Lipopolysaccharide-induced liver injury in rats treated with the CYP2E1 inducer pyrazole

2005 ◽  
Vol 289 (2) ◽  
pp. G308-G319 ◽  
Author(s):  
Yongke Lu ◽  
Xiaodong Wang ◽  
Arthur I. Cederbaum

Elevated LPS and elevated cytochrome P-450 2E1 (CYP2E1) in liver are two major independent risk factors in alcoholic liver disease. We investigated possible synergistic effects of the two risk factors in causing oxidative stress and liver injury. Sprague-Dawley rats were injected intraperitoneally with pyrazole (inducer of CYP2E1) for 2 days, and then LPS was injected via tail vein. Other rats were treated with pyrazole alone or LPS alone or saline. Eight hours later, blood was collected and livers were excised. Pathological evaluation showed severe inflammatory responses and necroses only in liver sections from rats in the pyrazole plus LPS group; blood transaminase levels were significantly elevated only in the combination group. Activities of caspase-3 and -9 and positive terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining were highest in the LPS alone and the LPS plus pyrazole group, with no significant difference between the two groups. Lipid peroxidation and protein carbonyls in liver homogenate as well as in situ superoxide production were maximally elevated in the LPS plus pyrazole group. Levels of nitrite plus nitrate and inducible nitric oxide (NO) synthase (iNOS) content were comparably elevated in LPS alone and the LPS plus pyrazole group; however, 3-nitrotyrosine adducts were elevated in the combined group but not the LPS group. It is likely that LPS induction of iNOS, which produces NO, coupled to pyrazole induction of CYP2E1 which produces superoxide, sets up conditions for maximal peroxynitrite formation and production of 3-nitrotyrosine adducts. CYP2E1 activity and content were elevated in the pyrazole and the LPS plus pyrazole groups. Immunohistochemical staining indicated that distribution of CYP2E1 was in agreement with that of necrosis and production of superoxide. These results show that pyrazole treatment enhanced LPS-induced necrosis, not apoptosis. The enhanced liver necrosis appears to involve an increase in oxidative and nitrosative stress generated by the combination of LPS plus elevated CYP2E1 levels.

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Chen Zhang ◽  
Xiao Shi ◽  
Zhongping Su ◽  
Chao Hu ◽  
Xianmin Mu ◽  
...  

Abstract Background Acetaminophen (APAP) overdose causes hepatotoxicity and even acute liver failure. Recent studies indicate that sterile inflammation and innate immune cells may play important roles in damage-induced hepatocytes regeneration and liver repair. The scavenger receptor CD36 has its crucial functions in sterile inflammation. However, the roles of CD36 in APAP induced acute liver injury remain unclear and warrant further investigation. Methods WT C57BL/6 J and CD36−/− mice were intraperitoneally injected with APAP (300 mg/kg) after fasting for 16 h. Liver injury was evaluated by serum alanine aminotransferase (ALT) level and liver tissue hematoxylin and eosin (H&E) staining. Liver inflammatory factor expression was determined by real-time polymerase chain reaction (PCR). The protein adducts forming from the metabolite of APAP and the metabolism enzyme cytochrome P450 2E1 (CYP2E1) levels were measured by Western blot. Liver infiltrating macrophages and neutrophils were characterized by flow cytometry. RNA sequencing and Western blot were used to evaluate the effect of damage-associated molecular patterns (DAMP) molecule high mobility group B1 (HMGB1) on WT and CD36−/− macrophages. Moreover, PP2, a Src kinase inhibitor, blocking CD36 signaling, was applied in APAP model. Results The expression of CD36 was increased in the liver of mice after APAP treatment. Compared with WT mice, APAP treated CD36−/− mice show less liver injury. There was no significant difference in APAP protein adducts and CYP2E1 expression between these two strains. However, reduced pro-inflammatory factor mRNA expression and serum IL-1β level were observed in APAP treated CD36−/− mice as well as infiltrating macrophages and neutrophils. Moreover, CD36 deficiency impaired the activation of c-Jun N-terminal kinase (JNK) caused by APAP. Interestingly, the lack of CD36 reduced the activation of extracellular regulated protein kinases (Erk) and v-akt murine thymoma viral oncogene homolog (Akt) induced by HMGB1. RNA transcription sequencing data indicated that HMGB1 has a different effect on WT and CD36−/− macrophages. Furthermore, treatment with PP2 attenuated APAP induced mouse liver injury. Conclusion Our data demonstrated that CD36 deficiency ameliorated APAP-induced acute liver injury and inflammatory responses by decreasing JNK activation. CD36 might serve as a new target to reduce acute liver injury.


