Roles of Suaeda vermiculata Aqueous-Ethanolic Extract, Its Subsequent Fractions, and the Isolated Compounds in Hepatoprotection against Paracetamol-Induced Toxicity as Compared to Silymarin.

Suaeda vermiculata, a halophyte consumed by livestock, is also used by Bedouins to manage liver disorders. The aqueous-ethanolic extract of S. vermiculata, its subsequent fractions, and pure compounds, i.e., pheophytin-A (1), isorhamnetin-3-O-rutinoside (2), and quercetin (3), were evaluated for their hepatoprotective efficacy. The male mice were daily fed with either silymarin, plant aq.-ethanolic extract, fractions, pure isolated compounds, or carboxyl methylcellulose (CMC) for 7 days (n = 6/group, p.o.). On the day 7th of the administrations, all, except the intact animal groups, were induced with hepatotoxicity using paracetamol (PCM, 300 mg/kg). The anesthetized animals were euthanized after 24 h; blood and liver tissues were collected and analysed. The serum aspartate transaminase (AST) and alanine transaminase (ALT) levels decreased significantly for all the S. vermiculata aq.-ethanolic extract, fraction, and compound-treated groups when equated with the PCM group (p < 0.0001). The antioxidant, superoxide dismutase (SOD), increased significantly (p < 0.05) for the silymarin-, n-hexane-, and quercetin-fed groups. Similarly, the catalase (CAT) enzyme level significantly increased for all the groups, except for the compound 2-treated group as compared to the CMC group. Also, the glutathione reductase (GR) levels were significantly increased for the n-butanol treated group than for the PCM group. The oxidative stress biomarkers, lipid peroxide (LP) and nitric oxide (NO), the inflammatory markers, IL-6 and TNF-α, and the kidney's functional biomarker parameters remained unchanged and did not differ significantly for the treated groups in comparison to the PCM-induced toxicity bearing animals. All the treated groups demonstrated significant decreases in cholesterol levels as compared to the PCM group, indicating hepatoprotective and antioxidant effects. The quercetin-treated group demonstrated significant improvement in triglyceride level. The S. vermiculata aq.-ethanolic extract, fractions, and the isolated compounds demonstrated their hepatoprotective and antioxidant effects, confirming the claimed traditional use of the herb as a liver protectant.

Therapeutic role of Typha elephantina leaves aqueous extract in paracetamol intoxicated rabbits.

Present study is aimed to investigate the hepatoprotective and hematopoietic effect of Typha elephantina leaves aqueous (T.E.AQ), extract in paracetamol (PCM) intoxicated rabbits. Experimental animals were divided into various groups. The blood was taken on day 7th (W1=Week 1), day 14th (W2 = week 2) and day 21st (W3 = week 3) of treatments and was analyzed for all hematological and serum biochemical markers. PCM administration caused marked increase in the levels of serum biochemical and hematological parameters. The leaves of T.E.AQ extract at dose rate 300mg/kg body weight significantly (P<0.05) reduced the elevated levels of serum biochemical and hematological indices towards normal values on third week (day 21st) of treatment while treatment in the first two weeks revealed non-significant effects even at all doses of extract. The levels of glutathione (GSH) and radical scavenging activity (RSA) were reduced and thiobarbituric acid reactive substances (TBARS) levels was high in the PCM feed animals. Administration of (T.E.AQ) extract at high dose (300mg/kg) significantly regulated and normalized these antioxidant values. The antioxidant capacity of (TE.AQ) extract, showed increase inhibition against various extract concentrations on the basis of percent scavenging of (DPPH) free radical. The histological sections of liver further supported the hepatoprotective activity of extract.

Paracetamol overdose in the newborn and infant: a life-threatening event.

