Hepatic Oxygen Research Articles

The triterpenoids-enriched extracts from Antrodia cinnamomea mycelia attenuate alcohol-induced chronic liver injury via suppression lipid accumulation in C57BL/6 mice

The major pathologic hallmark of the alcoholic liver disease (ALD) is the representation of chronic alcohol-induced hepatocyte lipid accumulation. This study aims to investigate the hepatoprotective role of triterpenoids-enriched extracts from Antrodia cinnamomea mycelia (ACT) in chronic alcohol-induced liver injury mice, establishing in C57BL/6 mice through gradient alcohol feeding for 24 weeks. In long-term alcohol consumption mice, the significantly lost body weight, increased organ indexes, hepatic alanine aminotransferase and aspartate aminotransferase levels were all remissed after 6-week ACT orally administration, showing its hepatoprotective property. ACT suppressed the triglyceride, total cholesterol and low-density lipoprotein levels, and enhanced high-density lipoprotein levels in serum or/and liver of chronic alcohol damaged mice. Combining with the pathological observations, ACT displayed an anti-steatosis effects to restrain the progress of ALD. Based on proteomic analysis and enzyme-linked immunosorbent assay, ACT had been confirmed to regulate the levels of lipid biogeneration-related factors and depressed the over-accumulation of hepatic reactive oxygen species. According to further data, ACT prevented alcoholic liver injury may be associated with mediating lipid metabolism-related to PGC-1α and NF-κB signaling. In summary, ACT protected the body against chronic alcohol ingest induced liver injury through its regulation lipid on metabolism.

Dose-dependent hepatic toxicity and oxidative stress on exposure to nano and bulk selenium in mice.

Selenium is an essential mineral naturally found in soil, water, and some of the food and is required as essential elements in human and animal body. Se supplementation is required especially for those having Se deficiency. Food supplement of selenium has several forms such as selenocysteine, selenite, selenomethionine, and selenate. Recently, Se supplement as selenium nanoparticles (SeNPs) has gained worldwide attention due to its bioactivities and properties. In the present study, we determined the potential hepatotoxicity of nano and bulk selenium using low and high doses in mice. Twenty-five Swiss albino mice (n=5) were randomly divided into 5 groups and treated orally for 28 days: Group 1: sterile saline (0.9%) as a control; Group 2: sodium selenite (1mg/kg); Group 3: sodium selenite (4mg/kg); Group 4: selenium nanoparticles (1mg/kg); and Group 5: selenium nanoparticles (4mg/kg). Administration of nano-selenium (70-90 nm) led to an increase in the activities of serum transaminases (ALT and AST), while no significant effects were noted on biochemical variables indicative of changes in heme synthesis pathway and oxidative stress like blood δ-aminolevulinic acid dehydratase (δ-ALAD), hepatic reactive oxygen species (ROS), catalase activity, superoxide dismutase (SOD), malondialdehyde assay (MDA), reduced glutathione (GSH) and oxidized glutathione (GSSG), glutathione peroxidase (GPx) compared to controls, and a high dose of sodium selenite. Our results suggest that nano-selenium at low dose (1mg/kg) exhibited antioxidant effects in the liver compared to the high dose (4mg/kg) of SeNPs and sodium selenite (1 and 4 mg/kg). The data from the present study might be useful for pharmacologists and toxicologists in providing future directions while designing selenium-based therapeutic strategies.

Severe Hyperbilirubinemia Associated With Thyrotoxicosis: Importance of Early Recognition

Abstract Thyroid storm (TS) is a rare and life-threatening condition due to a profound hypermetabolic state, leading to decompensation of homeostasis. It is commonly associated with a precipitating factor such as surgery, trauma, or infection. Occasionally, the clinical presentation may be non-specific, thus causing a potential delay in diagnosis. This could be problematic due to the condition’s high mortality rate, especially if not recognized early. Thyrotoxic jaundice presenting with a pattern of cholestatic hyperbilirubinemia (HBR) has been reported in the literature, although uncommon. We present the case of a 71-year-old woman with unexplained jaundice and direct HBR who was diagnosed with impending TS in the setting of toxic multinodular goiter (TMNG). This is a case of a 71-year-old woman with a remote history of hypothyroidism who presented with acute onset right upper quadrant abdominal pain, jaundice, a non-tender asymmetric nodular large goiter, and bilateral non-pitting leg edema. Ancillaries were significant for total and direct HBR of 4.3 and 3.5 mg/dL, respectively. An abdominal sonogram, abdomen CT and ERCP, all ruled out an obstructive biliary etiology. Unfortunately, the patient developed post-ERCP pancreatitis, with subsequent worsening of direct HBR. TSH was found to be suppressed, free T4 was significantly elevated at 4.3 ng/dL. A Burch-Wartofsky score of >40 was highly suggestive of TS. In addition, elevated thyroglobulin levels ruled out exogenous thyrotoxicosis, the absence of orbitopathy, pretibial myxedema, and negative TRAb pointed towards TMNG as the most likely etiology of hyperthyroidism. This diagnosis was confirmed through neck ultrasound, showing multiple nodules and the absence of high vascularity of the thyroid gland. The patient was managed in the ICU with beta-blockers, methimazole, potassium iodide solution, glucocorticoids, and bile acid sequestrants, leading to satisfactory and significant clinical improvement of thyrotoxicosis and bilirubin levels. Hepatic dysfunction has been described in patients with hyperthyroidism since the nineteenth century. Although the underlying mechanism remains unclear, it may be multifactorial. Different hypotheses have been proposed suggesting that the hypermetabolic state secondary to decompensated hyperthyroidism causes a supply-demand mismatch between hepatic oxygen consumption and hepatic blood flow, decreasing the oxygen tension in the centrilobular region resulting in cholestasis. Furthermore, hepatic hypermetabolism in response to excess thyroid hormone leads to the saturation of the bile flow rate. A possible direct toxic effect of T4 in the hepatocytes has been described although further research is needed. This case highlights the importance of considering decompensated hyperthyroidism as a differential diagnosis of cholestatic HBR.

