Prospective Protective Effects of Arthrospira platensis Against Acetaminophen Induced Hepato-Renal Toxicity in Rats / Efectos Protectores Prospectivos de Arthrospira platnesis Contra la Toxicidad Hepatorrenal Inducida por Paracetamol en Ratas

SUMMARY: The toxic effects of acetaminophen appear primarily in the liver and kidney. The protective effect of blue green alga Arthrospira platensis on hepato-renal toxicity caused by acetaminophen was evaluated in male rats. The obtained results showed that subcutaneous injection of acetaminophen at a dose 120 &240 սl acetaminophen/kg by weight resulted in an observed elevation in the enzyme activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Alkaline phosphatase (ALP), serum total lipids, total cholesterol, creatinine, total bilirubin, urea, nitric oxide (NO), L- malondialdehyde (MDA) and interleukins (IL-2 &IL-6). However, there is a decrease in the serum total protein, albumin and loss in antioxidant enzyme activities in liver including; superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GSH). This effect was found to be dose and time dependent. In spite of, pre- oral administration of Arthrospira platensis 1000 mg/kg .b. wt. prior acetaminophen injection succeeded to modulate the effect of the observed abnormalities caused by acetaminophen. Moreover, there were no remarkable changes in serum biomarkers of rats received Arthrospira platensis only at a dose of 1000 mg/kg by weight (group 2). The histopathological findings confirm the biochemical results that indicates the safety use of Arthrospira platensis at the selected dose in this study. Therefore, the present results clarified the protective effect of blue green alga Arthrospira platensis on oxidative stress, hepatic and nephrotoxicity induced by acetaminophen in male Wister rats.

Los efectos tóxicos del paracetamol aparecen principalmente en el hígado y el riñón. Se evaluó en ratas macho Wistar el efecto protector del alga verde azulada Arthrospira platensis sobre la toxicidad hepatorrenal causada por paracetamol. Los resultados obtenidos mostraron que la inyección subcutánea de paracetamol a dosis de 120 y 240 µl de paracetamol/kg, resultó en una elevación en las actividades enzimáticas de la aspartato aminotransferasa (AST), alanina aminotransferasa (ALT) y fosfatasa alcalina (ALP), lípidos séricos totales, colesterol total, creatinina, bilirrubina total, urea, óxido nítrico (NO), L- malondialdehído (MDA) e interleucinas (IL-2 e IL-6). Sin embargo, hay una disminución en la proteína sérica total, albúmina y pérdida en las actividades de las enzimas antioxidantes en el hígado, incluyendo; superóxido dismutasa (SOD), catalasa (CAT) y glutatión reductasa (GSH). Se encontró que este efecto era dependiente de la dosis y el tiempo. A pesar de la administración preoral de Arthrospira platensis 1000 mg/kg, la inyección previa de acetaminofeno logró modular el efecto de las anormalidades observadas causadas por el acetaminofeno. Además, no hubo cambios notables en los biomarcadores séricos de ratas que recibieron Arthrospira platensis solo a una dosis de 1000 mg/kg (Grupo 2). Los hallazgos histopatológicos confirman los resultados bioquímicos que indican la seguridad del uso de Arthrospira platensis a la dosis seleccionada en este estudio. Por lo tanto, los presentes resultados aclararon el efecto protector del alga verde azulada Arthrospira platensis sobre el estrés oxidativo, la toxicidad hepática y la nefrotoxicidad inducida por paracetamol en ratas Wistar macho.

Quercetin and resveratrol are associated with the downregulation of TNFalpha/NF-kB/inos axis-mediated acute liver injury in rats induced by paracetamol poisoning / La quercetina y el resveratrol están asociados con la regulación decreciente de la lesión hepática aguda mediada por el eje TNF-alfa/NF-kB/inos en ratas inducida por envenenamiento con paracetamol

SUMMARY: Paracetamol (known as acetaminophen, or APAP) poisoning causes acute liver damage that can lead to organ failure and death. We sought to determine that APAP overdose can augment tumor necrosis factor-alpha (TNF-α)/ nuclear factor kappa B (NF-kB)/induced nitic oxide synthase (iNOS) axis-mediated hepatotoxicity in rats, and the anti-inflammatory polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) can ameliorate these parameters. Therefore, we induced acute hepatotoxicity in rats using APAP overdose (2 g/kg, orally) and the protective group of rats were treated with 50 mg/kg QUR plus 30 mg/kg RES for one week before APAP ingestion. Animals were killed at day 8. APAP poisoning caused the induction of hepatic tissue levels of TNF-α, NF-kB, and iNOS, which were significantly (p<0.05) decreased by QUR+RES. QUR+RES, also inhibited liver injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, a link between liver injury and TNF-α /NF-kB / iNOS axis mediated hepatotoxicity was observed. Thus, the presented data backing the conclusion that intoxication by paracetamol increases TNF-α / NF-kB / iNOS axis -mediated hepatotoxicity, and is protected by a combination of quercetin and resveratrol.

El envenenamiento por paracetamol (conocido como acetaminofeno o APAP) causa daño hepático agudo que puede provocar una insuficiencia orgánica y la muerte. El objetivo de este trabajo fue determinar si la sobredosis de APAP puede aumentar la hepatotoxicidad mediada por el eje del factor de necrosis tumoral alfa (TNF-α)/factor nuclear kappa B (NF-kB)/óxido nítico sintasa inducida (iNOS) en ratas, y si el polifenólico antiinflamatorio compuesto por quercetina (QUR) más resveratrol (RES) pueden mejorar estos parámetros. Por lo tanto, inducimos hepatotoxicidad aguda en ratas usando una sobredosis de APAP (2 g/kg, por vía oral). El grupo protector de ratas se trató con 50 mg/ kg de QUR más 30 mg/kg de RES durante una semana antes de la ingestión de APAP. Los animales se sacrificaron el día 8. El envenenamiento con APAP en el tejido hepático provocó la inducción de niveles de TNF-α, NF-kB e iNOS, que se redujeron significativamente (p<0,05) con QUR+RES. QUR+RES, también inhibió los biomarcadores de daño hepático, la alanina aminotransferasa (ALT) y el aspartato aminotransferasa (AST). Además, se observó una relación entre la lesión hepática y la hepatotoxicidad mediada por el eje TNF-α /NF-kB/iNOS. Por lo tanto, los datos presentados respaldan la conclusión de que la intoxicación por paracetamol aumenta la hepatotoxicidad mediada por el eje TNF-α /NF-kB / iNOS, y está protegida por una combinación de quercetina y resveratrol.

