Liver Adenosine Triphosphate Research Articles

Yinhuang granule alleviates carbon tetrachloride-induced liver fibrosis in mice and its mechanism.

Liver fibrosis is a formidable global medical challenge, with no effective clinical treatment currently available. Yinhuang granule (YHG) is a proprietary Chinese medicine comprising Scutellariae Radix and Lonicerae Japonicae Flos. It is frequently used for upper respiratory tract infections, pharyngitis, as well as acute and chronic tonsillitis. To investigate the potential of YHG in alleviating carbon tetrachloride (CCl4)-induced liver fibrosis in mice. To induce a hepatic fibrosis model in mice, this study involved intraperitoneal injections of 2 mL/kg of CCl4 twice a week for 4 wk. Meanwhile, liver fibrosis mice in the low dose of YHG (0.4 g/kg) and high dose of YHG (0.8 g/kg) groups were orally administered YHG once a day for 4 wk. Serum alanine/aspartate aminotransferase (ALT/AST) activity and liver hydroxyproline content were detected. Sirius red and Masson's trichrome staining assay were conducted. Real-time polymerase chain reaction, western-blot and enzyme-linked immunosorbent assay were conducted. Liver glutathione content, superoxide dismutase activity level, reactive oxygen species and protein carbonylation amount were detected. The administration of YHG ameliorated hepatocellular injury in CCl4-treated mice, as reflected by decreased serum ALT/AST activity and improved liver histological evaluation. YHG also attenuated liver fibrosis, evident through reduced liver hydroxyproline content, improvements in Sirius red and Masson's trichrome staining, and lowered serum hyaluronic acid levels. Furthermore, YHG hindered the activation of hepatic stellate cells (HSCs) and ameliorated oxidative stress injury and inflammation in liver from CCl4-treated mice. YHG prompted the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of Nrf2-dependent downstream antioxidant genes. In addition, YHG promoted mitochondrial biogenesis in liver from CCl4-treated mice, as demonstrated by increased liver adenosine triphosphate content, mitochondrial DNA levels, and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha and nuclear respiratory factor 1. YHG effectively attenuates CCl4-induced liver fibrosis in mice by inhibiting the activation of HSCs, reducing inflammation, alleviating liver oxidative stress damage through Nrf2 activation, and promoting liver mitochondrial biogenesis.

Effect of Erchen Decoction on liver mitochondrial function by inhibiting mTORC1/SREBP1/CAV1 pathway in mice with high-fat diet

This study aims to investigate the effect of Erchen Decoction(ECD) on liver mitochondrial function in mice with a high-fat diet and its possible mechanism. A total of sixty C57BL/6J mice were randomly divided into a normal group, high-fat group, ECD group, mTORC1 activator(MHY) group, ECD+MHY group, and polyene phosphatidyl choline(PPC) group, with 10 rats in each group. The normal group was given a normal diet, and the other groups were fed a high-fat diet for 20 weeks. At the 17th week, the ECD group and ECD+MHY group were given ECD(8.7 g·kg~(-1)) daily, and the PPC group was given PPC(0.18 g·kg~(-1)) daily, while the remaining groups were given normal saline(0.01 mL·g~(-1)) daily for four weeks. In the 19th week, the MHY group and ECD+MHY group were injected intraperitoneally with MHY(5 mg·kg~(-1)) every other day for two weeks. During the experiment, the general conditions of the mice were observed. The contents of triglyceride(TG) and total cholesterol(TC) in serum were measured. Morphological changes in liver tissue were examined through HE and oil red O staining. The content of adenosine triphosphate(ATP) was determined using chemiluminescence, and mitochondrial membrane potential was assessed using a fluorescence probe(JC-1). Western blot was performed to detect the expression of rapamycin target protein complex 1(mTOR1), ribosomal protein S6 kinase B1(S6K), sterol regulatory element binding protein 1(SREBP1), and caveolin 1(CAV1). RESULTS:: revealed that compared with the normal group, the mice in the high-fat group exhibited significant increases in body weight and abdominal circumference(P<0.01). Additionally, there were significant increases in TG and TC levels(P<0.01). HE and oil red O staining showed that the boundaries of hepatic lobules were unclear; hepatocytes were enlarged, round, and irregularly arranged, with obvious lipid droplet deposition and inflammatory cell infiltration. The liver ATP content and mitochondrial membrane potential decreased significantly(P<0.01). The expression of p-mTOR, p-S6K, and n-SREBP1 increased significantly(P<0.01), while the expression of CAV1 decreased significantly(P<0.01). Compared with the high-fat group, the body weight and TG content of mice in the ECD group and PPC group decreased significantly(P<0.05). Improvements were observed in hepatocyte morphology, lipid deposition, and inflammatory cell infiltration. Furthermore, there were significant increases in ATP content and mitochondrial membrane potential(P<0.05 or P<0.01). The expression of p-mTOR, p-S6K, and n-SREBP1 decreased significantly in the ECD group(P<0.01), while CAV1 expression increased significantly(P<0.01). However, the indices mentioned above did not show improvement in the MHY group. When the ECD+MHY group was compared with the MHY group, there were significant reductions in body weight and TG contents(P<0.05). The morphological changes of hepatocytes, lipid deposition, and inflammatory cell infiltration were recovered. Moreover, there were significant increases in liver ATP content and mitochondrial membrane potential(P<0.05 or P<0.05). The expression of p-mTOR, p-S6K, and n-SREBP1 decreased significantly(P<0.01), while CAV1 expression increased significantly(P<0.01). In conclusion, ECD can improve mitochondrial function by regulating the mTORC1/SREBP1/CAV1 pathway. This mechanism may be involved in the resolution of phlegm syndrome and the regulation of lipid metabolism.