2018 ◽  
Vol 12 (1) ◽  
pp. 125-136 ◽  
Author(s):  
Behzad Hatami ◽  
Seyed Mohammad Hossein Kashfi ◽  
Mohammad Abbasinazari ◽  
Ehsan  Nazemalhosseini Mojarad ◽  
Mohammad Amin Pourhoseingholi ◽  
...  

Background: Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). The incidence of post-ERCP pancreatitis (PEP) ranges between 15 and 20% among patients at high risk of developing PEP. The efficacy of indomethacin administration in the prevention of PEP is rather debatable. In the present randomized trial study, we evaluated whether or not the combination of indomethacin and epinephrine in comparison to the single administration of indomethacin differs in the pathogenesis and prevention of post-ERCP pancreatitis. Patients and Methods: One hundred and ninety-two patients were randomized in a double-blinded manner into 3 groups: the epinephrine group (group A), the indomethacin group (group B), and the combined epinephrine and indomethacin group (group C). After the procedure, patients were evaluated for the PEP development. Results: During the procedure, 66 patients were randomized to the epinephrine group (group A), 68 cases to the indomethacin group (group B), and 58 individuals to the indomethacin-epinephrine group (group C). The mean age of patients in the epinephrine group was 59.59 ± 15.680 years, in the indomethacin group it was 58.06 ± 17.125 years, and in the combination group it was 59.62 ± 15.369 years. In the present study, we did not observe a significant difference between the 3 groups in sex, age, pre-ERCP amylase, lipase, and patient and procedure risk factors including pancreatic duct (PD) dilation (p = 0.404), PD cannulation (p = 0.329), and difficult cannulation (p = 0.076) among others. PEP developed in 7 of the 192 individuals (3.6%), 6 PEP cases occurred in the indomethacin group and 1 in the epinephrine group (p = 0.016). Univariate analysis of risk factors for PEP in patients with and without pancreatitis revealed no significant difference between the pancreatitis group and the non-pancreatitis group. Conclusion: In comparison to the administration of indomethacin alone, a single application of epinephrine and the combination of epinephrine and indomethacin seem to be effective in reducing the cases of PEP. A further randomized clinical trial with a larger sample size is required to confirm the efficacy of our medication in the prevention of pancreatitis after ERCP.


2020 ◽  
Vol 22 (6) ◽  
Author(s):  
Sara Zangiabadi ◽  
Shahrokh Navidpour ◽  
Hossein Zolfagharian ◽  
Gholamhassan Vaezi

