Centrilobular Hepatic Necrosis Research Articles

Impact of α-Tocopherol and Ascorbic Acid Pre-Treatment on Paracetamol Induced Liver Injury in Wistar Albino Male Rats

Background: Liver injury may occur by toxic dose of paracetamol administration where liver function markers are elevated and centrilobular hepatic necrosis is visible under a microscopic observation in hepatic lobule configuration. α-tocopherol and ascorbic acid are known antioxidant and they may have hepatoprotective effect against paracetamol induced liver damage. Aim of the study: The aim of this study was to evaluate the effects of α-tocopherol and ascorbic acid on paracetamol induced liver damage in Wistar albino male Rats. Methods: This was an animal model experimental study which was conducted in the Department of Physiology, Sir Salimullah Medical College, Dhaka, Bangladesh from 1st January to 31st December, 2017. Although primarily healthy Wister albino male rats, 90-120 days old, weighing from 160 to 200g were selected for this study, finally data were analyzed on 30 rats. Finalized 30 samples were divided into three groups Group I (baseline control group, n=10), Group II (paracetamol treated control group, n=10) and Group III (combined α-tocopherol with ascorbic acid pretreated & paracetamol treated group n=10). The dose of α-tocopherol 100 mg/kg Body weight and ascorbic acid 200 mg/kg Body weight per day orally were selected as pre-exposure prophylaxis. The statistical analyses were done by one-way ANOVA and Bonferroni test, paired ‘t’ test and Fisher’s Exact test as applicable. Results: The mean serum total bilirubin, ALT and AST were significantly increased in group II and III in comparison to that of group I except the serum levels of total bilirubin and ALT of group III which were increased than that of group I but it was not statistically significant. Again, the mean MDA concentration in liver was significantly increased in group II in comparison to that of group I whereas though this level was increased in group III than that of group I but it was statistically not significant. Furthermore, the mean serum levels of total bilirubin, ALT, AST and ...

DIFFERENT EXPERIMENTAL MODELS FOR HEPATOTOXICITY; A REVIEW A REVIEW

The Hepatic is midst the best industrious and pennon organs in the feasible body. Hepatotoxicity is a symbol intermediary of morbidity and lenity, and its extent is leave off increment appointment by steady old-fashioned in the industrialized nations. Hepatotoxicity is characterized by atomic pyknosis and eosinophilic cytoplasm, followed by copious rash hepatic poison, pudginess changes, lipid peroxidation leads to hepatic centrilobular necrosis. Paracetamol, reluctant tubercular drugs, demon rum, and azathioprine are meditate on to be the tricky venture factors implicated in the progression of hepatotoxicity. Unusual signaling mechanisms, such as activation of transmissible represent encode alike Kupffer cells, simple hew to pieces (NK) cells, and NKT, incendiary mediators, intracellular Ca2 concentration and reactive oxygen species are involved in the pathogenesis of hepatotoxicity. At realistic, helter-skelter is petite aglow panacea is at hand to squeamish patients give hepatotoxicity becoming to deficiency of colleague of signaling culprits involved in the pathogenesis of hepatotoxicity. Gross models are zoological seasoned to reform esteem the plague pathogenesis and develop drugs for hepatotoxicity. In the physical study, we take on submit discrete extremist models for hepatotoxicity, which may frankly vistas for developing new drugs to treat hepatotoxicity.

To study the Hepatoprotective Activity of the Fruit of Exogenous Plant of Xanthophyceae family Against Carbon Tetrachloride Induced Hepatotoxicity in Albino Rats.

The Hepatic is midst the best industrious and pennon organs in the feasible body. Hepatotoxicity is a symbol intermediary of morbidity and lenity, and its extent is leave off increment appointment by steady old-fashioned in the industrialized nations. Hepatotoxicity is characterized by atomic pyknosis and eosinophilic cytoplasm, followed by copious rash hepatic poison, pudginess changes, lipid peroxidation leads to hepatic centrilobular necrosis. Paracetamol, reluctant tubercular drugs, demon rum, and azathioprine are meditate on to be the tricky venture factors implicated in the progression of hepatotoxicity. Unusual signaling mechanisms, such as activation of transmissible represent encode alike Kupffer cells, simple hew to pieces cells, incendiary mediators, intracellular Ca2 concentration and reactive oxygen species are involved in the pathogenesis of hepatotoxicity. At realistic, helter-skelter is petite aglow panacea is at hand to squeamish patients give hepatotoxicity becoming to deficiency of colleague of signaling culprits involved in the pathogenesis of hepatotoxicity. Gross models are zoological seasoned to reform esteem the plague pathogenesis and develop drugs for hepatotoxicity. In the physical study, we take on submit discrete extremist models for hepatotoxicity, which may frankly vistas for developing new drugs to treat hepatotoxicity.