PURPOSE: Paracetamol is the only drug recommended to treat fever in neonates. At recommended doses, paracetamol has not been associated with liver injury in neonates, while hepatotoxicity may occur after intake of a single high dose or multiple excessive doses. The aim of this narrative review is to critically analyze and summarize the available literature on newborns and infants exposed to supratherapeutic doses of paracetamol, with special focus on their clinical features, outcome, and management. METHODS: The PubMed, SCOPUS, and Google Scholar search engines were used to collect data, without time limitation. The following keywords were used: paracetamol/acetaminophen, overdose, hepatotoxicity, N-acetylcysteine, newborn, infant. RESULTS: The literature search identified a total of 27 case reports, a number of review articles, and few other relevant publications. Neonatal poisoning from paracetamol resulted from transplacental drug transfer after maternal overdose in some published cases, while it was the consequence of medication errors in other cases. Newborns and infants who have received a single overdose and have paracetamol concentrations below the Rumack-Matthew nomogram limits are at low risk of serious hepatic damage, while those who have recently ingested more than one supratherapeutic dose of paracetamol should be managed with caution. The treatment of choice for paracetamol poisoning is N-acetylcysteine, a specific antidote which reduces paracetamol hepatotoxic effects. N-Acetylcysteine should be given according to specific regimens through weight-based dosing tables. CONCLUSIONS: Caution should be used when paracetamol is administered to the newborn. In the event of an overdose, careful patient monitoring and personalization of post-overdose procedures are recommended.

Hepatoprotective effect of Pandanus odoratissimus seed extracts on paracetamol-induced rats.

CONTEXT: Pandanus odoratissimus Linn. (Pandanaceae) seed extract is known to have antioxidant activities. However, the potential hepatoprotective effect is still unclear. OBJECTIVE: To investigate the hepatoprotection aspect of P. odoratissimus methanol extract towards paracetamol-induced rats. MATERIALS AND METHODS: Thirty male Sprague-Dawley rats were randomly divided into six equal groups: one group served as the healthy control and five groups with hepatotoxicity (hepatotoxic control and 4 treatment groups). The oral treatment of paracetamol-induced hepatotoxicity of 3 g/kg using three different concentrations of P. odoratissimus (300, 600 and 900 mg/kg), and silymarin (200 mg/kg) groups were administered once a day for 14 days. Enzyme activities and protein levels in serum were determined in rats at the end of the treatments. The histopathology of rat livers was observed under an electron microscope with 10× magnification. RESULTS: Pandanus odoratissimus significantly decreased the serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT) activities in induced-paracetamol rat serum (p < 0.05). Moreover, P. odoratissimus significantly decreased total bilirubin and direct bilirubin levels (p < 0.05). It significantly blocked the decline of serum albumin and protein levels (p < 0.05). Histopathological changes amplified paracetamol-induced liver damage and the hepatoprotective effect of P. odoratissimus in the liver. DISCUSSION AND CONCLUSIONS: Pandanus odoratissimus improved the hepatoprotective effect in a concentration-dependent manner by reducing related hepatic enzyme and protein markers, suggesting as a useful agent in hepatotoxicity treatment, and it can be generalized to a broader study population in different hepatotoxic animal models.

Hepatoprotective effect of Omega-3 PUFAs against acute paracetamol-induced hepatic injury confirmed by FTIR.

Acute paracetamol over dose-induced hepatotoxicity is considered an important medical hazard especially among women. Omega-3 long-chain polyunsaturated fatty acids (Omega-3 PUFAs) daily doses are nowadays recommended for their antioxidant and anti-inflammatory potentials. Fourier transform infrared (FTIR) spectroscopy is considered a reliable method in analyzing cellular alterations and is now efficiently used to diagnose several diseases and the efficacy of drugs even in the early stages. The aim of our study was to evaluate the hepatoprotective effect of Omega-3 PUFAs against paracetamol-induced hepatotoxicity in rats confirmed through measuring protein alterations in hepatocytes by FTIR. Rats were pretreated with Omega-3 PUFAs (50 and 100 mg/kg) for 21 days prior to oral ingestion of paracetamol. FTIR results revealed that Omega-3 PUFAs (50 mg/kg) limited the toxic effects of paracetamol by restoring the hepatic amide I to amide II ratio. In addition; biochemical analyses demonstrated that serum ALT, AST, Cholesterol, LDL-cholesterol and Il-6 levels as well as hepatic TNF-α, MDA, NOx levels were decreased. Besides; serum HDL-cholesterol level and hepatic GSH level were increased. Histopathological examinations of hepatic sections validated the hepatoprotective potential. The overall effect of this dose was comparable to those of the usual recommended hepatoprotective supplement; silymarin. In conclusion; it would be recommended to use Omega-3 PUFAs in low doses on daily bases as a hepatoprotective agent.

