25 mg/kg/day, 48 h interval) intracerebroventricularly. After, the mice were subcutaneously treated with 3j (8.62 mg/kg/day) for 25 days. The effects were assessed by evaluating hippocampal and cortical acetylcholinesterase and behavioral tasks. 3j toxicity was investigated for 10 (0, 21.55, or 43.10 mg/kg/day) and 37 (0, 4.31, or 8.62 mg/kg/day) days by assessing biometric parameters and glucose and urea levels, and alanine aminotransferase activity in blood plasma. 3j exposure did not alter the behavioral alterations induced by streptozotocin exposure. On the other hand, 3j exposure normalized hippocampus acetylcholinesterase activity, which is enhanced by streptozotocin exposure. Toxicity evaluation showed that the administration of 3j for either 10 or 37 days did not cause harmful effects on the biometric and biochemical parameters analyzed. Therefore, 3j does not present any apparent toxicity and reverts acetylcholinesterase activity increase induced by streptozotocin in young adult mice.

A flavonoid-rich extract of bergamot juice improves high-fat diet-induced intestinal permeability and associated hepatic damage in mice.

Consumption of high-fat diets (HFDs) is a contributing factor to obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD). Several studies suggested the protective role of bioactives present in Citrus fruits against the above mentioned chronic metabolic conditions. In this study, we evaluated if a flavonoid-rich extract of Citrus bergamia (bergamot) juice (BJe) could inhibit HFD-induced intestinal permeability and endotoxemia and, through this mechanism, mitigate the associated hepatic damage in C57BL/6J mice. After 12 weeks of the treatment, HFD consumption caused high body weight (BW) gain, hyperinsulinemia, hyperglycemia, and dyslipidemia, which were mitigated by BJe (50 mg per kg BW) supplementation. Furthermore, supplementation with BJe prevented HFD-induced liver alterations, including increased plasma alanine aminotransferase (ALT) activity, increased hepatic lipid deposition, high NAS, and fibrosis. Mice fed a HFD for 12 weeks showed (i) a decrease in small intestine tight junction protein levels (ZO-1, occludin, and claudin-1), (ii) increased intestinal permeability, and (iii) endotoxemia. All these adverse events were mitigated by BJe supplementation. Linking the capacity of BJe to prevent HFD-associated endotoxemia, supplementation with this extract decreased the HFD-induced overexpression of hepatic TLR-4, downstream signaling pathways (MyD88, NF-κB and MAPK), and the associated inflammation, evidenced by increased MCP-1, TNF-α, IL-6, iNOS, and F4/80 levels. Overall, we suggest that BJe could mitigate the harmful consequences of western style diet consumption on liver physiology by protecting the gastrointestinal tract from permeabilization and associated metabolic endotoxemia.

Lactobacillus plantarum ST-III culture supernatant protects against acute alcohol-induced liver and intestinal injury.

The beneficial effects of probiotics have been studied in inflammatory bowel disease, nonalcoholic steatohepatitis, and alcoholic liver disease (ALD). Probiotic supplements are safer and more effective; however, their potential mechanisms are unclear. An objective of the current study was to examine the effects of extracellular products of Lactobacillus plantarum on acute alcoholic liver injury. Mice on a standard chow diet were supplemented with Lactobacillus plantarum ST-III culture supernatant (LP-cs) for two weeks and administered alcohol at 6 g/kg body weight by gavage. Alcohol-induced liver injury was assessed by measuring plasma alanine aminotransferase activity levels and triglyceride content determined liver steatosis. Intestinal damage and tight junctions were assessed using histochemical staining. LP-cs significantly inhibited alcohol-induced fat accumulation, inflammation, and apoptosis by inhibiting oxidative stress and endoplasmic reticulum stress. LP-cs significantly inhibited alcohol-induced intestinal injury and endotoxemia. These findings suggest that LP-cs alleviates acute alcohol-induced liver damage by inhibiting oxidative stress and endoplasmic reticulum stress via one mechanism and suppressing alcohol-induced increased intestinal permeability and endotoxemia via another mechanism. LP-cs supplements are a novel strategy for ALD prevention and treatment.

Akkermansia muciniphila MucT attenuates sodium valproate-induced hepatotoxicity and upregulation of Akkermansia muciniphila in rats.

