Alison D. Pawlus

Cardiac glycosides as novel cancer therapeutic agents.

The class of steroid-like compounds designated cardiac glycosides includes well-known drugs such as digoxin, digitoxin, and ouabain. Their continued efficacy in treatment of congestive heart failure and as anti-arrhythmic agents is well appreciated. Less well known, however, is the emerging role of this category of compounds in the prevention and/or treatment of proliferative diseases such as cancer. New findings within the past five years have revealed these compounds to be involved in complex cell-signal transduction mechanisms, resulting in selective control of human tumor but not normal cellular proliferation. As such, they represent a promising form of targeted cancer chemotherapy. New clinical studies of their anticancer potential as single or adjuvant treatments may provide insight into these potentially valuable therapeutic options. This review focuses on recent findings on cellular pharmacology of cardiac glycosides as they relate to treatment of human cancer and attempts to explain why these agents have been overlooked in the past.

Ficus spp. (fig): Ethnobotany and potential as anticancer and anti-inflammatory agents

This review explores medieval, ancient and modern sources for ethnopharmacological uses of Ficus (fig) species, specifically for employment against malignant disease and inflammation. The close connection between inflammatory/infectious and cancerous diseases is apparent both from the medieval/ancient merging of these concepts and the modern pharmacological recognition of the initiating and promoting importance of inflammation for cancer growth. Also considered are chemical groups and compounds underlying the anticancer and anti-inflammatory actions, the relationship of fig wasps and fig botany, extraction and storage of fig latex, and traditional methods of preparing fig medicaments including fig lye, fig wine and medicinal poultices.

Neuroprotective properties of resveratrol and derivatives

Stilbenoid compounds consist of a family of resveratrol derivatives. They have demonstrated promising activities in vitro and in vivo that indicate they may be useful in the prevention of a wide range of pathologies, such as cardiovascular diseases and cancers, as well have anti‐aging effects. More recently stilbenoid compounds have shown promise in the treatment and prevention of neurodegenerative disorders, such as Huntington’s, Parkinson’s, and Alzheimers diseases. This paper primarily focuses on the impact of stilbenoids in Alzheimers disease and more specifically on the inhibition of β‐amyloid peptide aggregation.

Natural stilbenoids: distribution in the plant kingdom and chemotaxonomic interest in Vitaceae

Stilbenoids, a family of polyphenols known for the complexity of their structure and for their diverse biological activities, occur with a limited but heterogeneous distribution in the plant kingdom. The most prominent stilbene containing plant family, the Vitaceae, represented by the famous wine producing grape vines Vitis vinifera L., is one of the richest sources of novel stilbenes currently known, together with other families, such as Dipterocarpaceae, Gnetaceae and Fabaceae. This review focuses on the distribution of stilbenes and 2-arylbenzofuran derivatives in the plant kingdom, the chemical structure of stilbenes in the Vitaceae family and their taxonomic implication.

Review of the ethnobotany, chemistry, biological activity and safety of the botanical dietary supplement Morinda citrifolia (noni).

Morinda citrifolia, commonly called noni, has a long history as a medicinal plant and its use as a botanical dietary supplement has grown tremendously in recent years. This has prompted a concomitant increase in research on the phytochemical constituents and biological activity of noni. A relatively large number of scientific publications on noni have been published in recent years, including a number of review articles. The goals of this review are to provide an updated categorization of the phytochemical constituents found in noni and to provide perspective for its extensive utilization as a major botanical dietary supplement. Included herein are a comprehensive list of known ethno‐botanical uses and common names of M. citrifolia, a brief summary of relevant biological studies and a discussion of the safety of noni as a supplement.

Pomegranate Fruit Extract Impairs Invasion and Motility in Human Breast Cancer

Purpose. Pomegranate fruit extracts (PFEs) possess polyphenolic and other compounds with antiproliferative, pro-apoptotic and anti-inflammatory effects in prostate, lung, and other cancers. Because nuclear transcription factor-kB (NF-kB) is known to regulate cell survival, proliferation, tumorigenesis, and inflammation, it was postulated that PFEs may exert anticancer effects at least in part by modulating NF-kB activity. Experimental design. The authors investigated the effect of a novel, defined PFE consisting of both fermented juice and seed oil on the NF-kB pathway, which is constitutively active in aggressive breast cancer cell lines. The effects of the PFE on NF-kB—regulated cellular processes such as cell survival, proliferation, and invasion were also examined. Results. Analytical characterization of the bioactive components of the PFE revealed active constituents, mainly ellagitannins and phenolic acids in the aqueous PFE and conjugated octadecatrienoic acids in the lipid PFE derived from seeds.The aqueous PFE dose-dependently inhibited NF-kB—dependent reporter gene expression associated with proliferation, invasion, and motility in aggressive breast cancer phenotypes while decreasing RhoC and RhoA protein expression. Conclusion. Inhibition of motility and invasion by PFEs, coincident with suppressed RhoC and RhoA protein expression, suggests a role for these defined extracts in lowering the metastatic potential of aggressive breast cancer species.