Selenium improved mitochondrial quality and energy supply in the liver of high-fat diet-fed grass carp (Ctenopharyngodon idella) after heat stress.

This study aims to explore the effects of dietary selenium on hepatic mitochondrial quality and energy supply of grass carp (Ctenopharyngodon idella) fed with high-fat diet (HFD) after heat stress (HS). Grass carp were fed with HFD, and HFD contained 0.3mg/kg nano-selenium for 10weeks, thereafter exposed to HS from 26 to 34°C, and named the HFD + HS (control) group and the HFD + Se + HS group, respectively. The results show that selenium significantly prompted the growth, increased glutathione peroxidase (GPX) activity, but reduced malondialdehyde (MDA) content in the liver and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum of grass carp fed with HFD after HS. Further, selenium alleviated mitochondrial damage and increased the number of mitochondrial DNA copies in the liver of the grass carp fed with HFD after HS. And selenium also maintained mitochondrial homeostasis by upregulating the expression of mitochondrial quality control-related genes (pgc-1α, nrf1/2, tfam, opa1, mfn1/2, and drp1), mitophagy-related genes (beclin1, atg5, atg12, pink1, and parkin), and the protein expression of parkin and LC3-II/I in the liver of grass carp. Finally, selenium reduced the triglyceride (TG) level and increased the free fatty acid (FFA) level and adenosine triphosphate (ATP) production in the liver of grass carp fed with HFD after HS. In conclusion, dietary selenium alleviated liver damage and improved liver mitochondrial quality and ATP production by increasing liver antioxidant capacity and promoting liver mitochondrial quality in grass carp fed with HFD after HS, which help grass carp to resist these two stressors.

Development and validation of LC-MS/MS method for quantification of ATP, ADP and AMP in dried blood spot, liver and brain of neonate mice pups

The objective of this study was to develop and validate a method using liquid chromatography coupled with a mass spectrometer (LC–MS/MS) for simultaneous analysis of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) levels in dry blood spot (DBS), liver, brain (parietal and occipital regions) of BALB/c neonatal mice pups, using 13C10 ATP as internal standard (IS). Simultaneous nucleotides separation of the investigated samples was achieved in 5 min on a C18 column [Waters × Bridge C18, (4.6 × 50 mm, 3.5 μm)] using a gradient elution of 4 mM ammonium acetate and 100% acetonitrile as mobile phase A and mobile phase B, respectively. MS detection was performed in an ESI positive ionization mode. The method was validated according to the international council for harmonization guidelines. The standard calibration curve was linear over the concentration range of 0.1, 1, 5, 10, 15, 20 µg/ml of standard mixtures with known quantity of internal standards (IS) and the data showed good linearity (R2 0.999), with lower limit of quantification (LLOQ 0.1 µg/ml). The within run and between run precision of QCs (%CV) were ≤ 15% and accuracy (%) of measured concentration of QCs ranged between 88 and 110%. All the processed QCs were stable after applying the various storage conditions. The robustness study showed no significant variance in analyte peak quality and quantity with the smaller variation of temperature, pH and acetonitrile concentration. The matrix factor was in acceptable range. The present validation results show that the developed LC–MS/MS method is suitable to evaluate ATP, ADP and AMP levels in DBS, liver and brain tissues of neonatal mice pups.