Dibenzazepine combats acute liver injury in rats via amendments of Notch signaling and activation of autophagy.

Paracetamol is a commonly used over-the-counter analgesic and antipyretic drug. Nevertheless, an overdose of paracetamol leads to hepatic necrosis that can be lethal. This study aimed to assess the potential hepatoprotective effects of dibenzazepine, a Notch inhibitor, against acute liver injury in rats via interfering with oxidative stress, inflammation, apoptosis, autophagy, and Notch signaling. Silymarin (200 mg/kg, p.o.) or dibenzazepine (2 mg/kg, i.p.) were administered to rats for 5 days before a single hepatotoxic dose of paracetamol (800 mg/kg, i.p.). Pretreatment with silymarin and dibenzazepine significantly mitigated oxidative stress, inflammatory and apoptotic markers induced by paracetamol hepatotoxicity where dibenzazepine showed greater repression of inflammation. Furthermore, dibenzazepine was found to be significantly more efficacious than silymarin in inhibiting Notch signaling as represented by expression of Notch-1 and Hes-1. A significantly greater response was also demonstrated with dibenzazepine pretreatment with regard to the expression of autophagic proteins, Beclin-1 and LC-3. The aforementioned biochemical results were confirmed by histopathological examination. Autophagy and Notch signaling seem to play a significant role in protection provided by dibenzazepine for paracetamol-induced hepatotoxicity in rats, which could explain its superior results relative to silymarin. Graphical abstract.

The Effects of Silymarin on Acetaminophen-Induced Acute Hepatic and Renal Toxicities in Domestic Pigeons (Columba livia).

This study evaluated the effects of silymarin on acetaminophen-induced acute liver and kidney toxicities in domestic pigeons (Columba livia). Standard colorimetric methods with commercial kits were used to measure the serum activities or levels of biomarkers associated with liver and kidney damage, such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, urea, uric acid, total protein, albumin, and total cholesterol, in 21 pigeons randomly assigned into 3 groups (A, B, and C). Groups A and B were administered acetaminophen 3000 mg/ kg PO q24h at the beginning of the experiment (hour 0). Group B pigeons were further treated with silymarin 35 mg/kg, starting at 12 hours after acetaminophen exposure (post-AA), with the silymarin treatment continuing q12h for 3 days. Group C pigeons served as the control group and were given tap water as the placebo. Blood was collected from the pigeons at hours 0, 12, 24, 48, and 72 of the experiment for serum biochemistry analyses. The results showed that treatment of group B pigeons with silymarin decreased the serum levels of aspartate aminotransferase, alanine aminotransferase, urea, and uric acid compared with the untreated control (group A). It also prevented decreases in serum alkaline phosphatase, total protein, albumin, and cholesterol seen in Group A. Mortality, which was 86% in the untreated control (group A), was completely prevented in group B. It was concluded that silymarin remediated the effects of acetaminophen-induced acute toxic liver and kidney injuries, which may result in pigeon mortality.

Antidiabetic and hepatoprotective potential of whole plant extract and isolated compounds of Aeginetia indica.

