Yukiko Minamiyama

Antioxidant Properties of Bromocriptine, a Dopamine Agonist

Abstract: It has been suggested that free radicals may adversely influence the pathogenesis of Parkinsons disease. We conducted this study to determine whether bro‐mocriptine, an agent widely used for treating parkinsonism, possesses antioxidant effects. Bromocriptine scavenged superoxide produced from a superoxide generating system (hypoxanthine‐xanthine oxidase) by the spin‐trapping method using electron spin resonance. Bromocriptine had a strong scavenging effect on the 5,5‐dimethyl‐1‐pyrroline‐N‐oxide hydroxide signal produced from Fentons reaction. Bromocriptine also attenuated the stable free radical diphenyl‐p‐picrylhydrazyl signal. This drug inhibited the autooxidation of rat brain homogenates in a dose‐dependent manner in vitro. Autooxidation of brain homogenates collected from rats treated with bromocriptine (2.5 mg/kg, i.p., daily for 3 days) was significantly reduced as compared with values in untreated rat homogenates. These observations suggest that bromocriptine is a free radical scavenger and a potent antioxidant.

A mitochondrial superoxide theory for oxidative stress diseases and aging.

Fridovich identified CuZnSOD in 1969 and manganese superoxide dismutase (MnSOD) in 1973, and proposed ”the Superoxide Theory,” which postulates that superoxide (O2•−) is the origin of most reactive oxygen species (ROS) and that it undergoes a chain reaction in a cell, playing a central role in the ROS producing system. Increased oxidative stress on an organism causes damage to cells, the smallest constituent unit of an organism, which can lead to the onset of a variety of chronic diseases, such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and other neurological diseases caused by abnormalities in biological defenses or increased intracellular reactive oxygen levels. Oxidative stress also plays a role in aging. Antioxidant systems, including non-enzyme low-molecular-weight antioxidants (such as, vitamins A, C and E, polyphenols, glutathione, and coenzyme Q10) and antioxidant enzymes, fight against oxidants in cells. Superoxide is considered to be a major factor in oxidant toxicity, and mitochondrial MnSOD enzymes constitute an essential defense against superoxide. Mitochondria are the major source of superoxide. The reaction of superoxide generated from mitochondria with nitric oxide is faster than SOD catalyzed reaction, and produces peroxynitrite. Thus, based on research conducted after Fridovich’s seminal studies, we now propose a modified superoxide theory; i.e., superoxide is the origin of reactive oxygen and nitrogen species (RONS) and, as such, causes various redox related diseases and aging.

Generation of reactive oxygen species in sperms of rats as an earlier marker for evaluating the toxicity of endocrine-disrupting chemicals.

Abstract Bisphenol A (BPA) and diethylstilbestrol (DES) have been reported to cause sperm toxicity. To identify an earlier marker of toxicity of environmental substances or food additives, this study determined whether the levels of reactive oxygen species (ROS) in sperms could serve as indices for the prediction of sperm toxicity and quality. Male Wistar rats were given drinking water containing various doses of BPA or DES for 8 weeks. Some rats were treated with 0.45% N-acetyl cysteine (NAC) for 2 days prior to the administration of DES or BPA. Administration of BPA or DES to rats for 1 week dose-dependently increased the production of ROS, even at doses and time points which had no effect on sperm motility. 4-Hydroxy-2-nonenal modified proteins increased in sperms 8 weeks after BPA or DES treatment. NAC reversed oxidative stress and prevented the loss of sperm function in the DES or BPA-treated group. During observation, changes in the sperm motility, sperm count and morphology were not correlated to the increase in ROS levels. These results suggest that ROS levels may be used as an early indicator of sperm count and quality decreases which result from chronic toxicity.

Suppression of indomethacin-induced apoptosis in the small intestine due to Bach1 deficiency

Abstract BTB and CNC homologue 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1). This study hypothesized that Bach1 plays an important role in the indomethacin-induced apoptosis in the case of small-intestinal mucosal injury. Eight-week-old male C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice were included in this study. Mucosal injuries induced by subcutaneously administering indomethacin were evaluated macroscopically, histologically and biochemically. Indomethacin-induced injuries were improved in Bach1-deficient mice. Immunohistochemistry showed an increase in the number of HO-1-positive cells, which were mainly F4/80 positive macrophages, in Bach1-deficient mice. Indomethacin administration increased the expression of HO-1 mRNA and protein in the small intestine in Bach1-deficient mice. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining showed that the extent of apoptosis was suppressed in Bach1-deficent mice. In conclusion, deficiency of the Bach1 gene inhibited apoptosis and thus suppressed mucosal injury, indicating that Bach1 is a novel therapeutic target for indomethacin-induced intestinal injury.