Evaluation of Calorie Content of an All-natural Cane Sugar and Botanical Extract Sweetener: Studies in Wistar Rats

The purpose of the study was to evaluate the caloric content and biochemical effects of an all-natural cane sugar/botanical extract sweetener in comparison to reference glucose in Wistar rats. A total of 24 male Wistar rats aged 6-7 weeks, weighing 148-188 grams, free from disease, and possessing a functional health status were chosen for the study. The animals were divided into four sets and allocated to different treatment groups using a randomized block design. For the study, the test and reference substances were administered orally at approximately one-hour intervals from Day 8 until the end of the treatment period. A greater than 50% reduction (58.7%) of liver adenosine triphosphate (ATP) levels (a proxy for caloric content) was observed for the test item (TI) treatment group compared to the reference glucose group. In the preliminary oral glucose tolerance test (OGTT), treatment with TI at a dose of 5.8 g/kg bodyweight considerably decreased the normal post-prandial rise in serum glucose levels. Other biochemical parameters such as cholesterol, triglycerides, LDL, and VLDL also decreased in the test item high dose group as compared to the normal control (NC). The current study confirms a significant reduction in calories (>50%) and blood glucose levels in Wistar rats when cane sugar is combined with a formulation of botanical extracts. Based on these results, we feel that all-natural TI has potential as a reduced-calorie, low glycemic index (GI) alternative to standard sucrose and can be a valuable dietary aid in the fight against the global obesity epidemic and its associated metabolic disorders.

Dietary exposure to ochratoxin A reduces growth performance and impairs hepatic purinergic signaling in tambaqui (Colossoma macropomum).

The practice of replacing costly animal-derived proteins with more economical plant proteins has augmented the risk of mycotoxin contamination in fish feeds, including contamination with ochratoxin A (OTA). OTA is a secondary metabolite produced by molds commonly found in fish feeds that causes impairment of performance in several fish species and some hepatic biochemical alterations. However, the pathways involved in hepatic damage remain unknown and are limited to histopathological alterations. Purinergic signaling is a homeostatic system that continuously monitors the internal environment to detect injury primarily by two intercellular messengers: adenosine triphosphate (ATP) and adenosine (Ado). The objective of this study was to determine whether OTA-contaminated feed induces the release of nucleotides in the extracellular milieu, as well as whether ectoenzymes modulate ATP pro-inflammatory effects in liver of tambaqui (Colossoma macropomum). Final mean weight, weight gain (WG), and liver weight were significantly lower in tambaqui fed feeds containing 1.6 and 2.4mg OTA/kg feed than in the control group. Liver ATP and Ado levels were significantly higher in tambaqui fed feeds containing 1.6 and 2.4mg OTA/kg feed compared with control, while no significant difference was observed regarding adenosine diphosphate and adenosine monophosphate levels. Hepatic triphosphate diphosphohydrolase (NTPDase) activity (for ATP) was significantly greater in tambaqui fed feeds containing 1.6 and 2.4mg OTA/kg feed compared with control, while adenosine deaminase (ADA) activity was lower. No significant difference was observed with respect to hepatic NTPDase activity (for ADP) or for 5'-nucleotidase activity. Finally, levels of liver metabolites of nitric oxide were significantly higher in tambaqui fed feeds containing 1.6 and 2.4mg OTA/kg feed than in the control group. Based on these data, exposure to 1.6 and 2.4mg OTA/kg feed impaired tambaqui growth performance associated with final mean weight and WG. Levels of two important intercellular messengers, ATP and Ado, increased in the extracellular space as a consequence of hepatic damage, exerting opposite immune responses. Finally, liver NTPDase and ADA activities were altered to modulate ATP and Ado levels, respectively, exerting anti-inflammatory effects to counteract OTA-induced hepatic injury.