BACKGROUND: Aeginetia indica, a perennial herb from the Orobanchaceae family, generally grows as a root parasite and is widely distributed in the forests of South and South-Asian countries. The plant has valuable uses in herbal medicine against various diseases, such as diabetes, liver diseases, and arthritis. AIM OF THE STUDY: The present study was designed to investigate the antidiabetic and hepatoprotective effects of the methanol extract of the whole plant of A. indica in a mouse model followed by the isolation of bioactive compounds and their in-silico studies. METHODS: The hepatoprotective effects were evaluated in a paracetamol-induced hepatotoxicity mouse model. The antidiabetic effects were examined by an oral glucose tolerance test and in an alloxan-induced diabetes mouse model. RESULTS: The plant extract, at a dose of 400 mg/kg, caused a significant reduction (p < 0.001) in liver enzyme concentrations, including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, similar to the effects of standard drug silymarin. The plant extract, at 400 mg/kg, also significantly reduced (p < 0.001) the fasting blood glucose concentration by 27.33 % after 3 h, compared with a reduction of 45.31 % in response to glibenclamide. In the alloxan-induced diabetes model mice, significant reductions (p < 0.05) in elevated glucose concentrations were observed on days 10 and 20 in mice treated with plant extract and glibenclamide. Chromatographic analyses and nuclear magnetic resonance (NMR) studies identified the presence of ß-sitosterol, stigmasterol, and oleic acid in the extract. The possible mechanism underlying the antidiabetic effects was revealed by molecular docking analyses examining the binding of ß-sitosterol and stigmasterol with sirtuin 4, an NAD-dependent deacylase enzyme that downregulates leucine-induced and glutamate dehydrogenase-induced insulin secretion. The binding affinities between sirtuin 4 and ß-sitosterol, stigmasterol, and NAD were found to be -8.6 kcal/mol, -7.2 kcal/mol and -9.5 kcal/mol, respectively, indicating the probable competition between NAD and the isolated components for sirtuin 4. CONCLUSION: The present study revealed that A. indica exerted protective effects against alloxan-induced diabetes and paracetamol-induced hepatotoxicity in mice, which supports the findings regarding the use of A. indica during traditional medical practice.

Hepatoprotective and antioxidant activities of Dicranopteris linearis leaf extract against paracetamol-induced liver intoxication in rats.

Context: Dicranopteris linearis L. (Gleicheniaceae) leaves have been reported to exert hepatoprotective activity.Objective: The hepatoprotective and antioxidant effects of ethyl acetate partition of D. linearis (EADL) are investigated.Materials and methods: EADL was subjected to antioxidant and anti-inflammatory studies, and phytochemical analyses. In vivo study involved six groups (n = 6) of overnight fasted Sprague Dawley rats. The test solutions [10% DMSO (normal), 10% DMSO (negative), 200 mg/kg silymarin (positive) or EADL (50, 250 or 500 mg/kg)] were administered orally once daily for 7 consecutive days followed by oral vehicle (only for normal) or hepatotoxic induction using 3 g/kg paracetamol (PCM).Results: EADL exerted ≈ 90% radical scavenging effects based on the DPPH and superoxide anion radical scavenging assays, high antioxidant capacity in the oxygen radical absorbance capacity assay (≈ 555,000 units), high total phenolic content (≈ 350 mg GAE/100 g extract) (p < 0.05), but low anti-inflammatory effect. EADL also attenuated PCM-induced liver intoxication as indicated by reduced level of serum liver enzymes; increased activity of endogenous enzymatic antioxidant (superoxide dismutase - 8.3 vs. 4.0 U/g tissue; catalase - 119 vs. 52 U/g tissue) and; reduced level of lipid peroxidation marker (2.7 vs. 5.0 µM). Preliminary screening of EADL revealed the presence of saponins, tannins and flavonoids with further HPLC analysis demonstrating the presence of rutin and quercetin.Discussion and conclusion: EADL exerted hepatoprotective and antioxidant activities; thus, these data support the potential use of D. linearis as a new source for future hepatoprotective drug development.

Can maternal exposure to paracetamol impair reproductive parameters of male rat offspring?

Paracetamol is a widely used medication during gestation and lactation periods for the treatment of pain and fever. Several studies have shown that exposure to paracetamol can increase the incidence of cryptorchidism and decrease testosterone production. Therefore, the present study aimed to evaluate if maternal treatment with paracetamol during gestation and gestation/lactation periods can alter reproductive and behavioral parameters in male offspring. Female Wistar rats were treated daily by gavage with water or paracetamol (350 mg/kg/day) during gestation (CTRG and PARG) or gestation/lactation periods (CTRGL and PARGL). There were significant differences in histomorphometry (increased volume and total length of the seminiferous tubules) and weight of testes (PARG group) and copulatory behavior and testosterone levels (PARG and PARGL groups) at PND 120. Therefore, the present study showed that maternal exposure to paracetamol has an impact on the reproductive system and sexual behavior of male adult offspring suggesting an impaired in sexual hypothalamic differentiation at the beginning of the development of the brain.

Inhibitory activity of black mulberry (Morus nigra) extract against testicular, liver and kidney toxicity induced by paracetamol in mice.