Essential Involvement of Neutrophil Elastase in Acute Acetaminophen Hepatotoxicity Using BALB/c Mice.

Intense neutrophil infiltration into the liver is a characteristic of acetaminophen-induced acute liver injury. Neutrophil elastase is released by neutrophils during inflammation. To elucidate the involvement of neutrophil elastase in acetaminophen-induced liver injury, we investigated the efficacy of a potent and specific neutrophil elastase inhibitor, sivelestat, in mice with acetaminophen-induced acute liver injury. Intraperitoneal administration of 750 mg/kg of acetaminophen caused severe liver damage, such as elevated serum transaminase levels, centrilobular hepatic necrosis, and neutrophil infiltration, with approximately 50% mortality in BALB/c mice within 48 h of administration. However, in mice treated with sivelestat 30 min after the acetaminophen challenge, all mice survived, with reduced serum transaminase elevation and diminished hepatic necrosis. In addition, mice treated with sivelestat had reduced NOS-II expression and hepatic neutrophil infiltration after the acetaminophen challenge. Furthermore, treatment with sivelestat at 3 h after the acetaminophen challenge significantly improved survival. These findings indicate a new clinical application for sivelestat in the treatment of acetaminophen-induced liver failure through mechanisms involving the regulation of neutrophil migration and NO production.

A case of carboxyatractyloside intoxication by ingestion of the cocklebur (Xanthium strumarium) in a Korean native cow

A 19-month-old Korean native cow died the following day after consuming new silage. Grossly, the liver showed enlargement, redness, and haemorrhages in all the lobes. Additionally, many of the bur-shaped fruits of the cocklebur (Xanthium strumarium) were found in the gastric contents. The histological evaluation confirmed centrilobular hepatic necrosis. Additionally, carboxyatractyloside (CATR), a material fatal to animals found in the cocklebur, was detected in the gastric contents using high-performance liquid chromatography-quadrupole-time of flight mass spectrometry (HPLC-Q-TOF-MS). Based on the pathological findings and analytical confirmation, CATR intoxication was diagnosed. Therefore, careful feeding and elimination of the cocklebur is essential for minimising economic loss.

Platanosides, a Potential Botanical Drug Combination, Decrease Liver Injury Caused by Acetaminophen Overdose in Mice.

Oxidative stress plays an important role in acetaminophen (APAP)-induced hepatotoxicity. Platanosides (PTSs) isolated from the American sycamore tree (Platanus occidentalis) represent a potential new four-molecule botanical drug class of antibiotics active against drug-resistant infectious disease. Preliminary studies have suggested that PTSs are safe and well tolerated and have antioxidant properties. The potential utility of PTSs in decreasing APAP hepatotoxicity in mice in addition to an assessment of their potential with APAP for the control of infectious diseases along with pain and pyrexia associated with a bacterial infection was investigated. On PTS treatment in mice, serum alanine aminotransferase (ALT) release, hepatic centrilobular necrosis, and 4-hydroxynonenal (4-HNE) were markedly decreased. In addition, inducible nitric oxide synthase (iNOS) expression and c-Jun-N-terminal kinase (JNK) activation decreased when mice overdosed with APAP were treated with PTSs. Computational studies suggested that PTSs may act as JNK-1/2 and Keap1-Nrf2 inhibitors and that the isomeric mixture could provide greater efficacy than the individual molecules. Overall, PTSs represent promising botanical drugs for hepatoprotection and drug-resistant bacterial infections and are effective in protecting against APAP-related hepatotoxicity, which decreases liver necrosis and inflammation, iNOS expression, and oxidative and nitrative stresses, possibly by preventing persistent JNK activation.