Development of hybrid elution systems for efficient purification of stilbenoids using centrifugal partition chromatography coupled to mass spectrometry

The phytochemical study of the root extract of the stilbenoid-rich Vitis riparia×Vitis berlandieri grapevine was carried out by centrifugal partition chromatography (CPC). For this reason, we developed a new elution mode we named back-step, which allowed us to obtain cleaner fractions and a more efficient separation process when used in conjunction with a classical elution approach. Three hydroxystilbenes: (E)-resveratrol, (E)-ɛ-viniferin and (E)-vitisin C, with greater than 90% purity were thus obtained through such process, with minimal sample handling and purification steps. Online coupling of CPC to ESI mass spectrometry was used for optimization of the separation parameters and to facilitate the characterization of the stilbenoids. This study details the first phytochemical investigation of stilbenoids from the hybrid species together with a new elution mode able to widen the range of ARIZONA biphasic systems.

Evaluating solvent extraction systems using metabolomics approaches

Metabolic fingerprinting was performed on a set of botanical extracts to compare the extraction efficiency of different solvents to inform the construction of phytochemical libraries. We compared the extraction efficiency, examining both yield and chemical diversity, of eight single-solvent extractions prepared in parallel and using solvent–solvent partitioning. Three-dimensional data were reduced into features, which were used as unbiased metrics to identify solvents that would produce botanical extracts with the greatest chemical diversity. Chemical diversity and extract yield did not necessarily increase together. For each species and tissue, the total number of observable chemical features closely approached maximum values when three different single-solvent extractions were performed in parallel. The dynamic range of detectable compounds in plant extracts was increased significantly by performing solvent partitioning. Overall, maximum chemical diversity in a plant extract was most efficiently approached if solvent partitioning was performed on an extract made with 70% ethanol. We have shown that using metabolic fingerprinting is useful for assessing compound diversity in complex plant extracts.

Chemical dereplication of wine stilbenoids using high performance liquid chromatography-nuclear magnetic resonance spectroscopy.

Wine is a major dietary source of numerous potentially health promoting stilbenoids that have been the subject of many qualitative and quantitative studies. However, our initial HPLC-MS analyses of crude wine samples demonstrated the presence of compounds with molecular weights matching characteristic stilbenoid dimers, trimers, and tetramers that were unaccounted for in the literature. Due to the likelihood that these are known compounds, a chemical dereplication method is highly desirable. We developed such a method using LC-DAD-MS monitored fractionation steps, using adsorption and centrifugal partition chromatography (CPC), to obtain fractions rich in stilbenoids for analysis in stopped-flow LC-NMR. (1)H NMR spectra and MS data were cross-referenced with our laboratory database and the literature for identification. This method yielded highly useful structural information, allowing the characterization of previously unidentified stilbenoids in wine, ampelopsin C, isohopeaphenol, quadrangularin A, and E-ω-viniferin. These results demonstrate the usefulness of stop-flow LC-NMR in conjunction with LC-MS guided fractionation for the dereplication of compounds of interest in general, and specifically for expanding the current knowledge of wine chemistry.

Grapevine stilbenoids: Bioavailability and neuroprotection

Vine and wine are an abundant source of stilbenoids that constitute a large class of compounds, including a series of monomers and oligomers (dimers, trimers, tetramers). Stilbenoids can reach a level of over 100 mg L 1 in red wine. Several epidemiological studies have correlated the consumption of grapes and wines with significant health benefits. The most studied stilbenoid, resveratrol, exhibits multiple biological activities across multiple diseases including cancer and cardiovascular and neurodegenerative diseases. This compound shows promise in both the prevention and the treatment of these diseases. Moreover, resveratrol mimics calorie restriction and extends the lifespan in species ranging from yeast to multicellular animals (not in normal mammals) by a sirtuin-dependent mechanism. Resveratrol is well absorbed yet rapidly metabolized; however, the tissue concentrations found in some studies in animals and humans are compatible with its biological activities. Resveratrol is well tolerated at doses of up to 1 g day 1 in human and does not cause serious adverse events up to 5 g day . Interestingly, other wine and grape stilbenoids such as piceatannol, pterostilbene, viniferins, and vitisins also have beneficial activities. In this chapter, we have discussed chemistry and protective role of stilbenoids in general, and resveratrol in particular, during various pathological conditions such as neurodegeneration, neuroinflammation, cancer, cardiovascular diseases, and antiaging process. Works related to bioavailability and clinical trials of resveratrol are also presented.