Rutin inhibits DRP1-mediated mitochondrial fission and prevents ethanol-induced hepatotoxicity in HepG2 cells and zebrafish

ABSTRACT Excessive alcohol consumption causes the cellular and tissue damage. The toxic metabolites of ethanol are harmful to multiple organ systems, such as the central nervous system, skeletal muscles, and liver, and cause alcohol-induced diseases like cancer, as well as induce hepatotoxicity, and alcoholic myopathy. Alcohol exposure leads to a surge in hepatic alcohol metabolism and oxygen consumption, a decrease in hepatic ATP, and the rapid accumulation of lipid within hepatocytes. Several pathologies are closely linked to defective mitochondrial dynamics triggered by abnormal mitochondrial function and cellular homeostasis, raising the possibility that novel drugs targeting mitochondrial dynamics may have therapeutic potential in restoring cellular homeostasis in ethanol-induced hepatotoxicity. Rutin is a phytochemical polyphenol known to protect cells from cytotoxic chemicals. We investigated the effects of rutin on mitochondrial dynamics induced by ethanol. We found that rutin enhances mitochondrial dynamics by suppressing mitochondrial fission and restoring the balance of the mitochondrial dynamics. Mitochondrial elongation following rutin treatment of ethanol exposed cells was accompanied by reduced DRP1 expression. These data suggest that rutin plays an important role in remodeling of mitochondrial dynamics to alleviate hepatic steatosis and enhance mitochondrial function and cell viability.

An Elusive Prize: Transcutaneous Near InfraRed Spectroscopy (NIRS) Monitoring of the Liver.

Introduction: We postulate a relationship between a transcutaneous hepatic NIRS measurement and a directly obtained hepatic vein saturation. If true, hepatic NIRS monitoring (in conjunction with the current dual-site cerebral-renal NIRS paradigm) might increase the sensitivity for detecting shock since regional oxygen delivery changes in the splanchnic circulation before the kidney or brain. We explored a reliable technique for hepatic NIRS monitoring as a prelude to rigorously testing this hypothesis. This proof-of-concept study aimed to validate hepatic NIRS monitoring by comparing hepatic NIRS measurements to direct hepatic vein samples obtained during cardiac catheterization.Method: IRB-approved prospective pilot study of hepatic NIRS monitoring involving 10 patients without liver disease who were already undergoing elective cardiac catheterization. We placed a NIRS monitor on the skin overlying liver during catheterization. Direct measurement of hepatic vein oxygen saturation during the case compared with simultaneous hepatic NIRS measurement.Results: There was no correlation between the Hepatic NIRS values and the directly measured hepatic vein saturation (R = −0.035; P = 0.9238). However, the Hepatic NIRS values correlated with the cardiac output (R = 0.808; P = 0.0047), the systolic arterial blood pressure (R = 0.739; P = 0.0146), and the diastolic arterial blood pressure (R = 0.7548; P = 0.0116).Conclusions: Using the technique described, hepatic NIRS does not correlate well with the hepatic vein saturation. Further optimization of the technique might provide a better measurement. Hepatic NIRS does correlate with cardiac output and thus may still provide a valuable additional piece of hemodynamic information when combined with other non-invasive monitoring.

Qing-Yu-Mu, an Herbal Formula, Reduces Hepatic Oxidative Stress in Rats Fed a High-Frying Oil Diet and Ameliorates Carbon Tetrachloride-Induced Liver Injury.