Thioredoxin1 Gene Modulates Bcl2/p53/NF-KB Signaling Pathways in Strawberry Extract/Paracetamol-treated Rat Model of Acute Liver Injury

When used in excess, the analgesic paracetamol can cause hepatic centrilobular necrosis, which can be fatal. The goal of this study was to see if strawberry extract could protect rats' livers from paracetamol-induced hepatotoxicity. Strawberry (75 and 150 mg/kg bw) and vit C (1 g /kg bw) were given orally, daily for 15 days demonstrated a significant reduction in the effects of caused changes in plasma cholesterol, triacylglycerol, phospholipids and vit C, TBARS, GSH, TNF-α, IL-4 and NO, AST, ALT, ALP, LDH, SOD, GPx and GSH levels. Furthermore, strawberry extract significantly inhibits hepatocyte B-cell lymphoma 2 (Bcl2) but significantly induces p53, NF-KB and Trx1 gene expression compared to paracetamol- treated rats. Histological examination showed that significant normalization has been observed in strawberry extract treated rats. Conclusions Strawberry extract shows considerable hepatoprotective benefits in the case of paracetamol-induced liver damage, confirming it's essential use as a treatment for liver damage.

Hepatic SIRT6 Modulates Transcriptional Activities of FXR to Alleviate Acetaminophen-induced Hepatotoxicity

Background & AimsExcessive acetaminophen (APAP) intake causes oxidative stress and inflammation, leading to fatal hepatotoxicity; however, the mechanism remains unclear. This study aims to explore the protective effects and detailed mechanisms of sirtuin 6 (SIRT6) in the defense against APAP-induced hepatotoxicity.MethodsHepatocyte-specific SIRT6 knockout mice, farnesoid X receptor (FXR) knockout mice, and mice with genetic or pharmacological activation of SIRT6 were subjected to APAP to evaluate the critical role of SIRT6 in the pathogenesis of acute liver injury. RNA sequences were used to investigate molecular mechanisms underlying this process.ResultsHepatic SIRT6 expression was substantially reduced in the patients and mice with acute liver injury. The deletion of SIRT6 in mice and mice primary hepatocytes led to high N-acetyl-p-benzo-quinoneimine and low glutathione levels in the liver, thereby enhancing APAP overdose-induced liver injury, manifested as increased hepatic centrilobular necrosis, oxidative stress, and inflammation. Conversely, overexpression or pharmacological activation of SIRT6 enhanced glutathione and decreased N-acetyl-p-benzo-quinoneimine, thus alleviating APAP-induced hepatotoxicity via normalization of liver damage, inflammatory infiltration, and oxidative stress. Our molecular analysis revealed that FXR is regulated by SIRT6, which is associated with the pathological progression of ALI. Mechanistically, SIRT6 deacetylates FXR and elevates FXR transcriptional activity. FXR ablation in mice and mice primary hepatocytes prominently blunted SIRT6 overexpression and activation-mediated ameliorative effects. Conversely, pharmacological activation of FXR mitigated APAP-induced hepatotoxicity in SIRT6 knockout mice.ConclusionsOur current study suggests that SIRT6 plays a crucial role in APAP-induced hepatotoxicity, and pharmacological activation of SIRT6 may represent a novel therapeutic strategy for APAP overdose-induced liver injury.

PERINATAL CENTRILOBULAR HEPATIC NECROSIS IN GIANT PANDAS (AILUROPODA MELANOLEUCA): A RETROSPECTIVE STUDY.

Between 1983 and 2012, six giant panda cubs (Ailuropoda melanoleuca) born at a zoological institution were stillborn or died between the ages of 3 and 200 h. Two of the six cubs had panhepatic centrilobular hepatic necrosis (CHN), granulocytic extramedullary hematopoiesis (GEM), positive liver culture for Staphylococcus species, and terminal liver failure. Another low-weight cub was administered oxygen therapy immediately after birth and developed hyaline membranes in air spaces and hepatic necrosis restricted to the hilar region. A retrospective analysis of liver and lung lesions, pulmonary microanatomy, blood-gas barrier ultrastructure, and hepatic myofibroblast proliferation was conducted on the six cubs. Neonates with CHN had concurrent severe periportal GEM accompanied by severe myofibroblast proliferation. The pulmonary blood-gas barrier was markedly increased in one cub with CHN. Developmentally, the lungs of all but one cub were at the late saccular stage, and the lowest-weight cub was in early saccular stage, consistent with immaturity, and had pneumonia comparable to neonatal respiratory distress syndrome (RDS). Stage of lung development was eliminated as the primary factor leading to CHN. The pathogenesis of CHN in these neonates is proposed to be transformation of hepatic stellate cells to myofibroblasts initiating blockage and microvascular constriction of hepatic sinusoids, resulting in insufficient perfusion and cellular hypoxia of hepatocytes surrounding central veins in acinar zone 3.

