Effects Of Acute Liver Failure Research Articles

KHSRP ameliorates acute liver failure by regulating pre-mRNA splicing through its interaction with SF3B1

Acute liver failure (ALF) is characterized by the rapidly progressive deterioration of hepatic function, which, without effective medical intervention, results in high mortality and morbidity. Here, using proteomic and transcriptomic analyses in murine ALF models, we found that the expression of multiple splicing factors was downregulated in ALF. Notably, we found that KH-type splicing regulatory protein (KHSRP) has a protective effect in ALF. Knockdown of KHSRP resulted in dramatic splicing defects, such as intron retention, and led to the exacerbation of liver injury in ALF. Moreover, we demonstrated that KHSRP directly interacts with splicing factor 3b subunit 1 (SF3B1) and enhances the binding of SF3B1 to the intronic branch sites, thereby promoting pre-mRNA splicing. Using splicing inhibitors, we found that Khsrp protects against ALF by regulating pre-mRNA splicing in vivo. Overall, our findings demonstrate that KHSRP is an important splicing activator and promotes the expression of genes associated with ALF progression by interacting with SF3B1; thus, KHSRP could be a possible target for therapeutic intervention in ALF.

L-Arginine Improves the Diminished Cerebral Blood Flow in Rats With Acute Liver Failure: Uncertain Role of Asymmetric Dimethylarginine

Background and Aims: Dysregulated cerebral blood flow (CBF) contributes to neurological dysfunctions accompanying hepatic encephalopathy (HE). The well-documented increase in asymmetric dimethylarginine (ADMA) in CSF of patients and brains of animals with liver failure may impair CBF by inhibition of endothelial nitric oxide synthesis (eNOS). Therefore, the correction of l-arginine (l-arg)/ADMA ratio and thereby elevation of the availability of l-arg for NO production by l-arg supplementation may improve CBF. The aim of this study was to assess whether: (i) HE in the thioacetamide (TAA) model affects CBF in the prefrontal cortex (PFC) and cerebellum (CRBL), (ii) exogenous l-arg is capable of modulating CBF and (iii) CBF changes induced by l-arg and/or TAA are correlated with extracellular cortical ADMA, l-arg, cGMP, nitrite and citrulline levels. Methods: Male Sprague Dawley rats were subjected to three intraperitoneal (i.p.) injections of TAA (300 mg/kg) at 24 h intervals. Arterial spin labeling MRI measurement was performed 24 h after the last TAA injection using a 9.4 T scanner. High resolution anatomic images were acquired with spin echo RARE sequence. For T1 relaxation time and perfusion measurement FAIR-RARE sequence was used. l-arg (200 mg/kg) was administered once by intraperitoneal cannula. The regional changes in CBF were observed before, and 30 min after l-arg injection, at first in the PFC, then in the CRBL. In the second group of anesthetized rats, bilateral microdialysis of the PFC was carried out 24 h after the last TAA dose. Six fractions were collected every 40 min. l-arg (200 mg/kg) was injected i.p. after the beginning of the 3rd fraction. Extracellular levels of l-arg, ADMA, cGMP, nitrite, citrulline were measured using positive mode electrospray LC–DMS–MS/MS, cGMP enzyme immunoassay, NO Analyzer and HPLC-FD, respectively. A repeated-measures ANOVA was applied. Results and Discussion: TAA rats exhibited a decreased basal CBF both in the PFC and CRBL (70% and 65% of the control value, respectively). l-arg increased cortical CBF both in the control (by 20%) and TAA (by 15%) rats, and cerebellar CBF in TAA rats only (by 15%). Administration of l-arg evoked durable increase of the extracellular l-arg level in the PFC of TAA rats (by 85%), while in the control group the effect was much less pronounced (by 25%) and shorter-lasting. The diminished l-arg/ADMA ratio in the TAA brain was increased after l-arg administration, whereas no effect on ADMA was observed. The increase of CBF in TAA rats was not accompanied by changes in extracellular levels of nitrite, cGMP and citrulline. It can be assumed that beneficial effect of l-arg on CBF is, as a rule, associated with eNOS activity, whereas metabolic changes noted in the extracellular fluid reflect a combination of the variable effects of acute liver failure on each of the three NOSs isoforms (Figure 1). Disclosures: This study was supported by Grant N 2013/09/B/NZ4/00536 from the National Science Centre. The equipment used for dimethylarginine determination was sponsored in part by the Centre for Preclinical Research and Technology (CePT), a project cosponsored by Eu. The authors have none to declare.