Indicación de N-acetilcisteína en distintas formas de toxicidad por paracetamol / Indication of n-acetylcysteine in differents forms of paracetamol toxicity

Introducción: la hepatotoxicidad por paracetamol está relacionada con la formación del metabolito N-acetil-parabenzoquinoneimina (NAPQI) y su falta de detoxificación a través del glutatión, cuyas reservas se deplecionan en el contexto de una sobredosis. La administración de N-acetilcisteína (NAC) como sustancia dadora de grupos tioles (-SH) contribuye a la prevención del daño hepático que puede desarrollarse con dosis terapéuticas o tóxicas. Métodos: se comentan 5 casos de exposición a paracetamol en los cuales se administró NAC por alteración de la función hepática. La gravedad de los cuadros varió en función de las dosis y del tiempo de latencia hasta la consulta. Resultados: cuatro pacientes ingirieron una única dosis tóxica y una paciente recibió la dosis diaria máxima de paracetamol de 4000 mg/día durante 5 días. La paciente que consultó dentro de las 4 horas posteriores a la ingesta no presentó elevación de transaminasas. Todas las pacientes recibieron NAC y sus valores de enzimas hepáticas se normalizaron al momento del alta. Conclusión: la administración temprana de NAC puede ser útil para prevenir daño hepático tanto en ingestas de dosis tóxicas, como en casos de utilización de dosis terapéuticas máximas durante varios días. (AU)

Introduction: paracetamol hepatotoxicity is related to the formation of the metabolite N-acetyl-parabenzoquinoneimine (NAPQI) and its lack of detoxification through glutathione, whose reserves are depleted in paracetamol overdose. The administration of N-acetylcysteine (NAC) as a donor of sulfhydryl groups (-SH) can prevent liver damage that could even occur with therapeutic or toxic doses. Methods: 5 cases of exposure to paracetamol are discussed, in which NAC was administered due to impaired liver function. These manifestations presented different severity depending on the drug doses and the time until medical consultation. Results: four patients ingested single toxic doses and one patient received the maximum daily dose of paracetamol of 4000 mg/day for 5 days. The patient who consulted within 4 hours after ingestion did not present elevation of transaminases. All patients received NAC, with normal liver enzymes at discharge. Conclusion: the early administration of NAC may be useful to prevent liver damage both in toxic dose intakes and in cases of use of maximum therapeutic doses for several days. (AU)

Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Acetaminophen, also known as N-acetyl-p-aminophenol (APAP), is commonly used as an antipyretic and analgesic agent. APAP overdose can induce hepatic toxicity, known as acetaminophen-induced liver injury (AILI). However, therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting. Hence, there is a need to understand the potential pathological mechanisms underlying AILI. In this review, we summarize three main mechanisms involved in the pathogenesis of AILI: hepatocyte necrosis, sterile inflammation, and hepatocyte regeneration. The relevant factors are elucidated and discussed. For instance, N-acetyl-p-benzoquinone imine (NAPQI) protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis, danger-associated molecular patterns (DAMPs) are released to elicit sterile inflammation, and certain growth factors contribute to liver regeneration. Finally, we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists. This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.

Paracetamol poisoning induces acute liver injury in rats: inhibition of miR-155/cd45 axis-mediated antioxidant depletion and hepatotoxicity using quercetin and resveratrol / La intoxicación por paracetamol induce daño hepático agudo en ratas: inhibición de la depleción de antioxidantes mediado por el eje miR-155/cd45 y hepatotoxicidad usando quercetina y resveratrol

SUMMARY: Ingestion of an overdose of paracetamol (also called acetaminophen, or APAP) induces hepatotoxicity that can lead to liver failure. The link between the pro-inflammatory microRNA-155 (miR-155) and leukocyte infiltration (CD45) in APAP- antioxidant depletion and liver toxicity with and without the natural polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) has not been previously studied. Therefore, acute hepatic injury was induced in rats by 2 g/kg APAP (single dose, orally) and another group started QUR (50 mg/kg) plus RES (30 mg/kg) treatment one week prior to APAP ingestion. Animals were culled 24 hours post the paracetamol treatment. APAP overdose induced hepatic and blood levels of miR-155 expression, CD45 (leukocyte common antigen) immunostaining, degenerated hepatocytes, and hepatic injury enzymes; alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which were markedly decreased by QUR+RES. Whereas, APAP intoxication ameliorated liver tissue levels of the antioxidants, glutathione peroxidase and superoxide dismutase that were augmented by QUR+RES. Moreover, a significant (p<0.05) correlation between miR-155/CD45 axis and liver tissue injury was observed. These findings show that paracetamol intoxication augments miR- 155/CD45 axis-mediated modulation of antioxidants and liver injury in rats, and is protected by QUR+RES.

RESUMEN: La ingestión de una sobredosis de paracetamol (también llamado acetaminofeno o APAP) induce hepatotoxicidad que puede provocar insuficiencia hepática. El vínculo entre el microARN-155 proinflamatorio (miR-155) y la infiltración de leucocitos (CD45) en el agotamiento de APAP- antioxidante y la toxicidad hepática con y sin los compuestos polifenólicos naturales, quercetina (QUR) más resveratrol (RES) no ha sido previamente investigado. En este estudio, se indujo daño hepático agudo en ratas con 2 g/kg de APAP (dosis única, por vía oral) y otro grupo comenzó el tratamiento con QUR (50 mg/ kg) más RES (30 mg/kg) una semana antes de la ingestión de APAP. Los animales se sacrificaron 24 horas después del tratamiento con paracetamol. La sobredosis de APAP indujo niveles hepáticos y sanguíneos de expresión de miR-155, inmunotinción de CD45 (antígeno leucocitario común), degeneración de los hepatocitos y daño hepático enzimático; alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST), disminuyeron notablemente con QUR+RES. Mientras que la intoxicación con APAP mejoró los niveles de antioxidantes, glutatión peroxidasa y superóxido dismutasa en el tejido hepático los que aumentaron con QUR+RES. Además, se observó una correlación significativa (p<0,05) entre el eje miR-155/CD45 y la lesión del tejido hepático. Estos hallazgos muestran que la intoxicación por paracetamol aumenta la modulación mediada por el eje miR-155/CD45 de los antioxidantes y la lesión hepática en ratas, y está protegida por QUR+RES.

Mechanism of Tibetan medicine Ershiwuwei Songshi Pills against liver injury induced by acetaminophen in mice based on Keap1/Nrf2 and TLR4/NF-κB p65 signaling pathways / 中国中药杂志