Background: Mesobuthus eupeus venom is a member of Buthidae family, which can enter the blood circulation exerting detrimental effects on body organs, such as the liver and kidney through inflammation. Cyclosporine, known as an anti-inflammatory drug, is used to treat many inflammation-associated diseases. Objectives: In this study, cyclosporine was selected to inhibit the scorpion toxin effects on rat organs. Methods: This experimental study was conducted in the Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization, Karaj, Iran, from June to November 2019. Fifty male rats were randomly divided into five groups of 10, including the control (10 mg/kg olive oil i.p), M. eupeus venom (10 mg/kg i.p.), cyclosporine 10 mg/kg (venom 10 mg/kg for 30 min i.p followed by cyclosporine 10/kg mg for 7 day i.p.), cyclosporine 20 mg/kg (venom 10 mg/kg for 30 min i.p followed by cyclosporine 20 mg/kg for 7 day i.p.), and cyclosporine 30 mg/kg (venom 10 mg/kg for 30 min i.p followed by cyclosporine 30 mg/kg for 7 day i.p.). After treatment with cyclosporine, the liver and kidney function was analyzed by calculating some biochemical enzymes, including serum glutamate-pyruvate transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), nitric oxide (NO), interleukin-2 (IL-2), malondialdehyde (MDA), creatinine, and urea via ELISA and spectrophotometry. Then, to determine the rate of apoptosis in tissue, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method was done. Results: At the end of the study, the results showed a significant elevation in SGPT (164.5 ± 10 vs. 126.2 ± 7, P < 0.0001), SGOT (190.37 ± 11 vs. 148 ± 10, P < 0.0001), NO (24.4 ± 1.17 vs. 17.4 ± 1.4, P = 0.02), and MDA (0.42 ± 0.05 vs. 0.22 ± 0.04, P < 0.0001) in the venom group compared with the control group. There were no significant differences in the urea, IL-2, and creatinine between the venom and control groups. However, the group receiving cyclosporine (30 mg/kg) showed a significant decline in SGPT (96.42 ± 5.7 vs. 164.5 ± 10, P < 0.0001), SGOT (144.57 ± 9.24 vs. 190.37 ± 11, P < 0.0001), urea (28.83 ± 1.32 vs. 38.83 ± 1.6, P = 0.00), creatinine (0.023 ± 0.01vs. 0.29 ± 0.005, P < 0.0001), and MDA (0.10 ± 0.01 vs. 0.42 ± 0.05, P < 0.0001), as well as increased apoptosis rate (P < 0.05), compared with the venom group. No significant difference was observed between the cyclosporine and venom groups in NO and IL-2. Conclusions: Cyclosporine at a dose of 30 mg was able to decrease inflammatory responses and induce apoptosis rate. Therefore, it could be a suitable drug for patients bitten by a scorpion sting.


2020 ◽  
Author(s):  
Jingyuan Liu ◽  
Chunjing Du ◽  
Siyuan Yang ◽  
Lin Pu ◽  
Pan Xiang ◽  
...  

Abstract Background: The information regarding the clinical course of COVID-19 patients with liver injury is very limited, especially in severe and critical patients. The objective of this study was to describe the characteristics and clinical course of patients admitted with severe and/or critical SARS-CoV-2 infection in liver function, as well as explore the risk factors that affect liver function in the enrolled COVID-19 patients.Methods: Information on clinical characteristics of 63 severe and critical patients with confirmed COVID-19 were collected and analyzed.Results: The incidence of abnormal aspartate aminotransferase, alanine aminotransferase, and total bilirubin in the critical group was obviously higher than in the severe group (81.48%, 81.49%, 62.67%, and 45.71%, 63.88%, 22.86%, respectively, p<0.05). The time for liver parameters to reach their peak or trough was approximately 2-3 weeks. No significant difference was observed in cycle threshold values of open reading frame 1ab and nucleocapsid protein gene on admission or at the peak among liver injury group, abnormal group and normal group (p>0.05). Patients with invasive ventilator, decreased percentage of neutrophil, lymphocyte and monocyte, and SOFA score ≥ 2 (p<0.05) were the independent factors associated with liver injury.Conclusions: Abnormal liver tests are commonly observed in severe and critical patients with COVID-19. The time of 2-3 weeks after admission should be paid attention to patients with critical COVID-19 in case of the occurrence of liver injury. As independent risk factors for the occurrence of liver injury, regarding decreased ratio of neutrophils, lymphocytes and monocytes, the requirement of invasive ventilator, and SOFA score ≥2 , patients with these abnormal parameters should be of particular concerned during hospitalization.


2002 ◽  
Vol 22 (6) ◽  
pp. 711-722 ◽  
Author(s):  
Toru Matsui ◽  
Takashi Mori ◽  
Narito Tateishi ◽  
Yoshifumi Kagamiishi ◽  
Souichi Satoh ◽  
...  

An astrocytic protein S-100β enhances the expression of inducible nitric oxide synthase in cultured astrocytes at micromolar concentrations, leading to nitric oxide-mediated death of cocultured neurons. The present study examined whether S-100β production by reactive astrocytes accumulating within the periinfarct area was related to delayed expansion of infarct volume after permanent middle cerebral artery occlusion in the rat. After rapid increases during the initial 24 hours, the increase of infarct volume then decelerated while maintaining the increasing tendency until 168 hours in this model, attaining a significant difference compared with that at 24 hours. In the periinfarct area, the number of reactive astrocytes expressing both S-100 and glial fibrillary acidic protein, the tissue level of S-100β as measured by the sandwich enzyme-linked immunosolvent assay method using anti-S-100β monoclonal antibody, and the number of terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling-positive cells were significantly increased preceding the delayed expansion of infarct volume. The CSF concentration of S-100β showed a biphasic increase, presumably reflecting the immediate release from astrocytes within the ischemic core and the subsequent production in reactive astrocytes within the periinfarct area. These results show for the first time that the enhanced synthesis of S-100β by reactive astrocytes participates in the inflammatory responses within the periinfarct area, which may be related to the occurrence of delayed infarct expansion as a major component of the cytokine network.