Qing-Yu-Mu (QYM) is an herbal formula used to prevent and treat liver disease in Taiwan. In this study, the hepatoprotective effects of QYM were evaluated in two experimental models. First, rats were fed a high-frying oil (FO) diet containing 1.25% QYM for 5 weeks to investigate effects of QYM on hepatic oxidative stress and antioxidant enzyme activities. Then, protective effects of QYM on carbon tetrachloride (CCl4)-induced chronic liver injury were evaluated. Results show that QYM treatment reduced FO diet-induced hepatic lipid peroxidation and reactive oxygen species levels and increased glutathione (GSH) S-transferase activity. A higher reduced GSH/oxidized GSH (GSSG) ratio was observed after QYM treatment. Furthermore, QYM ameliorated CCl4-induced liver injury by reducing the activity of plasma alanine aminotransferase and histological lesions in the liver. QYM also increased the level of hepatic GSH and activities of GSH peroxidase and superoxide dismutase. Finally, chlorogenic acid, chrysophanol, and apigenin were found to be present in relative abundance in QYM. Results show that QYM may exhibit a hepatoprotective effect by reducing oxidative stress and increasing antioxidant activity in the liver.

Hyperspectral evaluation of hepatic oxygenation in a model of total vs. arterial liver ischaemia

Liver ischaemia reperfusion injury (IRI) is a dreaded pathophysiological complication which may lead to an impaired liver function. The level of oxygen hypoperfusion affects the level of cellular damage during the reperfusion phase. Consequently, intraoperative localisation and quantification of oxygen impairment would help in the early detection of liver ischaemia. To date, there is no real-time, non-invasive, and intraoperative tool which can compute an organ oxygenation map, quantify and discriminate different types of vascular occlusions intraoperatively. Hyperspectral imaging (HSI) is a non-invasive optical methodology which can quantify tissue oxygenation and which has recently been applied to the medical field. A hyperspectral camera detects the relative reflectance of a tissue in the range of 500 to 1000 nm, allowing the quantification of organic compounds such as oxygenated and deoxygenated haemoglobin at different depths. Here, we show the first comparative study of liver oxygenation by means of HSI quantification in a model of total vascular inflow occlusion (VIO) vs. hepatic artery occlusion (HAO), correlating optical properties with capillary lactate and histopathological evaluation. We found that liver HSI could discriminate between VIO and HAO. These results were confirmed via cross-validation of HSI which detected and quantified intestinal congestion in VIO. A significant correlation between the near-infrared spectra and capillary lactate was found (r = − 0.8645, p = 0.0003 VIO, r = − 0.7113, p = 0.0120 HAO). Finally, a statistically significant negative correlation was found between the histology score and the near-infrared parameter index (NIR) (r = − 0.88, p = 0.004). We infer that HSI, by predicting capillary lactates and the histopathological score, would be a suitable non-invasive tool for intraoperative liver perfusion assessment.

Lycopene Alleviates Hepatic Hypoxia/Reoxygenation Injury Through Nrf2/HO-1 Pathway in AML12 Cell.

[Figure: see text] Lycopene (lyc) has an effect on preventing cancer, yet its effects on hypoxia/reoxygenation (H/R) injury remained obscure. The study aimed at discovering its role in preventing hepatic cells against H/R injury. Hepatic cells were incubated in hypoxia incubator to simulate ischemia/reperfusion injury in vitro. Cell viability was detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after Lycopene treatment with or without ML385 (nuclear factor erythroid 2-related factor 2 [Nrf2] inhibitor). Lactate dehydrogenase (LDH) and malondialdehyde (MDA) content were detected. Cellular cytokine (tumor necrosis factor-α, TNF-α; interleukin-6, IL-6) levels were measured using enzyme-linked immunosorbent assay (ELISA). Hepatic cell apoptosis and cellular reactive oxygen species (ROS) content was detected by flow cytometry. Nrf2 transfer was observed using immunofluorescence staining. Nrf2 and heme oxygenase-1 (HO-1) expressions were detected with quantitative real-time polymerase chain reaction and western blot as needed. In hepatic cells, after H/R, the viability was dropped, TNF-α and IL-6 levels and LDH and MDA content were increased, with high apoptosis rate and ROS content. Lycopene led to a reversed effect, with promotion on Nrf2 transfer from cytoplasm into nucleus and Nrf2/HO-1 pathway activation. Further experiments showed that ML385 could reverse the effects of Lycopene. Lycopene could activate Nrf2/HO-1 pathway to protect hepatic cells against H/R injury.

Defense mechanisms to increasing back pressure for hepatic oxygen transport and venous return in porcine fecal peritonitis.