In the previous study, we found that the oral sodium valproate (SVP) increased the relative abundance of Akkermansia muciniphila (A. muciniphila) in rats, and plasma aspartate transaminase (AST) and alanine aminotransferase (ALT) activities were positively correlated with A. muciniphila levels. This study aimed to further investigate the role of A. muciniphila in SVP-induced hepatotoxicity by orally supplementing rats with the representative strain of A. muciniphila, A. muciniphila MucT. Additionally, the fresh faeces were incubated anaerobically with SVP to investigate the effect of SVP on faecal A. muciniphila in the absence of host influence. Results showed that A. muciniphila MucT ameliorated the hepatotoxicity and upregulation of A. muciniphila induced by SVP. SVP also induced a noteworthy elevation of A. muciniphila level invitro, supporting the observation invivo. Therefore, we speculate that A. muciniphila MucT may be a potential therapeutic strategy for SVP-induced hepatotoxicity. In addition, the increased A. muciniphila induced by SVP may differ from A. muciniphila MucT, but further evidence is needed. These findings provide new insights into the relationships between A. muciniphila and SVP-induced hepatotoxicity, highlighting the potential for different A. muciniphila strains to have distinct or even opposing effects on SVP-induced hepatotoxicity.

Determination of Weight and Biochemical Changes in Layers Experimentally Infected with Escherichia coli

This study determined the effect of experimental exposure of layer chickens to Escherichia coli (E. coli) on weight, egg production and some plasma biochemical parameters. A total of 20 laying chickens (20 weeks old) were acquired and assigned, at random, into infected and control groups, of 10 layers each. Birds in the infected group were challenged with 0.5 ml of bacterial aliquot containing 109 colony forming units (CFU) of the bacteria, administered intra tracheally. Five birds, from each group were selected at random and their live body weights were determined on days 0, 2, 4, 6, 14, 21, 28, 35 and 42. Also, egg production was monitored, and the weekly percentage egg production of birds was calculated. Two (2) ml of blood were collected from each bird in both groups and used for plasma biochemical analyses. Finding from the research showed that E. coli infection caused reduction in feed and water consumption by day 3 post infection (pi); with subsequent reduction in body weight and egg production. The mean plasma aspartate aminotransferase (AST) activity in the infected group progressively increased from day 6 pi to reach a significantly higher (p &lt; 0.05) value (66.4 ± 0.93 IU/L) on day 28 pi while the mean plasma alanine aminotransferase (ALT) activity progressively increased in the infected group from day 6 pi to attain the highest significant (p &lt; 0.05) value (74.4 ± 2.11 IU/L) on day 21 pi. The mean plasma total protein concentration in the infected group decreased from day 4 pi and reached the lowest significant (p &lt; 0.05) value (5.12 ± 0.28 mg/dl) on day 35 pi. In conclusion, the drop in egg production, loss of body weight, increase hepatic transaminases and decrease plasma protein may be attributed to anorexia or possible impairment of intestinal, renal reabsorption of nutrients from the infection.

Biochemical Response and Histopathologic Alterations in Papyrocranus afer from Banegbe River, Delta State, Nigeria

Aim: This study investigated the effects of pollutants on the biochemical and histopathological components of Papyrocranus afer obtained from the Banegbe River at different locations (upstream, middle-stream, and downstream). The effect of the pollutant on the checked were, levels of alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in blood samples of the fishes and the histopathologic alterations of the gills and liver of the fishes. &#x0D; Methodology: The gills and liver tissue of the fish were collected and processed using routine histologic techniques for fixing and embedding in paraffin and staining sections with hem eosin. All the indices of the enzyme tests were estimated with the aid of Randox Diagnostic Test Kits following the manufacturer’s methods. &#x0D; Results: Evaluation of the plasma enzymes showed significant increases (p&lt;0.05) in plasma ALT, AST, and ALP activity in all the sampled points of Banegbe River when compared to the control 1 (Orogodo river) with middle-stream having significant (p&lt;0.05) higher concentrations when compared to down-stream and up-stream. The main alterations observed in the liver of the fish at the Banegbe River were Kupffer cell hyperplasia and focal necrosis of the liver. While the gills showed alteration of the structure of the epithelium, hyperplasia of the epithelium of the primary lamella, epithelial lifting, vacuolization, alteration of the structure, and occurrence of aneurysms in the secondary lamella, all these alterations were as a result of pollutant in the river. Control 1 showed normal parenchymal cells of the liver and normal gill structure. &#x0D; Conclusion: The increase in enzyme activities suggests leakage of these enzymes from the liver cytosol into the bloodstream as a result of liver damage by contaminants. From our results, it can be concluded that the Banegbe River is polluted as a result of effluents channeled in the river by industries within the environs.

Effect of various dietary fructose concentrations on the gallstone formation process in mice.

