phenanthrenes and Liver-Diseases

Hemorrhagic shock (HS) is an important cause of high mortality in traumatized patients. Cryptotanshinone (CTS) is a bioactive compound extracted from Salvia miltiorrhiza Bunge (Danshen). The current study aimed to explore the effect and underlying mechanism of CTS on the liver injury induced by HS.. Male Sprague-Dawley rats were used to establish the HS model by hemorrhaging and monitoring mean arterial pressure (MAP). CTS was intravenously administered at concentration of 3.5 mg/kg, 7 mg/kg, or 14 mg/kg 30 minutes before resuscitation. Twenty-four hours after resuscitation, the liver tissue and serum samples were collected for the following examinations. Hematoxylin and eosin (H&E) staining was used to evaluate hepatic morphology changes. The myeloperoxidase (MPO) activity in liver tissue and the serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were examined to reveal the extent of liver injury. The protein expression of Bax and Bcl-2 in liver tissue was detected by western blot. The TUNEL assay determined the apoptosis of hepatocytes. Oxidative stress of liver tissue was assessed by the examination of reactive oxygen species (ROS) generation. The content of malondialdehyde (MDA), glutathione (GSH), and adenosine triphosphate (ATP), the activity of superoxide dismutase (SOD) and oxidative chain complexes (complex I, II, III, IV), as well as cytochrome c expression in cytoplasm and mitochondria, were also used to determine the extent of oxidative injury in the liver. Immunofluorescence (IF) was employed to estimate nuclear factor E2-related factor 2 (Nrf2) expression. The mRNA and protein levels of heme oxygenase 1 (HO-1), NAD(P)H: quinone oxidoreductases 1 (NQO1), cyclooxygenase-2 (COX-2), and nitric oxide synthase (iNOS) were assessed by real-time qPCR, western blot to investigate the mechanism of CTS regulating HS-induced liver injury.. H&E staining and a histological score of rat liver suggested that HS induced liver injury. The activity of ALT, AST, and MPO was significantly increased by HS treatment. After CTS administration the ALT, AST, and MPO activities were suppressed, which indicates the liver injury was alleviated by CTS. The HS-induced upregulation of the TUNEL-positive cell rate was suppressed by various doses of CTS. HS-induced ROS production was decreased and the protein expression of Bax and Bcl-2 in the HS-induced rat liver was reversed by CTS administration. In the liver of HS-induced rats, the upregulation of MDA content and the downregulation of GSH content and SOD activitywere suppressed by CTS. Additionally, CTS increases ATP content and mitochondrial oxidative complexes activities and suppressed the release of cytochrome c from mitochondria to the cytoplasm. Moreover, IF and western blot demonstrated that the activation of Nrf2 blocked by HS was recovered by different doses of CTS in liver tissue. The expression of downstream enzymes of the Nrf2 pathway, including HO-1, NQO1, COX-2, and iNOS, was reversed by CTS in the HS rat model.. The current study for the first time revealed the protective effect of CTS in HS-induced liver injury. CTS effectively recovered hepatocyte apoptosis, oxidative stress, and mitochondria damage induced by HS in the rat liver partly via regulating the Nrf2 signaling pathway.

Topics: Animals; bcl-2-Associated X Protein; Cyclooxygenase 2; Cytochromes c; Liver Diseases; Male; NF-E2-Related Factor 2; Phenanthrenes; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Shock, Hemorrhagic; Signal Transduction

Hepatic I/R injury is unavoidable in liver transplantation and surgery. This remains a significant problem in surgical procedures. The purpose of this study was to investigate the effects of triptolide on liver ischemia/reperfusion (I/R) injury and related mechanisms in mice.. Male C57BL/6 mice were randomized into four groups: (1) sham group; (2) sham-triptolide group; (3) I/R group; and (4) I-R/triptolide group. Ninety minutes of warm ischemia was induced and flow by 24 h reperfusion. Serum alanine aminotransferase and aspartate aminotransferase were assayed, pathologic alterations and (NF)-κB p65 immunohistochemistry were observed. Liver malondialdehyde (MDA) level, activity of endogenous antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, and activity of neutrophil accumulation marker myeloperoxidase (MPO) were measured. TNF-α, IL-6, and IL-1β mRNA were detected by RT-PCR, whereas nuclear factor (NF)-κB p65 and IκBα were assessed with Western blotting.. Plasma aminotransferase activity was higher in the I/R group than in the I/R-triptolide group. MDA level and neutrophil infiltration were also markedly reduced, while SOD, CAT, and GSH-Px levels increased in I/R-triptolide group compared with I/R group. In group 4, histopathologic changes were significantly attenuated in triptolide-treated livers. In comparison with group 3, triptolide reduced NF-κB p65 nuclear and IκBα expression, and effectively suppressed pro-inflammatory cytokine level during the I/R.. These results suggest that triptolide has protective effects against hepatic I/R injury. Its mechanisms might be related to reduction of oxidative stress and neutrophil infiltration and inhibition NF-κB p65 activity.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Diterpenes; Epoxy Compounds; I-kappa B Proteins; Immunosuppressive Agents; Interleukin-1beta; Interleukin-6; Liver Diseases; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Neutrophils; NF-kappa B; NF-KappaB Inhibitor alpha; Oxidative Stress; Peroxidase; Phenanthrenes; Reperfusion Injury; RNA, Messenger; Tumor Necrosis Factor-alpha

