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The incidence of liver diseases, such as nonalcoholic fatty liver disease and drug-induced liver injury, continues to rise and is one of the leading causes of acute hepatitis. Current trends suggest that these types of conditions will increase in the coming years. There are few drugs available for the prevention or treatment of hepatic diseases, and there is a growing need for the development of safe hepatoprotective agents. The medicinal plant, Turnera diffusa, has many ethnopharmacological uses, one of which is the production of a flavonoid named hepatodamianol, which is the principal component responsible for this plant's hepatoprotective properties. In the present study, we describe the development and standardization of an active extract obtained from T. diffusa. We conducted nuclear magnetic resonance spectroscopy to identify hepatodamianol unambiguously in each sample. Using this extract, hepatoprotection could be demonstrated in vivo for the first time. The hepatoprotective effect did not display a significant difference in vivo when compared with silymarin used as a positive control at the same doses. Implementation of quality criteria used for standardization, such as flavonoid and hepatodamianol content, hepatoprotective activity, and absence of residual solvents, will allow future preclinical trials with this herbal drug.
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BACKGROUND: Ischemia-reperfusion (IR) injury is one of the leading causes of early graft dysfunction in liver transplantation. Techniques such as ischemic preconditioning protect the graft through the activation of the hypoxia-inducible factors (HIF), which are downregulated by the EGLN family of prolyl-4-hydroxylases, a potential biological target for the development of strategies based on pharmacological preconditioning. For that reason, this study aims to evaluate the effect of the EGLN inhibitor sodium (S)-2-hydroxyglutarate [(S)-2HG] on liver IR injury in Wistar rats. METHODS: Twenty-eight female Wistar rats were divided into the following groups: sham (SH, n = 7), non-toxicity (HGTox, n = 7, 25 mg/kg of (S)-2HG, twice per day for two days), IR (n = 7, total liver ischemia: 20 minutes, reperfusion: 60 minutes), and (S)-2HG+IR (HGIR, n = 7, 25 mg/kg of (S)-2HG, twice per day for two days, total liver ischemia as the IR group). Serum ALT, AST, LDH, ALP, glucose, and total bilirubin were assessed. The concentrations of IL-1ß, IL-6, TNF, malondialdehyde, superoxide dismutase, and glutathione peroxidase were measured in liver tissue, as well as the expression of Hmox1, Vegfa, and Pdk1, determined by RT-qPCR. Sections of liver tissue were evaluated histologically, assessing the severity of necrosis, sinusoidal congestion, and cytoplasmatic vacuolization. RESULTS: The administration of (S)-2HG did not cause any alteration in the assessed biochemical markers compared to SH. Preconditioning with (S)-2HG significantly ameliorated IR injury in the HGIR group, decreasing the serum activities of ALT, AST, and LDH, and the tissue concentrations of IL-1ß and IL-6 compared to the IR group. IR injury decreased serum glucose compared to SH. There were no differences in the other biomarkers assessed. The treatment with (S)-2HG tended to decrease the severity of hepatocyte necrosis and sinusoidal congestion compared to the IR group. The administration of (S)-2HG did not affect the expression of Hmox1 but decreased the expression of both Vegfa and Pdk1 compared to the SH group, suggesting that the HIF-1 pathway is not involved in its mechanism of hepatoprotection. In conclusion, (S)-2HG showed a hepatoprotective effect, decreasing the levels of liver injury and inflammation biomarkers, without evidence of the involvement of the HIF-1 pathway. No hepatotoxic effect was observed at the tested dose.
