双相障碍抑郁发作患者氧化应激水平

目的:探讨自由基、抗氧化酶在双相障碍抑郁发作病理机制中的作用。方法:采用病例-对照研究设计,对56例符合美国精神障碍诊断与统计手册第4版诊断标准的门诊及住院双相障碍抑郁发作患者(包括双相Ⅰ型组23例及双相Ⅱ型组33例)以汉密尔顿抑郁量表(Hamilton Depression Scale,HAMD)评定抑郁症状,并检测血浆丙二醛(malondialdehyde,MDA)、超氧化物歧化酶(superoxide dismutase,SOD)、过氧化氢酶(catalase,CAT)以及谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)含量,选择32名正常健康人作为对照(对照组),使用单因素方差分析以及多元线性回归分析比较各参数在组间差异及其与HAMD评分之间的关系。结果:双相Ⅰ型和Ⅱ型组MDA水平均高于对照组,SOD、CAT及GSH-Px水平低于对照组,差异均有统计学意义;多因素分析显示,在控制身高、体质量指数和年龄等因素后HAMD评分与血浆MDA水平呈正相关(β=0.46,P<0.05),与SOD(β=-0.27,P<0.05)、CAT(β=-0.41,P<0.05)和GSH-PX(β=-0.34,P<0.05)水平呈负相关。结论:氧化应激反应可能参与双相障碍抑郁发作的发生过程,疾病严重程度可能与氧化应激反应失衡有关。     

Oxidative stress and antioxidant enzyme activities in patients with Hashimoto’s thyroiditis

We investigated the parameters of oxidative stress in 71 Hashimoto’s thyroiditis patients. They were divided into three sub-groups according to the thyroid function: group I—euthyroid subjects; group II—hypothyroid subjects; and group III—subjects treated with Levothyroxin. Thirty healthy subjects were studied as controls. The level of lipid peroxidation (malondialdehyde, MDA) in the plasma and the antioxidant defences such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activities in erythrocytes were measured. Concentrations of MDA and SOD activity were not different in sub-groups of patients and controls. CAT activity was significantly lower in group II in comparison with both controls (p = 0.01) and group III (p = 0.02) as well as in group I compared to the controls (p = 0.04). Activity of GPX in erythrocytes in hypothyroidism was significantly higher compared to controls (p = 0.02). GPX activity in both groups I and III tended to be lower in comparison with controls. Our results indicate a deficiency of cellular antioxidative defense in Hashimoto’s thyroiditis patients in all stages of disease. Accordingly, we suppose that the supplementation with antioxidants from an early stage of the disease, in addition to thyroid hormone replacement, may have a positive benefit in the treatment.     

Effect of chronic psychosocial stress on nonalcoholic steatohepatitis in mice

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which may progress towards inflammation (nonalcoholic steatohepatitis (NASH)). NAFLD is regarded as a consequence of a sedentary, food-abundant lifestyle which, in the modern world, often coincides with chronically high levels of perceived psychosocial stress. Here, we aimed to characterize the effect of chronic psychosocial stress on the development of NAFLD/NASH in male mice either fed with standard chow or NASH-inducing high fat diet. Chronic psychosocial stress was induced by chronic subordinate colony housing (CSC), a pre-clinically validated paradigm relevant for human affective and somatic disorders. Single housed (SHC) mice served as controls. Under standard chow conditions CSC mice revealed lower hepatic triglyceride levels but higher hepatic TNFα, MCP-1 and HMOX mRNA expression, while serum transaminase levels did not significantly differ from SHC mice. Under the NASH-inducing high-fat diet CSC and SHC mice showed similar body weight-gain and serum levels of glucose and adiponectin. Moreover, liver histology as well as TNFα, MCP-1 and HMOX expression were similar in CSC and SHC mice fed with HFD. Surprisingly, CSC showed even significantly lower transaminase levels than SHC mice fed with the same NASH-inducing diet. Together, these data indicate that under normal dietary conditions the CSC model induces noticeable hepatic oxidative stress and inflammation without causing manifest hepatocellular injury. In contrast, CSC exhibited a protective effect on hepatocellular injury in a dietary NASH-model. Identification of the underlying mechanisms of this phenomenon may lead to novel therapeutic strategies to prevent progression of NAFLD.     

