High-intensity interval training alleviates liver inflammation by regulating the TLR4/NF-κB signaling pathway and M1/M2 macrophage balance in female rats with cisplatin hepatotoxicity.

Cisplatin (CDDP) is an antineoplastic drug whose adverse effects include hepatotoxicity. The inflammatory process is crucial in the progression of liver injuries. Exercise is known for its anti-inflammatory effects, but the influence of different training modalities on hepatoprotection is still unclear. This study aims to compare the impacts between preconditioning with high-intensity interval training (HIIT) and traditional continuous training of low (LT) and moderate (MT) intensities on inflammatory markers in Wistar female rats with CDDP-induced hepatotoxicity. Thirty-five rats were divided into five groups: control and sedentary (C + Sed), treated with CDDP and sedentary (CDDP + Sed), treated with CDDP and subjected to LT (CDDP + LT), treated with CDDP and subjected to MT (CDDP + MT), and treated with CDDP and subjected to HIIT (CDDP + HIIT). The training protocols consisted of treadmill running for 8 weeks before CDDP treatment. The rats were euthanized 7 days after the treatment. Liver samples were collected to evaluate the expression of various inflammatory markers and types of macrophages. Our results indicated that HIIT was the only protocol to prevent the increase in all analyzed pro-inflammatory cytokines and reduce the number of ED-1-positive cells, attenuating the TLR4/NF-κB signaling pathway in the liver. Additionally, HIIT increased the anti-inflammatory cytokine IL-10 and regulated M1/M2 macrophage polarization. Thus, this study suggests that preconditioning with HIIT is more effective in promoting hepatoprotective effects than LT and MT, regulating inflammatory markers through modulation of the TLR4/NF-κB signaling pathway and M2 macrophage polarization in the hepatic tissue of female rats treated with CDDP.

Rapid liver self-recovery: A challenge for rat models of tissue damage.

Animal models, mainly murine, stay as a fundamental resource in diverse research pursuits, notably contributing to significant strides in discovering novel treatments for therapeutic applications. Preclinical assays must consider the existence of self-recovery mechanisms in the murine species to achieve a well-designed control group. This study focuses on unveiling the innate rapid regenerative capacity of rat liver by utilizing the thioacetamide-induced sub-chronic liver injury model. Employing histopathological, biochemical, and molecular liver function tests, we assessed the recovery of liver tissue functionality. Moreover, animals were housed with voluntary running wheels and locomotory activity was recorded and employed as an indirect index of overall animal recuperation. Remarkably, basal locomotory activity reestablished to normal levels only two weeks post-thioacetamide exposure. Our results raise vital considerations about the importance of temporal synchronicity in comparative assays to validate the real action of treatments, emphasizing the role of the rapid rat liver endogenous self-recovery.

Investigation of the effect of Myricetin on Cisplatin-induced liver hepatotoxicity.

OBJECTIVE: Cisplatin, a widely used anticancer agent, induces hepatotoxicity alongside organ damage. Understanding Cisplatin's toxicity mechanism and developing preventive measures are crucial. Our study explores Myricetin, a flavonoid, for its protective effects against Cisplatin-induced hepatotoxicity. METHODS: In our study, a total of 32 Wistar albino male rats were utilized, which were categorized into four distinct groups: Control, Myricetin, Cisplatin, and Myricetin+Cisplatin. For the histological assessment of hepatic tissues, hematoxylin-eosin and periodic acid Schiff staining were employed, alongside immunohistochemical measurements of TNF-α, interleukin-17, and interleukin-6 immunoreactivity. Additionally, aspartate transaminase and alanine transaminase values were examined by biochemical analysis. RESULTS: In the histological evaluation of the tissues, a normal healthy cell structure and a strong periodic acid Schiff (+) reaction were observed in the hepatocyte cells in the tissues of the Control and Myricetin groups, while intense eosinophilia, minimal vacuolization, congestion, and sinusoidal expansions were observed in the hematoxylin-eosin stainings, and a decrease in the positive reaction in the periodic acid Schiff staining was observed in the Cisplatin group. Consistent with these histological findings, an increase in TNF-α, interleukin-17, and interleukin-6 expressions (p<0.0001) and a concomitant increase in aspartate transaminase and alanine transaminase values were observed in the Cisplatin group. In the group protected by Myricetin, a significant improvement was observed in all these histological and biochemical values. CONCLUSION: Cisplatin induces notable histopathological alterations in the liver. In this context, Myricetin exhibits the potential to alleviate Cisplatin-induced damage by modulating histological parameters and biochemical processes.