2007 ◽  
Vol 293 (1) ◽  
pp. G91-G103 ◽  
Author(s):  
Aparajita Dey ◽  
Andres A. Caro ◽  
Arthur I. Cederbaum

Pyrazole treatment to induce cytochrome P-450 2E1 (CYP2E1) was recently shown to cause liver injury in ob/ob mice but not in lean mice. The present study investigated the effects of S-adenosyl-l-methionine (SAM) on the CYP2E1-dependent liver injury in ob/ob mice. Pyrazole treatment of ob/ob mice for 2 days caused necrosis, steatosis, and elevated serum transaminase and triglyceride levels compared with saline ob/ob mice. Administration of SAM (50 mg/kg body wt ip every 12 h for 3 days) prevented the observed pathological changes as well as the increase of apoptotic hepatocytes, caspase 3 activity, and serum TNF-α levels. SAM administration inhibited CYP2E1 activity but not CYP2E1 content. The pyrazole treatment increased lipid peroxidation, 4-hydroxynonenal and 3-nitrotyrosine protein adducts, and protein carbonyls. These increases in oxidative and nitrosative stress were prevented by SAM. Treatment of ob/ob mice with pyrazole lowered the endogenous SAM levels, and these were elevated after SAM administration. Mitochondrial GSH levels were very low after pyrazole treatment of the ob/ob mice; this was associated with elevated levels of malondialdehyde and 4-hydroxynonenal and 3-nitrotyrosine protein adducts in the mitochondria. All these changes were prevented with SAM administration. SAM protected against pyrazole-induced increase in serum transaminases, necrosis, triglyceride levels, caspase-3 activity, and lipid peroxidation even when administered 1 day after pyrazole treatment. In the absence of pyrazole, SAM lowered the slightly elevated serum transaminases, triglyceride levels, caspase-3 activity, and lipid peroxidation in obese mice. In conclusion, SAM protects against and can also reverse or correct CYP2E1-induced liver damage in ob/ob mice.


2010 ◽  
Vol 80 (3) ◽  
pp. 159-167 ◽  
Author(s):  
Gabriela Villaça Chaves ◽  
Gisele Gonçalves de Souza ◽  
Andréa Cardoso de Matos ◽  
Dra. Wilza Abrantes Peres ◽  
Silvia Elaine Pereira ◽  
...  

Objective: To evaluate retinol and β-carotene serum levels and their relationship with risk factors for cardiovascular disease in individuals with morbid obesity, resident in Rio de Janeiro. Methodology: Blood serum concentrations of retinol and β-carotene of 189 morbidly obese individuals were assessed. The metabolic syndrome was identified according to the criteria of the National Cholesterol Education Program (NCEP) and World Health Organization (WHO). Lipid profile, insulin resistance, basal insulin, glycemia, blood pressure, and anthropometry and their correlation with retinol and β-carotene serum levels were evaluated. Results: Metabolic syndrome diagnosis was observed in 49.0% of the sample. Within this percentage the levels of β-carotene were significantly lower when body mass index increased. Serum retinol didn't show this behavior. Serum retinol inadequacy in patients with metabolic syndrome (61.3%), according to WHO criterion, was higher (15.8%) than when the whole sample was considered (12.7%). When metabolic syndrome was diagnosed by NCEP criterion, β-carotene inadequacy was higher (42.8%) when compared to the total sample (37.5%). There was a significant difference between average β-carotene values of patients with and without metabolic syndrome (p=0.048) according to the classification of the NCEP. Lower values were found in patients with metabolic syndrome. Conclusion: Considering the vitamin A contribution in antioxidant protection, especially when risk factors for cardiovascular disease are present, it is suggested that great attention be given to morbidly obese. This could aid in prevention and treatment of cardiovascular disease, which affects a significant part of the population.