Spontaneous outbreak of Pascalia glauca poisoning in sheep in Argentina

Pascalia glauca is a native weed and one of the most common hepatotoxic plant affecting cattle in Argentina. Although experimental P. glauca poisoning have been reported in sheep, no spontaneous cases have been reported in this species. This work describes an outbreak of intoxication after spontaneous consumption of P. glauca, affecting 20% (6/30) sheep of a commercial flock. Affected sheep were ataxic, depressive, with mucous nasal discharge, cough and abdominal breathing. During post mortem examination, liver was swollen and a diffuse enhancement of the reticular pattern (“nutmeg liver”) was visible. Histopathological examination reveals severe and extensive acute diffuse centrilobular hepatic necrosis with hemorrhage. The presence of the toxic plant, the clinical and pathological findings allows us to confirm the etiology of this outbreak.

Spontaneously Occurring Chronic Copper Toxicosis in Pattanam Breed of Sheep

Background: Copper (Cu), an essential trace element, is toxic if consumed in excessive amounts. Ruminants, particularly sheep, are highly susceptible to chronic copper poisoning and cause acute death. Spontaneous copper poisoning in sheep was reported from many parts of the world however limited reports are available from India. Hence the present investigation was undertaken to report the occurrence of chronic copper poisoning in an intensively maintained Pattanam breed of sheep flock and its therapeutic management. Methods: An investigation was carried out to ascertain the possible cause of increased mortality in an intensively maintained 130 male lambs aged between 8 to 10 month old belongs to Pattanam breed during the month of September 2020 following death of 21 animals within a period of 15 days. Affected flock was inspected and samples were collected for biochemical analysis, toxicological, bacteriological and pathological examination.Result: Affected animals showed depression, anorexia, jaundice, hemoglobinurea and accelerated breathing. At necropsy, the dead animals showed generalized icterus, lung edema, yellow to orange coloured liver and gun metal kidney. Histopathological lesions include lung edema, centrilobular hepatic necrosis, bile stasis, renal tubular necrosis and formation of tubular cast. Toxicological analysis of liver revealed the copper level of 781 mg/kg dry matter basis. Source of copper was identified as a commercial mineral mixture supplement intended for cattle was supplemented along with concentrate feed. The flock was treated with chelating agent (D-penicllamine) and supportive therapies.

Study The protective Effects of Cichorium intybus L. Root Extract Against Carbon Tetrachloride-Induced Hepatotoxicity in Broiler Chickens

An existing survey was performed to assess the hepatoprotective effects of C. intybus root extract on carbon tetrachloride-induced hepatotoxicity in broiler chickens. A total of 240 one-day-old broiler chickens were divided into diverse groups of control, carbon tetrachloride (1 mL/kg body weight IM injection), C. intybus root extract (500 mg/kg body weight/daily orally) and finally both C. intybus root extract and carbon tetrachloride. Liver samples were dissected and examined histopathologically at the day 31 of maintenance. Numerical grading of histopathological findings was performed according to the types of lesions at different criteria. Liver samples of carbon tetrachloride-treated group harbored moderate fatty degeneration and necrosis. Those treated with C. intybus extract showed normal cellular and tissue structure. Chicks faced with carbon tetrachloride and treated with C. intybus extract exhibited mild fatty degeneration and normal tissue structure. Chicks treated with C. intybus extract displayed the lowermost scores of necrosis (1.08±0.28), degeneration (1.33±0.49), inflammation (1.16±0.38) and total pathologic indexes (3.58±0.79). Broilers faced with carbon tetrachloride displayed the uppermost scores of necrosis (2.83±0.57), degeneration (3.66±0.49), inflammation (2.16±0.38) and total pathologic indexes (8.66±0.98). C. intybus extract application to broilers faced with carbon tetrachloride caused statistically significant decrease in the scores give to necrosis, degeneration, inflammation and total pathologic indexes (P <0.05). Findings suggested that 10 days administration of C. intybus extract caused significant decrease in the formation of centrilobular hepatic necrosis, fatty changes, inflammation and degeneration of the hepatic cells of broilers faced with CCl4-induced hepatotoxicity.