Cytogenotoxicity and inflammatory response in liver of rats exposed to different doses of cannabis nano emulsions.

Cannabis is the most used illicit substance for recreational purposes around the world. However, it has become increasingly common to witness the use of approved cannabis preparations for symptoms management in various diseases. The aim of this study was to investigate the effects of cannabis nano emulsion in the liver of Wistar rats, with different proportions of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). For this, a total of 40 male Wistar rats were distributed into 5 groups, as follows (n = 8 per group): Control: G1, Experimental group (G2): treated with cannabis nano emulsion (THC and CBD) at a dose of 2.5 mg/kg, Experimental group (G3): treated with cannabis nano emulsion (THC and CBD) at a dose of 5 mg/kg, Experimental group (G4): treated with cannabis nano emulsion (CBD) at a dose of 2.5 mg/kg; Experimental group (G5): treated with cannabis nano emulsion (CBD) at a dose of 5 mg/kg. Exposure to the nano emulsion was carried out for 21 days, once a day, orally (gavage). Our results showed that cannabis nano emulsions at higher doses (5 mg/kg), regardless of the composition, induced histopathologic changes in the liver (G3 and G5) in comparison with the control group. In line with that, placental glutathione S-transferase (GST-P) positive foci increased in both G3 and G5 (p < 0.05), as well as the immune expression of Ki-67, vascular endothelial growth factor (VEGF) and p53 (p < 0.05). Also, the nano emulsion intake induced an increase in the number of micronucleated hepatocytes in G5 (p < 0.05) whereas G3 showed an increase in binucleated cells (p < 0.05). As for metanuclear alterations, karyolysis and pyknosis had an increased frequency in G3 (p < 0.05). Taken together, the results show that intake of cannabis nano emulsion may induce degenerative changes and genotoxicity in the liver in higher doses, demonstrating a clear dose-response relationship.

On a deterministic mathematical model which efficiently predicts the protective effect of a plant extract mixture in cirrhotic rats.

In this work, we propose a mathematical model that describes liver evolution and concentrations of alanine aminotransferase and aspartate aminotransferase in a group of rats damaged with carbon tetrachloride. Carbon tetrachloride was employed to induce cirrhosis. A second groups damaged with carbon tetrachloride was exposed simultaneously a plant extract as hepatoprotective agent. The model reproduces the data obtained in the experiment reported in [Rev. Cub. Plant. Med. 22(1), 2017], and predicts that using the plants extract helps to get a better natural recovery after the treatment. Computer simulations show that the extract reduces the damage velocity but does not avoid it entirely. The present paper is the first report in the literature in which a mathematical model reliably predicts the protective effect of a plant extract mixture in rats with cirrhosis disease. The results reported in this manuscript could be used in the future to help in fighting cirrhotic conditions in humans, though more experimental and mathematical work is required in that case.