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INTRODUCTION: Essential amino acid α-keto acid analogs are used in the treatment of chronic kidney disease to delay the symptoms of uremia. However, it is unknown whether essential amino acid α-keto acid analogs affect the oxidative stress and the inflammation in acute renal injury such as those produced by ischemia-reperfusion. OBJECTIVE: To evaluate the effect of essential amino acid α-keto acid analogs on renal ischemia-reperfusion injury in Wistar rats. MATERIALS AND METHODS: Rats were divided into 11 groups (n=6/group): Two groups received physiological saline with or without ischemia-reperfusion injury (45 min/24 h), six groups received essential amino acid α-keto acid analogs (400, 800, or 1,200 mg/kg/24 h/7d) with or without ischemia-reperfusion injury (essential amino acid α-keto acid analogs + ischemia-reperfusion), and two groups received allopurinol (50 mg/kg/24 h/7d) with or without ischemia-reperfusion injury. Biochemical markers included creatinine and blood urea nitrogen (BUN), proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), renal damage markers (cystatin C, KIM-1, and NGAL), and markers of oxidative stress such as malondialdehyde (MDA) and total antioxidant activity. RESULTS: The essential amino acid α-keto acid analog- and allopurinol-treated groups had lower levels of creatinine, BUN, renal damage markers, proinflammatory cytokines, and MDA than their corresponding ischemia-reperfusion groups. These changes were related to the essential amino acid α-keto acid analogs dosage. Total antioxidant activity was lower in essential amino acid α-keto acid analog- and allopurinol-treated groups than in the corresponding ischemia-reperfusion groups. CONCLUSIONS: This is a new report on the nephroprotective effects of essential amino acid α-keto acid analogs against ischemia-reperfusion injury. Essential amino acid α-keto acid analogs decreased the levels of biochemical markers, kidney injury markers, proinflammatory cytokines, and MDA while minimizing total antioxidant consumption.
Introducción. Los α-cetoanálogos de aminoácidos esenciales se utilizan en el tratamiento de la enfermedad renal crónica para retrasar los síntomas de la uremia. Sin embargo, se desconoce si los α-cetoanálogos de aminoácidos esenciales afectan el estrés oxidativo y la inflamación en la lesión renal aguda tal como en la producida por la isquemia-reperfusión. Objetivo. Evaluar el efecto de las α-cetoanálogos de aminoácidos esenciales sobre la lesión renal por isquemia-reperfusión en ratas Wistar. Materiales y métodos. Se emplearon 11 grupos de ratas (n=6): dos grupos recibieron solución salina fisiológica con lesión isquemia-reperfusión o sin ella (45 min/24 h), seis grupos recibieron α-cetoanálogos de aminoácidos esenciales (400, 800 o 1.200 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella (α-cetoanálogos de aminoácidos esenciales + isquemia-reperfusión), y dos grupos recibieron (50 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella. Los marcadores bioquímicos incluyeron creatinina y nitrógeno ureico en sangre (BUN), citocinas proinflamatorias (IL-1ß, IL-6 y TNF-α), marcadores de daño renal (cistatina C, KIM-1 y NGAL) y marcadores del estrés oxidativo como el malondialdehído (MDA) y la actividad antioxidante total. Resultados. Los grupos tratados con α-cetoanálogos de aminoácidos esenciales y alopurinol tuvieron niveles inferiores de creatinina, BUN, marcadores de daño renal, citocinas proinflamatorias, actividad antioxidante total y MDA que los grupos isquemia-reperfusión correspondientes. Estos cambios se asociaron con la dosis. La actividad antioxidante total fue menor en los grupos tratados con α-cetoanálogos de aminoácidos esenciales que en los grupos isquemia-reperfusión correspondientes. Conclusiones. Este es un nuevo informe de los efectos nefroprotectores de las α-cetoanálogos de aminoácidos esenciales contra la lesión isquemia-reperfusión. Los α-cetoanálogos de aminoácidos esenciales disminuyeron los niveles de los marcadores bioquímicos, de los de lesión renal, de las citocinas proinflamatorias y el MDA, a la vez que minimizaron el consumo total de antioxidantes.
