• 대한본초학회지
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• 제27권2호
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• pp.85-91
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• 2012

Objective : Myeongganbo (MGB) composited with Hovenia Semen, Puerariae Radix and Dioscoreae Rhizoma is the prescription for protection of liver function. The purpose of this study was to investigate the effects of MGB extract against acetaminophen (APAP)-induced liver injury in mice. Methods : MGB extract was prepared by extracting with hot distilled water. The extract was freeze-dried following filtration through vacuum distillation system. Mice fasted for overnight were orally administrated with or without MGB extract of different doses (25-200 mg/kg/day). After 30 min, APAP was orally applied with a single dose (400 mg/kg). The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured in plasmas of mice. Glutathione (GSH), glutathione peroxidase GSH-px), cyclooxygenase-2 (COX-2) activity and tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) level were investigated in liver homogenates. Liver sections were stained with haematoxylin & eosin, anti-TNF-${\alpha}$ and anti-mouse COX-2 antibodies. Results : APAP treatment remarkably increased AST and ALT activities in plasma but inhibited GSH and GSH-px levels in liver homogenates. Also, liver injury was significantly accelerated by APAP treatment. Furthermore, APAP remarkably elevated COX-2 activity and TNF-${\alpha}$ levels in liver homogenates. However, administration of MGB extract was able to counteract these effects. Histological studies provided supportive evidence for biochemical and molecular analysis Conclusions : These results suggest that MGB extract has potent hepatoprotective effect against APAP-induced liver injury, these properties may contribute to liver disease care.

• The Korean Journal of Physiology and Pharmacology
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• 제25권5호
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• pp.385-393
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• 2021

Tissue factor (TF) activates the coagulation system and has an important role in the pathogenesis of various diseases. Our previous study stated that retinoid receptors (RAR-α and RXR-α) are released as a lipid droplet in monocrotaline/lipopolysaccharide-induced idiosyncratic liver toxicity in mice. Herein, the interdependence between the release of retinoid receptors RAR-α and RXR-α and TF in N-acetyl-p-aminophenol (APAP)-induced mice liver toxicity, is investigated. Serum alanine transaminase (ALT) level, platelet and white blood cells (WBCs) counts, protein expression of fibrin, TF, cyclin D1 and cleaved caspase-3 in liver tissues are analyzed. In addition, histopathological evaluation and survival study are also performed. The results indicate that using of TF-antisense (TF-AS) deoxyoligonucleotide (ODN) injection (6 mg/kg), to block TF protein synthesis, significantly restores the elevated level of ALT and WBCs and corrects thrombocytopenia in mice injected with APAP. TF-AS prevents the peri-central overexpression of liver TF, fibrin, cyclin D1 and cleaved caspase-3. The release of RXR-α and RAR-α droplets, in APAP treated sections, is inhibited upon treatment with TF-AS. In conclusion, the above findings designate that the released RXR-α and RAR-α in APAP liver toxicity is TF dependent. Additionally, the enhancement of cyclin D1 to caspase-3-dependent apoptosis can be prevented by blocking of TF protein synthesis.

• 동의생리병리학회지
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• 제27권5호
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• pp.617-624
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• 2013

The purpose of this study is to investigate the protective effects of 25 herbal formulas on acetaminophen (APAP) or D-galactosamine (D-GalN)-induced hepatotoxicity in primary rat hepatocytes. Cell viability was measured using by Cell Counting Kit-8. 15 kinds of herbal formulas significantly reversed the cell viabilities of D-GalN-treated rat hepatocytes compared with D-GalN alone (p<0.05). In particular, 9 herbal formulas (Bangpungtongseong-san, Bojungikgi-tang, Galgeun-tang, Gumiganghwal-tang, Guibi-tang, Sagunja-tang, Samsoeum, Pyeongwi-san and Yijin-tang) showed the potent protective effects. However, 8 herbal formula exerted weak protective effects and 2 herbal formula did not exert effects on hepatotoxicity by D-GalN. On APAP-induced hepatotoxicity, 7 kinds of herbal formulas increased the viabilities of hepatocytes compare with APAP alone (p<0.05). These results could be provide a valuable information for the future in vivo or clinical studies to predict the hepatoprotective effects of herbal formulas.

