Tyrosinase plays a pivotal role in the synthesis of melanin pigment synthesis on skin utilizing tyrosine as a substrate. Melanin is responsible for the protection against harmful ultraviolet irradiation, which can cause significant pathological conditions, such as skin cancers. However, it can also create esthetic problems when accumulated as hyperpigmented spots. Various skin-whitening ingredients which inhibit tyrosinase activity have been identified. Some of them, especially ones with natural product origins, possess phenolic moiety and have been employed in cosmetic products. Semi-synthetic and synthetic inhibitors have also been developed under inspiration of the natural inhibitors yet some of which have no phenolic groups. In this review, tyrosinase inhibitors with natural, semi-synthetic and synthetic origins are listed up with their structures, activities and characteristics. Further, a recent report on the adverse effect of a natural melanin synthesis inhibitor which was included in skin-whitening cosmetics is also briefly discussed.

Platinum (Pt)-based anticancer drugs such as cisplatin have been used to treat various cancers. However, they have some limitations including poor selectivity and toxicity towards normal cells and increasing chemoresistance. Therefore, there is a need for novel metallo-anticancers, which has not been met for decades. Since the initial introduction of ruthenium (Ru) polypyridyl complex, a number of attempts at structural evolution have been conducted to improve efficacy. Among them, half-sandwich Ru-arene complexes have been the most prominent as an anticancer platform. Such complexes have clearly shown superior anticancer profiles such as increased selectivity toward cancer cells and ameliorating toxicity against normal cells compared to existing Pt-based anticancers. Currently, several Ru complexes are under human clinical trials. For improvement in selectivity and toxicity associated with chemotherapy, Ru complexes as photodynamic therapy (PDT), and photoactivated chemotherapy (PACT), which can selectively activate prodrug moieties in a specific region, have also been investigated. With all these studies on these interesting entities, new metalloanticancer drugs to at least partially replace existing Pt-based anticancers are anticipated. This review covers a brief description of Ru-based anticancer complexes and perspectives.

The overall current literature suggests that smoking was associated with increased risk of ARC, especially NC. Further efforts should be made to confirm these findings and clarify the underlying biological mechanisms.

Medically relevant roles of receptor-mediated sphingosine 1-phosphate (S1P) signaling have become a successful or promising target for multiple sclerosis or cerebral ischemia. Animal-based proof-of-concept validation for the latter is particularly through the neuroprotective efficacy of FTY720, a non-selective S1P receptor modulator, presumably via activation of S1P. In spite of a clear link between S1P signaling and cerebral ischemia, it remains unknown whether the role of S1P is pathogenic or neuroprotective. Here, we investigated the involvement of S1P along with its role in cerebral ischemia using a transient middle cerebral artery occlusion ("tMCAO") model. Brain damage following tMCAO, as assessed by brain infarction, neurological deficit score, and neural cell death, was reduced by oral administration of AUY954, a selective S1P modulator as a functional antagonist, in a therapeutic paradigm, indicating that S1P is a pathogenic mediator rather than a neuroprotective mediator. This pathogenic role of S1P in cerebral ischemia was reaffirmed because tMCAO-induced brain damage was reduced by genetic knockdown with an intracerebroventricular microinjection of S1P shRNA lentivirus into the brain. Genetic knockdown of S1P or AUY954 exposure reduced microglial activation, as assessed by reduction in the number of activated microglia and reversed morphology from amoeboid to ramified, and microglial proliferation in ischemic brain. Its role in microglial activation was recapitulated in lipopolysaccharide-stimulated primary mouse microglia, in which the mRNA expression level of TNF-α and IL-1β, well-known markers for microglial activation, was reduced in microglia transfected with S1P siRNA. These data suggest that the pathogenic role of S1P is associated with microglial activation in ischemic brain. Additionally, the pathogenic role of S1P in cerebral ischemia appears to be associated with the blood-brain barrier disruption and brain-derived neurotrophic factor (BDNF) downregulation. Overall, findings from the current study clearly identify S1P signaling as a pathogenic factor in transient focal cerebral ischemia, further implicating S1P antagonists including functional antagonists as plausible therapeutic agents for human stroke.

Cigarette smoking is known to aggravate Graves' orbitopathy (GO) severity by enhancing adipogenesis. We investigated the effect of quercetin, an antioxidant, on adipocyte differentiation induced by cigarette smoke extract (CSE) in primary cultured orbital fibroblasts (OFs) from GO patients. Freshly prepared CSE was added to the cells and H 2 O 2 was used as a positive control. Intracellular reactive oxygen species (ROS) generation and adipogenesis were measured. The expressions of proteins peroxisome proliferator-activated receptor (PPAR) g, CCAAT-enhancer-binding proteins (C/EBP) a and b, and heme oxygenase-1 (HO-1), an antioxidant enzyme, were examined during adipogenic differentiation. In result, CSE and H 2 O 2 dose-dependently stimulated intracellular ROS production in normal and Graves' OFs. The effect of 2% CSE was similar to that of 10 mM H 2 O 2 ; both concentrations were noncytotoxic and were used throughout the experiment. Quercetin pretreatment reduced the ROS generation stimulated by either CSE or H 2 O 2 in preadipocyte OFs. CSE and H 2 O 2 stimulated adipocyte differentiation in cultured OFs. The addition of quercetin (50 or 100 mM) suppressed adipogenesis. Quercetin also suppressed ROS generation in differentiating OFs during adipogenesis stimulated by CSE and H 2 O 2 . Additionally, the expressions of PPARg, C/EBPa, and C/EBPb proteins were reduced in the quercetin-treated OFs. Quercetin also reduced the CSE-and H 2 O 2 -induced upregulation of ROS and HO-1 protein in differentiated OFs and preadipocyte OFs. As shown in this study, quercetin inhibited adipogenesis by reducing ROS in vitro, supporting the use of quercetin in the treatment of GO. IntroductionOxidative stress is implicated in the pathogenesis of Graves' orbitopathy (GO), and cigarette smoking is known to be a major environmental factor that affects GO. Cigarette smoking has been shown to influence the incidence, severity, and responses to treatment of GO, and appears to do so in a dose-dependent and temporal manner. Reportedly, smokers with Graves' disease are approximately five times more likely to develop GO than Journal of Endocrinology Research J S YOON, H J LEE and othersTreatment of GO by quercetin, an antioxidant 216:2 145-156