Microbiota and nonalcoholic steatohepatitis

The recent rise in obesity-related diseases, such as nonalcoholic fatty liver disease and its strong association with microbiota, has elicited interest in the underlying mechanisms of these pathologies. Experimental models have highlighted several mechanisms connecting microbiota to the development of liver dysfunction in nonalcoholic steatohepatitis (NASH) such as increased energy harvesting from the diet, small intestine bacterial overgrowth, modulation of the intestinal barrier by glucagon-like peptide-2 secretions, activation of innate immunity through the lipopolysaccharide–CD14 axis caused by obesity-induced leptin, periodontitis, and sterile inflammation. The manipulation of microbiota through probiotics, prebiotics, antibiotics, and periodontitis treatment yields encouraging results for the treatment of obesity, diabetes, and NASH, but data in humans is scarce.     

Noninvasive predictors of nonalcoholic steatohepatitis in Korean patients with histologically proven nonalcoholic fatty liver disease

Background/Aims

The aims of this study were (1) to identify the useful clinical parameters of noninvasive approach for distinguishing nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD), and (2) to determine whether the levels of the identified parameters are correlated with the severity of liver injury in patients with NASH.

Methods

One hundred and eight consecutive patients with biopsy-proven NAFLD (age, 39.8±13.5 years, mean±SD; males, 67.6%) were prospectively enrolled from 10 participating centers across Korea.

Results

According to the original criteria for NAFLD subtypes, 67 patients (62.0%) had NASH (defined as steatosis with hepatocellular ballooning and/or Mallory-Denk bodies or fibrosis ≥2). Among those with NAFLD subtype 3 or 4, none had an NAFLD histologic activity score (NAS) below 3 points, 40.3% had a score of 3 or 4 points, and 59.7% had a score >4 points. Fragmented cytokeratin-18 (CK-18) levels were positively correlated with NAS (r=0.401), as well as NAS components such as lobular inflammation (r=0.387) and ballooning (r=0.231). Fragmented CK-18 was also correlated with aspartate aminotransferase (r=0.609), alanine aminotransferase (r=0.588), serum ferritin (r=0.432), and the fibrosis stage (r=0.314). A fragmented CK-18 cutoff level of 235.5 U/L yielded sensitivity, specificity, and positive and negative predictive values of 69.0%, 64.9%, 75.5% (95% CI 62.4-85.1), and 57.1% (95% CI 42.2-70.9), respectively, for the diagnosis of NASH.

Conclusions

Serum fragmented CK-18 levels can be used to distinguish between NASH and NAFL. Further evaluation is required to determine whether the combined measurement of serum CK-18 and ferritin levels improves the diagnostic performance of this distinction.     

Apoptosis markers in liver biopsy of nonalcoholic steatohepatitis in pediatric patients

The natural history of pediatric nonalcoholic steatohepatitis is still unknown; however, there are differences between adult and pediatric presentation. Apoptosis may play an important role in pathophysiologic pathways involved in liver damage and progression. Our aim was to detect early apoptosis markers, activated caspase-3 and cleaved cytokeratin-18, in hepatocytes and to correlate their presence with clinical, serologic, and histologic characteristics in pediatric nonalcoholic steatohepatitis. Twenty-five pediatric nonalcoholic steatohepatitis liver biopsies were evaluated by immunohistochemistry for presence of activated caspase-3 and cleaved cytokeratin-18. Biopsy specimens were semiquantitatively graded for activity (steatosis, inflammation, and ballooning) and fibrosis. Records were reviewed for serum aspartate aminotransferase, alanine aminotransferase, cholesterol, triglycerides, and body mass index, which was elevated in 92% of cases. Serum aspartate aminotransferase and alanine aminotransferase were elevated in 32% and 68% of cases, respectively. Sixty percent of biopsies exhibited lobular steatosis grade 3, 84% lobular inflammatory activity grade 1, 72% ballooning grade 1, and 76% fibrosis stage 3. Cleaved cytokeratin-18 was associated with milder fibrosis (P = .02) and inflammation (P = .07), although there was no association with steatosis grade. Activated caspase-3 detection was also associated with low inflammatory grade (P = .03) but not with fibrosis and steatosis. This study reveals interesting differential features concerning nonalcoholic steatohepatitis histologic characteristics and apoptosis markers compared with adult cases. Because, in this pediatric series, apoptosis seemed to be an early event in the cascade of liver injury steps, it would be useful to consider caspase inhibitors as potential therapeutic strategies to prevent liver damage progression.     