High central venous pressure (CVP) acutely decreases venous return. How this affects hepatic oxygen transport in sepsis remains unclear. The aim of this study was to evaluate the effects of repeated increases in CVP via standard nursing procedures (NPs) on hepato-splanchnic and renal oxygen transport in a prolonged porcine sepsis model. Twenty anesthetized and mechanically ventilated pigs with regional hemodynamics monitored were randomized to fecal peritonitis or controls (n = 10 pigs/group). Resuscitation was started after 8 h of observation and continued for 3 days. NPs were performed at baseline and 8 h, 32 h, 56 h, and 72 h after resuscitation started. NPs increased CVP by 4-7 mmHg in both groups. In controls, this was associated with less decrease in hepatic arterial (Qha; 62 ± 70 mL/min) than portal venous flow (Qpv; 364 ± 151 mL/min). Portal venous oxygen content and hepatic O2 delivery (Do2) and consumption (V̇o2) decreased by 11 ± 6 mL/dL and 0.9 ± 0.3 and 0.4 ± 0.3 mL·min-1·kg-1, respectively. In septic animals, hepatic Do2 decreased more in response to increasing CVP (1.5 ± 0.9 mL·min-1·kg-1), which was attributable to a larger fall in both Qha (88 ± 66 ml/min) and portal O2 content (14 ± 10 mL/dL, all P < 0.05). This resulted in numerically lower hepatic V̇o2 since O2 extraction did not increase significantly. In control conditions, a smaller decrease in Qha compared with Qpv helped to limit the reduction in hepatic V̇o2 in response to acute CVP increase. In sepsis, the contribution of Qha to maintain hepatic Do2 was reduced, which jeopardized hepatic V̇o2 further. Renal arterial flow was similarly affected by CVP increase as Qha.NEW & NOTEWORTHY Sepsis impairs intrinsic mechanisms to attenuate effects of increasing back pressure on hepatic oxygen transport.

Magnesium isoglycyrrhizinate alleviates fructose-induced liver oxidative stress and inflammatory injury through suppressing NOXs

Excessive fructose intake is a risk factor for liver oxidative stress injury. Magnesium isoglycyrrhizinate as a hepatoprotective agent is used to treat liver diseases in clinic. However, its antioxidant effects and the underlying potential mechanisms are still not clearly understood. In this study, magnesium isoglycyrrhizinate was found to alleviate liver oxidative stress and inflammatory injury in fructose-fed rats. Magnesium isoglycyrrhizinate suppressed hepatic reactive oxygen species overproduction (0.97 ± 0.04 a.u. versus 1.34 ± 0.07 a.u.) in fructose-fed rats by down-regulating mRNA and protein levels of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 1, NOX2 and NOX4, resulting in reduction of interleukin-1β (IL-1β) levels (1.13 ± 0.09 a.u. versus 1.97 ± 0.12 a.u.). Similarly, magnesium isoglycyrrhizinate reduced reactive oxygen species overproduction (1.07 ± 0.02 a.u. versus 1.35 ± 0.06 a.u.) and IL-1β levels (1.14 ± 0.09 a.u. versus 1.66 ± 0.07 a.u.) in fructose-exposed HepG2 cells. Furthermore, data from treatment of reactive oxygen species inhibitor N-acetyl-L-cysteine or NOXs inhibitor diphenyleneiodonium in fructose-exposed HepG2 cells showed that fructose enhanced NOX1, NOX2 and NOX4 expression to increase reactive oxygen species generation, causing oxidative stress and inflammation, more importantly, these disturbances were significantly attenuated by magnesium isoglycyrrhizinate. The molecular mechanisms underpinning these effects suggest that magnesium isoglycyrrhizinate may inhibit NOX1, NOX2 and NOX4 expression to reduce reactive oxygen species generation, subsequently prevent liver oxidative stress injury under high fructose condition. Thus, the blockade of NOX1, NOX2 and NOX4 expression by magnesium isoglycyrrhizinate may be the potential therapeutic approach for improving fructose-induced liver injury in clinic.

Кровоток и напряжение кислорода в печени при различных способах ее повреждения и гипероксии