Short-term feed intake regulation of dairy cows fed a total mixed ration or grazing forage oats

The integration of feeding behaviour with hepatic and endocrine–metabolic signals provides insights for a better understanding of short-term intake in dairy pasture-based systems. Therefore, the objective was to quantify hepatic and endocrine–metabolic signals before and after the first daily feeding event relating to feeding behaviour in a total mixed ration (TMR) versus a grazing pasture-based diet. During 15 days of adaptation and 5 days of measurements, 14 multiparous Holstein cows (days in milk = 148 ± 12.7; liveweight = 535 ± 10.9 kg; body condition score = 2.8 ± 0.08 (1–5 scale); milk yield = 28.9 ± 3.32 kg) were assigned to two treatments in a randomised block design: PAS = pasture (herbage allowance = 45 kgDM/cow.day; dry matter (DM) = 21%, net energy requirements for maintenance and lactation = 6.7 MJ/kgDM) + concentrate (0.9% of liveweight) or TMR (55:45 forage:concentrate ratio, as-dry basis; DM = 40%, net energy requirements for maintenance and lactation = 7.2 MJ/kgDM) ad libitum in a free stall facility. The DM intake of the first feeding event, feeding behaviour, and total DM intake and milk production, were measured. Blood and liver samples were taken before and after the first feeding event for hormones and metabolites determination. Comparing TMR versus PAS cows, total DM and net energy requirements for maintenance and lactation intake, milk production, and energy balance were greater (P < 0.05), eating and rumination activities were lower (9.2%, P < 0.01; 2.4%, P = 0.06 respectively) and resting activity was greater (11.6%, P < 0.01), whereas duration and DM intake of the first feeding event did not differ. The insulin:glucagon ratio and liver adenosine triphosphate:adenosine diphosphate ratio increased (P < 0.05), and plasma glucose decreased (P < 0.05) after the first feeding event only in TMR cows, probably due to greater flux of propionate to the liver. A negative correlation between post-feeding liver adenosine triphosphate:adenosine diphosphate ratio and post-feeding liver acetyl coenzyme A (r = –0.82, P = 0.045) was also observed only in TMR cows. It is concluded that hepatic and metabolic signals known to support the hepatic oxidation theory in TMR-fed cows appear not to affect the cessation of the first feeding event in mid-lactation cows grazing a pasture-based diet. Further research is required to relate intake rate, flux of nutrients to liver and its response in hepatic metabolism in grazing dairy cows.

The Effect of Preservation Temperature on Liver, Kidney, and Pancreas Tissue ATP in Animal and Preclinical Human Models.

The recent advances in machine perfusion (MP) technology involve settings ranging between hypothermic, subnormothermic, and normothermic temperatures. Tissue level adenosine triphosphate (ATP) is a long-established marker of viability and functionality and is universal for all organs. In the midst of a growing number of complex clinical parameters for the quality assessment of graft prior to transplantation, a revisit of ATP may shed light on the underlying reconditioning mechanisms of different perfusion temperatures in the form of restoration of metabolic and energy status. This article aims to review and critically analyse animal and preclinical human studies (discarded grafts) during MP of three abdominal organs (liver, kidney, and pancreas) in which ATP was a primary endpoint. A selective review of recent novel reconditioning approaches relevant to mitigation of graft ischaemia-reperfusion injury via MP and for different perfusion temperatures was also conducted. With a current reiterated interest for oxygenation during MP, a re-introduction of tissue ATP levels may be valuable for graft viability assessment prior to transplantation. Further studies may help delineate the benefits of selective perfusion temperatures on organs viability.

Measuring short-term liver metabolism non-invasively: postprandial and post-exercise ¹H and ³¹P MR spectroscopy.

The objective of this study was to determine the effects of a standardized fat rich meal and subsequent exercise on liver fat content by ¹H MRS and on liver adenosine triphosphate (ATP) content by ³¹P MRS in healthy subjects. Hepatic ¹H and proton decoupled ³¹P MRS were performed on nine healthy subjects on a clinical 3.0 T MR imager three times during a day: after (1) an overnight fast, (2) a following standardized fat rich meal and (3) a subsequent exercise session. Blood parameters were followed during the day to serve as a reference to MRS. Liver fat content increased gradually over the day (p = 0.0001) with an overall increase of 30 %. Also γ-NTP changed significantly over the day (p = 0.005). γ-NTP/tP decreased by 9 % (p = 0.019, post hoc) from the postprandial to the post-exercise state. Our study shows that in vivo MRS can depict short lived physiological changes; entering of fat into liver cells and consumption of ATP during exercise can be measured non-invasively in healthy subjects. The physiological state may have an impact on fat and energy metabolite levels. Hepatic ¹H and ³¹P MRS studies should be performed under standardized conditions.