Assuntos
Aminoácidos Essenciais/uso terapêutico , Antioxidantes/uso terapêutico , Cetoácidos/uso terapêutico , Rim/irrigação sanguínea , Traumatismo por Reperfusão/tratamento farmacológico , Alopurinol/uso terapêutico , Aminoácidos Essenciais/administração & dosagem , Animais , Antioxidantes/análise , Biomarcadores , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Cistatina C/sangue , Citocinas/sangue , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Cetoácidos/administração & dosagem , Rim/patologia , Lipocalina-2/sangue , Masculino , Malondialdeído/sangue , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controleRESUMO
BACKGROUND: Ischemia-reperfusion (IR) injury is the main cause of delayed graft function in solid organ transplantation. Hypoxia-inducible factors (HIFs) control the expression of genes related to preconditioning against IR injury. During normoxia, HIF-α subunits are marked for degradation by the egg-laying defective nine homolog (EGLN) family of prolyl-4-hydroxylases. The inhibition of EGLN stabilizes HIFs and protects against IR injury. The aim of this study was to determine whether the EGLN inhibitors sodium (S)-2-hydroxyglutarate [(S)-2HG] and succinic acid (SA) have a nephroprotective effect against renal IR injury in Wistar rats. METHODS: (S)-2HG was synthesized in a 22.96% yield from commercially available L-glutamic acid in a two-step methodology (diazotization/alkaline hydrolysis), and its structure was confirmed by nuclear magnetic resonance and polarimetry. SA was acquired commercially. (S)-2HG and SA were independently evaluated in male and female Wistar rats respectively after renal IR injury. Rats were divided into the following groups: sham (SH), nontoxicity [(S)-2HG: 12.5 or 25 mg/kg; SA: 12.5, 25, or 50 mg/kg], IR, and compound+IR [(S)-2HG: 12.5 or 25 mg/kg; SA: 12.5, 25, or 50 mg/kg]; independent SH and IR groups were used for each assessed compound. Markers of kidney injury (BUN, creatinine, glucose, and uric acid) and liver function (ALT, AST, ALP, LDH, serum proteins, and albumin), proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), oxidative stress biomarkers (malondialdehyde and superoxide dismutase), and histological parameters (tubular necrosis, acidophilic casts, and vascular congestion) were assessed. Tissue HIF-1α was measured by ELISA and Western blot, and the expression of Hmox1 was assessed by RT-qPCR. RESULTS: (S)-2HG had a dose-dependent nephroprotective effect, as evidenced by a significant reduction in the changes in the BUN, creatinine, ALP, AST, and LDH levels compared with the IR group. Tissue HIF-1α was only increased in the IR group compared to SH; however, (S)-2HG caused a significant increase in the expression of Hmox1, suggesting an early accumulation of HIF-1α in the (S)-2HG-treated groups. There were no significant effects on the other biomarkers. SA did not show a nephroprotective effect; the only changes were a decrease in creatinine level at 12.5 mg/kg and increased IR injury at 50 mg/kg. There were no effects on the other biochemical, proinflammatory, or oxidative stress biomarkers. CONCLUSION: None of the compounds were hepatotoxic at the tested doses. (S)-2HG showed a dose-dependent nephroprotective effect at the evaluated doses, which involved an increase in the expression of Hmox1, suggesting stabilization of HIF-1α. SA did not show a nephroprotective effect but tended to increase IR injury when given at high doses.
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Introduction: Essential amino acid α-keto acid analogs are used in the treatment of chronic kidney disease to delay the symptoms of uremia. However, it is unknown whether essential amino acid α-keto acid analogs affect the oxidative stress and the inflammation in acute renal injury such as those produced by ischemia-reperfusion. Objective: To evaluate the effect of essential amino acid α-keto acid analogs on renal ischemia-reperfusion injury in Wistar rats. Materials and methods: Rats were divided into 11 groups (n=6/group): Two groups received physiological saline with or without ischemia-reperfusion injury (45 min/24 h), six groups received essential amino acid α-keto acid analogs (400, 800, or 1,200 mg/kg/24 h/7d) with or without ischemia-reperfusion injury (essential amino acid α-keto acid analogs + ischemia-reperfusion), and two groups received allopurinol (50 mg/kg/24 h/7d) with or without ischemia-reperfusion injury. Biochemical markers included creatinine and blood urea nitrogen (BUN), proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), renal damage markers (cystatin C, KIM-1, and NGAL), and markers of oxidative stress such as malondialdehyde (MDA) and total antioxidant activity. Results: The essential amino acid α-keto acid analog- and allopurinol-treated groups had lower levels of creatinine, BUN, renal damage markers, proinflammatory cytokines, and MDA than their corresponding ischemia-reperfusion groups. These changes were related to the essential amino acid α-keto acid analogs dosage. Total antioxidant activity was lower in essential amino acid α-keto acid analog- and allopurinol-treated groups than in the corresponding ischemia-reperfusion groups. Conclusions: This is a new report on the nephroprotective effects of essential amino acid α-keto acid analogs against ischemia-reperfusion injury. Essential amino acid α-keto acid analogs decreased the levels of biochemical markers, kidney injury markers, proinflammatory cytokines, and MDA while minimizing total antioxidant consumption.