Ischemia and reperfusion have been identified as a complex cascade of inflammatory mediators that are involved in the pathogenesis of hepatic injury. Triptolide (diterpenoid triepoxide), was extracted from a purified component of a traditional Chinese Medicine, Tripterygium wilfondii Hook F. Currently, triptolide has been shown to have anti-inflammatory, immunosuppressive, and antineoplastic activity. Accumulated data have shown that Th17 cells might contribute to the pathogenesis of liver diseases. Triptolide has been shown to reduce interleukin (IL)-17 expression in inflammatory bowel disease and arthritis. However, the role of triptolide in liver ischemia/reperfusion (I/R) and whether it can attenuate injury and the potential mechanism have not been investigated. Mice were treated with triptolide (0.1mg/kg) for 1 week or IL-17 antibody (50 μg/mouse) 2 days before ischemic insult. Partial warm ischemia was produced in the hepatic lobes of C57BL/6 mice for 90 min, followed by various periods of reperfusion. We demonstrated that IL-17 was involved in the inflammatory response to hepatic I/R injury, and that triptolide inhibited IL-17 generation and suppressed neutrophil migration after liver I/R injury through downregulation of signal transducer and activator of transcription 3 (STAT3) transcription. Also, triptolide pretreatment protected the liver from warm I/R injury, at least in part, mediated by the upregulation of Foxp3 expression. These results could pave the way for the use of triptolide as a novel agent to attenuate I/R injury.

Topics: Animals; Antibodies, Monoclonal; Cell Movement; Disease Models, Animal; Diterpenes; Epoxy Compounds; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Interleukin-17; Liver; Liver Diseases; Mice; Mice, Inbred C57BL; Neutrophils; Phenanthrenes; Phytotherapy; Reperfusion Injury; STAT3 Transcription Factor; Tripterygium

Heat stroke is a life-threatening illness characterized by an increased core body temperature as a result of exposure to high ambient temperature. Despite advances in supportive care, heat stroke is often fatal, and no specific and effective therapies exist. The pathophysiological responses to heat stroke involve a systemic inflammatory response and a disseminated intravascular coagulation in the host, which lead to a multiorgan dysfunction syndrome. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear DNA-binding protein that has been shown to play a relevant role in cell necrosis and organ failure in various diseases associated with inflammation. Therefore, we set out to investigate whether inhibition of PARP activity might affect the heat stroke-induced injury.. Controlled animal study.. Research laboratory of an academic institution.. PARP-1-deficient mice (Parp-1(-/-)) and wild-type mice (C57BL/6J).. Wild-type mice untreated or treated with either PJ34 or 3-AB, two generic PARP inhibitors, and Parp-1(-/-) mice were subjected to heat exposure as a model to study heat stroke.. We measured rectal temperature, serum interleukin-1beta and interleukin-6, liver histology, and heat shock proteins expression. We found that the heat stroke-induced injury was attenuated in mice lacking PARP-1 and was markedly reduced in wild-type mice treated with PARP inhibitors. Interestingly, heat-induced expression of heat shock proteins 27 and 70 was boosted after PARP inhibition. Indeed, PARP inhibition increased expression of heat shock proteins 27 and 70 even in the absence of heat exposure. Accordingly, PARP inhibition increased thermal tolerance that may contribute to attenuate the clinical effects of heat stroke, resulting in increased survival.. Our results find a new protective function of PARP inhibitors and support their potential therapeutic application in the treatment of heat stroke.

Topics: Animals; Cytokines; Heat Stroke; Heat-Shock Proteins; Hematocrit; Liver Diseases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Weight Loss

