Targeting Apoptosis and Multiple Signaling Pathways with Icariside II in Cancer Cells

Cancer is the second leading cause of deaths worldwide. Despite concerted efforts to improve the current therapies, the prognosis of cancer remains dismal. Highly selective or specific blocking of only one of the signaling pathways has been associated with limited or sporadic responses. Using targeted agents to inhibit multiple signaling pathways has emerged as a new paradigm for anticancer treatment. Icariside II, a flavonol glycoside, is one of the major components of Traditional Chinese Medicine Herba epimedii and possesses multiple biological and pharmacological properties including anti-inflammatory, anti-osteoporosis, anti-oxidant, anti-aging, and anticancer activities. Recently, the anticancer activity of Icariside II has been extensively investigated. Here, in this review, our aim is to give our perspective on the current status of Icariside II, and discuss its natural sources, anticancer activity, molecular targets and the mechanisms of action with specific emphasis on apoptosis pathways which may help the further design and conduct of preclinical and clinical trials.Icariside II has been found to induce apoptosis in various human cancer cell lines of different origin by targeting multiple signaling pathways including STAT3, PI3K/AKT, MAPK/ERK, COX-2/PGE2 and β-Catenin which are frequently deregulated in cancers, suggesting that this collective activity rather than just a single effect may play an important role in developing Icariside II into a potential lead compound for anticancer therapy. This review suggests that Icariside II provides a novel opportunity for treatment of cancers, but additional investigations and clinical trials are still required to fully understand the mechanism of therapeutic effects to further validate it in anti-tumor therapy.     

Spindle checkpoint component Mad2 contributes to biorientation of homologous chromosomes

Cell cycle checkpoints sense defects in chromosome metabolism, halt the cell cycle, and activate pathways that repair the defects. The spindle checkpoint arrests the cell cycle in response to defects in the interaction between microtubules and kinetochores (the proteinaceous complex assembled on centromeric DNA), but no repair function has been demonstrated for this checkpoint. We show that the roles of two spindle checkpoint components, Mad2 and Mad3, differ in meiosis I. In the absence of Mad2, meiosis I nondisjunction occurs at a high frequency and can be corrected by delaying the onset of anaphase. The absence of Mad3 does not induce nondisjunction, even though mad3Delta cells cannot arrest the cell cycle in response to kinetochores that lack either microtubules or tension on the linkage between chromosomes and microtubules. The two proteins have different roles in chromosome alignment. Compared to wild type and mad3Delta cells, mad2Delta mutants are slower to attach homologous chromosomes to opposite poles of the spindle. This observation suggests that Mad2 plays a role in reorienting chromosomes that are incorrectly attached to the spindle as well as delaying the cell cycle, whereas Mad3 is needed for the cell cycle delay, but not for chromosome reorientation.     

Vertical Distribution and Feeding Activity of Metamorphosing Sole, Solea Solea, Before Immigration to the Bay of Vilaine Nursery (Northern Bay of Biscay, France)

To evaluate the impact of metamorphosis on the vertical distribution and feeding activity of sole, Solea solea, larvae passing from offshore spawning grounds to the Bay of Vilaine, sampling series at fixed stations were carried out in April 1991 and April 1993 at depths from 50 to 30 m. Comparisons between plankton and bottom samplin series indicated differences in vertical distribution of larvae in pre-metamorphic and metamorphic steps. Metamorphosing larvae displayed a tendency to concentrate in the lower part of the water column, mainly during the day. Gut contents, analysed for prey identification, fullness index and carbon content, indicated that metamorphosing larvae fed mostly on plankton. Variations in fullness index were observed not only during the day, but also depended on tide and wind-induced mixing conditions. Larvae sampled in mixed spring-tide waters had highly variable carbon estimates, resulting in unclear diel activity. More larvae fed actively at neap-tide, which allowed the observation of a diurnal feeding activity through hourly changes in carbon estimates. It is concluded that immigrating sole were not yet able to settle but prepared themselves for demersal life (i) without undergoing starvation and (ii) by modifying the patterns of vertical distributions. The presence of a larval swimbladder suggests they can adjust their vertical movements, depending on tidal cycles, which could in turn favour coastal accumulation of metamorphosing larvae and pulses of new settlers entering the nursery grounds.     

Dimethoate Induces Kidney Dysfunction, Disrupts Membrane-Bound ATPases and Confers Cytotoxicity Through DNA Damage. Protective Effects of Vitamin E and Selenium

Dimethoate (DM) is an organophosphate insecticide widely used in agriculture and industry and has toxic effects on non-target organisms especially mammalian. However, we still know little about DM-induced kidney injury and its alleviation by natural antioxidants. In the present study, selenium (Se), vitamin E, DM, Se+DM, vitamin E+DM, Se+vitamin E+DM were given to adult rats for 4 weeks. Plasma creatinine and uric acid, kidney MDA, PC, H₂O₂ and AOPP levels were higher, while Na⁺-K⁺-ATPase and LDH values were lower in the DM group than those of controls. A smear without ladder formation on agarose gel was shown in the DM group, indicating random DNA degradation and DM-induced genotoxicity. A decrease in kidney GSH, NPSH and plasma urea levels and an increase in GPx, SOD and catalase activities were observed in the DM group when compared to those of controls. Plasma cystatin C levels increased, indicating a decrease in glomerular filtration rate. When Se or vitamin E was added through diet, the biochemical parameters cited above were partially restored in Se+DM and vitamin E+DM than DM group. The joint effect of Se and vitamin E was more powerful against DM-induced oxidative stress and kidney dysfunction. The changes in biochemical parameters were substantiated by histological data. In conclusion, our results indicated a possible mechanism of DM-induced nephrotoxicity, where renal genotoxicity was noted, membrane-bound ATPases and plasma biomarkers were disturbed. Se and vitamin E ameliorated the toxic effects of this pesticide in renal tissue suggesting their role as potential antioxidants.