• Toxicological Research
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• 제17권
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• pp.299-304
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• 2001

Xenobiotics and their reactive intermediates bind to cellular macromolecules and/or generate oxidative stress. which provoke deleterious effects on the cell function. Induction of xenobiotic-biotrans-forming enzymes and antioxidant molecules is an important defense mechanism against such insults. A group of genes involved in the defense mechanism. e.g. genes encoding glutathione S-transferases. NAD(P)H: quinone oxidoreductase, UDP-glucuronosyltransferase (UDP-GT) and ${\gamma}$-glutamylcysteine synthetase (GGCS). have a common regulatory sequence, Antioxidant or Electrophile Responsive Element (ARE/EpRE). Recently. Nrf2. discovered as a homologue of erythroid transcription factor p45 NF-E2, was shown to bind ARE/EpRE and induce the expression of these defense genes. Mice that lack Nrf2 show low basal levels of expression and/or impaired induction of these genes. which makes the animals highly sensitive to xenobiotic toxicity. Indeed. we show here that nrf2-deficient mice had a higher mortality than did the wild-type mice when exposed to acetaminophen (APAP). Detailed analyses of APAP hepatotoxicity in the nrf2 knockout mice indicate that a large amount of reactive APAP metabolites was generated in the livers due to the impaired basal expression of two detoxifying enzyme genes, UDP-GT (Ugt1a6) and GGCS. while the cytochrome P450 content was unchanged. Thus. the studies using the nrf2 knockout mice clearly demonstrate significance of the expression of Nrf2-regulated enzymes in protection against xenobiotic toxicity.

• Archives of Pharmacal Research
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• 제21권5호
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• pp.508-513
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• 1998

The hepatoprotective effect of DA-9601, a quality-controlled extract of artemisisa asiatica, on liver damage induced by acetaminophen (APAP) and carbon tetrachloride ($CCI_{4}$) was investigated by means of serum-biochemical, hepatic-biochemical, and histopathological examinations. Doses of Da-9601 (10, 30, or 100 mg/kg) were administered intragastrically to each rat on three consecutive days i.e. 48 h, 24 h and 2 h before a single administration of APAP (640 mg/kg, i.p.) or $CCI_{4}$ (2 ml/kg, p.o.). Four h and 24 h after hepatotoxin treatment, the animals were sacrificed for evaluation of liver damage. Pretreatment of Da-9601 reduced the elevation of serum ALT, AST. LDH and histopathological changes such as centrilobular necrosis, vacuolar degeneration and inflammatory cell infiltration dose-dependently. Da-9601 also prevented APAP- and $CCI_{4}$-induced hepatic glutathione (GSH) depletion and $CCI_{4}$-induced increase of hepatic malondialdehyde (MDA), a parameter of lipid peroxidation, in a chemically induced liver injury by complex mechanisms which involve prevention of lipid peroxidation and preservation of hepatic GSH.

• International Journal of Advanced Culture Technology
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• 제7권4호
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• pp.118-124
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• 2019

There is a strong connection between the diet rich in antioxidants and the decreased incidence of cardiovascular and cancerous diseases. Diets that are rich in anti-oxidants particularly include fruits and vegetables containing the high amounts of vitamin A-E, carotenoids, and minerals. Different processing conditions applied for vegetables and plants results in the alteration of the nutrients present in them. Therefore the rationale of our study was to compare the antioxidant effects of different processed vegetables and plants and to see that which one of them showed best anti-oxidant activity. For this purpose, we have used acetaminophen induced oxidative stress model in mice to check the effects of processed apple, pear, carrot, cabbage, broccoli and radish. Our results have shown that the administration of these samples effectively decreased the expression of parameters related with oxidative stress like ALT, AST, catalase, superoxide dismutase, GPx and 8-OHdG. Moreover they also significantly protected the mice livers from APAP induced damage as shown by histological changes. Therefore our results have demonstrated the effects of processed fruits and vegetables in mice model of oxidative stress.

• 대한본초학회지
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• 제25권3호
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• pp.149-157
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• 2010

Objective：Gagam-Gongjin-dan (GGD) is an oriental medicinal prescription composited with Cervi parvum Cornu, Corni Fructus, Angelica Gigantis Radix, Lycii Fructus, Dioscoreae Rhizoma, Citri Pericarpium, Gastrodiae Rihzoma, Agastachis Herba, Cassiae cortex, Scutellariae Radix and Schisandrae Fructus. The purpose of this study was to investigate the effects of GGD extract against acetaminophen (APAP)-induced liver injury in mice. Methods：GGD extract was prepared by extracting with methanol for 7 days. The extract was freeze-dried following filtration through vacuum distillation system. The first, we investigated the antioxidant effects of GGD extract on electronic donating ability (DPPH), nitrite (NO) scavenging and superoxide dismutase (SOD)-like activity. The next, we investigated the possible hepatoprotective effect of GGD extract administration against acetaminophen-induced liver injury in mice. Mice were orally administrated with or without GGD extract of different doses (25-100 mg/kg/day) one times per day for 6 days. After 3 days, APAP was orally applied with a single dose (400 mg/kg). Results：GGD extract increased DPPH, NO and SOD-like activities in dose dependant. APAP treatment significantly increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in plasma. Also, APAP treatment significantly evaluated lipid peroxidation product thiobarbituric reacting substances (TBARS) and depleted some antioxidant enzymes (superoxide dismutase, catalase, d-aminolevulinate dehydratase and gluthathione peroxidase activities) in liver homogenates compared to the control group. However, the orally administration of GGD extract was able to counteract these effects. Histological studies provided supportive evidence for biochemical analysis Conclusions：These results suggest that GGD extract has a potential antioxidant and hepatoprotective effect against APAP-induced liver injury, these properties may contribute to liver disease care.