Salmonellosis in Calves by Serovar Dublin in Paraná State, Brazil - Clinicopathological Aspects

Background: Calf diarrhea remains one of the main diseases affecting the cattle industry. Persistence of this significant problem is associated with the complexity of factors that may be involved (infectious, environmental). An accurate diagnosis is essential for confirming the cause and helping clinicians and cattle producers to apply appropriate strategies in a timely manner. This report describes the histological changes according to the degree of salmonellosis severity, which is a contagious infectious disease caused by Salmonella enterica subsp. enterica, a Gram-negative bacterium, in two beef calves in northern Paraná State, southern Brazil. Cases: Two 90-day-old crossbred Angus and Nellore calves from a beef farm in northern Paraná State were referred to a Veterinary Hospital. Animal 1- developed acute clinical signs (enteritis, ataxia, and muscle rigidity) and died the day after the signs began. Gross findings included heavy and non-collapsed lungs, pulmonary oedema, hepatomegaly, enteritis, and severe diffuse typhlitis. Microscopic analysis revealed severe diffuse necrotic enteritis, typhlitis, severe diffuse interstitial pneumonia, moderate centrilobular hepatic necrosis, mild multifocal nephritis, and severe spleen and lymph node necrosis. Paratyphoid nodules were evidenced on the liver, spleen, and mesenteric lymph nodes. Animal 2- presented apathy, green fibrinous diarrhea, and died three days after the onset of clinical signs. The macroscopic examination showed moderate diffuse enteritis and hepatosplenomegaly. At the microscopic examination, many paratyphoid nodules were observed on the liver, spleen, kidneys, and Peyer's patches, which were associated with intralesional and intravascular bacilli. Additional findings included severe diffuse fibrinous necrotic enteritis with intralesional bacilli, diffuse interstitial pneumonia, multifocal splenic necrosis, lymphoid depletion, and moderate multifocal to coalescent lymphocytic nephritis. Histological Gram staining was performed on selected samples, revealing intralesional Gram-negative bacilli in the liver and intestine. Thus, liver and intestine fragments were used for the microbiological examination. Microbiological culture, isolation and biochemical tests identified the genus Salmonella spp. Then, the colonies were subjected to serological tests for serovar identification, according to ISO/TR 6579-3, which determined the serovar Dublin. After identifying the disease etiological agent, the outbreak was controlled by appropriate antibiotic therapy combined with the correction of sanitary measures.Discussion: Enteritis is a frequent disease in calves, posing a diagnostic challenge in identifying the etiological agent. In the present case, the histological, microbiological, and serological results confirmed a disseminated Salmonella spp. infection. The microscopic findings, such as interstitial pneumonia, fibrinous necrotic enteritis markedly in ileum and paratyphoid nodules in various organs, are the most common aspects of the disease. However, fibrinous cholecystitis, which is considered pathognomonic for salmonellosis, was not observed in this study. Therefore, the absence of such a lesion should not exclude the disease in sick animals. A microscopic injury score was used to determine lesion severity by assigning values from 1 to 4, wherein: 1 = no apparent lesions, 2 = mild lesions, 3 = moderate lesions, and 4 = severe lesions. Both calves were scored as 4. Multiple predisposing factors for the condition were identified in this farm such as different age animals in the same paddock and no specific paddock for sick animals, given that the infectious agent remains in feces, saliva, and nasal discharge. The serovar Dublin induces several clinical signs such as septicemic, respiratory, and enteric manifestations, making a clinical diagnosis a challenge. Keywords: dysbiosis, calf diarrhea, infection, paratyphoid nodules, septicemia.Descritores: disbiose, diarreia neonatal, infecção, nódulos paratifoides, septicemia.Título: Salmonelose em bezerros pelo sorovar Dublin no estado do Paraná, Brasil - aspectos clínico-patológicos

