Killing cancer with platycodin D through multiple mechanisms

Cancer is a multi‐faceted disease comprised of a combination of genetic, epigenetic, metabolic and signalling aberrations which severely disrupt the normal homoeostasis of cell growth and death. Rational developments of highly selective drugs which specifically block only one of the signalling pathways have been associated with limited therapeutic success. Multi‐targeted prevention of cancer has emerged as a new paradigm for effective anti‐cancer treatment. Platycodin D, a triterpenoid saponin, is one the major active components of the roots of Platycodon grandiflorum and possesses multiple biological and pharmacological properties including, anti‐nociceptive, anti‐atherosclerosis, antiviral, anti‐inflammatory, anti‐obesity, immunoregulatory, hepatoprotective and anti‐tumour activities. Recently, the anti‐cancer activity of platycodin D has been extensively studied. The purpose of this review was to give our perspectives on the current status of platycodin D and discuss its anti‐cancer activity and molecular mechanisms which may help the further design and conduct of pre‐clinical and clinical trials to develop it successfully into a potential lead drug for oncological therapy. Platycodin D has been shown to fight cancer by inducing apoptosis, cell cycle arrest, and autophagy and inhibiting angiogenesis, invasion and metastasis by targeting multiple signalling pathways which are frequently deregulated in cancers suggesting that this multi‐target activity rather than a single effect may play an important role in developing platycodin D into potential anti‐cancer drug.     

The Role of Physical Activity in Harm Reduction among Betel Quid Chewers from a Prospective Cohort of 419,378 Individuals

ObjectiveTo assess the benefits of regular exercise in reducing harms associated with betel quid (BQ) chewing.MethodsThe study cohort, 419,378 individuals, participated in a medical screening program between 1994 and 2008, with 38,324 male and 1,495 female chewers, who consumed 5–15 quids of BQ a day. Physical activity of each individual, based on “MET-hour/week”, was classified as “inactive” or “active”, where activity started from a daily 15 minutes/day or more of brisk walking (≥3.75 MET-hour/week). Hazard ratios for mortality and remaining years in life expectancy were calculated.ResultsNearly one fifth (18.7%) of men, but only 0.7% of women were chewers. Chewers had a 10-fold increase in oral cancer risk; and a 2-3-fold increase in mortality from lung, esophagus and liver cancer, cardiovascular disease, and diabetes, with doubling of all-cause mortality. More than half of chewers were physically inactive (59%). Physical activity was beneficial for chewers, with a reduction of all-cause mortality by 19%. Inactive chewers had their lifespan shortened by 6.3 years, compared to non-chewers, but being active, chewers improved their health by gaining 2.5 years. The improvement, however, fell short of offsetting the harms from chewing.ConclusionsChewers had serious health consequences, but being physically active, chewers could mitigate some of these adverse effects, and extend life expectancy by 2.5 years and reduce mortality by one fifth. Encouraging exercise, in addition to quitting chewing, remains the best advice for 1.5 million chewers in Taiwan.     

CFTR mediates bicarbonate-dependent activation of miR-125b in preimplantation embryo development

Although HCO₃⁻ is known to be required for early embryo development, its exact role remains elusive. Here we report that HCO₃⁻ acts as an environmental cue in regulating miR-125b expression through CFTR-mediated influx during preimplantation embryo development. The results show that the effect of HCO₃⁻ on preimplantation embryo development can be suppressed by interfering the function of a HCO₃⁻-conducting channel, CFTR, by a specific inhibitor or gene knockout. Removal of extracellular HCO₃⁻ or inhibition of CFTR reduces miR-125b expression in 2 cell-stage mouse embryos. Knockdown of miR-125b mimics the effect of HCO₃⁻ removal and CFTR inhibition, while injection of miR-125b precursor reverses it. Downregulation of miR-125b upregulates p53 cascade in both human and mouse embryos. The activation of miR-125b is shown to be mediated by sAC/PKA-dependent nuclear shuttling of NF-κB. These results have revealed a critical role of CFTR in signal transduction linking the environmental HCO₃⁻ to activation of miR-125b during preimplantation embryo development and indicated the importance of ion channels in regulation of miRNAs.     

Involvement of the acid sphingomyelinase pathway in uva-induced apoptosis

The sphingomyelin-ceramide pathway is an evolutionarily conserved ubiquitous signal transduction system that regulates many cell functions including apoptosis. Sphingomyelin (SM) is hydrolyzed to ceramide by different sphingomyelinases. Ceramide serves as a second messenger in mediating cellular effects of cytokines and stress. In this study, we find that acid sphingomyelinase (SMase) activity was induced by UVA in normal JY lymphoblasts but was not detectable in MS1418 lymphoblasts from Niemann-Pick type D patients who have an inherited deficiency of acid SMase. We also provide evidence that UVA can induce apoptosis by activating acid SMase in normal JY cells. In contrast, UVA-induced apoptosis was inhibited in MS1418 cells. Exogenous SMase and its product, ceramide (10-40 micrometer), induced apoptosis in JY and MS1418 cells, but the substrate of SMase, SM (20-80 micrometer), induced apoptosis only in JY cells. These results suggest that UVA-induced apoptosis by SM is dependent on acid SMase activity. We also provide evidence that induction of apoptosis by UVA may occur through activation of JNKs via the acid SMase pathway.     

Regulation of Xenopus oocyte meiosis arrest by G protein betagamma subunits

BACKGROUND: Progesterone induces the resumption of meiosis (maturation) in Xenopus oocytes through a nongenomic mechanism involving inhibition of an oocyte adenylyl cyclase and reduction of intracellular cAMP. However, progesterone action in Xenopus oocytes is not blocked by pertussis toxin, and this finding indicates that the inhibition of the oocyte adenylyl cyclase is not mediated by the alpha subunits of classical G(i)-type G proteins. RESULTS: To investigate the possibility that G protein betagamma subunits, rather than alpha subunits, play a key role in regulating oocyte maturation, we have employed two structurally distinct G protein betagamma scavengers (G(t)alpha and betaARK-C(CAAX)) to sequester free Gbetagamma dimers. We demonstrated that the injection of mRNA encoding either of these Gbetagamma scavengers induced oocyte maturation. The Gbetagamma scavengers bound an endogenous, membrane-associated Gbeta subunit, indistinguishable from Xenopus Gbeta1 derived from mRNA injection. The injection of Xenopus Gbeta1 mRNA, together with bovine Ggamma2 mRNA, elevated oocyte cAMP levels and inhibited progesterone-induced oocyte maturation. CONCLUSION: An endogenous G protein betagamma dimer, likely including Xenopus Gbeta1, is responsible for maintaining oocyte meiosis arrest. Resumption of meiosis is induced by Gbetagamma scavengers in vitro or, naturally, by progesterone via a mechanism that suppresses the release of Gbetagamma.     

药用植物浸提液抑制蛋白核小球藻生长的化感效应

研究了11种药用植物浸提液对水华藻种蛋白核小球藻的影响,结果显示:黄连、重楼、贯众、防己4种药用植物的浸提液均有抑藻效应。当药用植物浸提液的相对浓度为1g/L处理时,其半抑制效应时间LT50的排序为:防己重楼黄连贯众。进一步研究防己的相对浓度梯度抑藻效应,结果表明:在相对浓度为2g/L时,实验3d后的藻细胞几乎全部死亡;防己的抑藻效应受贮藏时间和贮藏温度的影响不显著。在所研究的药用植物中,防己的抑藻效果最好,在抑藻方面有较大应用前景,其它3种药用植物对轻度藻类爆发的控制也有潜在应用价值。