Black mulberry (Morus nigra) leaves is broadly used in traditional medicine worldwide. However, there are no scientific reports regarding testicular protection, hepato-and nephroprotective activities of M. nigra leaves. The present investigation was assessed the protective mechanism by which methanol extract from M. nigra leaves suppressed the damaging effects induced by paracetamol (APAP) in different mouse tissues. Male mice were orally given APAP (500 mg/kg) with or without M. nigra extract (150, 300, and 500 mg/kg) for four consecutive days. The results showed that crude extract possessed potent antioxidant activity (EC50 = 42.97 µg extract/mL) due to the presence of a high amount of polyphenol and flavonoid compounds. Gallic acid, chlorogenic acid, catechin, and rutin were isolated from the n-butanol fraction of M. nigra extract. Unexpectedly, oral administration of APAP did not induce chromosomal aberrations in mouse bone marrow; however, it produced damaging effects on testis, liver, and kidney tissues. Interestingly, M. nigra extract suppressed APAP-induced genotoxicity by lowering meiotic chromosomal aberrations in spermatocytes, morphological sperm abnormalities, and % DNA damage in comet tail in the liver and kidney tissues. The altered levels of glutathione S transferase activity, lipid peroxidation, liver, and kidney functions were significantly reversed when M. nigra was given to APAP group. The restoring of the histo-architectural distortions and decreasing over-expression of p53 protein as determined by immunohistochemistry in the liver, kidney, and testis sections were strengthened the protective activity of M. nigra extract. Conclusion, the bioactive components in the leaves of black mulberry appear to be a good candidate for genetic protection, treatment of oxidative stress-induced organotoxicity.

Hepatoprotective lignans and triterpenoids from the roots of Kadsura longipedunculata.

Two new tetrahydrobenzocyclooctabenzofuranone lignans (1-2), a new dibenzocyclooctadiene lignan (3) and three new schiartane-type triterpenoids (4-6), together with six known compounds (7-12), were isolated from the roots of Kadsura longipedunculata. Their structures were elucidated by extensive NMR and HRESIMS spectroscopic data analysis. The absolute configurations of these compounds were determined by comparison of the experimental and calculated ECD spectra. Compound 12 exhibited moderate hepatoprotective activity against N-acetyl-p-aminophenol (APAP)-induced toxicity in HepG2 cells with cell survival rates of 53.04%.

HEPATOPROTECTIVE EFFICACY OF METHANOLIC EXTRACT OF INDIGOFERA SUFFRUTICOSA (MILL) ON PARACETAMOL-INDUCED LIVER DAMAGE IN MICE.

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.

Chrysin Effect in Prevention of Acetaminophen-Induced Hepatotoxicity in Rat.

Acetaminophen is a commonly used analgesic drug that induces hepatotoxicity at high doses and produces the acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) through oxidase isoenzyme system. The antioxidant and anti-inflammatory activity of flavonoid chrysin has been reported in different studies. The present study was conducted to investigate the protective effect of chrysin on acute acetaminophen-induced hepatotoxicity. The cytotoxicity of chrysin on fibroblast cells was evaluated using MTT assay, and then, 54 rats were divided into nine groups of six, and acetaminophen (1500 mg/kg) was administered in all groups except for the control group, second and the seventh groups (40 mg/kg), and all groups were treated with chrysin for 14 days. Liver enzymes, inflammatory factors TNF-α and IL-2, and total antioxidant activity were measured in serum while liver tissue was histopathologically examined. Based on the MTT assay results, 31.25, 62.5, 125, 250, and 500 µg/mL chrysin had no adverse effects on healthy fibroblast cells (P < 0.05). Chrysin decreased the level of liver enzymes (ALT, AST, and ALP), which were previously increased after the use of acetaminophen (p < 0.05). The hepatoprotective effect and total antioxidant capacity increased in a dose-dependent manner and the effect of the highest concentration of chrysin was equal to the effect of silymarin (P < 0.05). TNF-α in groups 4 to 6 decreased in a dose-dependent manner (P = 0.04), and chrysin did not show any significant reducing effect on IL-2 compared to silymarin. Chrysin prevents the necrosis and injury of acute acetaminophen-induced hepatotoxicity by decreasing liver enzymes and TNF-α and increasing total antioxidant capacity and protecting the liver tissue.

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.