Carbon tetrachloride‐induced hepatotoxicity in weaning and adult mice

Age‐related differences in drug‐induced liver injury (DILI) have been reported, but DILI in children has been not fully understood as compared to that in adults. In the present study, male ICR mice at two different ages, 2 (weaning) and 8 (adult) week‐old, were intraperitoneally injected with CCl4 (15.4 mg/kg), and the time‐dependent liver damage and cellular events were compared. Significant elevation of serum ALT/AST levels and hepatic centrilobular necrosis were induced by CCl4 in weaning mice, while mild liver injury was observed in adult mice. CCl4‐treated weaning mice showed higher pro‐apoptotic proteins (Bax, cleaved caspase‐3, ‐7, and ‐9), activated MAPKs (p‐JNK and p‐Erk), and ER stress indicators (ATF6 and CHOP), but lower anti‐apoptotic Bcl‐2 in their livers than those in the adult mouse livers. Weaning mice showed higher basal level of hepatic GSH due to their higher GCL and lower CDO enzyme levels. However, after CCl4 injection, hepatic GSH in weaning mice was dramatically decreased, while that in adult mice was not changed. Hepatic malondialdehyde, 4‐hydroxynonenal, nitrotyrosine‐protein adducts, and oxidized proteins resulting from oxidative stress were highly detected in CCl4‐administered weaning mice compared to the corresponding adult mice. The higher levels of CYP2E1 and 3A in the weaning mouse livers appear to be the primary reason of their higher hepatic susceptibility, and the lower GST‐π and GR in these mice also could contribute to the liver damage.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (NRF‐2018M3A7B4071233 and NRF‐2019R1I1A3A01058584).

Weaning Mice and Adult Mice Exhibit Differential Carbon Tetrachloride-Induced Acute Hepatotoxicity.

Age is a risk factor for drug-induced liver injury (DILI). However, there is a limited understanding of pediatric DILI. Here, 2-week-old weaning and 8-week-old adult male ICR mice were intraperitoneally injected with CCl4 (0.1 mmol/kg equal to 15.4 mg/kg) to comparatively evaluate the time-dependent liver damage and cellular events. CCl4 significantly enhanced the serum alanine aminotransferase/aspartate aminotransferase levels and hepatic centrilobular necrosis in the weaning mice, whereas it induced mild liver injury in the adult mice. CCl4-treated weaning mice exhibited higher hepatic levels of pro-apoptotic proteins (Bax, cleaved caspase-3, -7, and -9), activated MAPKs (p-JNK and p-Erk), and endoplasmic reticulum stress indicators (ATF6 and CHOP) and lower hepatic anti-apoptotic Bcl-2 levels than the adult mice. The weaning mice exhibited enhanced basal hepatic glutathione (GSH) levels due to high glutamate cysteine ligase (GCL) and low anti-cysteine dioxygenase (CDO) enzyme levels. However, CCl4 markedly reduced the hepatic GSH levels only in the weaning mice. Furthermore, higher hepatic levels of oxidative stress-induced malondialdehyde, 4-hydroxynonenal, nitrotyrosine-protein adducts, and oxidized proteins were observed in CCl4-treated weaning mice than in CCl4-treated adult mice. The enhanced levels of hepatic cytochrome P450 (CYP) 2E1 and CYP3A, and decreased hepatic GSH S-transferase (GST)-π and GSH reductase (GR) levels in the weaning mice may contribute to their enhanced susceptibility to liver damage.

Protective effect of cimetidine in carbon tetrachloride-treated rats.

Cimetidine may have hepatoprotective effects. We looked for the impact of cimetidine on the hepatic changes induced by carbon tetrachloride. Male Wistar-Bratislava albino rats were randomized into four groups. Group I, control (C) received physiologic saline solution (PSS) for 3 days. Group II (CT) received PSS but the last administration being followed by a carbon tetrachloride (CT) subcutaneous (sc) injection. Group III (CT+CM) received Cimetidine (CM); at the last dose of CM there was an injection of CT as for group II. Group IV was treated only with CM. The rats were weighted at the beginning of the treatment and at the moment of the euthanasia. Blood sampled were collected. The organs were removed and weighted. A sample of left lobe of the liver was taken for histological analysis. We have analysed morphometric characteristics of the organs, histological and biochemical changes. The acute hepatotoxicity effect of CCl4 in rats after a single dose was demonstrated after 24 hours. CCl4 (group II) increases the relative weight of the liver and histologically induces fatty dystrophy and extended centrilobular necrosis. The increase of ASAT and ALAT were massive. The preventive administered cimetidine, associated with CCl4 (group III) has partially hepatic protection. The fatty infiltration is not present and the focal centrilobular necrosis is less extended. The effect of hepatic cytolysis enzymes is remarkable. Acute administering at rats, CCL4 has a characteristic hepatotoxicity spectrum, induces fatty dystrophy, hepatic centrilobular necrosis and massive increases of transaminases. Cimetidine in subacute treatment, preventive, for 3 days has protective action relative to CCl4.