Investigation of the protective effect of boric acid against hepatotoxic and nephrotoxic injury induced by acrylamide in rats / Investigación del efecto protector del ácido bórico contra lesiones hepatotóxicas y nefrotóxicas inducidas por acrilamida en ratas

SUMMARY: To investigate if the administration of boric acid (BA) would exert any protective effect against possible nephrotoxicity and hepatotoxicity induced by the exposure to acrylamide (ACR) in rats. In our study, we used a total of 28 rats that were divided into four equal groups. Group 1: the control group which was not treated with any procedure. Group 2: the ACR group that was administered ACR 50 mg/kg/day via intraperitoneal (i.p) route for 14 days. Group 3: the BA group that was administered BA 200 mg/kg/ day via gavage via peroral (p.o) route for 14 days. Group 4: the ACR+BA group that was administered BA simultaneously with ACR. Total antioxidant and oxidant (TAS/TOS) capacities were measured in all groups at the end of the experiment. In addition, the specimens obtained were evaluated with histopathological examination. Studies showed that the ACR and ACr+BA groups were not significantly different in terms of hepatic TAS level while the TOS level was higher in the ACR group than the ACR+BA group. The groups did not show any significant difference regarding renal TAS and TOS levels. In the histopathological examination of the hepatic tissue, the histopathological injury score of the ACR group was significantly higher than those of the other groups whereas it was significantly lower in the ACR+BA group than the ACR group. Our study concluded that Boric acid had a protective effect against acrylamide- induced hepatotoxicity, but not against nephrotoxicity.

El objetivo de este estudio fue investigar si la administración de ácido bórico (BA) ejercería algún efecto protector frente a la posible nefrotoxicidad y hepatotoxicidad inducida por la exposición a acrilamida (ACR) en ratas. En nuestro estudio, utilizamos un total de 28 ratas que se dividieron en cuatro grupos iguales. Grupo 1: grupo control que no fue tratado. Grupo 2: grupo ACR al que se le administró ACR 50 mg/kg/día por vía intraperitoneal (i.p) durante 14 días. Grupo 3: grupo BA al que se le administró BA 200 mg/kg/día por sonda por vía peroral (p.o) durante 14 días. Grupo 4: grupo ACR+BA al que se administró BA simultáneamente con ACR. Las capacidades antioxidantes y oxidantes totales (TAS/TOS) se midieron en todos los grupos al final del experimento. Además, los especímenes obtenidos fueron evaluados con examen histopatológico. Los estudios demostraron que los grupos ACR y ACr+BA no fueron significativamente diferentes en términos del nivel hepático de TAS, mientras que el nivel de TOS fue mayor en el grupo ACR que en el grupo ACR+BA. Los grupos no mostraron ninguna diferencia significativa con respecto a los niveles renales de TAS y TOS. En el examen histopatológico del tejido hepático, la puntuación de lesión histopatológica del grupo ACR fue significativamente mayor que la de los otros grupos, mientras que fue significativamente menor en el grupo ACR+BA que en el grupo ACR. Nuestro estudio concluyó que el ácido bórico tiene un efecto protector contra la hepatotoxicidad inducida por acrilamida, pero no contra la nefrotoxicidad.

Temporal analysis of paracetamol-induced hepatotoxicity.

Paracetamol-induced hepatotoxicity (APAP) causes severe damage that may be irreversible. Understanding the evolution of liver injury caused by overdose of the drug is important to assist in the treatment. In the present study, we evaluated the acute intoxication by APAP (500 mg/kg) in periods of 3 and 12 hours in C57BL/6 mice through biochemical, histological, inflammatory parameters, and the redox status. The results showed that in the 3-hour period there was an increase in creatinine dosage and lipid peroxidation (TBARS) compared to the control group. In the period of 12 hours after APAP intoxication all parameters evaluated were altered; there was an increase of ALT, AST, and necrosis, besides the increase of redox status biomarkers as carbonylated protein, TBARS, and MMP-9. We also observed activation of the inflammasome pathway as well as a reduction in the regenerative capacity of hepatocytes with a decrease in binucleated liver cells. In cytochrome gene expression, the mRNA level increased in CYP2E1 isoenzyme and reduced CYP1A2 expression. This study indicated that early treatment is necessary to mitigate APAP-induced acute liver injury, and alternative therapies capable of controlling the progression of intoxication in the liver are needed.