Effects of phenolic compounds from aqueous extract of Trifolium repens against acetaminophen-induced hepatotoxicity in mice.

The aqueous extract of Trifolium repens (TR) leaves was analyzed for the phenolic profile using reversed phase HPLC-DAD and administered to mice against acetaminophen-induced hepatoxicity. Twenty-four phenolic compounds were identified and quantified. The highest amounts present were of kaempferol-3-(caffeoyldiglucoside)-7-glucoside (983.7 µg/ml), followed by p-coumaroyl-4-glucoside (905.6 µg/ml) and daidzein-O-sulfate (808.3 µg/ml). The aqueous extract was administered to mice along with acetaminophen at different doses. Acetaminophen was found to significantly alter body weight, serum biochemistry, and hematological indices of mice, which were ameliorated by the co-administration of aqueous extract. Liver histopathological studies revealed that acetaminophen significantly induced toxicity, while TR aqueous extract provides curative functions. Lipid peroxidation and total reduced glutathione in the liver were also normalized by the aqueous extract of TR. The aqueous extract of TR was rich in important phenolic compounds, which can be used as a source of beneficial bioactive compounds with hepato-protective function. PRACTICAL APPLICATIONS: Acetaminophen has been widely used as antipyretic and analgesic. However, the major complication reported is hepatotoxicity. Synthetic or conventional drugs used for hepatic diseases or against hepatotoxicity are insufficient and causes severe side effects. For this purpose, traditional medicinal plants or nutraceuticals are used to decrease in the side effects of different hepatotoxic medicine are demanding. Food and neutraceuticals are rich in important polyphenolic compounds which are the best antioxidants. This study was aimed to evaluate the phenolic composition of aqueous extract of Trifolium repens and its potential protective action against the acetaminophen-induced toxicity in mice. This study showed for the first time that the aqueous extract of TR was protective against the hepatotoxicity induced by acetaminophen.

Hypothalamus - Response to early paracetamol exposure in male rats offspring.

One of the reasons for using paracetamol during pregnancy is fever. The brain structure responsible for maintaining proper body temperature, but also for controlling some endocrine aspects is hypothalamus. In this study we examined the effect of early pretreatment of paracetamol on hypothalamic neurotransmission in rats' offspring. We used two-month old rats previously exposed to paracetamol at doses of 5 (P5) and 15 mg/kg (P15) during gestational development and next postnatally. The concentration of monoamines, their metabolites and amino acids in hypothalamus was chromatographically determined. The results of biochemical analysis were compared with the Control animals (Con). We found differences between groups in the concentration of main noradrenaline metabolite in hypothalamus. The control group had significantly higher level of 3-methoxy-4-hydroxyphenylglycol (MHPG) compared with rats exposed to paracetamol (F(2,27) = 7.96, p < 0.005). Simultaneously the level of dopamine (DA) (F(2,27) = 4.33, p < 0.05) and its metabolite - homovanillic acid (HVA) (F(2,27) = 17.03, p < 0.005) was increased in the hypothalamus of animals treated with lower dose of the drug. Biochemical analyses show an increase in 3,4-dihydroxyphenyl acetic acid (DOPAC) concentration in P5 group compared to the control rats and group treated with higher dose of paracetamol (F(2,27) = 7.37, p < 0.005). In the hypothalamus significant decrease of glutamic acid concentration was also observed in the group treated with paracetamol at dose of 5 mg. These results demonstrated that paracetamol had a significant effect on dopaminergic and noradrenergic neurotransmission and changed the concentration of glutamic acid in hypothalamus - heat-regulating center and important element of hypothalamic-pituitary- gonadal axis.

Chemical profile, liver protective effects and analgesic properties of a Solanum paniculatum leaf extract.