Peripheral inflammatory activation after hippocampus irradiation in the rat

Purpose: To detect the possible biochemical signs of inflammatory activation in the peripheral circulation in a rodent model of hippocampus irradiation, and to examine the effects of L-alpha-glycerylphosphorylcholine (GPC) in this experimental protocol.Materials and methods: Anesthetized Sprague-Dawley rats were subjected to 40 Gy cobalt irradiation of both hemispheres of the hippocampus, with or without GPC treatment (50 mg/kg intravenously (i.v.), 5 min before the irradiation, n = 6, each). A third group (n = 6) served as saline-treated control. Blood samples were obtained 3 h after the end of irradiation in order to examine the changes in plasma histamine, tumor necrosis factor-alpha (TNF-α), interleukin 1-beta, interleukin 6 (IL-6) and interleukin 10 (IL-10); liver tissue samples were taken to determine adenosine triphosphate (ATP) concentrations.Results: The hepatic ATP levels were significantly declined, while plasma concentrations of circulating TNF-α, IL-6, IL-10 and histamine were significantly increased after hippocampus irradiation. GPC treatment significantly reduced the irradiation-induced release of cytokines and histamine, and the liver ATP level was maintained at the control value.Conclusions: Targeted brain irradiation produced measurable pro- and anti-inflammatory cytokine changes in the systemic circulation. GPC supplementation provides significant protection against irradiation-induced peripheral pro-inflammatory activation and ATP depletion.

Effects of acute ethionine injection on plasma ghrelin and obestatin levels in trained male rats

Ghrelin and obestatin are orexigenic and anorexigenic peptides, respectively, that are secreted from the stomach mucosa into the circulation. These peptides have opposing actions on food intake, weight gain, and adiposity. It is thought that ghrelin is sensitive to a negative energy environment and also plays a considerable role in short- and long-term energy balance and glucose homeostasis. It has been suggested that the levels of ghrelin and obestatin are upregulated by fasting, hypoglycemic status, and a physical-exercise–induced energy deficit. Ethionine (ETH), the ethyl analogue of methionine, has been shown to increase food intake, decrease adenosine triphosphate (ATP) and glycogen levels, and inhibit protein synthesis in the liver. The purpose of this study was to examine the effect of a single dose of ETH (0.7 mg/g of body weight) injection on resting plasma total ghrelin and obestatin concentrations in male trained rats. Thirty-two adult Wistar male rats weighing 180 to 200 g were randomly assigned to control (n = 16) and training (n =16) groups. The training group was exercised for 10 weeks (25 m/min, 0% grade, 60 minutes, and 5 d/wk). Seventy-two hours after the last exercise session, rats were injected with either saline (NaCl) or ETH and then killed. Ethionine compared with a NaCl injection resulted in significant ( P < .013) reductions in resting hepatic ATP and glycogen levels, and in a significant ( P < .001) increase in concentrations of plasma total ghrelin but not obestatin. The results indicate that ETH-induced liver ATP and glycogen deficiency could exert a powerful regulatory influence on plasma total ghrelin, but this is not the case for obestatin. Findings demonstrate the short-term energy-regulating capacity of ghrelin.

Bile duct obstruction is associated with early postoperative upregulation of liver uncoupling protein-2 and reduced circulating glucose concentration in the rat