The aim of study was to investigate hepatic blood flow and oxygen tension in mechanical, chemical, and combined injury of the liver and during a course of hyperbaric oxygenation (HBO). Methods. Experiments were performed on 143 white female rats weighing 180-220 g. Mechanical injury of the liver was modeled with partial hepatectomy (PHE) by removing a part of the left hepatic lobe (HL) (15-20% of liver weight). Chemical injury was modeled by subcutaneous injection of 50% ССl4 in olive oil (0.1 ml/100 g). Injections were performed every second day for 65 days. For the combined injury, PHE followed by HBO (3 ATA, 50 min) was performed on day 65 (last day) of ССl4 administration. HBO was applied three times, at 4-8, 24, and 48 hours after PHE. Hepatic blood flow was studied using hydrogen clearance in the operated, left HL (LHL) and in one of unoperated, middle HL (MHL). Hepatic oxygen tension (рО2) was evaluated by polarography with a platinum electrode; data were corrected for the temperature coefficient. Studies were performed on postoperative days 3, 7 and 14 (posthyperoxia days 1, 4, and 11). Results. In normal animals, PHE stimulated blood flow in both studied hepatic lobes and decreased рО2 only in the remaining LHL on postoperative days 3 and 7. On day 65 of ССl4 administration, blood flow was reduced by 42% and 39%, respectively, in remaining LHL and MHL while рО2 was reduced by 50%. These changes were not reversed by day 14 following the toxin withdrawal. PHE performed on day 65 of ССl4 administration caused an increase in blood flow on postoperative days 3 and 7 only in MHL; however, on day 14, the blood flow decreased to the level of the end of toxin administration. This was associated with a brief normalization of the reduced рО2 on postoperative day 7. In the remaining LHL of animals with chronic ССl4-induced hepatitis and PHE, values of blood flow and рО2 did not change and remained below the normal level at 14 days after PHE. The HBO exposure of healthy rats with PHE abolished the stimulating effect of surgery on blood flow in both studied hepatic lobes, thereby normalizing pO2 in the remaining LHL and decreasing pO2 in MHL on days 3 and 7. This was reversed by postoperative day 14 due to the stimulating effect of hyperoxia on blood flow in this HL. In animals with combined injury of the liver, HBO stimulated blood flow in both studied HLs, thereby increasing рО2 above the preoperative level; however, a complete recovery did not occur. The stimulating effect of HBO on blood flow in animals with combined injury remained by day 11 of the posthyperoxic period. Conclusion. A prolonged exposure to ССl4 reduced the sensitivity of hepatic blood flow to the stimulating effect of PHE, which facilitated development of persistent hypoxia in both injured and uninjured HLs. Responses to HBO of blood flow and tissue рО2 in operated liver directly depend on the state of liver at the moment of hyperoxia exposure.

Changes to hepatic tissue oxygenation, abdominal perfusion and its association with enteral feeding with liberal transfusion threshold in anaemic preterm infants: A prospective cohort study.

In anaemic preterm infants who receive packed red blood cell (PRBC) transfusions, changes to mesenteric tissue oxygenation and perfusion have been reported using a restrictive haemoglobin (Hb)-based threshold. We aimed to investigate changes to hepatic tissue oxygenation and abdominal blood flow after PRBC transfusion and its association with enteral feeding using a liberal Hb threshold (as shown inTable1). [Table: see text] MATERIAL AND METHODS: We prospectively studied a cohort of preterm infants born at < 32 weeks' gestation who received at least one PRBC transfusion and monitored them immediately before (Time 1), immediately after (Time 2) and 24hours after transfusion (Time 3). Data obtained included physiological parameters, the hepatic tissue oxygenation index and pulsed Doppler ultrasound measurements in the abdominal arterial circulation. Additionally, the effects of withholding enteral feeds were investigated. We monitored 50 PRBC transfusion episodes in 40 preterm infants, in whom the mean gestational age was 26.72 weeks (±1.6weeks) and the mean birth weight was 855.25g (±190.7g). We observed significant changes to pulsed Doppler measurements in abdominal arterial circulation (coeliac artery mean peak systolic velocity Time 2 [75.08 cm/sec] versus Time 3 [71.13 cm/sec]; mean end-diastolic velocity Time 2 [15.71 cm/sec] versus Time 3 [13.76 cm/sec]; mean resistive index Time 2 0.78 versus Time 3 0.80, right renal artery mean peak systolic velocity Time 1 58.28 cm/sec versus Time 2 50.97 cm/sec, left renal artery mean peak systolic velocity Time 1 49.20 cm/sec versus Time 2 45.40 cm/sec), but not to hepatic tissue oxygenation after PRBC transfusion (Time 1 mean 53.66 [SD, 13.34]; Time 2 mean 54.93 [SD, 9.3]; Time 3 mean 55.64 [SD, 12.86]). There were no changes to hepatic tissue oxygenation or mesenteric blood flow from withholding enteral feeds during PRBC transfusion. There were no local adverse effects from hepatic tissue oxygenation monitoring. In mildly anaemic preterm infants, when allowing a liberal Hb threshold-based trigger for PRBC transfusion, changes in abdominal arterial circulation were present, but not in hepatic tissue oxygenation. Withholding enteral feeds during PRBC transfusion had no impact on hepatic tissue oxygenation or mesenteric flows.

Abstract IA20: Gut microbiota dysbiosis and dietary fermentable fibers in a pickle: A brew for liver cancer

