Nature-derived compounds modulating Wnt/β-catenin pathway: a preventive and therapeutic opportunity in neoplastic diseases

Abstract The Wnt/β-catenin signaling is a conserved pathway that has a crucial role in embryonic and adult life. Dysregulation of the Wnt/β-catenin pathway has been associated with diseases including cancer, and components of the signaling have been proposed as innovative therapeutic targets, mainly for cancer therapy. The attention of the worldwide researchers paid to this issue is increasing, also in view of the therapeutic potential of these agents in diseases, such as Parkinson's disease (PD), for which no cure is existing today. Much evidence indicates that abnormal Wnt/β-catenin signaling is involved in tumor immunology and the targeting of Wnt/β-catenin pathway has been also proposed as an attractive strategy to potentiate cancer immunotherapy. During the last decade, several products, including naturally occurring dietary agents as well as a wide variety of products from plant sources, including curcunim, quercetin, berberin, and ginsenosides, have been identified as potent modulators of the Wnt/β-catenin signaling and have gained interest as promising candidates for the development of chemopreventive or therapeutic drugs for cancer. In this review we make an overview of the nature-derived compounds reported to have antitumor activity by modulating the Wnt/β-catenin signaling, also focusing on extraction methods, chemical features, and bio-activity assays used for the screening of these compounds

Twelve-Week Treatment of Acute Hepatitis C Virus with Pegylated Interferon- -2b in Injection Drug Users

n/

Blastic plasmacytoid dendritic cell neoplasm : State of the art and prospects

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare tumour, which usually a_ects elderly males and presents in the skin with frequent involvement of the bone-marrow, peripheral blood and lymph nodes. It has a dismal prognosis, with most patients dying within one year when treated by conventional chemotherapies. The diagnosis is challenging, since neoplastic cells can resemble lymphoblasts or small immunoblasts, and require the use of a large panel of antibodies, including those against CD4, CD56, CD123, CD303, TCL1, and TCF4. The morphologic and in part phenotypic ambiguity explains the uncertainties as to the histogenesis of the neoplasm that led to the use of various denominations. Recently, a series of molecular studies based on karyotyping, gene expression profiling, and next generation sequencing, have largely unveiled the pathobiology of the tumour and proposed the potentially beneficial use of new drugs. The latter include SL-401, anti-CD123 immunotherapies, venetoclax, BET-inhibitors, and demethylating agents. The epidemiologic, clinical, diagnostic, molecular, and therapeutic features of BPDCN are thoroughly revised in order to contribute to an up-to-date approach to this tumour that has remained an orphan disease for too long

Batch and Flow Synthesis of Nucleosides by Enzymatic Transglycosylation

Enzymatic methods for the preparation of high-value products have clearly shown their potential in many areas, including nucleic acid chemistry. Enzymes of nucleic acid metabolism such as nucleoside phosphorylases (NPs, EC 2.4.2) can be conveniently used as biocatalysts in the synthesis of nucleoside analogues. These enzymes catalyze the reversible cleavage of the glycosidic bond of (deoxy)ribonucleosides in the presence of inorganic phosphate (Pi) to generate the nucleobase and \u3b1-D-(deoxy)ribose-1-phosphate (phosphorolysis). If a second nucleobase is added to the reaction medium, the formation of a new nucleoside can result (transglycosylation). Because of its broad substrate specificity [1,2], a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP) was exploited to catalyze the \u201cone-pot, one-enzyme\u201d transglycosylation of 7-methylguanosine iodide with a series of 6-substituted purines, resulting in a moderate to high conversion (18-65%) of the bases into a 22-compound library of 6-substituted purine ribonucleosides [2]. Successively, AhPNP was covalently immobilized [3,4] in a pre-packed column containing aminopropyl silica particles. The resulting AhPNP-IMER (Immobilized Enzyme Reactor) was coupled on-line to a HPLC apparatus containing a semi-preparative chromatographic column. In such a system, \u201cone-enzyme\u201d transglycosylation and product purification were run in a single platform, affording a set of 6-modified purine ribonucleosides at a mg scale [4]. Using this \u201cflow-based\u201d approach, the synthesis of adenine nucleosides through a \u201ctwo-enzyme\u201d transglycosylation was carried out by connecting the AhPNP-IMER to uridine phosphorylase from Clostridium perfringens, immobilized on a silica monolithic column (CpUP-IMER)

An enzymatic flow-based preparative route to vidarabine

The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from Clostridium perfringens (CpUP) and a purine nucleoside phosphorylase fromAeromonas hydrophila (AhPNP), was re-designed under continuous-flow conditions. Glyoxyl-agarose and EziGTM1 (Opal) were used as immobilization carriers for carrying out this preparative biotransformation. Upon setting-up reaction parameters (substrate concentration and molar ratio, temperature, pressure, residence time), 1 g of vidarabine was obtained in 55% isolated yield and >99% purity by simply running the flow reactor for 1 week and then collecting (by filtration) the nucleoside precipitated out of the exiting flow. Taking into account the substrate specificity of CpUP and AhPNP, the results obtained pave the way to the use of the CpUP/AhPNP-based bioreactor for the preparation of other purine nucleosides