Pharmacokinetic changes of tramadol in rats with hepatotoxicity induced by ethanol and acetaminophen in perfused rat liver model.

Tramadol is an opioid agonist with activation monoaminergic properties. It can be administered orally, rectally, intravenously, or intramuscularly as a centrally acting analgesic. Liver injury can lead to changes in the metabolism of tramadol. In this study, the rate of tramadol metabolism in rats with damaged liver induced by ethanol and acetaminophen was assessed in a recirculation perfusion system. Acetaminophen is a mild analgesic and antipyretic agent, which can cause centrilobular hepatic necrosis in toxic doses, whereas alcohol causes death due to liver diseases. Alcoholic liver disease (ALD), such as alcoholic fatty liver, alcoholic hepatitis, and alcoholic fibrosis, is the most common liver disease. The aim of this study was to investigate the alteration in tramadol metabolism in different hepatotoxicity conditions in animal models. Male rats were randomly assigned to three groups. The control group received normal saline, group 2 received acetaminophen at the dose of 250mg/kg/day, and group 3 received ethanol at the beginning dose of 3g/kg/day, which was slowly increased to 6g/kg/day. Tramadol was added to the perfusion solution at the concentration of 500ng/mL. Samples were collected during 180min, and analyte concentrations were determined by the High-Performance Liquid Chromatography (HPLC) method. The concentration of tramadol and its three main metabolites, O-desmethyltramadol (M1), N-desmethyltramadol (M2), and N,O-didesmethyltramadol (M5), were determined in perfusate samples. Ethanol and acetaminophen significantly affected the pattern of weight gain and liver weights before perfusion and caused a significant increase in enzyme activities. Moreover, histopathologic examination revealed that ethanol and acetaminophen caused liver damage. An increase in the elimination half-life and reduced clearance rate of tramadol were seen in the acetaminophen and ethanol groups, in comparison to the control group. Additionally, significant reductions in the Area Under the Curve (AUC) of metabolites of tramadol (M1, M2, and M5) were observed in the acetaminophen and ethanol groups in the perfused rat liver model. Liver damage caused by ethanol and acetaminophen during 45 days in animals leads to a significant reduction in the level of tramadol metabolites. Therefore, in patients with liver damage caused by ethanol and acetaminophen, caution needs to be considered when prescribing tramadol.

A SURVEY OF PARASITE LESIONS IN WILD RED DEER ( CERVUS ELAPHUS) FROM ARGENTINA.

In Argentina there is little information about diseases that affect exotic ungulates and the health risks that they pose to native wildlife, livestock, and humans. The aim of this study was to evaluate the health status of red deer ( Cervus elaphus) in the Nahuel Huapi National Park and surrounding areas in Patagonia, Argentina. During three consecutive hunting seasons, necropsies were performed on 101 red deer, and tissues were examined histologically. The most common lesions were those associated with hepatic and pulmonary parasites. Fasciola hepatica was observed in 15 red deer and was associated with cholangiohepatitis (8%) and/or cholangitis (10%). Dictyocaulus sp. (likely Dictyocaulus eckerti) was associated with interstitial pneumonia (5%), bronchitis (5%), pulmonary emphysema (13%), and bronchus-associated lymphoid tissue hyperplasia (13%). Other findings included Sarcocystis spp. cysts in the myocardium (89%) associated with interstitial, focal, lymphoplasmacytic myocarditis (8%); periportal lymphoplasmacytic hepatitis (8%); hepatic centrilobular necrosis (6%); lymphoplasmacytic interstitial nephritis (25%); and follicular hyperplasia in mediastinal, prescapular, and prefemoral lymph nodes (86%). Our report of lesions caused by endemic parasites of livestock in free-ranging exotic red deer in Patagonia sets the foundation for a health-monitoring and -surveillance system of wildlife in this region, which is essential for the sustainable management of threatened Argentinean native fauna.