Abstract Dietary soluble fibers are fermented by gut bacteria into short-chain fatty acids (SCFA), which are considered broadly health promoting. Accordingly, consumption of such fibers ameliorates metabolic syndrome in a subset (40%) of Toll-like receptor 5-deficient (TLR5KO) mice. However, incorporating fermentable fiber inulin, but not nonfermentable fiber cellulose, into a compositionally defined purified diet induced hyperbilirubinemia and cholemia as primary clinical symptoms and hallmarks of cholestasis. These cholestatic mice eventually developed robust, multinodular hepatocellular carcinoma (HCC; a type of liver cancer) within 6 months. Inulin-induced HCC progressed via early onset of cholestasis, hepatocyte death, followed by liver inflammation primarily driven by neutrophils. Such neutrophilic inflammation is characterized by elevated levels of neutrophil elastase and myeloperoxidase, and hepatic reactive oxygen species, malondialdehyde and 8-hydroxy-2’-deoxyguanosine, a marker of DNA damage. Pathogenesis of such HCC was microbiota dependent and observed in multiple strains of dysbiotic mice, but not in germ-free or antibiotics-treated TLR5KO mice. Furthermore, inulin-enriched diet induced both dysbiosis and HCC in wild-type (WT) mice co-housed or cross-fostered with TLR5KO mice. Pharmacologic inhibition of fermentation or depletion of fermenting bacteria markedly reduced intestinal SCFA and prevented HCC. Intervening with cholestyramine to prevent enterohepatic recirculation of bile acids also conferred protection against such HCC. Thus, notwithstanding the health benefits of inulin, enrichment of foods with fermentable fiber should be approached with great caution as it may increase risk of HCC and warrants that refined fibers need to be redefined. Citation Format: Matam Vijay-Kumar. Gut microbiota dysbiosis and dietary fermentable fibers in a pickle: A brew for liver cancer [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA20.

Serum Extracellular Vesicles Derived From Obese Mice Control Energy Expenditure and Promote Liver Steatosis in Lean Mice

Cells can communicate with neighboring or distant cells trough extracellular vesicles (EVs). EVs have been shown to participate in many diseases, however, little is known about their role in metabolic diseases. Obesity is a major risk factor for noncommunicable diseases, and represents a threat to global public health. Indeed, obesity is rising in incidence, prevalence, and economic burden. Once the number of released EVs and its cargo are altered during obesity, we hypothesize that EVs intercellular communication may play a role in obesity pathophysiology. In order to investigate the metabolic changes caused by EVs in obesity, C57BL/6 male mice fed a control balanced diet were injected (i.p.) with serum EVs derived from diet‐induced obese mice (400ug/mouse) every 3 days for 8 weeks. Body weight was assessed every week. Visceral and subcutaneous fat depots, liver and gastrocnemius and soleus muscles were dissected and weighed. Serum biochemical analysis were conducted, and the content of hepatic triglyceride and total cholesterol was measured. Glucose, insulin and pyruvate tolerance tests were performed, as well as body composition analysis and indirect calorimetry. Differences at p&lt;0.05 were considered significant. Compared to the control group, EVs injection attenuated weight gain, reduced the weight of subcutaneous fat depot, gastrocnemius muscle and liver, decreased the respiratory exchange ratio and increased hepatic triglyceride content, oxygen consumption and insulin sensitivity. Our results suggest that EVs released in obesity can modulate lean mice metabolism. Altogether, these data provide initial insights on EVs function and signaling during obesity.Support or Funding InformationThis study was financed in part by grants #2018/05426‐0 and #2019/14999‐6, São Paulo Research Foundation (FAPESP) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ Brasil (CAPES) ‐ Finance Code 001.

Tamarix chinensis Lour inhibits chronic ethanol-induced liver injury in mice.

BACKGROUNDTamarix chinensis Lour (TCL) is a shrub that usually grows in arid or semiarid desert areas and saline-alkali fields. It is a traditional Chinese herbal medicine with hepatoprotective, antioxidant, antibacterial, and antitumor activities.AIMTo investigate the possible protective effects of TCL against liver injury induced by chronic ethanol intake.METHODSC57BL/6J male mice were fed a Lieber-DeCarli lipid diet containing alcohol and received (by gavage) a water-alcohol extract (80%) of TCL (100 and 200 mg/kg BW) or distilled water for 4 wk. After euthanasia, liver tissues were observed histologically with hematoxylin and eosin staining and Oil red O staining, and the levels of alanine aminotransferase, aspartate transaminase, hepatic lipids, reactive oxygen species, malondialdehyde, and superoxide dismutase were measured. In addition, expression of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and downstream proinflammatory cytokines were determined.RESULTSCompared with the ethanol group, mice in the TCL-treated group (200 mg/kg) had significantly lower serum levels of alanine aminotransferase (mean, 34.1 IU/L vs 45.3 IU/L, P < 0.01) and aspartate transaminase (mean, 89.6 IU/L vs 115.7 IU/L, P < 0.01), as well as marked reduction of hepatic tissue reactive oxygen species (decreased by 27.5%, P < 0.01) and malondialdehyde (decreased by 76.6%, P < 0.01) levels, with a significant increase of superoxide dismutase (Increased by 73.2%, P < 0.01). Expression of the NLRP3 inflammasome and its downstream cytokines [interleukin (IL)-1β, tumor necrosis factor-α, and IL-6], and recruitment of natural killer T cells to the liver, were reduced in the TCL-treated incubation with a Lieber-DeCaril ethanol lipid diet group.CONCLUSIONThese findings suggest that a TCL extract (200 mg/kg) protects against chronic ethanol-induced liver injury, probably by inhibiting the NLRP3-caspase-1-IL-1β signaling pathway and suppressing oxidative stress.

