Nonalcoholic steatohepatitis (NASH) is a clinicopathological condition that comprises a wide spectrum of liver damage, ranging from steatohepatitis, advanced fibrosis and cirrhosis. NASH is the most common liver disease in the United States, with a high prevalence in the obese, type 2 diabetic population and metabolic syndrome. Although the pathophysiology of NASH remains to be clarified, insulin resistance, free fatty acids and oxidative stress are the most important causes. In this review article, I focused on insulin resistance, free fatty acids and oxidative stress as main causes of NASH, and described the outlines of the pathophysiology of NASH.
Epidemiologic studies have demonstrated acute and serious adverse effects of particulate air pollution on respiratory health, especially in people who are susceptible to bacterial infection. The underlying mechanism remains to be elucidated. Diesel exhaust particles (DEP) derived from diesel engine-powered automobiles are major constituents of the atmospheric particular matter in metropolitan areas. DEP reportedly enhance airway inflammation and lung injury. Bacterial endotoxin in a purified form known as lipopolysaccharide is also implicated as an environmental factor that exacerbates lung diseases. In this article, we review the synergistic enhancing effects of DEP and bacterial endotoxin on airway inflammation and determine the components in DEP responsible for these effects. Oxygen free radicals and proinflammatory cytokines are proposed mediators for DEP-induced airway inflammation. We elucidate the role of oxidative stress and proinflammatory cytokine expression in the enhancement.
Free heme, i.e., protein-unbound heme, can be toxic to cells because it catalyzes the production of reactive oxygen species. To cope with this problem, the body is equipped with various defense mechanisms against high free heme concentrations. Heme oxygenase is the key molecule in the elimination of the prooxidant heme, which catalyzes the conversion of free heme to iron, biliverdin IXα and carbon monoxide. Heme oxygenase-1 is a signature of oxidative tissue injury and plays a critical role in the defense against oxidative stress, while heme oxygenase-2 is now also recognized as an oxygen sensor. Both biliverdin IXα and carbon monoxide have been shown to be important in the protective response against oxidative tissue injuries. Thus, the breakdown products of heme have their own biological functions. Recent evidence suggests that there may be oscillatory control of both heme synthesis and oxidative stress. These findings suggest that heme metabolites may also be important in tissue protection, oxygen sensing, and circadian control of oxidative tissue injury.
All diseases in the large intestine represented by inflammatory bowel disease develop due to destruction of the balance between aggressive factors inducing lesions and defensive factors protecting the mucosa or the body itself. This mechanism is similar to that for the development of gastric lesions. However, compared with gastric disease, the mechanism of large intestinal disease has been studied mainly in terms of aggressive factors inducing mucosal injury but rarely in terms of cytoprotection or mucosal repair. Heat shock protein (HSP) in the large intestine is induced by external stimulation, inflammatory cell infiltration, and stimulation of the intestinal bacterial flora. The induced HSP cytoprotectively acts as a molecular chaperon or by other mechanisms. Therefore, the effective induction of HSP expression has a potentiality for the development of new treatment methods for inflammatory intestinal disease.
To determine whether lipid peroxidation induced by reactive oxygen species (ROS) is a causal factor of neurodegeneration during brain aging, we investigated whether F2-isoprostanes, non-cyclooxygenase-derived prostanoids, are formed in the rat brain and plasma by hyperoxia as oxidative stress, and whether their formation is associated with vitamin E status in vivo in association with changes that occur during brain aging. Young rats subjected to hyperoxia for 48 h revealed a marked increase in the levels of F2-isoprostanes in the brain, but not in plasma. A similar increase in F2-isoprostane level was observed in aged rats kept in normal atmosphere. Vitamin E supplementation to young rats markedly inhibited F2-isoprostane formation even after hyperoxia. In contrast, vitamin E-deficient young rats kept in normal atmosphere showed a significant increase in F2-isoprostane level in the brain. These findings indicate that F2-isoprostane formation in the brain has important implications in the etiology of neurodegenerative diseases including Alzheimer’s disease during aging, and that the analysis of F2-isoprostane level in plasma does not always reflect neuronal damage cause by oxidative stress. Vitamin E may protect neuronal damage in the brain caused by oxidative stress experienced for a long period during aging.
Although much information about the apoptotic and other detrimental actions of polychlorinated biphenyls (PCBs) has been accumulated, the critical role of mitochondrial damage in such toxic action remains to be clarified. We have previously shown that PCBs affect various functions in isolated mitochondria. Recent studies have revealed that mitochondria play an important role in apoptosis through membrane permeability transition (MPT), and that Ca2+ induces classic MPT characterized by depolarization and swelling of the mitochondria, thereby releasing cytochrome c in a cyclosporin A-sensitive mechanism [Free Rad. Res. 38, 29–35, 2004]. In the present study we investigated the effect of 4-hydroxy-3,5,3',4'-tetrachlorobiphenyl (4-OH-TCB) on isolated rat liver mitochondria in order to help clarify the effect of PCBs on MPT. Biochemical analysis revealed that 4-OH-TCB induced calcium release, reactive oxygen species (ROS) generation, depolarization, swelling and cytochrome c release in isolated rat liver mitochondria in a time and concentration dependent manner. These 4-OH-TCB-induced changes in mitochondrial function were found to be inhibited by the presence of cyclosporin A, suggesting an classic type of MPT. It is concluded that 4-OH-TCB induces MPT together with ROS generation, causing apoptosis in certain cells.