S-Allyl cysteine improves nonalcoholic fatty liver disease in type 2 diabetes Otsuka Long-Evans Tokushima Fatty rats via regulation of hepatic lipogenesis and glucose metabolism

It is important to prevent and improve diabetes mellitus and its complications in a safe and low-cost manner. S-Allyl cysteine, an aged garlic extract with antioxidant activity, was investigated to determine whether S-allyl cysteine can improve type 2 diabetes in Otsuka Long-Evans Tokushima Fatty rats with nonalcoholic fatty liver disease. Male Otsuka Long-Evans Tokushima Fatty rats and age-matched Long-Evans Tokushima Otsuka rats were used and were divided into two groups at 29 weeks of age. S-Allyl cysteine (0.45% diet) was administered to rats for 13 weeks. Rats were killed at 43 weeks of age, and detailed analyses were performed. S-Allyl cysteine improved hemoglobinA1c, blood glucose, triglyceride, and low-density lipoprotein cholesterol levels. Furthermore, S-allyl cysteine normalized plasma insulin levels. S-Allyl cysteine activated the mRNA and protein expression of both peroxisome proliferator-activated receptor α and γ, as well as inhibiting pyruvate dehydrogenase kinase 4 in Otsuka Long-Evans Tokushima Fatty rat liver. Sterol regulatory element-binding protein 1c and forkhead box O1 proteins were normalized by S-allyl cysteine in Otsuka Long-Evans Tokushima Fatty rat liver. In conclusions, these findings support the hypothesis that S-allyl cysteine has diabetic and nonalcoholic fatty liver disease therapeutic potential as a potent regulating agent against lipogenesis and glucose metabolism.

Comparison of in Vivo and in Vitro Antioxidative Parameters for Eleven Food Factors

In vivo antioxidative activity assays against reactive oxygen species generated in mitochondria, together with in vitro two radical-scavenging assays, electrochemical measurements, and theoretical calculations of ionization potentials (IP), were carried out for eleven food factors. Lycopene, with the smallest IP value, showed the highest anti-apoptotic activity.

Red ginseng extracts attenuate skin inflammation in atopic dermatitis through p70 ribosomal protein S6 kinase activation

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease with increased immunoglobulin E (IgE) levels. Activation of the mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) signaling is known to occur in the inflammatory regions of AD skin. We previously demonstrated that red ginseng extract (RGE), as an anti-inflammatory agent, had potential for treating AD. However, it is still unclear whether RGE inhibits mTOR/p70S6K signaling. Thus, we examined the anti-inflammatory effects of RGE on IgE or interferon-γ (IFN-γ) induced signaling pathways. In KU812 human basophils, activation of Fcε receptor type Iα (FCεRI), also known as the high affinity IgE receptor, induced phosphorylation of both mTOR and p70S6K. Moreover, levels of phosphorylated p70S6K (p-p70S6K), but not p-mTOR, were decreased by RGE. RGE also decreased p-p70S6K levels in IFN-γ-stimulated human keratinocytes, suppressing the IFN-γ induced increase in levels of C-C chemokine ligand 2 mRNA. Interestingly, the increased p70S6K phosphorylation in skin lesions of AD model mice was attenuated by RGE treatment. In conclusion, RGE is a potential therapy against inflammatory responses involving the p70S6K signaling pathway.

Effects of platinum and palladium nanocolloid on macrophage polarization in relevance to repigmentation of vitiligo

Elevated oxidative stress is accepted to be the initial event in vitiligo leading to the final pathological regulation of immune systems known as autoimmune reaction, which destroys melanin‐forming cells, melanocytes. Recently, we reported an efficient topical use of PAPLAL, nanocolloid of platinum and palladium, having intense catalase‐like activity to vitiligo patients. In addition, we found that PAPLAL has dual effects on the AhR and Nrf‐2 pathways in keratinocytes, and suggested its contribution to the recovery of immune state in vitiligo. The precise mechanism developing autoimmune reaction in vitiligo, however, remains to be clarified. It is important to clarify what kinds of cells play an essential role in the development of vitiligo.