Introducción. Los α-cetoanálogos de aminoácidos esenciales se utilizan en el tratamiento de la enfermedad renal crónica para retrasar los síntomas de la uremia. Sin embargo, se desconoce si los α-cetoanálogos de aminoácidos esenciales afectan el estrés oxidativo y la inflamación en la lesión renal aguda tal como en la producida por la isquemia-reperfusión. Objetivo. Evaluar el efecto de las α-cetoanálogos de aminoácidos esenciales sobre la lesión renal por isquemia-reperfusión en ratas Wistar. Materiales y métodos. Se emplearon 11 grupos de ratas (n=6): dos grupos recibieron solución salina fisiológica con lesión isquemia-reperfusión o sin ella (45 min/24 h), seis grupos recibieron α-cetoanálogos de aminoácidos esenciales (400, 800 o 1.200 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella (α-cetoanálogos de aminoácidos esenciales + isquemia-reperfusión), y dos grupos recibieron (50 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella. Los marcadores bioquímicos incluyeron creatinina y nitrógeno ureico en sangre (BUN), citocinas proinflamatorias (IL-1ß, IL-6 y TNF-α), marcadores de daño renal (cistatina C, KIM-1 y NGAL) y marcadores del estrés oxidativo como el malondialdehído (MDA) y la actividad antioxidante total. Resultados. Los grupos tratados con α-cetoanálogos de aminoácidos esenciales y alopurinol tuvieron niveles inferiores de creatinina, BUN, marcadores de daño renal, citocinas proinflamatorias, actividad antioxidante total y MDA que los grupos isquemia-reperfusión correspondientes. Estos cambios se asociaron con la dosis. La actividad antioxidante total fue menor en los grupos tratados con α-cetoanálogos de aminoácidos esenciales que en los grupos isquemia-reperfusión correspondientes. Conclusiones. Este es un nuevo informe de los efectos nefroprotectores de las α-cetoanálogos de aminoácidos esenciales contra la lesión isquemia-reperfusión. Los α-cetoanálogos de aminoácidos esenciales disminuyeron los niveles de los marcadores bioquímicos, de los de lesión renal, de las citocinas proinflamatorias y el MDA, a la vez que minimizaron el consumo total de antioxidantes.
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Isquemia , Traumatismo por Reperfusão , Estresse Oxidativo , Insuficiência Renal Crônica , Inflamação , Modelos TeóricosRESUMO
BACKGROUND: Oxidative stress and the inflammatory process are involved in ischemia-reperfusion (I/R) injury. Juglans mollis has been reported as having antioxidant activity, which could attenuate the damage caused by I/R. We evaluated whether a methanolic extract of Juglans mollis (JM) exhibits nephroprotective activity in a Wistar rat model of I/R injury. METHODS: Four groups of six rats were used: Sham, I/R, JM, and JM + I/R. Two groups were dosed with JM (300 mg/kg) for 7 days before I/R. I/R injury was induced by clamping the renal hilums for 45 min and then reperfusing the kidneys for 15 h. Blood samples were taken to evaluate the levels of alanine aminotransferase (ALT), blood urea nitrogen, creatinine, superoxide dismutase (SOD), malondialdehyde (MDA), interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF-α). RESULTS: The levels of creatinine, ALT, MDA, IL-1ß, IL-6, and TNF-α were lower in JM + I/R than in I/R rats, whereas SOD level only was higher in JM + I/R than in Sham rats. No biochemical or histological damage was observed in JM rats compared with Sham rats; however, less histological damage was observed in JM + I/R rats compared with I/R rats. CONCLUSIONS: To our knowledge, this is the first report of nephroprotective activity of J. mollis against damage induced by I/R. This activity may be related to decreased levels of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) and modulation of oxidative stress markers (SOD and MDA) observed in the present study.