Nanospheres as a technological alternative to suppress hepatic cellular damage and impaired bioenergetics caused by nerolidol in Nile tilapia (Oreochromis niloticus).

Nerolidol is a sesquiterpene found in essential oils of several plant species. It is found commonly in human and animal diets and is approved by the US Food and Drug Administration as a flavoring agent. Nevertheless, recent studies have suggested that nerolidol has potent hepatotoxic effects. Because use of plant-based products in human and animal food has expanded considerably, it is essential to develop approaches such as nanotechnology to avoid or reduce hepatic toxic effects. Therefore, the aim of the study was to determine whether nerolidol dietary supplementation elicited hepatic damage associated with impairment of energy homeostasis, as well as whether supplementation with nerolidol-loaded in nanospheres prevented hepatotoxic effects in Nile tilapia (Oreochromis niloticus). Nile tilapia were divided into five groups (A-E, n = 10 per group) with four replicates each, as follows: group A received basal feed (without supplementation); group B received feed containing 0.5mL free nerolidol/kg; group C received feed containing 1.0mL free nerolidol/kg; group D received feed containing 0.5mL nanospheres nerolidol/kg; and group E received feed containing 1.0mL nanospheres nerolidol/kg. All groups received experimental feed once a day (10% total biomass) at 2p.m. for 60 consecutive days. Hepatic liver weight and relative liver weight were significantly lower in fish fed 1.0mL free nerolidol/kg feed than in fish given basal diet (control group). Hepatic pyruvate kinase (1.0mL free nerolidol/kg) and adenylate kinase (0.5 and 1.0mL free nerolidol/kg) activities were significantly lower than in the control group, while hepatic reactive oxygen species and lipid damage levels were significantly higher. Finally, the comet assay revealed significant increases in the frequency of damage and the damage index in fish given 0.5 and 1.0mL free nerolidol/kg in a dose-dependent manner. Nerolidol-loaded in nanospheres prevented all alterations elicited by free nerolidol. Based on these data, we concluded that dietary supplementation with free nerolidol elicited severe impairment of hepatic bioenergetics homeostasis that appeared to be mediated by excessive ROS production and lipid damage, contributing to a genotoxic effect. Dietary supplementation with nerolidol-loaded in nanospheres did not elicit hepatic damage, and therefore, should be considered as a replacement so as to limit toxicity, permitting its continued use as a dietary supplement.

Oxidative stress in liver of grass carp Ctenopharyngodon idella naturally infected with Saprolegnia parasitica and its influence on disease pathogenesis

Fungal diseases are one of the major problems in freshwater fish culture and have been linked to significant losses and high mortality rate, and saprolegniosis caused by Saprolegnia parasitica is the most important oomycete affecting freshwater fish worldwide. The hepatic pathophysiology of infection remains poorly understood and is limited only to histopathological alterations. Thus, the aim of this study was to evaluate whether tissue oxidative damage can be considered a pathway linked to liver damage during S. parasitica infection in grass carp (Ctenopharyngodon idella). Grass carp was divided into two groups (n = 12 per tank, in triplicate), as follows: uninfected group (without cotton-like tuft) used as control; and infected group (with presence of cotton-like tuft; naturally infected with S. parasitica). Hepatic reactive oxygen species (ROS) and lipid peroxidation (LPO) levels were higher in fish naturally infected by S. parasitica compared with uninfected fish, while no significant difference was observed regarding hepatic carbonyl protein levels. Hepatic antioxidant capacity against peroxyl radical (ACAP) levels, as well as superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione S-transferase (GST) activities, was lower in fish naturally infected by S. parasitica compared with uninfected fish. No significant difference was observed between groups regarding glutathione reductase (GR) activity. Histopathological analyses of infected fish revealed generalized cytoplasmic necrosis, and condensation and pyknosis of the hepatocyte nucleus. Based on these evidences, S. parasitica infection elicits oxidative damage via (a) increased ROS production, (b) decreased ROS elimination, and (c) inhibition of enzymatic and non-enzymatic antioxidant defense system. In summary, a disease causes oxidative stress in fish naturally infected, and this oxidative disturbance may contribute directly speed up to disease pathogenesis.

The Anti-Oxidation and Mechanism of Essential Oil of Paederia scandens in the NAFLD Model of Chicken.