BACKGROUND/AIM: Solanum paniculatum L. (Solanaceae) is a plant native to South America where it is used in traditional medicine for different therapeutic indications. This study evaluated the chemical composition and the hepatoprotective and analgesic activities of S. paniculatum leaf extracts. MATERIAL AND METHODS: The chemical profile of an ethyl acetate partition (SPOE) of a S. paniculatum leaf infusion (SPAE) was analysed by high performance liquid chromatography coupled to high-resolution electrospray mass spectrometry (HPLC-ESIMS). Liver protective effects of SPAE (600 and 1200 mg/kg bw, po), or SPOE (300 mg/kg bw, po) were evaluated in a C57BL/6 mouse model of acetaminophen (AP, 600 mg/kg bw, ip) hepatotoxicity by measuring alanine (ALT) and aspartate (AST) aminotransferase activity in the serum, and reduced glutathione (GSH), and thiobarbituric acid reactive species (TBARs) levels in the hepatic tissue. RESULTS: HPLC-ESIMS analysis of the SPOE fraction tentatively identified 35 flavonoids, esters of hydroxycinnamic acid and isomers of chlorogenic acid. SPAE (600 and 1200 mg/kg bw) and SPOE (300 mg/kg bw) antagonized the rise in ALT and AST, and the depletion of GSH, and elevation of TBARs levels in the liver caused by AP. The liver protective effects of SPOE (300 mg/kg bw) against AP-induced liver toxicity mimicked those of N-acetyl-cysteine (NAC 300 or 600 mg/kg bw ip). The mouse writhing assay showed that SPOE (300 mg/kg bw po) has anti-nociceptive effects comparable to those of AP (180 mg/kg bw po). CONCLUSION: This study suggests that an extract of S. paniculatum leaves (SPOE), rich in phenolic compounds, is a promising herbal drug to prevent and treat AP poisoning and presents analgesic properties as well.

Triterpenoids from fruits of Sorbus pohuashanensis inhibit acetaminophen-induced acute liver injury in mice.

Drug-related hepatotoxicity has become a serious social issue nowadays. Acetaminophen (APAP) was widely used in clinical treatment, although commonly acknowledged that it is a general material that caused drug-related hepatotoxicity. In this study, triterpenoids (Trds) which are mainly composed of ursolic acid and oleanolic acid, were isolated and prepared from fruits of Sorbus pohuashanensis. Further, the effect of Trds against APAP-induced liver injury and the pharmacological mechanism were investigated. The results showed that Trds treatment significantly restrained the increase of serum aspartate transaminase (AST), alanine aminotransferase (ALT), tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6), and hepatic malondialdehyde (MDA) levels, as well as evidently reversed the decrease of hepatic superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) levels induced by APAP. There are further evidences provided by liver histopathology which demonstrated Trds treatment observably inhibited hepatic tissues necrosis, hemorrhage and infiltration of inflammatory cell induced by APAP. According to the results of western-blot and RT-PCR, the over-expressions of inducible nitric oxide synthase (iNOS) and Cyclooxygenase-2 (COX-2) were inhibited by Trds. Moreover, Trds also effectively restrained APAP-induced phosphorylation of mitogen-activated protein kinase (MAPK) family signals such as p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). These results demonstrated the liver-protection effects that Trds exhibited were related to its property of anti-oxidantion and anti-inflammation.

Protective effect of cinnamon against acetaminophen-mediated cellular damage and apoptosis in renal tissue.

Acetaminophen, APAP, is a common over-the-counter drug with antipyretic-analgesic action. When APAP is used in large doses, it causes hepatotoxicity and nephrotoxicity but safe at therapeutic doses. Cinnamon (Cinnamomum zeylanicum) is extensively used in folk medicine due to its high content of natural antioxidants. The current investigation was planned to study the possible ameliorative effect of cinnamon toward induced APAP-apoptosis and cellular damage in renal cells. Four groups (nine rats each) were used; negative control group administrated distilled water for 15 days; positive control APAP group administrated a single dose of APAP (1 g/kg) orally on the last day; APAP+Cin L (200 mg/kg) and APAP+Cin H (400 mg/kg) aqueous extract of cinnamon orally once a day for 15 days. An hour after the last dose of cinnamon, all rats in the third and fourth group were administrated a single dose of APAP (1 g/kg) orally. GC/MS analysis was performed to identify the plant used in the study. APAP markedly increased serum levels of creatinine, BUN, and glucose and decreased levels of albumin and total protein. In addition, APAP could also exert severe alteration in the kidney histopathology along with upregulation of caspase-3 and PCNA. However, pre-treatment with cinnamon ameliorated the APAP-induced cellular alterations and apoptosis, possibly through its high content of antioxidants.