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Anti-Inflamatórios/administração & dosagem , Juglans/química , Extratos Vegetais/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Creatinina/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/imunologia , Rim/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Introducción. La obesidad es un problema de salud pública mundial y la enfermedad crónica no transmisible más frecuente. Se asocia con la elevación de proteínas inflamatorias de fase aguda y citocinas proinflamatorias. Objetivo. Evaluar los niveles de proteínas de fase aguda en niños y adolescentes obesos con esteatosis hepática y síndrome agudo metabólico. Metodología. Se incluyeron 45 niños con índice de masa corporal ≥ percentil 95, de edades entre 5,0 y 15,5 años. Se determinaron reactantes de fase aguda: proteína C reactiva, haptoglobina, a-2 macroglobulina y apolipoproteína A-1, y se realizó una ecografía para evaluar la esteatosis hepática. Resultados. Todos los pacientes mostraron una elevación de proteína C reactiva. Los pacientes con síndrome metabólico también tuvieron un incremento en la apolipoproteína A-1 y la haptoglobina. Los pacientes con esteatosis hepática tuvieron un aumento significativo en la a-2 macroglobulina además de la protenína C reactiva.
Introduction. Obesity is a worldwide public health problem and the most common non-communicable chronic disease. It is associated with an increase in inflammatory acute phase proteins and proinflammatory cytokines. Objective. To assess the levels of acute phase proteins in obese children and adolescents with hepatic steatosis and metabolic syndrome. Methodology. Forty-five children with a body mass index ≥ 95th percentile aged 5.0-15.5 years were included. The following acute phase reactants were determined: C-reactive protein, haptoglobin, alpha-2-macroglobulin, and apolipoprotein A-1; besides, an ultrasound was done to assess hepatic steatosis. Results. C-reactive protein levels increased in all patients. Patients with metabolic syndrome also had high levels of apolipoprotein A-1 and haptoglobin. Patients with hepatic steatosis had a significant increase in alpha-2-macroglobulin in addition to high C-reactive protein.
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Humanos , Criança , Adolescente , alfa-Macroglobulinas , Proteína C-Reativa , Haptoglobinas , Apolipoproteína A-I , ObesidadeRESUMO
INTRODUCTION: Obesity is a worldwide public health problem and the most common non-communicable chronic disease. It is associated with an increase in inflammatory acute phase proteins and proinflammatory cytokines. OBJECTIVE: To assess the levels of acute phase proteins in obese children and adolescents with hepatic steatosis and metabolic syndrome. Methodology. Forty-five children with a body mass index ≥ 95th percentile aged 5.0-15.5 years were included. The following acute phase reactants were determined: C-reactive protein, haptoglobin, alpha-2-macroglobulin, and apolipoprotein A-1; besides, an ultrasound was done to assess hepatic steatosis. RESULTS: C-reactive protein levels increased in all patients. Patients with metabolic syndrome also had high levels of apolipoprotein A-1 and haptoglobin. Patients with hepatic steatosis had a significant increase in alpha-2-macroglobulin in addition to high C-reactive protein.
Introducción. La obesidad es un problema de salud pública mundial y la enfermedad crónica no transmisible más frecuente. Se asocia con la elevación de proteínas inflamatorias de fase aguda y citocinas proinflamatorias. Objetivo. Evaluar los niveles de proteínas de fase aguda en niños y adolescentes obesos con esteatosis hepática y síndrome agudo metabólico. Metodología. Se incluyeron 45 niños con índice de masa corporal ≥ percentil 95, de edades entre 5,0 y 15,5 años. Se determinaron reactantes de fase aguda: proteína C reactiva, haptoglobina, alpha-2 macroglobulina y apolipoproteína A-1, y se realizó una ecografía para evaluar la esteatosis hepática. Resultados. Todos los pacientes mostraron una elevación de proteína C reactiva. Los pacientes con síndrome metabólico también tuvieron un incremento en la apolipoproteína A-1 y la haptoglobina. Los pacientes con esteatosis hepática tuvieron un aumento significativo en la alpha-2 macroglobulina además de la protenína C reactiva.
