Clinical relevance of the relationship between changes in gut microbiota and bile acid metabolism in patients with intrahepatic cholangiocarcinoma

Although only 10-15%of liver cancers are cholangiocarcinomas(CCAs),which derive from the epithelial cells of the biliary tree,these cancers constitute a serious and growing health problem worldwide.The rate of mortality due to this tumor is very high because CCA usually appears in aged people and very often,in more than 70%of cases,are diagnosed late because of:(I)their anatomical localization in a big organ like the liver;(II)the lack of specific symptoms during most time of their development;and(III)the absence of available accurate,specific and sensitive biomarkers(1).These characteristics reduce the rate of success of surgical resection,which is the only curative option for CCA patients,because the response of this aggressive cancer to the available pharmacological armamentarium is extremely feeble(2).This justifies the interest of many groups to identify non-invasive markers to achieve early diagnosis that also permit to distinguish CCA from non-malignant biliary diseases and from hepatocellular carcinoma(HCC),the most frequent liver cancer,which derives from hepatocytes(3).

Expanding the Therapeutic Spectrum of Artemisinin:Activity Against Infectious Diseases Beyond Malaria and Novel Pharmaceutical Developments

The interest of Western medicine in Traditional Chinese Medicine(TCM) as a source of drug leads/new drugs to treat diseases without available efficient therapies has been dramatically augmented in the last decades by the extensive work and the outstanding findings achieved within this kind of medicine. The practice of TCM over thousands of years has equipped scientists with substantial experience with hundreds of plants that led to the discovery of artemisinin(qinghaosu), which is extracted from the medicinal plant Artemisia annua L.(qinghao). The unexpected success of artemisinin in combating malaria has drawn strong attention from the scientific community towards TCM. Artemisinin was discovered by Youyou Tu in 1972. Since then, several novel pharmacological activities based on the well-known properties of the sesquiterpene lactone structure with the oxepane ring and an endoperoxide bridge have been unravelled. Beyond malaria, artemisinin and its derivatives(artemisinins) exert profound activities towards other protozoans(Leishmania, Trypanosoma, amoebas, Neospora caninum, and Eimeria tenella), trematodes(Schistosoma, liver flukes), and viruses(human cytomegalovirus, hepatitis B and C viruses). Less clear is the effect against bacteria and fungi. Based on the promising results of artemisinin and the first generation derivatives(artesunate, artemether, arteether), novel drug development strategies have been pursued.These included the synthesis of acetal-and non-acetal-type artemisinin dimeric molecules as well as developing nanotechnological approaches, e.g.artemisinin-based liposomes, niosomes, micelles, solid lipid nanocarriers, nanostructured lipid carriers, nanoparticles, fullerenes and nanotubes. The current review presents an overview on different aspects of artemisinins, including sources, chemistry, biological/pharmacological properties, types of infectious pathogens that are susceptible to artemisinins in vitro and in vivo, in addition to the advancement in their drug delivery systems utilizing pharmaceutical technology. It would be expected that different therapeutic strategies based on the second and third generation artemisinin derivatives and artemisinin-based drug technologies would be available in the near future to treat specific infectious diseases.

Further understanding of mechanisms involved in liver cancer chemoresistance

An important limitation for the success of chemotherapy in the treatment of primary liver cancer (hepatocellular carcinoma,hepatoblastoma and cholangiocarcinoma) is the marked efficacy of mechanisms of chemoresistance (MOC).These have been previously classified into five groups depending on whether they result in:a reduced drug uptake or enhanced drug export (MOC-1);poor intracellular activation of prodrugs or higher inactivation of active drugs (MOC-2);changes in the molecular targets that impairs the action of the drug by increasing the activity of the metabolic route to be inhibited or stimulating alternative routes (MOC-3);ability of tumor cells to repair drug-induced modifications in the target molecule,usually DNA (MOC-4);and the activation or inhibition of intracellular signaling pathways that lead to a change in the balance between proand anti-apoptotic factors favoring tumor cell survival (MOC-5).Nevertheless,novel information appeared over the last few years has recommended to consider two additional groups,MOC-6 and MOC-7,based on changes in tumor microenvironment,mainly hypoxia and acidity,and epithelial-mesenchymal transition,respectively.These contribute to the defensive armamentaria developed or enhanced in liver cancer cells to resist the pharmacological attack,which accounts for a negligible beneficial effect of commonly used antitumor drugs and only a modest response to novel targeted therapies based on tyrosine kinase inhibitors,such as sorafenib.Therefore,further advances are urgently needed to better understand the molecular and cellular bases of the chemoresistant barrier and help scientists in this field to develop new tools able to overcome cancer cell defenses.

Pharmacogenetics of hepatocellular carcinoma and cholangiocarcinoma

Primary liver cancers constitute the fourth most deadly group of cancers.Their poor prognosis is due in part to the pre-existence and/or development,often during treatment,of powerful mechanisms accounting for the poor response of cancer cells to antitumor drugs.These include both impaired gene expression and the appearance of spliced variants,polymorphisms and mutations,affecting the function of genes leading to the reduction in intracellular concentrations of active agents,changes in molecular targets and survival pathways,altered tumor microenvironment and phenotypic transition.The present review summarizes available information regarding the role of germline and somatic mutations affecting drug transporters,enzymes involved in drug metabolism,organelles and signaling molecules related to liver cancer chemoresistance.A more complete picture of the actual complexity of this problem is urgently needed for carrying out further pharmacogenomic studies aimed to improve the management of patients suffering from hepatocellular carcinoma or cholangiocarcinoma.