Background: little information is availaible on the effect of fructose on bile lipids. The first stage in the formation of gallstones corresponds to biliary cholesterol crystallization, derived from the vesicular transporters. The aim of this study was to investigate the influence of consuming diets with different fructose concentrations on serum lipids and their implications on gallstones formation. Methods: BALB/c mice divided into a control group as well as groups were treated with different fructose concentrations (10 %, 30 %, 50 % or 70 %) for different periods (1, 2 or 5 months). Blood, liver and bile samples were obtained. In bile samples, cholesterol and phospholipids levels were analyzed, and cholesterol transporters (vesicles and micelles) were separated by gel filtration chromatography. Results: treated animals showed: 1) increases in body weight similar to the control group; 2) a significant increase in plasma triglycerides only at very high fructose concentrations; 3) a significant increase in total serum cholesterol in the treatment for 1 month; 4) no variations in HDL-cholesterol; 5) a significant increase in serum glucose only at very high fructose concentrations in the second month of treatment; 6) no differences in the plasma alanine-aminotransferase activity; 7) a significant increase in liver triglyceride levels only at very high fructose concentrations; 8) no change in biliary lipid concentrations or in micellar and vesicular phospholipids. Conclusion: changes in plasma, liver and bile lipids were only observed at very high fructose concentrations diets. We conclude that fructose apparently does not alter the gallstone formation process in our experimental model.

Comparison of the Retention Rates of Synthetic and Natural Astaxanthin in Feeds and Their Effects on Pigmentation, Growth, and Health in Rainbow Trout (Oncorhynchus mykiss).

The coloring efficiency and physiological function of astaxanthin in fish vary with its regions. The aim of this study was to compare the retention rates of dietary astaxanthin from different sources and its effects on growth, pigmentation, and physiological function in Oncorhynchus mykiss. Fish were fed astaxanthin-supplemented diets (LP: 0.1% Lucantin® Pink CWD; CP: 0.1% Carophyll® Pink; EP: 0.1% Essention® Pink; PR: 1% Phaffia rhodozyma; HP: 1% Haematococcus pluvialis), or a diet without astaxanthin supplementation, for 56 days. Dietary astaxanthin enhanced pigmentation as well as the growth of the fish. The intestinal morphology of fish was improved, and the crude protein content of dorsal muscle significantly increased in fish fed with astaxanthin. Moreover, astaxanthin led to a decrease in total cholesterol levels and alanine aminotransferase and aspartate aminotransferase activity in plasma. Fish fed on the CP diet also produced the highest level of umami amino acids (aspartic acid and glutamic acid). Regarding antioxidant capacity, astaxanthin increased Nrf2/HO-1 signaling and antioxidant enzyme activity. Innate immune responses, including lysozyme and complement systems, were also stimulated by astaxanthin. Lucantin® Pink CWD had the highest stability in feed and achieved the best pigmentation, Essention® Pink performed best in growth promotion and Carophyll® Pink resulted in the best flesh quality. H. pluvialis was the astaxanthin source for achieving the best antioxidant properties and immunity of O. mykiss.

Neutrophil Depletion Attenuates Acute Liver Stress after Exhaustive Exercise in Mice.

Exhaustive exercise induces acute liver stress; however, the precise mechanisms remain unclear. We investigated the effects of neutrophil depletion in male C57BL/6J mice. Male C57BL/6J mice were divided into four groups: sedentary with control antibody ( n = 20), sedentary with antineutrophil antibody ( n = 20), exhaustive exercise with control antibody ( n = 20), and exhaustive exercise with antineutrophil antibody ( n = 20). Antineutrophil antibodies (1A8) or control antibodies were administered intraperitoneally before running on a treadmill. Immediately and at 24 h after running to exhaustion on a treadmill at a 7% gradient and a speed of 24 m·min -1 , blood neutrophil counts were measured by flow cytometry. Plasma activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also measured. Hematoxylin-eosin staining was performed to calculate the liver stress score, and hepatic tumor necrosis factor-α was measured using enzyme-linked immunosorbent assay. Exercise increased blood neutrophil and neutrophil infiltration into the liver. Plasma AST and ALT activities were significantly higher immediately after exhaustive exercise than after sedentary control (AST, sedentary with control antibody: 52.2 ± 0.4, exhaustive exercise with control antibody: 210.0 ± 19.8; ALT, sedentary with control antibody: 29.8 ± 2.2, exhaustive exercise with control antibody: 87.2 ± 15.8). However, AST and ALT activities were significantly decreased with the 1A8 antibody (AST, 102.2 ± 12.9; ALT, 39.2 ± 4.0). In addition, the liver stress score increased after exercise but was significantly reduced by prior 1A8 antibody administration. The 1A8 antibody treatment also decreased hepatic tumor necrosis factor-α levels after exhaustive exercise. These results suggested that neutrophils play a critical role in increasing liver stress by regulating inflammation.