ObjectiveTo evaluate whether upregulation of liver and muscle uncoupling protein 2 (UCP-2) is an acute phenomenon in obstructive jaundice and associated with secondary metabolic effects. MethodsMale Sprague-Dawley rats were divided into four groups: bile duct ligated (BDL) and sham-operated pair-fed (PF), ad libitum fed (AL), and controls. BDL, PF, and AL rats were further divided into subgroups according to the interval postoperatively when they were reanesthetized and sampled for tissue and blood: 2, 4, and 8 d, respectively. Bilirubin, liver enzymes, glucose, free fatty acids, and insulin in blood plasma were analyzed. Liver and muscle tissue were sampled for UCP-2 and adenosine triphosphate analysis. ResultsThe BDL rats showed an increase of the liver UCP-2 expression compared with PF and AL rats (P<0.05) 4 d postoperatively. Liver adenosine triphosphate in BDL rats showed a decrease compared with sham-operated controls at all intervals (P<0.05). Plasma glucose concentration in BDL rats was decreased compared with the other groups. Free fatty acids showed an initial increase 2 d postoperatively compared with sham-operated controls and PF and AL rats (P<0.05) at the corresponding time point. ConclusionObstructive jaundice is associated with an early upregulation of liver UCP-2, reduced liver adenosine triphosphate content, and decreased plasma glucose concentration, supporting the hypothesis that obstructive jaundice results in impaired energy homeostasis in the liver, which might cause decreased glucose output and hypoglycemia as a consequence.

Effects of Amrinone in an Experimental Model of Hepatic Ischemia-Reperfusion Injury

During some surgical interventions, temporary occlusion of the hepatic blood supply may cause ischemia-reperfusion (IR) injury. Recent studies suggest that type 3 phosphodiesterase inhibitors may have a beneficial effect on liver IR injury. The aim of this study was to investigate whether amrinone, a type 3 phosphodiesterase inhibitor, could have a protective effect on liver having experimental liver IR injury. Sixty Wistar albino rats were randomly divided into three groups. The IR and amrinone groups were subjected to 1 h total hepatic ischemia, followed by 2 h of reperfusion. The sham group underwent midline laparotomy only. Amrinone 10 microg/kg/min was infused to the amrinone group during the 3 h of the IR period. Histopathological examination, biochemical liver function, and liver adenosine triphosphate concentration after reperfusion and survival rate on the seventh day after the IR insult were recorded. Serum aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase levels, and histological damage scores in the amrinone and IR groups were significantly higher compared with the sham group (P < 0.01). However, all of these values were significantly lower in the amrinone group than in the IR group (P < 0.05). Liver adenosine triphosphate levels and the rat survival rate in the amrinone and IR groups were significantly lower than those in the sham group (P < 0.01). However, these values were significantly higher in the amrinone group compared to those in the IR group (P < 0.01). These results suggest that amrinone plays a significant role in the protection of liver against IR injury and that this treatment may be a novel pharmacological agent for safe and efficient liver surgery.

Pharmacology Review: Sodium Phenylacetate and Sodium Benzoate in the Treatment of Neonatal Hyperammonemia

Ammonia is present in all body fluids and exists primarily as ammonium ion at physiologic pH. Hyperammonemia is defined as a blood ammonia concentration greater than about 100 mcmol/L in neonates or 50 mcmol/L in children and adults (precise cut-offs vary, depending on individual laboratory normative ranges). The concentration of ammonia is 10 times higher in tissue than in blood. A 5- to 10-fold increase in blood ammonia concentration usually is toxic to the nervous system. Hyperammonemia in the neonatal period, especially when due to inborn errors of metabolism, can progress rapidly and cause severe neurologic damage or early death. Hyperammonemia can be caused by inborn errors of metabolism as well as by a variety of acquired conditions (Tables 1 and 2). Urgent treatment is required because of the potential for irreversible neurologic sequelae that can, in many cases, be prevented by prompt diagnosis and institution of therapy. | Urea cycle defects | || | Amino acid transporter deficiencies | | Organic acidemias | | Fatty acid oxidation defects | | Pyruvate carboxylase deficiency | | Mitochondrial disorders | | Hyperinsulinism/hyperammonemia syndrome (glutamate dehydrogenase mutations) | | Delta1-pyrroline-5-carboxylate synthase deficiency | Table 1. Inborn Errors of Metabolism Associated With Hyperammonemia | Sampling artifact | || | Cardiovascular | | Perinatal asphyxia | | Liver failure | | Bacterial colonization (urease-positive organisms) | | Iatrogenic | Table 2. Causes of Acquired Hyperammonemia The combination of sodium phenylacetate (NAPA) and sodium benzoate (NABZ) in a 10%/10% solution is an intravenously administered United States Food and Drug Administration (FDA)-approved drug used as adjunctive therapy for …

Effect of Cordyceps Sinensis on Uncoupling Protein 2 in Experimental Rats with Nonalcoholic Fatty Liver