The present study investigated the mechanism of the Tibetan medicine Ershiwuwei Songshi Pills(ESP) against the liver injury induced by acetaminophen(APAP) in mice based on the kelch-like ECH-associated protein 1(Keap1)/nuclear transcription factor E2 related factor 2(Nrf2) and Toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) p65 signaling pathways. Kunming mice were randomly divided into a blank control group, a model group, an N-acetyl-L-cysteine(NAC) group, and high-(400 mg·kg~(-1)), medium-(200 mg·kg~(-1)), and low-dose(100 mg·kg~(-1)) ESP groups. After 14 days of continuous administration, except for those in the control group, the mice were intraperitoneally injected with 200 mg·kg~(-1) APAP. After 12 h, the serum and liver tissues of mice were collected. Hematoxylin-eosin(HE) staining was performed on pathological sections of the liver, and the levels of aspartate aminotransferase(AST) and alanine aminotransferase(ALT) in the serum and the levels of glutathione(GSH), malondialdehyde(MDA), superoxide dismutase(SOD), catalase(CAT), myeloperoxidase(MPO), and total antioxidant capacity(T-AOC) in liver tissue homogenate were detected to observe and analyze the protective effect of ESP on APAP-induced liver injury in mice. The serum levels of tumor necrosis factor-alpha(TNF-α), interleukin-1 beta(IL-1β), and interleukin-6(IL-6) were determined by enzyme-linked immunosorbent assay(ELISA). The protein expression of Nrf2, Keap1, TLR4, and NF-κB p65 in the liver was determined by Western blot. Quantitative real-time was used to determine the mRNA expression of glutamate-cysteine ligase catalytic subunit(GCLC), glutamate-cysteine ligase regulatory subunit(GCLM), heme oxygenase-1(HO-1), and NAD(P)H dehydrogenase quinone 1(NQO-1) in the liver to explore the mechanism of ESP in improving APAP-induced liver damage in mice. As revealed by results, compared with the model group, the ESP groups showed improved liver pathological damage, decreased ALT and AST levels in the serum and MDA and MPO content in the liver, increased GSH, SOD, CAT, and T-AOC in the liver, reduced TNF-α and IL-6 levels in the serum, down-regulated expression of Keap1 in the liver cytoplasm and NF-κB p65 in the liver nucleus, up-regulated expression of Nrf2 in the liver nucleus, insignificant change in TLR4 expression, and elevated relative mRNA expression levels of antioxidant genes GCLC, GCLM, HO-1, and NQO-1. ESP can reduce the oxidative damage and inflammation caused by APAP, and the mechanism may be related to the Keap1/Nrf2 signaling pathway and the signal transduction factors on the TLR4/NF-κB p65 pathway.

Comparative characterization of cinnamon, cinnamaldehyde and kaempferol for phytochemical, antioxidant and pharmacological properties using acetaminophen-induced oxidative stress mouse model / Caracterización comparativa de canela, cinamaldehído y kaempferol para propiedades fitoquímicas, antioxidantes y farmacológicas utilizando el modelo de ratón con estrés oxidativo inducido por acetaminofeno

This study was aimed to explore the comparative efficacy of cinnamon bark extract, cinnamaldehyde and kaempferol against acetaminophen (APAP)-induced oxidative stress. Cinnamon bark extract, cinnamaldehyde and kaempferol were utilized or in-vivo analysis. From the results of in-vitro screening tests, cinnamon ethanolic extract was selected for in-vivo study in mouse model. For this, Balb/c albino mice were treated with cinnamon ethanolic extract (200 mg/kg), cinnamaldehyde (10 mg/kg) and kaempferol (10 mg/kg) orally for 14 days followed by single intraperitoneal administration of APAP during 8 hours. Blood and organ samples were collected for biochemical and histopathological analysis. The results showed that cinnamon bark ethanolic extract, cinnamaldehyde and kaempferol ameliorated APAP-induced oxidative stress and organ toxicity in mice. In conclusion, cinnamaldehyde and kaempferol possess comparable antioxidant potential even at 20-times less dose as compared to cinnamon bark ethanolic extract suggesting therapeutic potential in oxidative stress-related disorders.

Este estudio tuvo como objetivo explorar la eficacia comparativa del extracto de corteza de canela, cinamaldehído y kaempferol contra el estrés oxidativo inducido por acetaminofén (APAP). Se utilizaron extracto de corteza de canela, cinamaldehído y kaempferol para el análisis in vivo. De los resultados de las pruebas de detección in vitro, se seleccionó el extracto etanólico de canela para estudio in vivo en modelo de ratón. Para ello, los ratones albinos Balb/c fueron tratados con extracto etanólico de canela (200 mg/kg), cinamaldehído (10 mg/kg) y kaempferol (10 mg/kg) por vía oral durante 14 días, seguido de la administración intraperitoneal única de APAP durante 8 horas. Se recogieron muestras de sangre y órganos para análisis bioquímicos e histopatológicos. Los resultados mostraron que el extracto etanólico de la corteza de canela, el cinamaldehído y el kaempferol mejoraron el estrés oxidativo inducido por APAP y la toxicidad orgánica en ratones. En conclusión, el cinamaldehído y el kaempferol poseen un potencial antioxidante comparable, incluso a una dosis 20 veces menor en comparación con el extracto etanólico de la corteza de canela, lo que sugiere un potencial terapéutico en los trastornos relacionados con el estrés oxidativo.

Poisoning in domestic cats in Brazil: toxicants, clinical signs, and therapeutic approaches / [Intoxicação em gatos domésticos no Brasil: toxicantes, sinais clínicos e abordagens terapêuticas]

This study evaluated the most common toxic agents affecting domestic cats, the clinical signs of toxicity, and the therapeutic approaches for recovery. A survey on poisoning in cats was conducted among small animal veterinary practitioners from 2017 to 2018. Of the 748 completed questionnaires, 543 (72.6%) were evaluated. Pesticides and household cleaning supplies were the most common causes of poisoning in cats. The toxicant groups included pesticides and household cleaning supplies (organophosphates), human drugs (acetaminophen), plants/plant derivatives (lily), and veterinary drugs (tramadol). The major clinical signs for these four groups of toxicants were (1) acetaminophen poisoning, which caused oxidative erythrocyte damage; (2) muscarinic and nicotinic cholinergic syndrome, which resulted from organophosphate poisoning; (3) acute kidney injury, which resulted from intoxication of lily; and (4) serotonin syndrome, which resulted from tramadol toxicosis. Interventions for treating poisoning in cats were based on the clinical presentation of animals. In the present study, the significant toxins identified to be dangerous for cats were characterized using the obtained data in Brazil as well as the main associated clinical signs and therapy recommended by veterinarians.(AU)

Objetiva-se com este trabalho caracterizar os principais toxicantes para gatos domésticos, bem como os prevalentes sinais clínicos e a terapêutica associada. Uma pesquisa sobre envenenamento em gatos foi realizada entre médicos veterinários no período de 2017 a 2018. Dos 748 questionários preenchidos, 543 (72,6%) foram avaliados. Pesticidas e domissanitários foram os principais causadores de intoxicação em gatos. Entre os grupos tóxicos, destacaram-se, na categoria pesticidas e domissanitários (organofosforados), medicamentos humanos (acetaminofeno), plantas e derivados de planta (lírio) e medicamentos veterinários (tramadol). Os principais sinais clínicos para os quatro grupos de substâncias tóxicas foram: (1) intoxicação por acetaminofeno, que causou dano eritrocitário oxidativo; (2) síndrome colinérgica muscarínica e nicotínica, resultante do envenenamento por organofosforado; (3) lesão renal aguda, causada pela intoxicação por lírio; e (4) síndrome serotoninérgica, resultante da exposição ao tramadol. As intervenções realizadas para o tratamento dos envenenamentos foram justificáveis mediante a apresentação clínica dos animais. Por meio dos dados obtidos, puderam-se caracterizar os principais tóxicos para gatos no Brasil, bem como os principais sinais clínicos associados e a terapêutica preconizada pelos médicos veterinários.(AU)

Investigation of the possible protective effect of Smilax fluminensis steud. leaf in mice subjected to oxidative stress by paracetamol

