One of the main difficulties in the management of patients with advanced cholangiocarcinoma (CCA) is their poor response to available chemotherapy. This is the result of powerful mechanisms of chemoresistance (MOC) of quite diverse nature that usually act synergistically. The problem is often worsened by altered MOC gene expression in response to pharmacological treatment. Since CCA includes a heterogeneous group of cancers their genetic signature coding for MOC genes is also diverse; however, several shared traits have been defined. Some of these characteristics are shared with other types of liver cancer, namely hepatocellular carcinoma and hepatoblastoma. An important goal in modern oncologic pharmacology is to develop novel strategies to overcome CCA chemoresistance either by increasing drug specificity, such as in targeted therapies aimed to inhibit receptors with tyrosine kinase activity, or to increase the amounts of active agents inside CCA cells by enhancing drug uptake or reducing efflux through export pumps. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

The chemical composition of the inflorescences from four Cannabis sativa L. monoecious cultivars (Ferimon, Uso-31, Felina 32 and Fedora 17), recently introduced in the Lazio Region, was monitored over the season from June to September giving indications on their sensorial, pharmaceutical/nutraceutical proprieties. Both untargeted (NMR) and targeted (GC/MS, UHPLC, HPLC-PDA/FD and spectrophotometry) analyses were carried out to identify and quantify compounds of different classes (sugars, organic acids, amino acids, cannabinoids, terpenoids, phenols, tannins, flavonoids and biogenic amines). All cultivars in each harvesting period showed a THC content below the Italian legal limit, although in general THC content increased over the season. Citric acid, malic acid and glucose showed the highest content in the late flowering period, whereas the content of proline drastically decreased after June in all cultivars. Neophytadiene, nerolidol and chlorogenic acid were quantified only in Felina 32 cultivar, characterized also by a very high content of flavonoids, whereas alloaromadendrene and trans-cinnamic acid were detected only in Uso-31 cultivar. Naringenin and naringin were present only in Fedora 17 and Ferimon cultivars, respectively. Moreover, Ferimon had the highest concentration of biogenic amines, especially in July and August. Cadaverine was present in all cultivars but only in September. These results suggest that the chemical composition of Cannabis sativa L. inflorescences depends on the cultivar and on the harvesting period. Producers can use this information as a guide to obtain inflorescences with peculiar chemical characteristics according to the specific use.

Cholangiocarcinoma (CCA) is an aggressive group of biliary tract cancers, characterized by late diagnosis, low effective chemotherapies, multidrug resistance, and poor outcomes. In the attempt to identify new therapeutic strategies for CCA, we studied the antiproliferative activity of a combination between doxorubicin and the natural sesquiterpene β-caryophyllene in cholangiocarcinoma Mz-ChA-1 cells and nonmalignant H69 cholangiocytes, under both long-term and metronomic schedules. The modulation of STAT3 signaling, oxidative stress, DNA damage response, cell cycle progression and apoptosis was investigated as possible mechanisms of action. β-caryophyllene was able to synergize the cytotoxicity of low dose doxorubicin in Mz-ChA-1 cells, while producing cytoprotective effects in H69 cholangiocytes, mainly after a long-term exposure of 24 h. The mechanistic analysis highlighted that the sesquiterpene induced a cell cycle arrest in G2/M phase along with the doxorubicin-induced accumulation in S phase, reduced the γH2AX and GSH levels without affecting GSSG. ROS amount was partly lowered by the combination in Mz-ChA-1 cells, while increased in H69 cells. A lowered expression of doxorubicin-induced STAT3 activation was found in the presence of β-caryophyllene in both cancer and normal cholangiocytes. These networking effects resulted in an increased apoptosis rate in Mz-ChA-1 cells, despite a lowering in H69 cholangiocytes. This evidence highlighted a possible role of STAT3 as a final effector of a complex network regulated by β-caryophyllene, which leads to an enhanced doxorubicin-sensitivity of cholangiocarcinoma cells and a lowered chemotherapy toxicity in nonmalignant cholangiocytes, thus strengthening the interest for this natural sesquiterpene as a dual-acting chemosensitizing and chemopreventive agent.

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A growing body of in vitro and in vivo evidences shows a possible role of polyphenols in counteracting neurodegeneration: curcumin and resveratrol are attractive substances in this regard. In fact, epidemiological studies highlight a neuroprotective effect of turmeric (rhizome of Curcuma longa L.), the main source of curcumin. Moreover, the consumption of red wine, the main source of resveratrol, has been related to a lower risk of developing dementia. In this review, we analyzed the published clinical trials investigating curcumin and resveratrol in the prevention or treatment of cognitive disorders. The ongoing studies were also described, in order to give an overview of the current search on this topic. The results of published trials (five for curcumin, six for resveratrol) are disappointing and do not allow to draw conclusions about the therapeutic or neuroprotective potential of curcumin and resveratrol. These compounds, being capable of interfering with several processes implicated in the early stages of dementia, could be useful in preventing or in slowing down the pathology. To this aim, an early diagnosis using peripheral biomarkers becomes necessary. Furthermore, the potential preventive activity of curcumin and resveratrol should be evaluated in long-term exposure clinical trials, using preparations with high bioavailability and that are well standardized.