Preclinical exploration of combined glucagon inhibition and liver-preferential insulin for treatment of diabetes using in vitro assays and rat and mouse models

Aims/hypothesisNormalisation of blood glucose in individuals with diabetes is recommended to reduce development of diabetic complications. However, risk of severe hypoglycaemia with intensive insulin therapy is a major obstacle that prevents many individuals with diabetes from obtaining the recommended reduction in HbA1c. Inhibition of glucagon receptor signalling and liver-preferential insulin action have been shown individually to have beneficial effects in preclinical models and individuals with diabetes (i.e. improved glycaemic control), but also have effects that are potential safety risks (i.e. alpha cell hyperplasia in response to glucagon receptor antagonists and increased levels of liver triacylglycerols and plasma alanine aminotransferase activity in response to glucagon receptor antagonists and liver-preferential insulin). We hypothesised that a combination of glucagon inhibition and liver-preferential insulin action in a dual-acting molecule would widen the therapeutic window. By correcting two pathogenic mechanisms (dysregulated glucagon signalling and non-physiological distribution of conventional insulin administered s.c.), we hypothesised that lower doses of each component would be required to obtain sufficient reduction of hyperglycaemia, and that the undesirable effects that have previously been observed for monotreatment with glucagon antagonists and liver-preferential insulin could be avoided.MethodsA dual-acting glucagon receptor inhibitor and liver-preferential insulin molecule was designed and tested in rodent models (normal rats, rats with streptozotocin-induced hyperglycaemia, db/db mice and mice with diet-induced obesity and streptozotocin-induced hyperglycaemia), allowing detailed characterisation of the pharmacokinetic and pharmacodynamic properties of the dual-acting molecule and relevant control compounds, as well as exploration of how the dual-acting molecule influenced glucagon-induced recovery and spontaneous recovery from acute hypoglycaemia.ResultsThis molecule normalised blood glucose in diabetic models, and was markedly less prone to induce hypoglycaemia than conventional insulin treatment (approximately 4.6-fold less potent under hypoglycaemic conditions than under normoglycaemic conditions). However, compared to treatment with conventional long-acting insulin, this dual-acting molecule also increased triacylglycerol levels in the liver (approximately 60%), plasma alanine aminotransferase levels (approximately twofold) and alpha cell mass (approximately twofold).Conclusions/interpretationWhile the dual-acting glucagon receptor inhibitor and liver-preferential insulin molecule showed markedly improved regulation of blood glucose, effects that are potential safety concerns persisted in the pharmacologically relevant dose range.Graphical abstract

Effects of dietary Hyssop, Hyssopus officinalis, extract on physiological and antioxidant responses of rainbow trout, Oncorhynchus mykiss, juveniles to thermal stress.

The present study aimed at assessing the effects of dietary Hyssop, Hyssopus officinalis, extract on rainbow trout, Oncorhynchus mykiss, responses to thermal stress. The juveniles (69.8 ± 0.38 g) were stocked in 12 through-flow tanks at a density of 12 fish per tank. Methanolic extract of Hyssop (HME) was added to diet at 0, 100, 250, and 500 mg/kg and the fish were fed (3% of biomass) over a 70-d period: 62 d at 13.3 ± 0.08°C and 7 d at 21-22°C. At the end of the trial, the plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), triiodothyronine (T3), thyroxin (T4), cortisol, glucose, lactate, total antioxidant capacity (TAC), ascorbate, and the gill glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), and malondialdehyde (MDA). The results showed that HME had no significant effects on fish growth performance, survival, and feed efficiency. Dietary 250 mg/kg HME significantly decreased plasma ALT activity (P < 0.001), but showed no significant effects on plasma AST) (P = 0.106) activity, T3 (P = 0.992), and T4 (P = 0.070) levels. Thermal stress significantly (P < 0.001) increased plasma ALT and AST activities, but lowered plasma T3 and T4 levels. Dietary HME and thermal stress had interaction effects on plasma cortisol (P < 0.001), glucose (P = 0.007), lactate (P = 0.010), LDH (P = 0.005), TAC (P = 0.038), ascorbate (P < 0.001), and the gill GPx (P = 0.001), GR (P < 0.001), GST (P < 0.001), and MDA (P = 0.001). Thermal stress significantly increased plasma cortisol, glucose, lactate, and LDH, the gill GPX, GR, and GST, but dietary HME supplementation significantly reduced such elevations, particularly at 250 mg/kg level. Dietary HME significantly increased plasma TAC before the thermal stress and mitigated the stress-induced decreased in TAC, particularly at 250 mg/kg level. Dietary HME significantly decreased the gill MDA before and after the thermal stress, and lowest MDA was observed in 250 mg/kg HME level. Based on the present results, 250 mg/kg HME is recommended as suitable dose to improve antioxidative responses and hepatoprotection in rainbow trout under heat stress.