Paracetamol (PCM) is a drug widely used by the population as an antipyretic and analgesic. If administered in high doses it can cause liver damage, leading to hepatoxicity. The genus Smilax, found in temperate and tropical regions, is traditionally used by the population through the extract of leaves and roots for several conditions, such as in the treatment of syphilis, diabetes, asthma and as a diuretic action. Through this, Smilax fluminensis leaf extracts were used to evaluate the protective effect against oxidative stress induced by a high dose of PCM in mice that received the drug and after receiving treatment with crude extract and fractions. Plasma analysis was performed using as partate aminotransferase (AST), alanine aminotransferase (ALT), glucose, triglycerides and cholesterol, in addition to biochemical techniques such as catalase (CAT), glutathione-S-transferase (GST), reduced glutathione (GSH), ascorbic acid (ASA), substances reactive to thiobarbituric acid (TBARS) and carbonylated proteins (CARBONYL) of liver, brain and kidneys. Fraction 1 of the extract was the most promising, decreasing the plasma levels of AST and ALT, the levels of CAT and GST of the liver, together with GSH and in the renal and brain tissue there was a decrease in carbonylated proteins (PCM + F1 versus PCM ). Besides, fraction 1 proved to be hypoglycemic and hypocholesterolemic. It is concluded that fraction 1 of Smilax fluminensis leaves has good antioxidant activity in the face of the damage caused by the high dose of paracetamol.

Hepatotoxicity-induced by the therapeutic dose of acetaminophen and the ameliorative effect of oral co-administration of selenium/Tribulus terrestris extract in rats / Hepatotoxicidad inducida por la dosis terapéutica de acetaminofén y el efecto de mejora de la administración conjunta de extracto de selenio Tribulus terrestris en ratas

SUMMARY: Over dose or long-term clinical use of therapeutic doses of acetaminophen (APAP) causes hepatotoxicity. Various strategies attempted to ameliorate APAP-hepatotoxicity have been found to be unsuitable for clinical practice. This study was aimed to illustrate the histopathological changes induced by therapeutic dose of APAP and investigate the hepatoprotective role of oral co-administration of selenium/ Tribulus terrestris (TT) extract concurrently against hepatotoxicity induced by APAP in rats. Fifty-four healthy male albino Wistar rats were randomized into nine groups (G1-G9) of six rats each, and administered with APAP and TT orally for 30 days as follows: Control (2ml normal saline), APAP (470 mg/kg), APAP (470 mg/kg) + selenium (2 mg/kg), APAP (470 mg/kg) + TT (98 mg/kg), APAP (470 mg/kg) + selenium (2mg/kg) + TT (98 mg/kg), APAP (470 mg/kg) + silymarin (200 mg/kg), selenium (2 mg/ kg), TT (98 mg/kg) and silymarin (200 mg/kg) groups. The results demonstrated that exposure of rats to therapeutic dose of APAP for 30 days caused significant histopathological changes parallel to elevated blood chemistry parameters. Co-administration of selenium/TT extract showed significantly reduced histopathological lesions and, restored or decreased levels of the examined blood chemistry parameters. Liver histology in selenium/TT extract showed normal hepatic architecture with mild changes and silymarin treated rats showed no histopathological changes. Histochemically PAS staining, showed that APAP-induced hepatotoxicity was characterized by hepatocytes glycogen depletion. Selenium/TT co-supplementation plays a potential role in preventing APAP-induced glycogen depletion by increasing detoxification and scavenging the reactive metabolites. Selenium/TT extract oral co-administration possesses a significant hepatoprotective property and mitigates APAP-induced hepatotoxicity by enhancing its antioxidant role and improving tissue integrity. Selenium/TT supplementation could represent an effective treatment against APAP-induced hepatotoxicity. Further studies are needed to elucidate the exact mechanism underlying the protective role of TT extract.

RESUMEN: La dosis excesiva o el uso clínico a largo plazo de dosis terapéuticas de acetaminofeno (APAP) causa hepatotoxicidad. Se ha descubierto que varias estrategias que intentaron mejorar la hepatotoxicidad por APAP no son adecuadas para la práctica clínica. Este estudio tuvo como objetivo ilustrar los cambios histopatológicos inducidos por la dosis terapéutica de APAP e investigar el papel hepatoprotector de la administración conjunta de extracto de selenio / Tribulus terrestris (TT) simultá- neamente contra la hepatotoxicidad inducida por APAP en ratas. Cincuenta y cuatro ratas Wistar albino machos sanas se aleatorizaron en nueve grupos (G1 - G9) de seis ratas cada una, y se administraron con APAP y TT por vía oral durante 30 días de la siguiente manera: Control (2 ml de solución salina normal), APAP (470 mg / kg), APAP (470 mg / kg) + selenio (2 mg / kg), APAP (470 mg / kg) + TT (98 mg / kg), APAP (470 mg / kg) + selenio (2 mg / kg) + TT (98 mg / kg), APAP (470 mg / kg) + silimarina (200 mg / kg), selenio (2 mg / kg), TT (98 mg / kg) y silimarina (200 mg / kg). Los resultados demostraron que la exposición de las ratas a la dosis terapéutica de APAP durante 30 días causó cambios histopatológicos significativos paralelos a parámetros elevados de química sanguínea. La administración conjunta de extracto de selenio / TT mostró lesiones histopatológicas significativamente reducidas y niveles restaurados o disminuidos de los parámetros de química sanguínea. La histología hepática en el extracto de selenio / TT mostró una arquitectura hepática normal con cambios leves y las ratas tratadas con silimarina no mostraron cambios histopatológicos. La tinción histoquímica de PAS mostró que la hepatotoxicidad inducida por APAP se caracterizó por la pérdida de glucógeno de los hepatocitos. La suplementación con selenio / TT juega un papel potencial en la prevención de la pérdida de glucógeno inducido por APAP al aumentar la desintoxicación y eliminar los metabolitos reactivos. La administración conjunta de extracto de selenio / TT posee una propiedad hepatoprotectora significativa y mitiga la hepatotoxicidad inducida por APAP al mejorar su papel antioxidante y la integridad del tejido. La suplementación con selenio / TT podría representar un tratamiento efectivo contra la hepatotoxicidad inducida por APAP. Se necesitan más estudios para dilucidar el mecanismo exacto que subyace a la función protectora del extracto TT.

Quercetin protects against acetaminophen-induced acute nephrotoxicity associated with the inhibition of biomarkers of acute kidney injury in rats / La quercetina protege contra la nefrotoxicidad aguda inducida por acetaminofén asociada con la inhibición de biomarcadores de lesión renal aguda en ratas

Acetaminophen (also called paracetamol, or APAP) causes acute kidney injury after accidental or intentional ingestion of a toxic dose of the drug. We tested whether the antioxidant and anti-inflammatory agent, quercetin (QUR) given alone can protect against acute nephrotoxicity induced by APAP overdose in a rat model of APAP-induced acute kidney injury. Rats were either given a single dose of APAP (2 g/kg) before being sacrificed after 24 hours or were pre-treated for 7 days with QUR (50 mg/kg) before being given a single dose of APAP and then sacrificed 24 hours post APAP ingestion. Kidneys were examined by light microscopy after staining with hematoxylin and eosin (H&E) and collected blood samples were assayed for biomarkers of oxidative stress, inflammation, and kidney injury. H&E stained sections of kidney from the model group of rats (APAP) showed substantial damage to the kidney architecture as demonstrated by widening of Bowman's space, tubular dilatation, vacuolization of tubular epithelium, and congested dilated blood vessels, which were partially protected by QUR. In addition, APAP significantly (p<0.05) increased blood levels of urea, creatinine, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-a), and interleukin-6 (IL-6), which were significantly (p<0.05) reduced by QUR. These results indicate that quercetin partially protects against APAP-induced acute kidney injury in rats, which is associated with the inhibition of biomarkers of oxidative stress and inflammation and kidney injury.