The mortality associated with acute pancreatitis (AP) is largely attributable to abnormalities that occur in distant organs and supportive care remains the only treatment for patients with these complications. Recently, prophylactic pharmacological blockade of poly(ADP-ribose) polymerase (PARP) enzymes has been shown to attenuate the severity of the disease. However, the clinical relevance of PARP inhibitors administered after the onset of AP remains uncertain. The aim of the present study was to investigate the therapeutic effects of PARP inhibitors in established AP.. Mice were fed a choline/methionine-deficient/ethionine-supplemented (CMDE) diet to induce AP. PARP inhibitors were given at 36 h after the onset of CMDE diet. Severity of pancreatitis was assessed by measurements of serum amylase, lipase, IL-1beta and IL-6, and histological grading. Serum hepatic enzymes, myeloperoxidase (MPO) activity and morphological changes were measured as indicators of hepatic insult. Lung injury was evaluated by MPO activity and morphological changes. Survival rates of mice were monitored for 7 days.. CMDE diet administration resulted in a significant increase in serum amylase, lipase, IL-1beta, IL-6, alanine aminotransferase and aspartate aminotranferase levels, indicating AP and associated liver injury. Analysis of the histopathological changes in pancreas, liver and lung revealed extensive tissue damage. Treatment of mice with PARP-inhibitors after the onset of AP was associated with a reduction in the severity of AP and, accordingly, with a reduced mortality rate.. Our results support the therapeutic application of PARP inhibitors in the treatment of established AP.

Topics: Acute Disease; Alanine Transaminase; Amylases; Animals; Aspartate Aminotransferases; Choline; Dietary Supplements; Enzyme Inhibitors; Ethionine; Female; Interleukin-1beta; Interleukin-6; Lipase; Liver Diseases; Lung Diseases; Methionine; Mice; Mice, Inbred Strains; Pancreatitis; Peroxidase; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Severity of Illness Index; Time Factors; Treatment Outcome

To observe the protective effects of tanshinones (tanshinone IIA, tanshinone I, cryptotanshinone and dihydrotanshinone) against liver injury in mice loaded with restraint stress.. The liver injury model was established under 12 h restraint stress in mice 5 days after tanshinones treatment. The hepatoprotective effects were evaluated by assessing alanine aminotransferase (ALT) levels in plasma. The contents of vitamin C, GSH and malondialdehyde (MDA) in liver were performed by HPLC and TBARS methods, respectively. Oxygen radical absorbance capacity (ORAC) assay was used to measure the antioxidant capacity.. Tanshinones decreased ALT and MDA levels, and increased ORAC, vitamin C and GSH levels in liver tissues as compared with restraint stress control. Tanshinones also significantly inhibited oxidation in vitro. Among four tanshinones, dihydrotanshinone was more effective than others both in vivo and in vitro test.. Tanshinones possesses potent antioxidant activity in vitro and in vivo, and protected against liver injury induced by restraint stress. The active mechanisms may be related to their antioxidant capability.

Topics: Abietanes; Alanine Transaminase; Animals; Antioxidants; Ascorbic Acid; Drugs, Chinese Herbal; Glutathione; Liver; Liver Diseases; Male; Malondialdehyde; Mice; Phenanthrenes; Plants, Medicinal; Protective Agents; Reactive Oxygen Species; Restraint, Physical; Salvia miltiorrhiza; Stress, Physiological

The high mortality of patients with severe acute pancreatitis (SAP) is due to multiorgan dysfunction. The mechanisms of SAP are still obscure. The aim of this study was to investigate the role of nuclear factor-kappa B (NF-kappaB) activation in rats with SAP associated with liver injury and the protection effect of triptolide against liver injury in rats with SAP.. Ninety Wistar rats were randomly divided into three groups (n=30 each group): severe acute pancreatitis (group P), treatment with triptolide (group T), and sham operation (group S). SAP models were induced by retrograde injection of 5% sodium taurocholate to the pancreatic duct. After the model was successfully established, no treatment was given to group P. In group T, triptolide (0.05 mg/ml) was injected intraperitoneally (0.2 mg/kg). In group S, the abdominal walls of rats were opened, sutured, but not treated. The rats were sacrificed after operation at 2, 6, and 12 hours, respectively. The serum levels of amylase (AMY), alanine aminotransferase (ALT), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were determined at three time points (10 rats for each time point). Liver tissues were obtained to detect the activity of NF-kappaB and to observe their pathological changes with light and electron microscopes.. The serum levels of AMY and ALT were higher in groups P and T than in group S. The serum AMY levels were significantly lower in group T than in group P at 12 hours after operation. The serum ALT levels were significantly lower in group T than in group P at 6, 12 hours after operation. At the three time points, the levels of TNF-alpha and IL-6 in groups P and T increased more significantly than in group S. In group T they were decreased more significantly than in group P at the three time points. In groups P and T, NF-kappaB activity in liver tissue increased more significantly than in group S at the three time points. The activity of NF-kappaB was higher in group P than in groups S and T at the three time points. Liver pathological damages were milder in group T than in group P under light and electron microscopes.. NF-kappaB plays an important role in the pathogenesis of liver injury in rats with SAP. Triptolide can reduce pathological damage to the liver. Its mechanism is to inhibit the activity of NF-kappaB and to decrease the release of inflammatory mediators.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Diterpenes; Epoxy Compounds; Female; Immunohistochemistry; Interleukin-6; Liver; Liver Diseases; Male; NF-kappa B; Pancreatitis; Phenanthrenes; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