The role of advanced glycation endproducts (AGEs) as the initiator of tumor induction was investigated in SENCAR mice. Initiation with AGEs-modified bovine serum albumin (AGEs–BSA) increased both the incidence of tumor-bearing mice and the mean number of tumors per mouse. An immunohistochemical study revealed an increase in 8-hydroxy-2'-deoxyguanosine (8-OhdG) in nuclei of epidermal cells in the AGEs-BSA treated mice. Furthermore, a Salmonella mutagenicity test revealed that AGEs-BSA was mutagenic only in Salmonella TA104, a strain more sensitive to oxidative stress than other strains. These results suggest that AGEs are mutagenic through a mechanism associated with oxidative stress.
Dietary supplements for body fat reduction have become popular, particularly in developed countries. Garcinia cambogia (GA) is one such supplement, and its active component is (−)-hydroxycitric acid ((−)-HCA), a competitive inhibitor of ATP citrate lyase, which is responsible for producing acetyl CoA from citric acid. Recently we have found that administration of (−)-HCA-containing GA markedly reduces testis weight in male Zucker obese rats. In particular, histopathological examinations revealed testicular atrophy and impairment of spermatogenesis. In the present study, we investigated the cause of the impaired spermatogenesis after ingestion of GA containing (−)-HCA at 102 mmol/kg diet in young Fischer 344 male rats. Among hormones related to spermatogenesis, the serum level of inhibin-B was significantly lower and that of follicle-stimulating hormone (FSH) was higher in the GA group. The level of testis meiosis-activating sterol (T-MAS), which is an intermediate in cholesterol biosynthesis from acetyl CoA and is presumed to transmit a signal for spermatogenesis, was statistically lower in the testes of rats administered GA. We hypothesize from these results that (−)-HCA-mediated inhibition of ATP citrate lyase in rats fed GA leads to diminished accumulation of MAS substances, thus resulting in impairment of spermatogenesis.
We investigated the effect of administering Garcinia cambogia (GA), which contains (−)-hydroxycitric acid ((−)-HCA), to female rats, focusing especially on changes in sexual hormones and its safety in terms of histopathological changes. A diet containing a high level of (−)-HCA (154 mmol/kg diet) was given to seven-week-old female rats with matched estrous cycles for two or four weeks. There were no significant differences in any of the serum hormones tested (follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone) between the control group and the GA group during the observation period. Also, there were no abnormal morphological findings in the follicle and corpus luteum, nor were there any significant differences in the ovarian 4,4-dimethyl-5α-cholesta 8,14,24-triene-3β-ol (follicular fluid meiosis-activating sterol; FF-MAS) and 4,4-dimethyl-5α-cholesta-8,24-diene-3β-ol (testis meiosis-activating sterol; T-MAS) concentrations between the control and the GA groups. On the other hand, the final body weight of the GA group was statistically lower than that of the control group. The weight of abdominal fat in the GA group was markedly lower than that in the control group even after two weeks of feeding. Therefore, although we had confirmed in our previous study that GA had a marked effect on sexual maturation in male rats, no such deleterious influence was observed in the female rats.
Because there is mounting evidence to suggest that oxidative stress is involved in the pathophysiology of albinism, albino amphibians are useful tools for studies on imbalances in the oxidant-antioxidant system. In the course of maintaining albino mutant frog strains it was found that crosses between albino males and heterozygous females of Rana nigromaculata sometimes produce offspring displaying pigmentary mosaicism. After hatching hypopigmented portions appear on the left or right side of the body, and this is accompanied by such abnormalities as poor viability, asymmetrical curvature of the body toward the hypopigmented side, and limb deformity. Histological examination of mosaics showed the cells of various tissues (except kidney) to be smaller on the hypopigmented side and larger on the pigmented side compared to corresponding cells in wild type offspring. Cytogenetic analysis of cultured skin cells revealed that wild type and albino individuals were diploidal with 26 chromosomes, the same as normal R. nigromaculata. In mosaics on the other hand, cells of hypopigmented portions were almost exclusively haploidal with 13 chromosomes, while pigmented portions were a mixture of roughly 75% triploidal, 39 chromosome cells and roughly 25% haploidal, 13 chromosome cells.
This study aimed to investigate the antioxidant effect of lutein, human macula pigment, and pycnogenol, which contains several flavonoids, on lipid peroxidation induced in 10% porcine retinal homogenate by the addition of 1 mM Ferric chloride (FeCl3), 50 mM 2,2'-azobis (2-amidino-propane) dihydrochloride (AAPH), or 25 mM 2,2'-azobis (2,4-dimethyl-valeronitrile) (AMVN). Lipid hydroperoxide concentration was determined from the amount of thiobarbituric acid reactive substances (TBARS) in the sample following treatment. After 60 min of oxidation with FeCl3, AAPH and AMVN, the TBARS content in the retinal homogenates increased from 28.6 ± 1.6 to 85.4 ± 0.9, from 27.9 ± 1.2 to 57.2 ± 1.1, and from 26.0 ± 1.0 to 77.5 ± 2.0 nmol MDA/mg protein, respectively. Lutein did not show remarkable antioxidant activity in this experimental system. However, IC50 of pycnogenol for TBARS formation was decreased by combining 10 μM lutein in each initiator; from 12 to 5 μg/mL in FeCl3, from 2.8 to 0.5 μg/mL in AAPH, from 465 to 110 μg/mL in AMVN. These results suggested that a combination treatment of lutein and pycnogenol is more effective for inhibiting lipid peroxidation in porcine retinal homogenate. This synergy might be due to efficient functional antioxidants acting in both hydrophilic and lipophilic cellular environments.