4-Phenylselanyl-7-chloroquinoline attenuates hepatic injury triggered by neonatal exposure to monosodium glutamate in rats.

AIMS: Obesity is associated with a spectrum of hepatic abnormalities that can be experimentally induced by injections of monosodium glutamate (MSG) in neonatal rodents. We investigated the protective actions of the repeated therapy with 4-phenylselenyl-7-chloroquinoline (4-PSQ), a quinoline derivative containing selenium, on damage to the liver triggered by early postnatal administration of MSG in male Wistar rats. MAIN METHODS: Neonatal rats received MSG (4 g/kg, subcutaneous route) or saline (1 ml/kg) from 5 to 14 postnatal day (PND) to induce obesity with consequent damages in the liver. 4-PSQ treatment (5 mg/kg) or canola oil (1 ml/kg) was administered from 60 to 76 PND by the intragastric route. On 76 PND, animals were anesthetized for blood and liver collection. Plasma markers of hepatic function, hepatic lipoperoxidation levels and histology analysis of liver tissue were assessed. KEY FINDINGS: Our data revealed that treatment with 4-PSQ reverted the increase in plasma transaminases activities observed in MSG rats. Treatment with 4-PSQ reduced plasma lactate levels in obese rats. In the liver, MSG elevated the content of lipoperoxidation which was reverted by 4-PSQ administrations. Lastly, 4-PSQ therapy attenuated the histological alterations induced by MSG. SIGNIFICANCE: Together, the results indicate a hepatoprotective action of repeated treatment with 4-PSQ in obese rats.

Can the exposure system adopted influence the results of the atrazine toxicity in hepatic tissue of fish?

The widespread use of atrazine, a herbicide used to control weeds, has contributed to the increased contamination of aquatic environments. To assess the toxicological effects of a xenobiotic on a nontarget organism in the laboratory, different models of toxicological exposure systems have been widely used. Therefore, the aim of this study was to evaluate and compare the action of sublethal concentrations of atrazine on the hepatic histology of Oreochromis niloticus, considering two models of exposure: static (where atrazine was only added once) and semi-static (where atrazine was periodically renewed). Fish were exposed to a concentration of 2 ppm atrazine for 15 days, which was verified by high-performance liquid chromatography. The livers were stained with hematoxylin and eosin and histopathological data were collected. In addition, they were submitted to immunohistochemistry for inducible nitric oxide synthase (iNOS). A maximum variation of 45% (static) and 12.5% (semi-static) was observed between the observed and nominal atrazine concentration. Nuclear and cytoplasmic changes were observed in both experimental models. Hepatocytes from the livers of the static system showed a degenerative appearance, while in the semi-static system, intense cytoplasmic vacuolization and necrosis were observed. iNOS positive cells were identified only in macrophages in the hepatocytes of fish in the semi-static system. These results directly showed how the choice of exposure system can influence the results of toxicological tests. However, future analysis investigating the by-products and nitrogen products should be carried out since the histopathological findings revealed the possibility of these compounds serving as secondary contamination routes.

Protective effects of Bidens pilosa on hepatoxicity and nephrotoxicity induced by carbon tetrachloride in rats.