El acetaminofeno (también llamado paracetamol o DCI) causa daño renal agudo después de la ingestión accidental o intencional de una dosis tóxica del medicamento. En el estudio analizamos si el agente antioxidante y antiinflamatorio, la quercetina (QUR) administrada sola, puede proteger contra la nefrotoxicidad aguda inducida por sobredosis de DCI en un modelo de rata. Las ratas recibieron una dosis única de DCI (2 g / kg) antes de ser sacrificadas después de 24 horas o fueron pretratadas durante 7 días con QUR (50 mg / kg) antes de recibir una dosis única de DCI y luego sacrificadas 24 horas post ingestión. Los riñones se examinaron mediante microscopía óptica después de la tinción con hematoxilina y eosina (H&E) y las muestras de sangre recolectadas se analizaron para detectar biomarcadores de estrés oxidativo, inflamación y daño renal. Las secciones de riñón teñidas con H&E del grupo modelo de ratas (DCI) mostraron un daño sustancial a la arquitectura del riñón, como lo demuestra la ampliación del espacio de Bowman, la dilatación tubular, la vacuolización del epitelio tubular y los vasos sanguíneos dilatados congestionados, que estaban parcialmente protegidos por QUR. Además, DCI aumentó significativamente (p <0,05) los niveles sanguíneos de la urea, creatinina, malondialdehído (MDA), factor de necrosis tumoral alfa (TNF-a) e interleucina-6 (IL-6), los que fueron reducidos significativamente (p < 0,05) por QUR. Estos resultados indican que la quercetina protege parcialmente contra la lesión renal aguda inducida por DCI en ratas, asociada con la inhibición de biomarcadores de estrés oxidativo, inflamación y lesión renal.

Acetaminophen induces alterations to the renal tubular ultrastructure in a rat model of acute nephrotoxicity protected by resveratrol and quercetin / El acetaminofeno induce alteraciones en la ultraestructura tubular renal en un modelo de rata con nefrotoxicidad aguda protegida por resveratrol y quercetina

Acetaminophen (also called paracetamol, or APAP) induced nephrotoxicity is reported after accidental or intentional ingestion of an overdose of the drug. Renal tubular ultrastructural alterations induced by APAP overdose associated with the induction of biomarkers of kidney injury have not been investigated before. Also, we investigated whether the combined polyphenolic anti-inflammatory and antioxidants agents, resveratrol (RES) and quercetin (QUR) can protect against APAP-induced acute kidney injury. The model group of rats received a single dose of APAP (2 g/kg), whereas the protective group of rats was pre-treated for 7 days with combined doses of RES (30 mg/kg) and QUR (50 mg/kg) before being given a single dose of APAP. All rats were then sacrificed one day post APAP ingestion. Harvested kidney tissues were prepared for transmission electron microscopy (TEM) staining and blood samples were assayed for urea, creatinine, and biomarkers of inflammation and oxidative stress. TEM images and blood chemistry analysis showed that APAP overdose induced kidney damage as demonstrated by substantial alterations to the proximal convoluted tubule ultrastructure, and a significant (p<0.05) increase in urea, creatinine, tumor necrosis factor-alpha (TNF-a), and malondialdehyde (MDA) blood levels, which were protected by RES+QUR. These findings indicate that APAP induces alterations to the renal tubular ultrastructure, which is inhibited by resveratrol plus quercetin, which also decreases blood levels of kidney injury biomarkers.

El objetivo de este trabajo fue estudiar la nefrotoxicidad inducida por acetaminofeno (también llamado paracetamol o APAP) después de la ingestión accidental o intencional de una sobredosis de la droga. Las alteraciones ultraestructurales tubulares renales inducidas por sobredosis de APAP asociadas con la inducción de biomarcadores de daño renal no se han investigado. Además, estudiamos si los agentes combinados antiinflamatorios y antioxidantes polifenólicos, el resveratrol (RES) y la quercetina (QUR) pueden proteger contra la lesión renal aguda inducida por APAP. El grupo modelo de ratas recibió una dosis única de APAP (2 g / kg), mientras que el grupo protector de ratas se trató previamente durante 7 días con dosis combinadas de RES (30 mg / kg) y QUR (50 mg / kg) antes de recibir una dosis única de APAP. Todas las ratas se sacrificaron un día después de la ingestión de APAP. Los tejidos renales fueron preparados para el análisis a través de la microscopía electrónica de transmisión (MET). En las muestras de sangre se determinaron la urea, creatinina y los biomarcadores de inflamación y estrés oxidativo. Las imágenes MET y el análisis químico de la sangre mostraron que la sobredosis de APAP inducía daño renal, como lo demuestran las alteraciones sustanciales en la ultraestructura del túbulo contorneado proximal, y además, de un aumento significativo (p <0,05) de la urea, creatinina, factor de necrosis tumoral alfa y niveles sanguíneos de malondialdehído, protegidos por RES + QUR. Estos hallazgos indican que APAP induce alteraciones en la ultraestructura tubular renal, inhibida por el resveratrol más quercetina, que también disminuye los niveles sanguíneos de biomarcadores de daño renal.

Suppression of hepatic apoptosis induced by acetaminophen using a combination of resveratrol and quercetin: an association of oxidative stress and interleukin-11 / Suspensión de la apoptosis hepática inducida por acetaminofén mediante una combinación de resveratrol y quercetina: una asociación de estrés oxidativo e interleucina-1

We sought to determine whether the combined polyphenolic compounds, resveratrol and quercetin can substantially protect against modulation of hepatic biomarkers of apoptosis and survival, p53-Bax axis and B-cell lymphoma 2 (Bcl-2) in an animal model of acetaminophen-induced acute liver injury via the association of oxidative stress and interleukin-11 (IL-11). The model group of rats received a single dose of acetaminophen (2 g/kg), whereas the protective group of rats was pre-treated for 7 days with combined doses of resveratrol (30 mg/kg) and quercetin (50 mg/kg) before being given a single dose of acetaminophen. All rats were then sacrificed 24 hours post acetaminophen ingestion. Acetaminophen overdose induced acute liver injury as demonstrated by profound liver parenchymal damage and increased levels of the liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Acetaminophen significantly (p<0.05) modulated malondialdehyde (MDA), p53, apoptosis regulator Bax, Bcl-2, IL-11, interleukin-6 (IL-6), ALT, AST, superoxide dismutase (SOD), and glutathione peroxidase (GPx), which were significantly protected by resveratrol plus quercetin. We further demonstrated a significant (p<0.01) correlation between IL-11 scoring and the levels of p53, Bax, Bcl-2, and MDA. Thus, resveratrol plus quercetin effectively protect against acetaminophen-induced apoptosis, which is associated with the inhibition of oxidative stress and IL-11.