[Objective] To investigate the effect of cordyceps sinensis (CS) on expression of uncoupling protein-2 (UCP2) and so to elucidate the role of UCP2 in development of nonalcoholic fatty liver diseases (NAFLD). [Methods] Rats were administrated with high-fat diet to produce NAFLD animal model and intervened by cordyceps sinensis. Triglyceride (TG), total cholesterol (TC) in liver were measured by biochemistry, adenosine triphosphate (ATP) by luciferin-luciferinase, and UCP2 expression by Northern blotting and immunohistochemistry. Liver histopathology was evaluated. [Results] High-fat diet fed rats developed obesity and showed a gradual increase in body weight, liver index, and a decrease in ATP level. More advanced liver disease was found histopathologically for longer high-fat diet. Up-regulation of liver UCP2 by high-fat diet stopped after week 12. However codyceps sinensis induced UCP2 up-regulation continuously, and kept liver ATP a relatively high level. [Conclusion] NAFLD rat models were produced successfully. Liver UCP2 up-regulation in NAFLD rats may be a definite beneficial adaptation to lipid exposure. Cordyceps sinensis may serve a protective role to prevent NAFLD from progression. One of the possible mechanisms involves in modulating UCP2 expression and thereby, regulating fat metabolism, energy homeostasis.

Lack of UCP2 reduces fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression

Fatty liver is vulnerable to conditions that challenge hepatocellular energy homeostasis. Lipid-laden hepatocytes highly express uncoupling protein-2 (UCP2), a mitochondrial carrier that competes with adenosine triphosphate (ATP) synthesis by mediating proton leak. However, evidence for a link between UCP2 expression and susceptibility of liver to acute injury is lacking. We asked whether absence of UCP2 protects ob/ob mice from Fas-mediated acute liver damage. UCP2-deficient ob/ob mice (ob/ob:ucp2-/-) and UCP2-competent littermates (ob/ob:ucp2+/+) received a single dose of agonistic anti-Fas antibody (Jo2). Low-dose Jo2 (0.15 mg/kg intraperitoneally) caused less serum alanine aminotransferase (ALT) elevation and lower apoptosis rates in ob/ob:ucp2-/- mice. High-dose Jo2 (0.40 mg/kg intraperitoneally) proved uniformly fatal; however, ob/ob:ucp2-/- mice survived longer with less depletion of liver ATP stores, indicating that fatty hepatocytes may benefit from lack of UCP2 during Jo2 challenge. Although UCP2 reportedly controls mitochondrial oxidant production, its absence had no apparent effect on fatty liver tissue malondialdehyde levels augmented by Jo2. This finding prompted us to determine UCP2 expression in Kupffer cells, a major source of intrahepatic oxidative stress. UCP2 expression was found diminished in Kupffer cells of untreated ob/ob:ucp2+/+ mice, conceivably contributing to increased oxidative stress in fatty liver and limiting the impact of UCP2 ablation. In conclusion, whereas UCP2 abundance in fatty hepatocytes exacerbates Fas-mediated injury by compromising ATP stores, downregulation of UCP2 in Kupffer cells may account for persistent oxidative stress in fatty liver. Our data support a cell-specific approach when considering the therapeutic effects of mitochondrial uncoupling in fatty liver disease.

The role of the glucocorticoid-dependent mechanism in the progression of sodium taurocholate-induced acute pancreatitis in the rat.

The effects of glucocorticoids on acute pancreatitis (AP) have remained contradictory. The aim of this study was to investigate the time courses of the effects of the exogenous glucocorticoid agonists dexamethasone (DEX) and hydrocortisone (HYD) and a glucocorticoid antagonist (RU-38486) and to characterize the local and systemic responses in AP in rats. The glucocorticoid antagonist and agonists were administered just before AP induction. Serum amylase activity determinations, IL-6 bioassays, pancreatic weight/body weight ratio measurements, and survival analysis were performed. Liver and lung injuries were assessed via neutrophil leukocyte infiltration in myeloperoxidase (MPO) assays, tissue adenosine triphosphate (ATP) level determinations, and histology. In the glucocorticoid agonist groups, the survival rate increased, while the serum amylase level, the IL-6 activity, and the pancreatic weight/body weight ratio decreased significantly as compared with the control and RU-treated groups. AP resulted in significant decreases in tissue ATP levels in both the liver and the lung. In the DEX- or HYD-treated groups, the liver ATP levels were significantly elevated, while both the liver and the lung MPO levels were attenuated as compared with the AP and RU-treated groups. These results suggest that glucocorticoids may play important roles in mitigating the progression of the inflammatory reaction during the early phases of AP.