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Fígado Gorduroso/epidemiologia , Mediadores da Inflamação/metabolismo , Síndrome Metabólica/epidemiologia , Obesidade Infantil/epidemiologia , Adolescente , Apolipoproteína A-I/metabolismo , Biomarcadores/metabolismo , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Criança , Pré-Escolar , Citocinas/metabolismo , Fígado Gorduroso/fisiopatologia , Feminino , Haptoglobinas/metabolismo , Humanos , Estudos Longitudinais , Masculino , Síndrome Metabólica/fisiopatologia , Obesidade Infantil/fisiopatologia , Estudos Prospectivos , alfa-Macroglobulinas/metabolismoRESUMO
INTRODUCTION: Kidney ischemia-reperfusion (I/R) injury is the main cause of delayed graft function in solid organ transplantation. Sonchus oleraceus is a plant with well-known antioxidant and anti-inflammatory activities; however, its effects on renal I/R are unknown. OBJECTIVE: To evaluate whether S. oleraceus extract (S.O.e.) has nephroprotective activity in an I/R model in Wistar rats. MATERIALS AND METHODS: Animal groups (n = 6): sham, I/R (45 min/15 h), S.O.e (300 mg/kg p.o.), and S.O.e + I/R (300 mg/kg, p.o.; 45 min/15 h). Renal function, proinflammatory cytokines, alanine aminotransferase, markers of oxidative stress, and histology were evaluated. RESULTS: None of the mediators evaluated differed significantly between the S.O.e and sham groups. Levels of blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and proinflammatory cytokines were higher, and superoxide dismutase (SOD) was lower in the I/R group than in the sham group. Histology showed tubular epithelial necrosis in the medulla and cortex in the I/R group. In the S.O.e + I/R group, S.O.e pretreatment attenuated the I/R-induced increases in BUN, creatinine, MDA, and proinflammatory cytokines induced, SOD was maintained, and histology showed discontinuous necrosis in the medulla but no necrosis in the cortex. CONCLUSIONS: S.O.e was neither hepatotoxic nor nephrotoxic. S.O.e. pretreatment showed a nephroprotective effect against I/R.
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Rim/irrigação sanguínea , Extratos Vegetais/farmacologia , Insuficiência Renal/prevenção & controle , Traumatismo por Reperfusão/tratamento farmacológico , Sonchus/química , Animais , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/etiologia , Traumatismo por Reperfusão/patologiaRESUMO
BACKGROUND AND AIMS: The protective effect of ischemic preconditioning (IP) in liver transplantation (LT) has been studied with controversial results. We undertook this study to investigate whether IP of cadaveric donor livers is protective to allografts. METHODS: IP (LT + IP, n = 6) was induced by 10-min hilar clamping. These were compared to cadaver donors with no IP (LT, n = 7). Clinical data and blood were obtained in donors and recipients for biochemical and inflammatory mediator (IM) measurements (P-selectin, leukotriene B4, myeloperoxidase, ICAM-1, IL-1, IL-6, and TNF-α). Liver tissue samples were obtained from donors and recipients (90 min after reperfusion). RESULTS: No significant differences were found in demographic characteristics between donors and recipients. When comparing both groups (LT + IP vs. LT only), ICU stay was longer in LT + IP group. For biochemical parameters, a significant difference was found only with a higher total bilirubin at postoperative day 3 in LT + IP group. There was no statistical difference in IM between LT and LT + IP groups at different stages of the study. Histological analysis of donor grafts indicated the presence of steatosis (50%) in one graft from the LT + IP group. However, in post-reperfusion biopsies neither neutrophil infiltration nor grade of necrosis showed significant difference between groups. No incidence of primary graft nonfunction (PGNF) was observed and graft and patient survival was similar in the two groups at 24 months. CONCLUSION: IP does not seem to protect against I/R injury in cadaveric LT, and no PGNF was seen.