We recently reported that (Lamiaceae) may alleviate CCl(4)-induced acute hepatotoxicity in rats, possibly blocking the formation of free radicals generated during CCl(4) metabolism. Carnosol, one of the main constituents of Rosmarinus, has been shown to have antioxidant and scavenging activities. Therefore, it is plausible to expect that carnosol may mediate some of the effects of Rosmarinus on oxidative stress consequences induced by CCl(4) in the liver.. We evaluated the effectiveness of carnosol to normalize biochemical and histological parameters of CCl(4)-induced acute liver injury.. Male Sprague Dawley rats (n = 5) injured by CCl(4) (oral dose 4 g/kg of body weight) were treated with a single intraperitoneal dose (5 mg/kg) of carnosol. Twenty-four hours later, the rats were anaesthetized deeply to obtain the liver and blood, and biochemical and histological parameters of liver injury were evaluated.. Carnosol normalized bilirubin plasma levels, reduced malondialdehyde (MDA) content in the liver by 69%, reduced alanine aminotransferase (ALT) activity in plasma by 50%, and partially prevented the fall of liver glycogen content and distortion of the liver parenchyma.. Carnosol prevents acute liver damage, possibly by improving the structural integrity of the hepatocytes. To achieve this, carnosol could scavenge free radicals induced by CCl(4), consequently avoiding the propagation of lipid peroxides. It is suggested that at least some of the beneficial properties of Rosmarinus officinalis are due to carnosol.

Topics: Abietanes; Acute Disease; Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Hepatocytes; Liver; Liver Diseases; Male; Phenanthrenes; Rats; Rats, Sprague-Dawley

Topics: Antimalarials; Blood Coagulation Disorders; Humans; Liver Diseases; Malaria; Phenanthrenes; Serum Albumin

Male Sprague-Dawley rats were treated ip with beta-naphthoflavone (BNF, 40 mg/kg/day) in dimethylsulfoxide (DMSO, 26.7 mg BNF/ml) for three days. At 24 hr after the pretreatment DMSO (3.0 ml/kg), phenanthrene (150 mg/kg), ozonized or nitrated products of phenanthrene (150 mg/kg), pyrene (150 mg/kg), or ozonized or nitrated products of pyrene (150 mg/kg) were injected ip. Phenanthrene, pyrene, and their ozonized or nitrated products were dissolved in DMSO (50 mg/ml). No increase in the level of aspartate aminotransferase (AST), alanine aminotransferase (ALT) or sorbitol dehydrogenase (SDH) was seen in the pretreated rats 48 hr after the treatment. This is in contrast to what was seen in previous work without the BNF pretreatment. BNF pretreatment induced a small but significant increase in gamma-glutamyl transpeptidase (GGTP) levels. No treatment group receiving BNF differed from another with respect to GGTP. A decrease in lactate dehydrogenase (LDH) levels was noted in the nitro-PAH treatment groups; the same phenomenon was observed earlier in rats treated with nitro-PAH without BNF treatment. These results suggest that the mixed-function oxidase systems specifically induced by BNF have a protective effect against the hepatotoxicity of the oxonized or nitrated products of phenanthrene and pyrene.

Topics: Animals; Benzoflavones; beta-Naphthoflavone; Chemical and Drug Induced Liver Injury; Flavonoids; L-Lactate Dehydrogenase; Liver Diseases; Male; Nitrogen Dioxide; Ozone; Phenanthrenes; Pyrenes; Rats; Rats, Inbred Strains

An h.p.l.c.-fluorescence technique was used to estimate relative concentrations of metabolites of xenobiotics in bile of 103 English sole (Parophrys vetulus) from both polluted and minimally polluted (reference) sites in Puget Sound, WA. Fish from polluted sites had concentrations of xenobiotics in bile with naphthalene-, phenanthrene- and benzo[a]pyrene-like fluorescence that averaged 9, 14 and 19 times, respectively, those of fish from reference sites. Within a polluted site, fish with liver lesions had significantly higher bile concentrations of xenobiotics with benzo[a]pyrene-like fluorescence than did fish without liver lesions. Individual metabolites of fluorene, phenanthrene, anthracene, biphenyl and dimethylnaphthalene were determined by g.l.c.-mass spectrometry in extracts of hydrolysed bile of three English sole from polluted waterways; concentrations ranged from 90 to 19000 ng/g, wet wt. Other xenobiotics were tentatively identified, but not quantified.

Topics: Animals; Benzo(a)pyrene; Bile; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Fish Diseases; Fishes; Hydrocarbons; Liver Diseases; Naphthalenes; Phenanthrenes; Spectrometry, Fluorescence; Water Pollutants; Water Pollutants, Chemical