Altered phenotype and functionality of circulating immune cells characterize adult patients with nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory liver disease associated with insulin resistance and its metabolic consequences. Leukocyte mobilization, intrahepatic activation, and an exacerbated production of reactive oxygen species (ROS) and cytokines contribute to the development of NASH. Though alterations in peripheral blood (PB) T cell proportions and functionality remain unidentified, they might play a main role in NASH progression. We have compared the phenotype and Th1/Th2 commitment of peripheral immune cell reservoirs in adult patients and controls as well as the ability of neutrophils and monocytes to handle an ex vivo challenge. Also, we correlated those parameters with the main histological characteristics in NASH. Compared with controls, patients showed increased numbers of CD4⁺ cells and both CD4⁺ and CD8⁺ CD45RO subsets together with a higher frequency of IFN-γ-producing CD4⁺ and CD8⁺ T cells. We also found a decreased number of CD4⁺ and CD8⁺ CD45RA subsets. The distinctive production of IFN-γ highlights the significance of the observed skewed frequencies of PB T cells. Whereas ROS production by monocytes from NASH patients did not differ from controls, circulating neutrophils displayed a particularly higher phorbol myristate acetate-induced production of ROS. A negative correlation between oxidative burst and fibrosis grade was observed. This study reveals the presence of a characteristic profile of peripheral immune cells in NASH. We also discuss the probable influence of obesity on some of our present findings.     

Vitamin combinations reduce oxidative stress and improve antioxidant status in patients with iron deficiency anemia

The purpose of the present study was to investigate whether oxidative stress occurs at the clinical onset of iron deficiency anemia and to find the influence of iron therapy and antioxidant vitamins on the oxidative stress parameters. A comparison was made with two other categories of anaemia, pernicious anaemia and haemolytic anaemia that are not characterized with iron deficiency. Oxidative stress was measured through the level of plasma lipid peroxidation (MDA) and the activities of ceruloplasmin (CP), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px); important extracellular and intracellular antioxidants. Significantly increased lipid peroxidation was demonstrated in the plasma of patients with iron deficiency anemia (P=0.005). While the activity of erythrocyte antioxidant enzyme GSH-Px remained unaltered, SOD was significantly decreased (P <0.05), CAT and plasma CP were significantly increased (P <0.001). Repletion of iron deficient patients with iron promotes oxidative stress: MDA was found to remain high, the activities of SOD and GSH-Px remained lower and CAT remained very high as before iron treatment. When iron deficient patients were treated with iron along with the antioxidant vitamins A, E and C, the oxidative stress was reduced and the activity of SOD was normalized. The combination of Vitamins A+E and Vitamin C is more effective than Vitamin C in reversing antioxidant status. In conclusion, our results demonstrated that increased oxidative stress is present in patients with iron deficiency anemia which appears to be compromised by imbalance in antioxidant defense systems. The repletion of iron deficient patients with iron promotes the oxidative stress. Patients with iron deficiency anemia after iron treatment actually are at risk of oxidative injury. Iron in the presence of the antioxidant vitamins A+E and ascorbic acid reduced the oxidative stress.     

Immunological and molecular basis of nonalcoholic steatohepatitis and nonalcoholic fatty liver disease

The prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is rising worldwide with the increasing incidence of obesity, Type 2 diabetes mellitus and metabolic syndrome. NASH is currently one of the most common indications of liver transplantation in the United States. The immune system plays a major role in the pathogenesis of NAFLD/NASH. The metabolic changes, associated with obesity and metabolic syndrome, induce immunological responses resulting in NAFLD and further aggravation of the metabolic derangement in a feed-forward loop. Genetic and endocrine factors modulate the immunological and metabolic responses and determine the pathophysiological features of NAFLD. Histologically, NAFLD is a spectrum that ranges from simple hepatic steatosis to severe steatohepatitis, liver cirrhosis and/or hepatocellular carcinoma. Liver cirrhosis and hepatocellular carcinoma are responsible for the morbidity and mortality of the disease. This article is a critical evaluation of our current knowledge of the immunological and molecular basis of the disease.     

Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease

In animals, the combination of oxidative liver damage and inhibited hepatocyte proliferation increases the numbers of hepatic progenitors (oval cells). We studied different murine models of fatty liver disease and patients with nonalcoholic fatty liver disease or alcoholic liver disease to determine whether oval cells increase in fatty livers and to clarify the mechanisms for this response. To varying degrees, all mouse models exhibit excessive hepatic mitochondrial production of H(2)O(2), a known inducer of cell-cycle inhibitors. In mice with the greatest H(2)O(2) production, mature hepatocyte proliferation is inhibited most, and the greatest number of oval cells accumulates. These cells differentiate into intermediate hepatocyte-like cells after a regenerative challenge. Hepatic oval cells are also increased significantly in patients with nonalcoholic fatty liver disease and alcoholic liver disease. In humans, fibrosis stage and oval cell numbers, as well as the number of intermediate hepatocyte-like cells, are strongly correlated. However, cirrhosis is not required for oval cell accumulation in either species. Rather, as in mice, progenitor cell activation in human fatty liver diseases is associated with inhibited replication of mature hepatocytes. The activation of progenitor cells during fatty liver disease may increase the risk for hepatocellular cancer, similar to that observed in the Solt-Farber model of hepatocarcinogenesis in rats.     

Oxidative stress in patients with primary pulmonary hypertension

We studied the role of oxidative stress in the pathogenesis of primary pulmonary hypertension. In patients with primary pulmonary hypertension the content of malonic dialdehyde in the plasma was higher than in healthy volunteers (5.18±0.46 and 2.95±0.14 nmol/liter, respectively, p<0.01). However, glutathione peroxidase activity in the plasma decreased in these patients (0.50±0.17 vs. 1.19±0.14 U/ml in the control, p<0.05). By contrast, glutathione peroxidase activity in erythrocytes from patients surpassed the control (6.13±0.39 and 4.63±0.45 U/h hemoglobin, p<0.05). The increase in malonic dialdehyde content in the plasma and glutathione peroxidase activity in erythrocytes and the decrease in glutathione peroxidase activity in the plasma were most pronounced in patients with severe cardiac insufficiency and pulmonary hypertension. Our results indicate that antioxidant preparations improve the prognosis in patients with primary pulmonary hypertension.     

慢性乙型肝炎患者氧化损伤的研究

目的　探讨慢性乙型肝炎 (乙肝 )患者体内氧化损伤的情况。方法　检测 30例慢性乙肝患者氧化损伤指标 (丙二醛、总抗氧化能力、抗坏血酸 )、肝功能、乙型肝炎病毒 (HBVDNA) ,并做出统计分析。结果　慢性乙肝患者组与正常对照组比较 :丙二醛浓度明显升高 (P <0 0 5 ) ;ALT正常组与正常对照组比较 :抗坏血酸血清浓度明显升高 (P <0 0 1) ;ALT异常组与正常对照组及ALT正常组比较 :丙二醛血清浓度均明显升高 (P <0 0 5 )。在慢性乙型肝炎患者中 ,丙二醛浓度与ALT水平呈明显正相关 (r=0 6 1) ,抗坏血酸浓度与ALT水平呈明显负相关 (r =- 0 6 4 )。乙肝HBVDNA与抗氧化指标间无联系 (P >0 0 5 )。总抗氧化能力指标在各组间比较均无明显改变。结论　乙肝患者体内有氧化 抗氧化功能障碍。慢性乙肝患者ALT升高时 ,体内氧化损伤程度加重。慢性乙型肝炎患者ALT正常者 ,体内氧化损伤程度不高。氧化损伤指标与HBVDNA是肝炎患者中相对独立的检查指标。     

Oxidant / antioxidant status in patients with psoriasis

Psoriasis is a common, chronic inflammatory skin disease with unknown etiology. Recently it has been suggested that increased ROS production and deficient function of antioxidant systems activities may be involved in the pathogenesis of the disease. Although there are several studies investigating oxidant/antioxidant systems in psoriatic patients, the data obtained from these studies is not concordant. In this study, superoxide dismutase (SOD) enzyme activity, and malondialdehyde (MDA) and antioxidant potential (AOP) levels in thirty-five patients with psoriasis were investigated and compared with those of twenty-four control subjects. Clinical severity of the disease was determined according to the Psoriasis Area and Severity Index (PASI) scores in the patients. Plasma SOD activity and MDA levels were significantly higher (p=0.012 and p=0.005 respectively), whereas AOP levels were lower, in patients than controls (p=0.001). There was no correlation between PASI scores and plasma SOD, MDA, and AOP levels. Our findings may provide some evidence for a potential role of increased ROS production and decreased antioxidant activity in psoriasis.