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Doença Hepática Terminal/cirurgia , Precondicionamento Isquêmico , Transplante de Fígado/métodos , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Adulto , Biomarcadores/sangue , Cadáver , Doença Hepática Terminal/sangue , Feminino , Humanos , Fígado/patologia , Fígado/cirurgia , Transplante de Fígado/efeitos adversos , Masculino , México , Pessoa de Meia-Idade , Projetos Piloto , Traumatismo por Reperfusão/etiologia , Doadores de Tecidos , Adulto JovemRESUMO
BACKGROUND AND AIMS: We undertook this study to evaluate the virological response to and presence of adverse events to natural interferon α (nIFNα; Multiferon®) treatment in previously nonresponsive Mexican patients chronically infected with genotype 1 hepatitis C. METHODS: Thirty-nine patients received a 4-week induction of 5 days/week of 6 MU nIFNα plus weight-based ribavirin followed by 3 MU of nIFNα three times a week for 44 weeks. The relationship between viral response and incidence of adverse events was analyzed. RESULTS: Early viral response (EVR) was age- and sex-dependent, with older male patients being less responsive. Sustained viral response (SVR) was evaluated according to: a) intention to treat analysis, b) 48-week treatment and 24-week follow-up (16 patients), and c) patients with EVR (11 patients). None of the factors was significantly different in groups a) and b); however, in group c) there was a better response with a marked viral load decline in younger patients and in patients aged 50 years and older. Five of 39 (13%) patients who completed treatment presented with an SVR. The most common adverse effect was asthenia in 27% of patients. CONCLUSIONS: nIFNα could be a useful strategy for re-treatment in chronic hepatitis C, genotype 1, in previously nonresponsive patients. Confirmation of these data in a larger population is required.
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Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Interferon-alfa/administração & dosagem , Antivirais/efeitos adversos , Astenia/induzido quimicamente , Esquema de Medicação , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/efeitos adversos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Projetos Piloto , Estudos Prospectivos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico , Retratamento , Ribavirina/administração & dosagem , Carga Viral/efeitos dos fármacosRESUMO
OBJECTIVE: It is essential to identify a serological marker of injury in order to study the pathophysiology of intestinal ischemia reperfusion. In this work, we studied the evolution of several serological markers after intestinal ischemia reperfusion injury in rats. The markers of non-specific cell damage were aspartate aminotransferase, alanine aminotransaminase, and lactic dehydrogenase, the markers of inflammation were tumor necrosis factor alpha, interleukin-6, and interleukin-1 beta, and the markers of intestinal mucosal damage were intestinal fatty acid binding protein and D-lactate. We used Chiús classification to grade the histopathological damage. METHODS: We studied 35 Wistar rats divided into groups according to reperfusion time. The superior mesenteric artery was clamped for 30 minutes, and blood and biopsies were collected at 1, 3, 6, 12, 24, and 48 hours after reperfusion. We plotted the mean ± standard deviation and compared the baseline and maximum values for each marker using Student's t-test. RESULTS: The maximum values of interleukin-1 beta and lactic dehydrogenase were present before the maximal histopathological damage. The maximum tumor necrosis factor alpha and D-lactate expressions coincided with histopathological damage. Alanine aminotransaminase and aspartate aminotransferase had a maximum expression level that increased following the histopathological damage. The maximum expressions of interluken-6 and intestinal fatty acid binding protein were not significantly different from the Sham treated group. CONCLUSION: For the evaluation of injury secondary to acute intestinal ischemia reperfusion with a 30 minute ischemia period, we recommend performing histopathological grading, quantification of D-lactate, which is synthesized by intestinal bacteria and is considered an indicator of mucosal injury, and quantification of tumor necrosis factor alpha as indicators of acute inflammation three hours after reperfusion.
Assuntos
Biomarcadores/sangue , Intestinos/irrigação sanguínea , Traumatismo por Reperfusão/sangue , Animais , Aspartato Aminotransferases/sangue , Biópsia , Citocinas/sangue , Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Intestinos/patologia , Lactato Desidrogenases/sangue , Ratos , Ratos Wistar , Valores de Referência , Fatores de TempoRESUMO
OBJECTIVE: It is essential to identify a serological marker of injury in order to study the pathophysiology of intestinal ischemia reperfusion. In this work, we studied the evolution of several serological markers after intestinal ischemia reperfusion injury in rats. The markers of non-specific cell damage were aspartate aminotransferase, alanine aminotransaminase, and lactic dehydrogenase, the markers of inflammation were tumor necrosis factor alpha, interleukin-6, and interleukin-1 beta, and the markers of intestinal mucosal damage were intestinal fatty acid binding protein and D-lactate. We used Chiús classification to grade the histopathological damage. METHODS: We studied 35 Wistar rats divided into groups according to reperfusion time. The superior mesenteric artery was clamped for 30 minutes, and blood and biopsies were collected at 1, 3, 6, 12, 24, and 48 hours after reperfusion. We plotted the mean ± standard deviation and compared the baseline and maximum values for each marker using Student's t-test. RESULTS: The maximum values of interleukin-1 beta and lactic dehydrogenase were present before the maximal histopathological damage. The maximum tumor necrosis factor alpha and D-lactate expressions coincided with histopathological damage. Alanine aminotransaminase and aspartate aminotransferase had a maximum expression level that increased following the histopathological damage. The maximum expressions of interluken-6 and intestinal fatty acid binding protein were not significantly different from the Sham treated group. CONCLUSION: For the evaluation of injury secondary to acute intestinal ischemia reperfusion with a 30 minute ischemia period, we recommend performing histopathological grading, quantification of D-lactate, which is synthesized by intestinal bacteria and is considered an indicator of mucosal injury, and quantification of tumor necrosis ...