The aim of this study was to assess the protective effects of oral and topical treatment with Bidens pilosa (BP) against carbon tetrachloride (CCl4)- induced toxicity. Fifty-six rats were divided into seven groups: A: CCl4 only; B: CCl4+oral BP; C: CCl4 and topical BP; D: CCl4+oral and topical BP; E: oral BP only; F: negative control; and G: positive control (cyclophosphamide). The animals were treated for 10 weeks. Blood samples were collected for tests of hepatic and renal function, and fragments of the liver, spleen, pancreas, kidney, and intestine were collected for histopathological analyses. Cells from the femoral bone marrow were used for a micronucleus test and 'comet assay'. Statistically significant differences were observed in the levels of gamma-glutamyl transpeptidase (GGT), albumin, urea and creatinine, hepatic inflammation, renal tubular lesion, and inflammation of the intestinal mucosa between the BP-treated groups and untreated group. The median number of micronuclei in group A was 4.00, in group G was 9.00 and in the other groups was 0.00. Group A had the lowest number of cells with a score of 0 and the greatest number with scores of 3 and 4, similar to the results obtained from group G using the 'comet assay'. Thus, BP effectively protected against the toxic effects of CCl4 on the liver, kidney, and intestine and exerted an antimutagenic effect on rats exposed to CCl4.

Uso de corticosteroides no tratamento da lesão hepática aguda grave decorrente de anabolizante estanazolol / Use of corticosteroids in the treatment of stanazolol-induce severe acute liver injury

A busca pelo corpo perfeito pode gerar graves consequências para a população que faz uso indiscriminado de substâncias visando a resultados rápidos. O caso relatado se refere a um pa- ciente de 21 anos, do sexo masculino, na cidade de São Paulo (SP), que apresentou quadro de síndrome colestática 15 dias após uso do anabolizante estanazolol para fins estéticos na ativi- dade física, evoluindo com hepatite medicamentosa grave, com aumento de transaminases, hiperrubilinemia às custas de bilirrubina direta e fatores de coagulação, sem resposta satis- fatória ao tratamento de suporte convencional, com melhora significativa após introdução de corticoterapia.

Searching for the perfect body image can cause severe conse- quences to the population using substances indiscriminately to reach results fast. The case reported refers to a male patient, 21 years old, from the city of São Paulo (SP), who developed choles- tatic syndrome 15 days after the use of the steroid Stanazol for aesthetic purposes during physical activity, progressing with se- vere drug-induced hepatitis, transaminases, bilirubin, and coagu- lation factors increase with no satisfactory response to the con- ventional support treatment, and significant improvement after the introduction of corticotherapy.

[D-Leu1]MC-LR Has Lower PP1 Inhibitory Capability and Greater Toxic Potency than MC-LR in Animal and Plant Tissues.

Two microcystins, MC-LR and [D-Leu1]MC-LR, present in La Plata Basin blooms, are differentiated by substitution of D-Alanine for D-Leucine at position 1. Our objective was to evaluate acute toxicity of [D-Leu1]MC-LR and MC-LR in mice (N:NIH Swiss) and beans (Phaseolus vulgaris). We observed variations in [D-Leu1]MC-LR lethal doses with respect to those reported for MC-LR (100 µg/kg), with an increased liver/body weight ratio and intrahepatic hemorrhages in mice exposed to 50-200 µg [D-Leu1]MC-LR/kg and slight steatosis after a single 25 µg [D-Leu1]MC-LR/kg i.p. dose. Our study in the plant model showed alterations in germination, development, morphology and TBARs levels after a single contact with the toxins during imbibition (3.5 and 15 µg/mL), those treated with [D-Leu1]MC-LR being more affected than those treated with the same concentration of MC-LR. Protein phosphatase 1 (PP1) IC50 values were 40.6 nM and 5.3 nM for [D-Leu1]MC-LR and MC-LR, respectively. However, the total phosphatase activity test in root homogenate showed 60% inhibition for [D-Leu1]MC-LR and 12% for MC-LR. In mouse liver homogenate, 50% inhibition was observed for [D-Leu1]MC-LR and 40% for MC-LR. Our findings indicate the need for further research into [D-Leu1]MC-LR toxicity since together with oxidative stress, the possible inhibition of other phosphatases could explain the differences detected in the potency of the two toxins.

ORY supplementation mitigates acetaminophen-induced acute liver failure in male mice: role of oxidative stress and apoptotic markers.