En el estudio se intentó determinar si los compuestos polifenólicos combinados, el resveratrol y la quercetina pueden proteger sustancialmente contra la modulación de los biomarcadores hepáticos de apoptosis y supervivencia, el eje p53-Bax y el linfoma de células B 2 (Bcl-2) en un modelo animal de lesión hepática aguda inducida por acetaminofén, a través de la asociación del estrés oxidativo y la interleucina-11 (IL-11). El grupo modelo de ratas recibió una dosis única de acetaminofén (2 g / kg), mientras que el grupo protector de ratas fue tratado durante 7 días con dosis combinadas de resveratrol (30 mg / kg) y quercetina (50 mg / kg) antes de recibir una dosis única de acetaminofén. Todas los animales fueron sacrificados 24 horas después de la ingestión de acetaminofén. La sobredosis de acetaminofén indujo una lesión hepática aguda, como se observó en el daño profundo del parénquima hepático y el aumento de los niveles de las enzimas en la lesión hepática, alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). Acetaminofén moduló significativamente (p <0.05) malondialdehído (MDA), p53, regulador de apoptosis Bax, Bcl2, IL-11, interleucina-6 (IL-6), ALT, AST, superóxido dismutasa (SOD) y glutatión peroxidasa ( GPx), los que se encontraron significativamente protegidos por el resveratrol y quercetina. Además se determinó una correlación significativa (p <0.01) entre la puntuación de IL-11 y los niveles de p53, Bax, Bcl-2 y MDA. En conclusión, el resveratrol más la quercetina protegen de manera efectiva contra la apoptosis inducida por acetaminofén, asociada con la inhibición del estrés oxidativo y la IL-11.

Possible protective effect of olive leaves extract on paracetamol induced hepatotoxicity in male albino rats / Possível efeito protetor do extrato de folhas de oliveira na hepatotoxicidade induzida por paracetamol em ratos albinos machos

Paracetamol (PCM) overdose can cause hepatotoxicity with oxidative stress; the present study was carried out to establish the possible protective effect of olive leaves extract (OLE) on toxicity induced by paracetamol in adult male rats. Twenty four adult male rats were divided into four equal groups; control, olive leaves extract group, paracetamol group and olive leaves extract plus paracetamol group. Some biochemical parameters and liver histopathology were evaluated. PCM treatment significantly increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), urea, creatinine and alpha-fetoprotein. Paracetamol was found to significantly increase malonaldehyde (MDA) and decrease glutathione reductase (GR) activity in tissue and significantly decrease total antioxidant capacity (TAC) and superoxide dismutase (SOD) in serum. Administration of OLE caused a significant decrease serum AST, ALT enzyme, total bilirubin, GGT, LDH, creatinine, urea, alpha-fetoprotein. Also, amelioration of oxidant ­ antioxidant status with olive leaves extract was observed in addition to a significant decrease in MDA and a significant increase in TAC in liver tissue with a significant increase in glutathione reductase (GR) and SOD in serum compared to paracetamol treated group The chemical pathological changes were in step with histopathological observation suggesting marked hepatoprotective result of olive leaves extract. It could be concluded that olive leaves extract (OLE) treatment may be effective in decreasing hepatic injury and oxidative stress induced by paracetamol overdose in male albino rats

A sobredosagem de paracetamol (PCM) pode causar hepatotoxicidade com estresse oxidativo; o presente estudo foi realizado para estabelecer o possível efeito protetor do extrato de folhas de oliveira (OLE) na toxicidade induzida pelo paracetamol em ratos machos adultos. Vinte e quatro ratos machos adultos foram divididos em quatro grupos iguais: controle, grupo extrato de folhas de oliveira, grupo paracetamol e extrato de folhas de oliveira mais grupo paracetamol. Alguns parâmetros bioquímicos e histopatologia hepática foram avaliados. O tratamento com PCM aumentou significativamente aspartato aminotransferase sérica (AST), alanina aminotransferase (ALT), bilirrubina total, gama-glutamiltransferase (GGT), lactato desidrogenase (LDH), uréia, creatinina e alfa-fetoproteína. Verificou-se que o paracetamol aumenta significativamente o malonaldeído (MDA) e diminui a atividade da glutationa redutase (GR) no tecido e diminui significativamente a capacidade antioxidante total (TAC) e a superóxido dismutase (SOD) no soro. A administração de OLE causou uma diminuição significativa de AST, enzima ALT, bilirrubina total, GGT, LDH, creatinina, uréia, alfa-fetoproteína. Também foi observada melhora do status oxidante - antioxidante com extrato de folhas de oliveira, além de uma diminuição significativa no MDA e um aumento significativo no TAC no tecido hepático, com um aumento significativo na glutationa redutase (GR) e SOD no soro em comparação ao grupo tratado com paracetamol. As alterações patológicas químicas acompanharam a observação histopatológica, sugerindo resultado hepatoprotetor acentuado do extrato de folhas de oliveira. Pode-se concluir que o tratamento com extrato de folhas de oliveira (OLE) pode ser eficaz na diminuição da lesão hepática e do estresse oxidativo induzido pela overdose de paracetamol em ratos albinos machos

Inhibition of paracetamol-induced acute kidney damage in rats using a combination of resveratrol and quercetin / Inhibición de daño renal agudo inducido por paracetamol en ratas usando una combinación de resveratrol y quercetina

Paracetamol (also called acetaminophen, or APAP) overdose causes acute damage to the liver and kidneys in both humans and experimental animal models via the induction of the oxidative stress pathway. We sought to determine whether the combined antioxidants and anti-inflammatory compounds, resveratrol (RES) and quercetin (QUR) can protect against kidney injury induced by a toxic dose of APAP in a rat model of APAP-induced acute kidney injury. Rats were either received a single dose of APAP (2 g/kg) before being sacrificed after 24 hours or were pre-treated for 7 days with combined doses of RES (30 mg/kg) and QUR (50 mg/kg) before being given a single dose of APAP and then sacrificed 24 hours post APAP ingestion. Harvested kidney tissues were prepared for light microscopy staining, and tissue samples were assayed for (i) biomarkers of oxidative stress and antioxidant, malondialdehyde (MDA) and superoxide dismutase (SOD); and (ii) biomarkers of inflammation, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Hematoxylin and eosin (H&E) stained images showed that APAP overdose induced acute kidney injury as demonstrated by widening of glomeruli space (Bowman space), tubular dilatation, numerous cellular debris in the renal tubules with tubular epithelial degeneration, and vacuolization, which were effectively protected by RES+QUR except a partial protection of the glomeruli space was observed. In addition, APAP significantly (p<0.05) modulated tissue levels of MDA, SOD, TNF-α, and IL-6, which were protected by RES+QUR. Furthermore, a significant (p<0.0001) positive correlation was observed between glomeruli space and TNF-α, (r=0.8899), IL-6 (r=0.8986), and MDA (r=0.8552), whereas glomeruli space scoring versus SOD showed negative correlation (r= - 0.7870). We conclude that resveratrol plus quercetin substantially protects against APAP-induced acute kidney injury in rats, possibly via the augmentation of antioxidants and inhibition of oxidative stress and inflammation.