Comparação dos efeitos das folhas de Cestrum axillare Vell. com as saponinas isoladas em caprinos

ABSTRACT: Cestrum axillare Vell. (formerly Cestrum laevigatum Schltd.), family Solanaceae, is the most important hepatotoxic plant in Brazil that causes acute poisoning. It occurs in the Southeast and Center-West regions and in coastal areas of the Northeast Brazil. Spontaneous poisoning was described in cattle, goats and sheep, with clinical signs evidenced within 24 hours after ingestion of the leaves and death within 48 hours after signs onset. The clinical signs observed in acute poisoning are apathy, anorexia, ruminal arrest, arched back, constipation with feces in small spheres, sometimes covered with mucus and blood streaks, muscle tremors, staggering gait and sometimes sialorrhoea. Neurological signs may be observed, due to interference in the urea cycle due to hepatic insufficiency resulting in hyperammonemia (hepatic encephalopathy). The main pathological finding is centrilobular hepatic necrosis. The toxic principle present in C. axillare was not yet definitively proven, but some authors attribute the toxicity of the plant to the presence of saponins gitogenin and digitogenin. However, it has not been determined whether the saponins present in C. axillare are responsible for the hepatotoxic effect of the plant. Thus, the objective of this work is to determine if the saponins are the compounds responsible for the hepatotoxic effects produced by the ingestion of the leaves of C axillare, using goats as experimental model. For this, the effects of the administration of the leaves were compared with those produced by the saponins isolated from the leaves in goats. Six goats were randomly assigned to three experimental groups that received [1] dry leaves of C. axillare (animals A1 and A2), [2] saponins extract from leaves (animals S1 and S2) or [3] control group (animals C1 and C2). For goats receiving the dry leaves the administered dose of plant was 10g/kg for one animal (A1) and 5g/kg for the other one (A2). For animals receiving the saponins extract, administration was done at a dose equivalent to 20g/kg repeated after 24 hours. The dry leaves administered at a dose of 10g/kg to a goat produced toxic effects, with alterations in biochemistry (indicating hepatic lesion) and histopathology showing centrilobular hepatic necrosis. At the dose of 5 g/kg of dry leaves, clinical signs of poisoning were not observed, but hepatic necrosis was found; after 15 days after the last administration, the hepatic parenchyma of this animal was already normal, with only hemorrhagic areas, demonstrating full regeneration. The administration of extracts of saponins containing gitogenin and digitogenin to goats did not produce significant toxic effects, proving that these compounds are not responsible for intoxication. In addition, goats are a good experimental model for studies of this intoxication.

Ethyl pyruvate attenuates acetaminophen-induced liver injury and prevents cellular injury induced by N-acetyl-p-benzoquinone imine

Acetaminophen, a common analgesic/antipyretic, is a frequent cause of acute liver failure in Western countries. The development of an effective cure against acetaminophen hepatotoxicity is crucial. Ethyl pyruvate, an ethyl ester derivative of pyruvic acid, has been identified as a possible candidate against acetaminophen hepatotoxicity in animal experiments. However, the mode of the hepatoprotective action of ethyl pyruvate remains unclear. We examined the hepatoprotective effect of ethyl pyruvate against hepatocyte injury and oxidative stress in a mouse model of acetaminophen hepatotoxicity. In addition, to examine whether ethyl pyruvate has direct hepatocellular protection against acetaminophen hepatotoxicity to counteract the influence of inflammatory cells, such as macrophages, we examined the effects of ethyl pyruvate on cellular injury induced by N-acetyl-p-benzoquinone imine, a toxic metabolite of acetaminophen, in a human hepatocyte cell line, HepG2 cells. Treatment with ethyl pyruvate significantly prevented increases in serum transaminase levels and hepatic centrilobular necrosis induced with an acetaminophen overdose in mice in a dose-dependent manner. Although hepatic DNA fragmentation induced by acetaminophen was also attenuated with ethyl pyruvate, nitrotyrosine formation was not inhibited. Ehyl pyruvate significantly attenuated mitochondria dehydrogenase inactivity induced by N-acetyl-p-benzoquinone imine in HepG2 cells. The attenuating effect was also observed in a rat hepatocyte cell line. Increases in annexin V and propidium iodide-stained cells induced by N-acetyl-p-benzoquinone imine were prevented with ethyl pyruvate in HepG2 cells. Pyruvic acid, a parent compound of ethyl pyruvate, tended to attenuate these changes. The results indicate that ethyl pyruvate has direct hepatocellular protection against N-acetyl-p-benzoquinone imine induced injury observed in acetaminophen overdose. The in vivo and in vitro results suggest that ethyl pyruvate attenuates acetaminophen-induced liver injury via, at least in part, its cellular protective potential.