The aim of the present study was to assess the possible protective effect of γ-oryzanol (ORY) supplementation in a model of acute liver failure (ALF) induced by acetaminophen (APAP) in mice. Male Swiss strain mice were supplemented with ORY (10 and 50 mg/kg, per oral route) daily for 7 days. One hour after the last supplementation, animals received APAP (300 mg/kg, intraperitoneal). Twenty-four hours after APAP administration, mice were euthanized, and biochemical and histopathological determinations were performed. Histopathological analysis revealed that APAP caused vascular congestion, loss of cellular structure, and cellular infiltration in hepatocytes. Moreover, it caused oxidative damage (enzymatic and non-enzymatic analysis of oxidative stress), with loss of hepatic function leading to cell apoptosis (apoptotic parameters). ORY supplementation (ORY-10 and ORY-50) protected against all changes in ALF model. Thus, the protective effect of ORY supplementation was due to modulation of antioxidant defenses avoiding the apoptotic process.

Curcumin downregulates Smad pathways and reduces hepatic stellate cells activation in experimental fibrosis.

INTRODUCTION AND OBJECTIVES: Curcumin, a polyphenol, is a natural compound that has been widely studied as a hepatoprotector; however, only a few studies have examined its ability to reduce fibrosis in previously established cirrhosis. The objective of this study was to investigate whether curcumin could reduce carbon tetrachloride (CCl4)-induced fibrosis and if so, to determine the action mechanisms involved in the reduction process. MATERIALS AND METHODS: CCl4 was administered to male Wistar rats (400 mg/kg, three times a week, i. p.) for 12 weeks; curcumin (100 mg/kg body weight twice per day, p. o.) was administered from week 9-12 of CCl4 treatment. Biochemical markers of hepatic injury and oxidative stress were evaluated. Hematoxylin and eosin, Masson's trichrome stains, transmission electron microscopy; immunohistochemistry, and zymography assays were carried out. Moreover, Smad3 and α-SMA mRNA and protein levels were studied. Western blotting by TGF-ß, CTGF, Col-I, MMP-13, NF-κB, IL-1, IL-10, Smad7, pSmad3, and pJNK proteins was developed. RESULTS AND CONCLUSIONS: Curcumin reduced liver damage, oxidative stress, fibrosis, and restored normal activity of MMP-9 and MMP-2. Besides, curcumin restored NF-κB, IL-1, IL-10, TGF-ß, CTGF, Col-I, MMP-13, and Smad7 protein levels. On the other hand, curcumin decreased JNK and Smad3 phosphorylation. Furthermore, curcumin treatment decreased α-SMA and Smad3 protein and mRNA levels. Curcumin normalized GSH, and NF-κB, JNK-Smad3, and TGF-ß-Smad3 pathways, leading to a decrement in activated hepatic stellate cells, thereby producing its antifibrotic effects.

Prolonged neutrophil survival at necrotic sites is a fundamental feature for tissue recovery and resolution of hepatic inflammation.

Neutrophils were classically described as powerful effectors of acute inflammation, and their main purpose was assumed to be restricted to pathogen killing through production of oxidants. As consequence, neutrophils also may lead to significant collateral damage to the healthy tissues, and after performing these tasks, these leukocytes are supposed to die within tissues. However, there is a growing body of evidence showing that neutrophils also play a pivotal role in the resolution phases of inflammation, because they can modulate tissue environment due to secretion of different kind of cytokines. Drug-induced liver injury (DILI) is a worldwide concern being one of the most prevalent causes of liver transplantation, and is well established that there is an intense neutrophil recruitment into necrotic liver during DILI. However, information if such abundant granulocyte infiltration is also linked to the tissue repairing phase of hepatic injury is still largely elusive. Here, we investigated the dynamics of neutrophil trafficking within blood, bone marrow, and liver during hepatic inflammation, and how changes in their gene expression profile could drive the resolution events during acetaminophen (APAP)-induced liver injury. We found that neutrophils remained viable during longer periods following liver damage, because they avidly patrolled necrotic areas and up-regulated pro-resolutive genes, including Tgfb, Il1r2, and Fpr2. Adoptive transference of "resolutive neutrophils" harvested from livers at 72 h after injury to mice at the initial phases of injury (6 h after APAP) significantly rescued organ injury. Thus, we provide novel insights on the role of neutrophils not only in the injury amplification, but also in the resolution phases of inflammation.