The Preliminary Results for Evaluating Cocoa Butter's Hepatoprotective Effects against Lipid Accumulation and Inflammation in Adult Male Rats Chronically Fed Ethanol.

The purpose of this study was to clarify the role of saturated fats from cocoa butter (plant source) compared with lard (animal source) on alcoholic liver damage in rats. Male Wistar rats were fed either a control diet (C) or an ethanol diet (E), and the dietary fats (corn oil, olive oil, and safflower oil) of these two diets were further replaced by lard (CL, EL) or cocoa butter (CC, EC). After 8-week feeding, plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, hepatic triglyceride (TG) levels, plasma intercellular adhesion molecular (ICAM)-1 levels, hepatic cytochrome P450 2E1 (CYP2E1) protein expression, and hepatic interleukin (IL)-1β significantly increased in the E group compared to the C group. In addition, hepatic histopathological scores of fatty changes, inflammatory cell infiltration, and degeneration and necrosis in the E group were significantly higher compared to those in the C group. However, fatty changes were significantly inhibited only in the EC group as well as hepatic inflammatory cell infiltration, degeneration, and necrosis being significantly lower in the EL and EC groups. Plasma ICAM-1 and hepatic tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-10 levels were significantly lower in the EL and EC groups than those in the E group. Moreover, a correlation analysis showed that hepatic histopathological scores of degeneration and necrosis were significantly positively correlated with erythrocytic oleic acid (C18:1) and were negatively correlated with linoleic acid (C18:2). In conclusion, cocoa butter protected the liver against lipid accumulation and inflammation in rats chronically fed ethanol.

Effect of Dietary Ginger Rhizome Powder Addition on Reproductive Performance of Rabbit Bucks

This study was conducted to evaluate the effect of the addition of ginger rhizome powder (GRP) to the rabbit bucks ration on semen quality and semen plasma traits. A total of 28 male New Zealand rabbits (7- month- old), divided into four groups; the first treatment served as a control (Con; 0% ginger); the second, third, and fourth treatments were supplemented with 0.5%, 1.0%, and 1.5% ginger powder in the diet, respectively. The results revealed no change in ejaculate volume, a significant increase in the mass sperm motility, sperm concentration, total sperm output, total motile sperm, live sperm, and Total functional sperm fraction. Dietary ginger reduced the reaction time, semen pH, and the percentage of abnormal sperm. Bucks that received 1.0% or 1.5% dietary ginger had a higher seminal plasma total proteins, albumin, globulin concentrations, alkaline phosphatase and acid phosphatase activities. Conversely, seminal plasma aspartate aminotransferase and alanine aminotransferase activities were significantly decreased compared to the control group. Practically, it can be concluded that ginger is a suitable supplement for improving semen quality and semen plasma in adult male rabbits.

ANGPTL4 silencing via antisense oligonucleotides reduces plasma triglycerides and glucose in mice without causing lymphadenopathy

Angiopoietin-like 4 (ANGPTL4) is an important regulator of plasma triglyceride (TG) levels and an attractive pharmacological target for lowering plasma lipids and reducing cardiovascular risk. Here, we aimed to study the efficacy and safety of silencing ANGPTL4 in the livers of mice using hepatocyte-targeting GalNAc-conjugated antisense oligonucleotides (ASOs). Compared with injections with negative control ASO, four injections of two different doses of ANGPTL4 ASO over 2 weeks markedly downregulated ANGPTL4 levels in liver and adipose tissue, which was associated with significantly higher adipose LPL activity and lower plasma TGs in fed and fasted mice, as well as lower plasma glucose levels in fed mice. In separate experiments, injection of two different doses of ANGPTL4 ASO over 20 weeks of high-fat feeding reduced hepatic and adipose ANGPTL4 levels but did not trigger mesenteric lymphadenopathy, an acute phase response, chylous ascites, or any other pathological phenotypes. Compared with mice injected with negative control ASO, mice injected with ANGPTL4 ASO showed reduced food intake, reduced weight gain, and improved glucose tolerance. In addition, they exhibited lower plasma TGs, total cholesterol, LDL-C, glucose, serum amyloid A, and liver TG levels. By contrast, no significant difference in plasma alanine aminotransferase activity was observed. Overall, these data suggest that ASOs targeting ANGPTL4 effectively reduce plasma TG levels in mice without raising major safety concerns.