La sobredosis de paracetamol (también llamado acetaminofen o APAP) causa un daño agudo en el hígado y los riñones, tanto en humanos como en modelos animales experimentales, a través de la inducción de la vía del estrés oxidativo. Intentamos determinar si los antioxidantes y los compuestos antiinflamatorios combinados, el resveratrol (RES) y la quercetina (QUR) pueden proteger contra la lesión renal inducida por una dosis tóxica de APAP en un modelo de rata de lesión renal aguda inducida por APAP. Las ratas recibieron una dosis única de APAP (2 g / kg) antes de ser sacrificadas después de 24 horas o se trataron previamente durante 7 días con dosis combinadas de RES (30 mg / kg) y QUR (50 mg / kg), antes de ser tratadas, se administró una dosis única de APAP y luego fueron sacrificadas 24 horas después de la ingestión. Los tejidos renales recolectados se tiñeron con H-E y fueron observados a través de microscopía óptica. Las muestras de tejido se analizaron para (i) biomarcadores de estrés oxidativo y antioxidante, malondialdehído (MDA) y superóxido dismutasa (SOD); y (ii) biomarcadores de inflamación, factor de necrosis tumoral alfa (TNF-α) e interleucina-6 (IL-6). Las imágenes teñidas con H & E mostraron que la sobredosis de APAP indujo daño renal agudo como lo demuestra la ampliación del espacio glomerular, la dilatación tubular, numerosos desechos celulares en los túbulos renales con degeneración epitelial tubular y la vacuolización, que se protegieron eficazmente con RES + QUR Se observó una protección parcial del espacio glomerular. Además, APAP modificó significativamente (p <0.05) los niveles tisulares de MDA, SOD, TNF-α e IL-6, que estaban protegidos por RES + QUR. Además, se observó una correlación positiva significativa (p <0,0001) entre el espacio glomerular y el TNF-α, (r = 0,8899), IL-6 (r = 0,8986) y MDA (r = 0,8552), mientras que la puntuación del espacio glomerular versus SOD mostró correlación negativa (r = - 0,7870). Concluimos que el resveratrol más quercetina protege sustancialmente contra la lesión renal aguda inducida por APAP en ratas, posiblemente a través del aumento de antioxidantes y la inhibición del estrés oxidativo y la inflamación.

Eficácia hepatoprotetora do extrato metanólico de Indigofera suffruticosa (Mill) em lesão hepática induzido por paracetamol em camundongos / Hepatoprotective efficacy of methanolic extract of indigofera suffruticosa (mill) on paracetamol-induced liver damage in mice

ABSTRACT BACKGROUND: Indigofera suffruticosa Mill (Fabaceae) is abundant in northeastern Brazil and popularly used in the treatment of infectious and inflammatory processes. Several biological properties, such as anti-inflammatory, anticancer, antitumor, hepatoprotective and low toxicity, are reported for this plant. OBJECTIVE: This study investigated hepatoprotective activity and the antioxidant effect of methanolic extract of I. suffruticosa leaves (MEIS) on Swiss albino mice submitted to experimental models of acetaminophen-induced liver injury. METHODS: MEIS (50 mg/kg; p.o.) was standardized according to the LD50 and its hepatoprotective property on Swiss albino mice evaluated during a 7-day period. On the eighth day, the acetaminophen-induced hepatic injury was performed. Histomorphometric analysis of liver tissue, antioxidant activity and serum levels of alanine aminotransferase (AST), aspartate aminotransferase (ALT) and bilirubin were measured. RESULTS: MEIS (50 mg/kg; p.o.) restored serum enzyme levels and results were close to those of positive control (silymarin) when compared to the negative control. Histopathological and histomorphometric analyzes confirmed MEIS hepatoprotective activity, showing reorganization of structural units of cells, nuclei and sinusoidal capillaries of hepatocytes, reducing the damage on liver tissue and increasing organ regeneration rate. MEIS showed high antioxidant potential at concentrations of 1000 and 500 µg/mL. CONCLUSION: This study suggests that MEIS has hepatoprotective activity and high antioxidant potential.

RESUMO CONTEXTO: Indigofera suffruticosa Mill (Fabaceae) é abundante no nordeste do Brasil e popularmente utilizada no tratamento de processos infecciosos e inflamatórios. Várias propriedades biológicas, como anti-inflamatório, anticâncer, antitumoral, hepatoprotetor e baixa toxicidade, são relatadas para esta planta. OBJETIVO: Este estudo investigou a atividade hepatoprotetora e o efeito antioxidante do extrato metanólico de folhas de I. suffruticosa (MEIS) em camundongos albinos suíços submetidos a modelos experimentais de lesão hepática induzida por paracetamol. MÉTODOS: O MEIS na dose de 50 mg/kg (via oral) foi padronizado de acordo com a LD50 e sua propriedade hepatoprotetora em camundongos albinos Swiss avaliados durante um período de sete dias. No oitavo dia, a lesão hepática foi induzida por paracetamol em todos grupos pre-tratados. Foram medidos os níveis sericos enzimaticos, alanina aminotransferase, aspartato aminotransferase e bilirrubina, análise histomorfométrica do tecido hepático e atividade antioxidante. RESULTADOS: O MEIS restaurou os níveis séricos de enzimas e os resultados foram próximos aos do controle positivo (silimarina) quando comparados ao controle negativo. As análises histopatológicas e histomorfométricas confirmaram a atividade hepatoprotetora do MEIS, mostrando reorganização das unidades estruturais das células, núcleos e capilares sinusoidais dos hepatócitos, reduzindo os danos no tecido hepático e aumentando a taxa de regeneração de órgãos. O MEIS apresentou alto potencial antioxidante nas concentrações de 1000 e 500 µg/mL. CONCLUSÃO: Este estudo sugere que I. suffruticosa tem atividade hepatoprotetora e alto potencial antioxidante.