Subacute Liver Failure Following Gene Replacement Therapy for Spinal Muscular Atrophy Type 1.

Spinal muscular atrophy is a neurodegenerative disease resulting from irreversible loss of anterior horn cells owing to biallelic deletions/mutations in the survival motor neuron (SMN) 1 gene. Gene replacement therapy using an adeno-associated virus vector containing the SMN gene was approved by the US Food and Drug Administration in May 2019. We report 2 cases of transient, drug-induced liver failure after this therapy.

Comparing alpha-cypermethrin induced dose/gender-dependent responses of lizards in hepatotoxicity and nephrotoxicity in a food chain.

Pesticides are proposed as one reason for the worldwide decline in the reptile. Effects of pesticides on food intake and organ toxicity could affect wildlife populations dynamics. To explore the hepatotoxicity of alpha-cypermethrin (ACP) in reptiles, we designed a tri-trophic food chain with three concentrations (0, 2, and 20 mg/kgwet weight). Although the enzymes changes were similar between male and female lizards, the significant variations in anti-oxidative enzymes' activities, lactic dehydrogenase activities and acetylcholine esterase activities in liver and kidney suggesting that oxidative stress, decreased metabolic ability and neurotoxicity on lizards. The results of hepatic metabolomics showed that ACP could affect amino acid, energy and lipid metabolism on lizards. Comparing with female lizards, there were more significant changes of metabolites in male lizards. The histopathology analysis in the liver (such as hepatic lobule congestion and hepatocyte vacuolation) and kidney (such as renal tubule necrosis and glomerulus necrosis), dose- and gender dependent changes of lesions suggested the functions of organ were damaged. In summary, the reduction of detoxification and elimination capacities of the liver and kidney showed dose/gender-dependent in lizards.

Flucloxacillin-Induced Hepatotoxicity - Association with HLA-B*5701.

Drug-induced liver injury (DILI) to flucloxacillin is rare and is classified as idiosyncratic, as it is dependent on individual susceptibility, unpredictable, and dose-independent. The authors present the case of a 74 - year - old man with a history of monoclonal gammopathy under investigation and alcoholic habits of 24 g/day, with asthenia, anorexia, nausea, abdominal discomfort, and fever with three days of evolution. He was treated with two courses of antibiotic therapy with flucloxacillin to erysipelas previously (3 months and 2 weeks before admission). Lab tests showed serum AST levels of 349 U/L, ALT 646 U/L, alkaline phosphatase 302 U/L, GGT 652 U/L, total bilirubin 3.3 mg/dL and direct bilirubin 2.72 mg/dL. Infectious, autoimmune, and metabolic causes were ruled out. Magnetic resonance cholangiopancreatography showed normal results. Liver biopsy showed mild multifocal (predominantly microvesicular) steatosis; marked changes in the centrilobular areas (sinusoidal dilatation, marked congestion, hemorrhage, and multifocal hepatocyte collapse); expansion of the portal areas with the formation of bridges; proliferated bile ducts and inflammatory infiltrate of variable density, predominantly mononuclear type. The HLA-B*5701 screening test was positive. Hepatic biochemical tests remain abnormal with a significative increase in total bilirubin, which reached levels of 24.1 mg/dL, with the development of jaundice, pruritus, and choluria. DILI was assumed, and the patient was treated with ursodeoxycholic acid. There was favorable evolution, without evidence of blood coagulation dysfunction or encephalopathy. The analytic normalization was, however, slow, with evolution to chronicity. The authors present this case to remind the possibility of moderate/severe drug-induced liver injury to flucloxacillin, an antibiotic commonly used in clinical practice and association with the HLA-B * 5701 allele reported in the literature.