Simple SummaryThe essential oil of Paederia scandens can remedy non-alcoholic fatty liver disease of chicken, but the mechanisms remain unclear. In this study, proteomics technology was used to declare the anti-non-alcoholic fatty liver disease mechanism of Paederia scandens essential oil. The results show that the essential oil of Paederia scandens significant decreased the oxidative stress of non-alcoholic fatty liver disease in chicken, which was mainly due to the center regulation protein of HSP7C being significantly inhibited.The aim of the study is to determine the underlying pathogenic mechanisms of oxidative stress and detect the anti-oxidative target of essential oil of Paederia scandens in non-alcoholic fatty liver disease (NAFLD). Chicken NAFLD was modeled by feeding with a high-capacity diet and Paederia scandens essential oil was used to treat the disease. The levels of hepatic reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and the differential proteins and network of protein–protein interactions were investigated in model and drug-treated groups. The results showed that essential oil of Paederia scandens down regulated the hepatic ROS and MDA level significantly (p < 0.05 and 0.01, respectively). The heat shock cognate 71 kDa protein (HSP7C) was down regulated significantly, which was in the center of the network and interacted with 22 other proteins. The results showed that oxidative stress played an important role in the pathogenesis of chicken NAFLD. The essential oil of Paederia scandens showed good anti-oxidation activity by down regulating the HSP7C protein, which can be used as a potential therapeutic target in chicken NAFLD.

1127 Hepatic Blood Flow and Oxygen Delivery in Metabolic Syndrome

INTRODUCTION: Metabolic syndrome MS is defined as the co-occurrence of metabolic risk factors for both DMII and cardiovascular disease. There is no consensus on the diagnostic criteria of the MS due to unclear pathogenesis uniting its components. We propose that compromised hepatic arterial blood supply and oxygen delivery as a response to a nutrient load in patients with MS will lead to hepatorenal activation of sympathetic overdrive, which can be the single common factor in MS pathogenesis METHODS: This prospective case-control study included patients 18-65 y/o diagnosed with MS and control healthy individuals with BMI 30-50 kg/m2. Subjects underwent an initial pre-prandial US, followed by drinking 8 oz of TwoCal high calorie drink immediately and in 15 mins. A second post-prandial US was performed 15mins after completing the second drink. US using the standard procedure for mesenteric artery examination for intestinal ischemia was performed to evaluate the diameter, velocity and flow of the superior mesenteric artery, hepatic artery, and portal vein. Both US images were interpreted by experienced diagnostic US radiologist. The results were analyzed using t-test RESULTS: Ten MS patients (age 55 ± 8) and ten control subjects (age 38 ± 11) with BMI 30-50 kg/m2 (37.6 ± 6.1) were compared. The relative change in blood flow in response to the nutrient load was reflected by the ratio of post- to pre-prandial readings. Total hepatic blood flow was calculated as the sum of HA and PV blood flow. The mean difference between post to pre-prandial ratio of total hepatic blood flow and total blood flow in all three vessels in MS group vs control group were 1.66 ± 0.57 vs 1.37 ± 0.40 (P = 0.162), 1.80 ± 0.42 vs 1.42 ± 0.27 (P = 0.025); respectively. The increase in postprandial total hepatic blood was 17.65% less in MS group. CONCLUSION: Why some obese patients develop MS while others don't raises the question of what is different between these cohorts. Excessive eating can produce obesity by causing chronic relative hypoxia in the liver. This produces sympathetic overdrive which causes insulin resistance, hypertension and dyslipidemia. Bariatric surgeries limit contact of nutrient with the GI mucosa resulting in increased splanchnic O2 delivery to the liver and preventing the hepatorenal reflex. The relative increase in total hepatic blood flow in response to a nutrient load was less in patients with MS compared to healthy obese controls. The difference was not statistically significant. Further studies with larger sample size needed.

The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus.

Diabetes mellitus (DM) is considered as a risk factor for the progress of liver diseases. After tissue damage, there is the highest amplitude of ubiquitously sterile inflammatory response in the liver, resulting in a major clinical consequence concerning a high prevalence of steatohepatitis in DM patients. This study aimed to investigate the inhibitory efficacy of dapagliflozin (DAPA), a sodium glucose cotransporter-2 (SGLT2) inhibitor, on experimental steatohepatitis with DM. DM-steatohepatitis model was established by dual intraperitoneal injection of streptozotocin (STZ) and feeding with the high-fat diet (HFD) in apolipoprotein E-deficient (ApoE-/-) mice (n=40). The mice were concurrently treated with DAPA (1 mg/kg/d) by gavage for 12 weeks. In ApoE-/- mice, dual HFD/STZ dramatically induced hepatic damage and inflammation as compared with HFD alone. DAPA treatment was effective to protect from hepatic damage and inflammation in dual HFD/STZ treated ApoE-/- mice. DAPA also significantly the probability decreased the blood glucose, hepatic lipid accumulation, liver steatosis, and fibrotic response in dual HFD/STZ treated ApoE-/- mice. Further mechanistic investigations indicated that the protection of DAPA on diabetic liver injury was associated with the suppressed production of hepatic reactive oxygen species (ROS) and malondialdehyde (MDA) and the inhibited activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. These data demonstrate the efficacy of DAPA for protecting liver damage, inflammation and steatosis from experimental steatohepatitis with DM, and indicate a possible involvement of the inhibited activity of ROS-NLRP3 inflammasome.