Role of ischemic preconditioning and the portosystemic shunt in the prevention of liver and lung damage after rat liver transplantation1

This study evaluates whether surgical strategies such as the portosystemic shunt and ischemic preconditioning can protect against hepatic and pulmonary injury associated with liver transplantation. The effect of the portosystemic shunt, ischemic preconditioning, and both surgical procedures together were evaluated in rat liver transplantation. Alanine aminotransferase, hyaluronic acid levels in plasma, adenosine triphosphate and nucleotide levels in liver and edema, malondialdehyde levels, and myeloperoxidase activity were measured 24 hr posttransplantation. Plasmatic tumor necrosis factor (TNF) levels were measured as a possible proinflammatory factor responsible for hepatic and pulmonary damage associated with liver transplantation. Hepatocyte and cell endothelial damage were observed in liver grafts subjected to 8 hr of cold ischemia. This was associated with increased plasma TNF levels and lung inflammatory response. Portosystemic shunt application in the recipient protected endothelial cells but did not confer an effective protection from hepatocyte damage or reduce the increased plasma TNF levels and lung damage after liver transplantation. However, preconditioning of the donor liver conferred protection against both the endothelial cell and hepatocyte damage observed after liver transplantation. Preconditioning also attenuated the increased plasma TNF release and pulmonary damage. The combination of both surgical strategies resulted in levels of liver injury, TNF, and lung damage similar to those seen after liver transplantation. These findings indicate that ischemic preconditioning could be a preferred treatment to reduce hepatic and pulmonary damage associated with liver transplantation. However, this strategy may not be effective in several clinical situations requiring a portosystemic shunt.

Perflubron emulsion in prolonged hemorrhagic shock: influence on hepatocellular energy metabolism and oxygen-dependent gene expression.

Liver dysfunction as a result of impaired oxygen availability frequently occurs following hemorrhage and contributes to delayed mortality. Artificial oxygen carriers may improve oxygen supply to vital organs while avoiding the need for allogeneic transfusion. Rats were subjected to hemorrhagic hypotension (mean arterial pressure = 35-40 mmHg for 120 min) and were subsequently resuscitated with (1) stored whole rat blood, (2) pentastarch, or (3) pentastarch combined with perflubron emulsion (PFE; 2.7 or 5.4 g/kg body weight), a second-generation artificial oxygen carrier. Recovery of liver adenosine triphosphate, hepatocellular injury, and expression of glutamine synthetase 1, a gene that is induced by exposure of hepatocytes to low partial pressure of oxygen, were studied at 4 h of resuscitation. Stored whole blood or pentastarch failed to restore liver adenosine triphosphate concentrations after prolonged shock as compared to sham controls and resulted in increased gene expression of glutamine synthetase 1. Addition of 2.7 g PFE/kg restored liver adenosine triphosphate to control, whereas 5.4 g PFE/kg resulted in adenosine triphosphate concentrations significantly above control. Improved hepatocellular oxygen supply was also confirmed by restoration of the physiologic expression pattern of glutamine synthetase 1. Serum enzyme concentrations were highest after resuscitation with stored blood, whereas addition of PFE failed to further decrease enzyme concentrations as compared to pentastarch alone. Resuscitation with PFE is superior to stored blood or asanguineous resuscitation with respect to restoration of hepatocellular energy metabolism. The improved hepatocellular oxygen availability is reflected in normalization of oxygen-dependent gene expression. However, improved oxygen availability failed to affect early hepatocellular injury.

Suppression of autophagy by ethionine administration in male rat liver in vivo

The administration of ethionine to male rats decreased the liver adenosine triphosphate (ATP) levels to about 20% of that in control rats and prevented leupeptin-induced intralysosomal accumulation of cytosolic proteins, including lactate dehydrogenase sequestered into lysosomes by autophagy, and leupeptin-induced increase of lysosomal density. These actions of ethionine were reversed by the subsequent administration of adenine plus methionine. All these findings show that the administration of ethionine to male rats suppresses the autophagic sequestration of intracellular proteins into lysosomes, probably due to ethionine-induced ATP depletion.