Cortical Synaptic Transmission and Plasticity in Acute Liver Failure Are Decreased by Presynaptic Events

Neurological symptoms of acute liver failure (ALF) reflect decreased excitatory transmission, but the status of ALF-affected excitatory synapse has not been characterized in detail. We studied the effects of ALF in mouse on synaptic transmission and plasticity ex vivo and its relation to distribution of (i) synaptic vesicles (sv) and (ii) functional synaptic proteins within the synapse. ALF-competent neurological and biochemical changes were induced in mice with azoxymethane (AOM). Electrophysiological characteristics (long-term potentiation, whole-cell recording) as well as synapse ultrastructure were evaluated in the cerebral cortex. Also, sv were quantified in the presynaptic zone by electron microscopy. Finally, presynaptic proteins in the membrane-enriched (P2) and cytosolic (S2) fractions of cortical homogenates were quantitated by Western blot. Slices derived from symptomatic AOM mice presented a set of electrophysiological correlates of impaired transmitter release including decreased field potentials (FPs), increased paired-pulse facilitation (PPF), and decreased frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs/mEPSCs) accompanied by reduction of the spontaneous transmitter release-driving protein, vti1A. Additionally, an increased number of sv per synapse and a decrease of P2 content and/or P2/S2 ratio for sv-associated proteins, i.e. synaptophysin, synaptotagmin, and Munc18–1, were found, in spite of decreased content of the sv-docking protein, syntaxin-1. Slices from AOM-treated asymptomatic mice showed impaired long-term potentiation (LTP) and increased PPF but no changes in transmitter release or presynaptic protein composition. Our findings demonstrate that a decrease of synaptic transmission in symptomatic ALF is associated with inefficient recruitment of sv proteins and/or impaired sv trafficking to transmitter release sites.

Integrated transcriptomic and proteomic analysis of the bile stress response in probiotic Lactobacillus salivarius LI01

Lactobacillus salivarius LI01, isolated from healthy humans, has demonstrated probiotic properties in the prevention and treatment of liver failure. Tolerance to bile stress is crucial to allow lactobacilli to survive in the gastrointestinal tract and exert their benefits. In this work, we used a Digital Gene Expression transcriptomic and iTRAQ LC-MS/MS proteomic approach to examine the characteristics of LI01 in response to bile stress. Using culture medium with or without 0.15% ox bile, 591 differentially transcribed genes and 347 differentially expressed proteins were detected in LI01. Overall, we found the bile resistance of LI01 to be based on a highly remodeled cell envelope and a reinforced bile efflux system rather than on the activity of bile salt hydrolases. Additionally, some differentially expressed genes related to regulatory systems, the general stress response and central metabolism processes, also play roles in stress sensing, bile-induced damage prevention and energy efficiency. Moreover, bile salts appear to enhance proteolysis and amino acid uptake (especially aromatic amino acids) by LI01, which may support the liver protection properties of this strain. Altogether, this study establishes a model of global response mechanism to bile stress in L. salivarius LI01. Biological significanceL. salivarius strain LI01 exhibits not only antibacterial and antifungal properties but also exerts a good health-promoting effect in acute liver failure. As a potential probiotic strain, the bile-tolerance trait of strain LI01 is important, though this has not yet been explored. In this study, an analysis based on DGE and iTRAQ was performed to investigate the gene expression in strain LI01 under bile stress at the mRNA and protein levels, respectively. To our knowledge, this work also represents the first combined transcriptomic and proteomic analysis of the bile stress response mechanism in L. salivarius.

Study concerning the frequency of fluid exchanges, the dwell time and their impact in peritoneal dialysis in cats

A 11-year-old 3.1 kg, castrated, female Sphinx cat was referred to the Clinic of the Faculty of Veterinary Medicine Bucharest for acute onset vomiting, loss of appetite, anorexia, faintness, sharp breath, inability to exercise, oliguria and lethargy. Results from a complete blood (cell) count (CBC), serum chemical profile, and urinalysis submitted at that time were abnormal. The patient had hyperglycaemia (Glu-164 mg/dl), acute renal failure (Crea-3.4 mg/dl, BUN-117 mg/dl) and acute liver failure (ALT-744U/L, TBIL-11.8 mg/dl). The ALKP was 155U/L. The rectal temperature was 37,4 °C, the patient presented anaemic mucous membranes, mild dehydration (persistent skin fold thickness 2-3 seconds) and slight sensitivity to palpation in the renal lanyard. The established treatment consisted in peritoneal dialysis, rehydration and electrolyte balance, parenteral nutrition. We used PD4 peritoneal dialysis Dianeal 200 ml (1000 ml / sqm). The patient was submitted to intravenous fluidotherapy with 5% Dextrose, Sodium Chloride 0.9%, Aspatofort, Ondansetron, Metoclopramide and Duphalyte, CRI for 18 days. Abdominal ultrasound showed bile duct obstruction, abundant sludge in the gallbladder and mild modification in kidneys. Recommendation for oral treatment: Ipakitine bid, Azodyl bid and kidney diet food. The patient started to eat voluntary after 8 days of treatment. TBIL went up to 23.3 mg/ml after the first 7 days and then started to decrease until it reached 0.9 mg/dl at the end of the parenteral treatment. BUN and Creatinine values decreased to normal after the first 7 days of peritoneal dialysis and parenteral treatment. Peritoneal dialysis therapy plays an important role in renal failure in cats, especially in the elderly and weighing up to 10 kg. Elevated levels of creatinine and urea, hyperkalemia, hyper phosphatemia, or metabolic acidosis which do not yield to treatment can be solved using peritoneal dialysis. It also has a good effect in acute liver failure, cleaning the high levels of bilirubine.