Assuntos
Animais , Feminino , Ratos , Biomarcadores/sangue , Intestinos/irrigação sanguínea , Traumatismo por Reperfusão/sangue , Aspartato Aminotransferases/sangue , Biópsia , Citocinas/sangue , Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo/sangue , Intestinos/patologia , Lactato Desidrogenases/sangue , Ratos Wistar , Valores de Referência , Fatores de TempoRESUMO
Ischemia/reperfusion (I/R) is a condition that stimulates an intense inflammatory response. No ideal treatment exists. Triflusal is an antiplatelet salicylate derivative with anti-inflammatory effects. S-adenosylmethionine is a metabolic precursor for glutathione, an endogenous antioxidant. Dextromethorphan is a low-affinity N-methyl-D-aspartate receptor inhibitor. There is evidence that these agents modulate some of the pathways involved in I/R physiopathology. Intestinal I/R was induced in rats by clamping the superior mesenteric artery for 60 minutes, followed by 60 minutes of reperfusion. Rats either received saline or the drugs studied. At the end of the procedure, serum concentrations of tumor necrosis factor-alpha (TNF-alpha), malonaldehyde (MDA), and total antioxidant capacity (TAC) were determined and intestinal morphology analyzed. I/R resulted in tissue damage, serum TNF-alpha and MDA elevations, and depletion of TAC. All drugs showed tissue protection. Only triflusal reduced TNF-alpha levels. All drugs lowered MDA levels, but only triflusal and S-adenosylmethionine maintained the serum TAC.
Assuntos
Dextrometorfano/uso terapêutico , Intestinos/irrigação sanguínea , Inibidores da Agregação Plaquetária/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , S-Adenosilmetionina/uso terapêutico , Salicilatos/uso terapêutico , Animais , Antioxidantes/metabolismo , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Centaurea americana, Krameria ramosissima, Juglans mollis and Turnera diffusa are used by traditional healers in the northeastern region of Mexico to protect against liver damage. However, the hepatoprotective properties of these plants have not been investigated scientifically. This study reports on the protective effects of these plants using an in vitro assay. MATERIAL AND METHODS: Extracts of plants were tested for antioxidant activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method. The effects of extracts from these plants on a human hepatoma cell line (Huh7) were evaluated according to cell viability and aspartate aminotransferase and malondialdehyde levels before and after exposure of the cells to carbon tetrachloride (CCl(4)). RESULTS: All extracts reduced DPPH levels by more than 50%. C. americana flower and stem/leaf extracts, the aerial part of T. diffusa, and the nut, leaf and bark of J. mollis extracts were used to assess hepatoprotective activity. The extract of the aerial part of K. ramosissima was toxic. Pretreatment of Huh7 cells with extracts from the flower of C. americana (FCA), the stem/leaf fraction of C. americana (S/LCA), the leaf of J. mollis (LJM) and the bark of J. mollis (BJM) prior to the CCl(4) challenge, protected against CCl(4)-induced liver damage, as evidenced by a significant decrease in the activity of the medium enzyme. The FCA, S/LCA, LJM and BJM extracts showed significant antilipid peroxidant effects in vitro. In conclusion, the hepatoprotective effects of the FCA, S/LCA, LJM and BJM extracts observed in this study may result from their antioxidative properties.