• Biomolecules & Therapeutics
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• 제17권4호
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• pp.438-445
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• 2009

We investigated global gene expression from both mouse liver and mouse hepatic cell lines treated with acetaminophen (APAP) in order to compare in vivo and in vitro profiles and to assess the feasibility of the two systems. During our analyses of gene expression profiles, we picked up several down-regulated genes, such as the cytochrome P450 family 51 (Cyp51), sulfotransferase family cytosolic 1C member 2 (Sult1c2), 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (Hmgcs1), and several genes that were up-regulated by APAP, such as growth arrest and DNA-damage-inducible 45 alpha (Gadd45a), transformation related protein 53 inducible nuclear protein 1 (Trp53inp1) and zinc finger protein 688 (Zfp688). For validation of gene function, synthesized short interfering RNAs (siRNAs) for these genes were transfected in a mouse hepatic cell line, BNL CL.2, for investigation of cell viability and mRNA expression level. We found that siRNA transfection of these genes induced down-regulation of respective mRNA expression and decreased cell viability. siRNA transfection for Cyp51 and others induced morphological alterations, such as membrane thickening and nuclear condensation. Taken together, siRNA transfection of these six genes decreased cell viability and induced alteration in cellular morphology, along with effective inhibition of respective mRNA, suggesting that these genes could be associated with APAP-induced toxicity. Furthermore, these genes may be used in the investigation of hepatotoxicity, for better understanding of its mechanism.

• Archives of Pharmacal Research
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• 제28권4호
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• pp.493-501
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• 2005

Effect of solvents on physical characteristics and release characteristics of monolithic acetaminophen (APAP) hydroxypropylmethylcellulose (HPMC) matrix granules and tablets were examined. Various types and amounts of solvents were employed for granulation and coating. APAP and other excipients were mixed and were then wet-granulated in a high-speed mixer. The dried granules were then directly compressed and film-coated with low viscosity grade HPMC. As the amount of water increased, the size of granules also increased, showing more spherical and regular shape. However, manufacturing problems such as capping and lamination in tableting occurred when water was used alone as a granulating solvent. The physical properties of HPMC matrix granules were not affected by the batch size. The initial release rate as well as the amount of APAP dissolved had a tendency to decrease as the water level increased. Addition of nonaqueous solvent like ethanol to water resulted in good physical properties of granules. When compared to water/ethanol as a coating solvent, the release rate of film-coated HPMC matrix tablets was more sensitive to the conditions of coating and drying in methylene chloride/ethanol. Most of all, monolithic HPMC matrix tablet when granulated in ethanol/water showed dual release with about $50\%$ drug release immediately within few minutes followed by extended release. It was evident that the type and amount of solvents (mainly water and ethanol) were very important for wet granulation and film-coating of monolithic HPMC matrix tablet, because the plastic deforming and fragmenting properties of material were changed by the different strengths of the different solvents.

• 생명과학회지
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• 제28권6호
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• pp.708-717
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• 2018

본 연구에서는 멀꿀 열매 추출물의 세포수준에서 항산화 활성과 아세트아미노펜(APAP)으로 유도된 간 독성 동물모델에서의 간 기능 보호효과를 연구하였다. 멀꿀 열매 추출물의 총 폴리페놀 함량과 플라보노이드 함량은 각각 $16.13{\pm}0.27mg$ gallic acid equivalent/g 및 $4.7{\pm}0.80mg$ catechin equivalent/g이었다. 또한 DPPH 라디컬 소거능과 ORAC도 각각 $63.62{\pm}4.10{\mu}g/ml$ 및 $90.63{\pm}5.29{\mu}M$ trolox equivalent/g이었다. 과산화수소로 유도된 산화적 손상에 대한 멀꿀 열매 추출물의 간세포 보호효과를 실험한 결과, $200{\mu}g/ml$에서 세포생존율이 증가하고 증가된 LDH 활성이 감소함을 확인하였다. 간세포에서 과산화수소로 산화적 스트레스를 유도하여 감소된 항산화 효소(SOD, CAT, GR, GPx)의 활성은 멀꿀 열매 추출물 처리로 활성이 증가하여 간세포를 보호하였다. 아테트아미노펜(APAP) 유도 간 손상 생쥐 모델에서 간 보호활성을 평가하였다. 간 손상 혈청 표지지표인 ALT 및 AST수준이 APAP 단독 처리군에 비해 멀꿀 열매 추출물 200 mg/kg군에서 유의적으로 감소되었으며, 간의 과산화지질함량도 감소한 것으로 나타났다. 간 조직의 병리학 검사에서도 간조직이 정상 회복되는 형태를 보였다. 이상의 결과를 토대로 멀꿀 열매 추출물이 항산화 기전을 통해 간기능 보호 효과를 나타냄을 확인할 수 있었다.