Peritoneal Dialysis in Acute Renal and Liver Failure

Abstract A 11-year-old 3.1 kg, castrated, female Sphinx cat was referred to the Clinic of the Faculty of Veterinary Medicine Bucharest for acute onset vomiting, loss of appetite, anorexia, faintness, sharp breath, inability to exercise, oliguria and lethargy. Results from a complete blood (cell) count (CBC), serum chemical profile, and urinalysis submitted at that time were abnormal. The patient had hyperglycaemia (Glu-164 mg/dl), acute renal failure (Crea-3.4 mg/dl, BUN-117 mg/dl) and acute liver failure (ALT-744U/L, TBIL-11.8 mg/dl). The ALKP was 155U/L. The rectal temperature was 37,4 °C, the patient presented anaemic mucous membranes, mild dehydration (persistent skin fold thickness 2-3 seconds) and slight sensitivity to palpation in the renal lanyard. The established treatment consisted in peritoneal dialysis, rehydration and electrolyte balance, parenteral nutrition. We used PD4 peritoneal dialysis Dianeal 200 ml (1000 ml / sqm). The patient was submitted to intravenous fluidotherapy with 5% Dextrose, Sodium Chloride 0.9%, Aspatofort, Ondansetron, Metoclopramide and Duphalyte, CRI for 18 days. Abdominal ultrasound showed bile duct obstruction, abundant sludge in the gallbladder and mild modification in kidneys. Recommendation for oral treatment: Ipakitine bid, Azodyl bid and kidney diet food. The patient started to eat voluntary after 8 days of treatment. TBIL went up to 23.3 mg/ml after the first 7 days and then started to decrease until it reached 0.9 mg/dl at the end of the parenteral treatment. BUN and Creatinine values decreased to normal after the first 7 days of peritoneal dialysis and parenteral treatment. Peritoneal dialysis therapy plays an important role in renal failure in cats, especially in the elderly and weighing up to 10 kg. Elevated levels of creatinine and urea, hyperkalemia, hyper phosphatemia, or metabolic acidosis which do not yield to treatment can be solved using peritoneal dialysis. It also has a good effect in acute liver failure, cleaning the high levels of bilirubine.

The dimethylarginine (ADMA)/nitric oxide pathway in the brain and periphery of rats with thioacetamide-induced acute liver failure: Modulation by histidine

Hepatic encephalopathy (HE) is related to variations in the nitric oxide (NO) synthesis and oxidative/nitrosative stress (ONS), and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases (NOSs). In the present study we compared the effects of acute liver failure (ALF) in the rat TAA model on ADMA concentration in plasma and cerebral cortex, and on the activity and expression of the ADMA degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), in brain and liver. ALF increased blood and brain ADMA, and the increase was correlated with decreased DDAH activity in both brain and liver. An i.p. administration of histidine (His), an amino acid reported to alleviate oxidative stress associated with HE (100 mg/kg b.w.), reversed the increase of brain ADMA, which was accompanied by the recovery of brain DDAH activity (determined ex vivo), and with an increase of the total NOS activity. His also activated DDAH ex vivo in brain homogenates derived from control and TAA rats. ALF in this model was also accompanied by increases of blood cyclooxygenase activity and blood and brain TNF-α content, markers of the inflammatory response in the periphery, but these changes were not affected by His, except for the reduction of TNF-α mRNA transcript in the brain. His increased the total antioxidant capacity of the brain cortex, but not of the blood, further documenting its direct neuroprotective power.

OP08 Evidence for early astrocyte activation, cellular stress and compensatory microglial related transforming growth factor-α responses in bile-duct ligated rats

IntroductionInflammation and ammonia are important mediators in the pathogenesis of hepatic encephalopathy and though the mechanisms are unclear astrocytes are thought to have a central role. Recently Microglia, which also...

Long-term prognosis for transplant-free survivors of paracetamol-induced acute liver failure

The prognosis for transplant-free survivors of paracetamol-induced acute liver failure remains unknown. To examine whether paracetamol-induced acute liver failure increases long-term mortality. We followed up all transplant-free survivors of paracetamol-induced acute liver injury, hospitalized in a Danish national referral centre during 1984-2004. We compared age-specific mortality rates from 1 year post-discharge through 2008 between those in whom the liver injury led to an acute liver failure and those in whom it did not. We included 641 patients. On average, age-specific mortality rates were slightly higher for the 101 patients whose paracetamol-induced liver injury had caused an acute liver failure (adjusted mortality rate ratio = 1.70, 95% CI 1.02-2.85), but the association was age-dependent, and no survivors of acute liver failure died of liver disease, whereas suicides were frequent in both groups. These observations speak against long-term effects of acute liver failure. More likely, the elevated mortality rate ratio resulted from incomplete adjustment for the greater prevalence of substance abuse among survivors of acute liver failure. Paracetamol-induced acute liver failure did not affect long-term mortality. Clinical follow-up may be justified by the cause of the liver failure, but not by the liver failure itself.