Antioxidant and hepatoprotective effects of ethanolic and ethyl acetate stem bark extracts of Copaifera multijuga (Fabaceae) in mice / Efeitos antioxidante e hepatoprotetor dos extratos brutos etanólico e acetato de etila da casca do caule da Copaifera multijuga(Fabaceae) em camundongos

The properties of oil-resin of copaiba, Copaifera multijuga are commonly mentioned in the literature, but there are few studies on extracts from its stem bark. We evaluated the antioxidant effects of ethanolic (EE) and ethyl acetate (EA) crude stem bark extracts from copaiba and compared them to rutin in a paracetamol (PCM)-induced oxidative stress model in mice. All test comparisons differed significantly. Hepatic catalase (CAT) and glutathione-S-transferase (GST) activity decreased in the PCM group, and there was an increase of protein carbonyls in the liver, kidney and brain. However, the protein carbonyls decreased in the liver for the PCM + EE group, in the kidneys for the PCM + EA and PCM + Rutin groups, and in the brain for all treatments. Hepatic GSH decreased in the PCM group and increased in the PCM + EE group. The extracts showed a positive effect on ascorbic acid (ASA), since they were able to restore the levels of parameters that had been changed by PCM. There was an increase of ALT and AST activity in the plasma within the PCM group. Even though ALT decreased in the PCM + Rutin, PCM + EE and PCM + EA groups, EE and EA did not have an effect on AST. The strongest antioxidant effect was observed for EE, due to the presence of the phenolic compounds epicatechin and epiafzelechin, as well as the highest concentration of total phenols and an excellent antioxidant potential observed in the DPPH· test.

As propriedades do óleo-resina da copaíba, Copaifera multijuga são comumente citadas na literatura, mas há poucos estudos sobre extratos da casca do caule. Avaliamos os efeitos antioxidantes de extratos brutos etanólico (EE) e acetato de etila (EA) da casca do caule da copaíba e os comparamos à rutina no modelo de estresse oxidativo induzido por paracetamol (PCM) em camundongos. Todas as comparações de teste diferiram significativamente. A atividade da catalase hepática (CAT) e da glutationa-S-transferase (GST) diminuiu no grupo PCM, e houve um aumento de proteínas carboniladas no fígado, rim e cérebro. No entanto, as proteínas carboniladas diminuíram no fígado para o grupo PCM + EE, nos rins para os grupos PCM + EA e PCM + rutina, e no cérebro para todos os tratamentos. A GSH hepática diminuiu no grupo PCM e aumentou no grupo PCM + EE. Os extratos mostraram um efeito positivo sobre o ácido ascórbico (ASA), uma vez que foram capazes de restaurar os níveis dos parâmetros que foram alterados pelo PCM. Houve um aumento da atividade de ALT e AST no plasma dentro do grupo PCM. Embora a ALT tenha diminuído nos grupos PCM + rutina, PCM + EE e PCM + EA, EE e EA não afetaram a AST. O efeito antioxidante mais forte foi observado para o EE, provavelmente devido à presença dos compostos fenólicos epicatequina e epiafzelequina, assim como à maior concentração de fenóis totais e um excelente potencial antioxidante observado no teste DPPH·

Time-course changes in the expression levels of miR-122, -155, and -21 as markers of liver cell damage, inflammation, and regeneration in acetaminophen-induced liver injury in rats

Drug-induced liver injury (DILI) is a significant threat to patient health and a major concern during drug development. Recently, multiple circulating microRNAs (miRNAs) have been reported to be potential biomarkers for DILI. To adapt and validate miRNAs for clinical use, we investigated the time-course changes in miR-122 expression levels in an acetaminophen-induced liver injury model in rats. In addition, miR-155 and miR-21 were evaluated as makers of inflammation and regeneration, respectively, to characterize liver status. Our results revealed that miR-122 is an early and sensitive biomarker of hepatocellular injury at a stage when alanine transaminase, aspartate transaminase, and total bilirubin were not detectable. However, no significant differences in the expression levels of other miRNAs (miR-155 and -21) were observed between treatment and vehicle groups. Collectively, these time-course changes in the expression levels of miRNAs may be useful as markers for clinical decision-making, in the diagnosis and treatment of DILI.

Attenuation of copaiba oil in hepatic damage in rats

PURPOSE: To investigate the copaiba oil on the hepatic damage induced by acetaminophen, comparing against corn oil. METHODS: Fifty four rats were distributed into nine study groups (N=6): control group, that didn't receive the acetaminophen; Acetaminophen Group, that only received the acetaminophen; Prophylactic Copaiba Group 1, that received copaiba oil two hours before the acetaminophen; Prophylactic Copaiba Group 7, that received copaiba oil seven days, once by day, before the acetaminophen; Therapy Copaiba Group, that received the copaiba oil two hours after the acetaminophen, the corn's groups were similar than copaiba oil groups; and N-Acetyl-Cysteine Group, that received the N-Acetyl-Cysteine two hours after the acetaminophen. Euthanasia was performed after 24 hours. The serum levels transaminases, bilirubin and canalicular enzymes were analyzed. RESULTS: The prophylactic copaiba group 7, therapy copaiba group and N-Acetyl-Cysteine Group showed amounts of AST and ALT similar to the control group; and the prophylactic copaiba group 1 and corn's groups showed similar levels to the acetaminophen group. There was no significant difference between the groups regarding the amount of alkaline phosphatase and ɤ GT (p>0.05). The therapy copaiba group showed the highest levels of total bilirubin and was statistically different from the other groups (p<0.01). CONCLUSIONS: Copaiba oil administered prophylactically for seven days and therapeutically 2 hours after the acetaminophen acute intoxication offered a potential hepato protection against paracetamol-induced hepatic damage, normalizing the biochemical parameters similarly to N-Acetyl-Cysteine, and the treatment with corn oil shows no effect on the liver damage. .

Evaluación del potencial hepatoprotector de la Mentha piperita L previo a la inducción de hepatotoxicidad con acetaminofen / Evaluation of hepatoprotective potential of Mentha piperita L before induction of hepatotoxicity with acetaminophen

A preclinical pharmacological study was conducted to evaluate the hepatoprotective effect of Mentha piperita L. against paracetamol induced toxicity. Adult male NMRI mice who were administered orally soft plant extracts in doses of 200mg/kg and 400mg/kg, three consecutive days prior to the induction of hepatotoxicity were used. Clinical signs of toxicity, hepatic biochemical parameters and morphological analysis of the liver was evaluated. The biochemical parameters analyzed showed significant differences, but none of the two groups showed a similar untreated control group behavior. No macroscopic changes in the liver were confirmed. Microscopically, the study groups with Mentha piperita L. showed mild to moderate damage with significant differences from the untreated control group. The evaluation of hepatoprotective potential on the M. piperita L. extract at doses studied did not behave as hepatoprotective agent...

Se realizó un estudio farmacológico preclínico para evaluar el efecto hepatoprotector de Mentha piperita L. frente a la toxicidad inducida por el paracetamol. Se emplearon ratones adultos machos NMRI a los que se administró por vía oral extractos blandos de la planta a dosis de 200 mg/kg y 400 mg/kg, tres días consecutivos previos a la inducción de la hepatotoxicidad. Se evaluaron los signos clínicos de toxicidad, parámetros bioquímicos hepáticos y el análisis morfológico del hígado. Los parámetros bioquímicos analizados mostraron diferencias altamente significativas, pero ninguno de los dos grupos presentaron un comportamiento similar al grupo control no tratado. No se confirmaron alteraciones macroscópicas del hígado. A nivel Microscópico, los grupos en estudio con Mentha piperita L. presentaron daños de leves a moderados con diferencias significativas respecto al grupo control no tratado. Se puede afirmar que según la evaluación del potencial hepatoprotector del extracto de M. piperita L. a las dosis estudiadas no se comportó como agente hepatoprotector...