Vitamin C administration attenuated artemether induced hepatic injury in rats / La aAdministración de vitamina C atenúa la lesión hepática inducida por artemeter en ratas

This research was designed to investigate the potential protective effect of vitamin C supplementation against hepatocyte ultrastructural alterations induced by artemether (antimalarial drug) administration. Twenty-four adult male albino rats were used in this study and were divided into four groups (n=6). Group I served as a control and rats in group II administrated artemether (4 mg/kg B.W) orally for three consecutive days. Group III administered artemether plus a low dose of vitamin C (2.86 mg/kg/l water) while group IV received artemether plusa high dose of vitamin C (8.56 mg/kg). At the end of the experimental period (14 days), the harvested liver tissues were examined by transmission electron microscopy (TEM), and blood samples were assayed for biomarkers of liver injury and oxidative stress. Artemether significantly (p<0.05) augmented biomarkers of liver injury such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and oxidative stress such as superoxide dismutase (SOD), Glutathione Peroxidase (GPX), and caused degeneration and damage of the rough endoplasmic reticulum and disrupted mitochondria. The blood sinusoids were also damaged with distortion of their canaliculi. Administration of vitamin C showed improvement of liver biomarkers, and liver parenchyma, especially in a high dose of vitamin C.We concludes that vitamin C is a partial protective agent against artemether-induced liver injury.

Esta investigación fue diseñada para investigar el posible efecto protector de la vitamina C contra las alteraciones ultraestructurales de los hepatocitos, inducidas por la administración de arteméter (medicamento antipalúdico). En el estudio se utilizaron 24 ratas albinas macho adultas y se dividieron en cuatro grupos (n = 6). El grupo I fue designado como control y las ratas en el grupo II se adminstró Arteméter (4 mg / kg de peso corporal) por vía oral durante tres días consecutivos. En el grupo III se administró arteméter, además de una dosis baja de vitamina C (2,86 mg / kg / l de agua) mientras que el grupo IV recibió arteméter más una dosis alta de vitamina C (8,56 mg / kg). Al final del período experimental (14 días), los tejidos hepáticos recolectados se examinaron por microscopía electrónica de transmisión (MET), y las muestras de sangre se analizaron en busca de biomarcadores de daño hepático y estrés oxidativo. El arteméter aumentó significativamente (p <0,05) los biomarcadores de daño hepático como alanina aminotransferasa (ALT), aspartato aminotransferasa (AST) y estrés oxidativo como superóxido dismutasa (SOD), glutatión peroxidasa (GPX) y causó degeneración y daño de la retículo endoplásmico rugoso y mitocondrias alteradas. Los sinusoides sanguíneos también fueron dañados con la distorsión de sus canalículos. La administración de vitamina C mostró una mejoría de los biomarcadores hepáticos y el parénquima hepático, especialmente en una dosis alta de vitamina C. Concluimos que la vitamina C es un agente protector parcial contra la lesión hepática inducida por arteméter.

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 0.5 mL free nerolidol/kg; group C received feed containing 1.0 mL free nerolidol/kg; group D received feed containing 0.5 mL nanospheres nerolidol/kg; and group E received feed containing 1.0 mL nanospheres nerolidol/kg. All groups received experimental feed once a day (10% total biomass) at 2 p.m. for 60 consecutive days. Hepatic liver weight and relative liver weight were significantly lower in fish fed 1.0 mL free nerolidol/kg feed than in fish given basal diet (control group). Hepatic pyruvate kinase (1.0 mL free nerolidol/kg) and adenylate kinase (0.5 and 1.0 mL 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 1.0 mL 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.