Author(s):  
Habib Yarizadeh ◽  
Alireza Bahiraee ◽  
Sara Asadi ◽  
Niloofar Sadat Maddahi ◽  
Leila Setayesh ◽  
...  

Abstract. Objective: The genetic variants near the melanocortin-4 receptor gene (MC4R), a key protein regulating energy balance and adiposity, have been related to obesity and cardiovascular risk factors. However, qualitative and quantitative aspects of diet may modulate the association of this polymorphism with obesity and cardiovascular diseases (CVDs). The aim of this study was to evaluate interactions among MC4R rs17782313, the Dietary Approaches to Stop Hypertension (DASH) diet and risk factors for CVDs. Method: This cross-sectional study was conducted on 266 Iranian women categorized by body mass index (BMI) range of 25–40 kg/m2 as overweight or obese. CVD risk factors included waist circumference (WC), lipid profile, blood pressure, insulin circulation and fasting blood sugar (FBS). Insulin and FBS were used to calculate homeostatic model assessment insulin resistance (HOMA-IR) Body composition was assessed by a multi-frequency bioelectrical impedance analyzer, InBody 770 scanner. Results: The findings of this study show that high adherence to the DASH diet in the CC groups were associated with decreased SBP and DBP compared to the TT group. In addition, a significant difference between women with high adherence to the DASH diet compared to low adherence was observed for body weight (p < 0.001), fat free mass (FFM) (p = 0.01) and BMI (p = 0.02). Women with the CC genotype had higher insulin (mg/dl) (mean and SD, for TT: 14.6 ± 4.6, TC: 17.3 ± 9.2, CC: 15.3 ± 4.8, p = 0.04) and HOMA-IR (mean for and SD, TT: 3.1 ± 1.07, TC: 3.9 ± 2.4, CC: 3.2 ± 1.1, p = 0.01) than TT group. Inclusion of potential confounding variables (age, physical activity, BMI and daily caloric intake) did not attenuate the difference. Conclusion: Among overweight/obese Iranian women with the CC genotype, incorporating the DASH diet may serve as a dietary prescription to decrease CVD risk. A dietary intervention trial is warranted.


2018 ◽  
Vol 1 (3) ◽  
pp. 26-38
Author(s):  
Abdulghani Mohamed Alsamarai ◽  
Shler Ali Khorshed

Background: Urinary tract infection is common with health impact in women and characterised by failure to treatment and recurrent episodes. Aim: This study was conducted to determine the risk factors for the development of urinary tract infection in diabetic and pregnant women in comparison to student female. Materials and methods: A prospective cross-sectional study conducted during the period from 1st of June 2015 to the end of January 2016. The population included in the study are 563 women, of them 425 were outpatients, and 138 were inpatients. Their age range between 18 and 80 years, with a mean age of 33.59±15.29 years. Urine samples collected and cultured on blood agar and MacConkey agar by spread plate technique. Bacterial colonies with different morphology were selected, purified and identified according to their biochemical characteristics using conventional standard methods. Results: In diabetic women, there were no significant difference in mean age and BMI values between culture positive and culture negative groups. However, pus cell mean scale was significantly higher [P=0.000] in women with urinary tract infection [1.76±1.25] than in those with negative culture [0.69±1.00]. In pregnant women, BMI mean value was significantly [P=0.013] lower in pregnant women with UTI [26.14] as compared to those without infection [26.99]. Pus cell scale mean value was significantly [P=0.000] higher in pregnant women with UTI [1.55] than women with negative UTI [0.85]. While there was no significant difference in mean age between UTI positive and negative pregnant women. In female student, there was a significant difference between UTI infected and non-infected in mean age [P=0.041] and pus cell scale [P=0.000]. However, BMI was not significantly different between infected and non-infected female student. Other risk factors association are variables in the 3 groups when analysed using X2, while AUC and OR show different trends of association between risk factors and UTI. Conclusion: BMI, pus cell scale, child number, delivery method, operation history and hospital setting were significantly associated with culture positivity in the 3 studied groups as determined by AUC. While OR confirmed association with pus sale scale in the 3 groups.


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