Date of Degree

2-2018

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Edward J. Kennelly

Committee Members

Jeanine D’Armiento

Amy Litt

Moira Sauane

Prabodhika Mallikaratchy

Subject Categories

Analytical Chemistry | Food Chemistry | Medicinal-Pharmaceutical Chemistry | Plant Biology

Keywords

chemometrics, Vaccinium macrocarpon, blueberry, COPD, procyanidin B2, tobacco, HSV-1, OPLS-DA

Abstract

Smoking is a global epidemic that creates serious health and economic burden. It is the primary, preventative factor for the majority of causes of death worldwide. Analysis of publicly available data revealed that smoking prevalence rates among the youth in developing countries, especially in Bulgaria, are alarmingly high. The Bulgarian population has one of the highest percentages of smokers and the second highest rate among teenage girls. Consequently, chronic diseases affected by smoking, such as chronic obstructive pulmonary disorder (COPD), have been increasing there in the last five years. Poland, on the other hand, is an exemplary outlier for the region with much lower smoking prevalence rates and COPD incidence growth like those in the developed countries, such as the United States.

A survey among college-aged people at Lehman College, City University of New York, determined that there were behavioral sensitivities predictive of cigarette use. Experimenters were highly sensitive to fun seeking and reward responsiveness. A larger portion of the experimenters knew people that have COPD but were not related to them. Most experimenters were not interested in learning more about smoke-related diseases. Hispanics were the majority within the experimenter group and they seemed to eat antioxidant-rich foods less often than others. Therefore, tailored anti-tobacco efforts focused on developing countries are needed to reduce country disparities of smoking prevalence and chronic diseases, such as COPD.

COPD is a disease for which there is no cure and current therapies only temporarily control symptoms. Still, evidence suggests a diet rich in polyphenol-rich foods, such as apples and berries, may hold a promise in the treatment of the disease. Antioxidant-rich blueberries, cranberries, and lingonberries are temperate species in the Vaccinium genus, which produce several classes of secondary metabolites potent against aging and chronic diseases, such as COPD. A literature review of their chemistry, bioavailability, and bioactivity was conducted. Growing consumer awareness of the health-promoting effects of cranberry and blueberry compounds combined with trends towards organic farming may offer further areas of growth and development for these crops.

Vaccinium berries have been studied for centuries, but their full potential to ameliorate lung and viral diseases remains to be established. These studies focused on a class of berry compounds that have not been studied extensively – the oligomeric procyanidins. Procyanidin dimer B2 and an A-type trimer were found to counteract smoke-induced responses in airway epithelial cells by decreasing an inflammatory marker interleukin 8 (IL-8) and downregulating proteolytic enzyme collagenase matrix metalloproteinase-1 (MMP-1). In contrast, procyanidin dimer A2 induced inflammation alone. Furthermore, jaboticabin, an anti-inflammatory depside, was found in several Vaccinium berries for the first time.

Procyanidins have low bioavailability and upon ingestion most of these compounds pass unabsorbed through the small intestine as they enter the colon where they get metabolized by the gut microflora. Consumption of foods rich in procyanidins has been found to impact the concentration of certain microbial metabolites. The study investigated four of these metabolites for their anti-inflammatory potency in small airway epithelium, and hippuric acid was determined to significantly inhibit smoke-induced IL-8 levels. Other indirect, favorable health effects of procyanidin B2 were explored in relation to its ability to modify gene expression of antioxidant enzymes and epigenetics factors.

The tested procyanidins were selected with an improved natural product discovery approach whose success was further measured by searching for the most antiviral compounds from three highbush blueberry cultivars. The approach builds on previous chemometric methods which prioritized markers with higher relative abundance in the bioactive samples. The improved approach utilized a vast chemical data set from state-of-the-art LC-MS techniques, but reduced the number of highest-ranked, potentially active markers. This first improvement was achieved by employing very similar samples, such as parallel fractions from the three cultivars. Additionally, the approach helped prioritize compounds with strong anti-HSV-1 activity while decreasing the priority of markers with weaker antiviral potency. This second improvement accounted for different levels of fractions’ antiviral activity by making two separate chemometric comparisons among the three fractions and considering only the overlapping markers. Out of the tested compounds, quercetin 3-β-D-glucoside was determined to have the strongest viricidal effect against acyclovir resistant HSV-1 strain. This study also led to the identification of antiviral cinchonain in the fruits of blueberry species for the first time.

The novel chemometric approach integrates improvements in the analysis of big chemical data sets that could make the natural products drug discovery process more targeted and efficient. Procyanidin dimer B2 and the A-type trimers, prioritized through this approach, merit additional studies of their pharmacological potential for chronic lung diseases. Dark-colored berries should be further investigated for other potent antimicrobial compounds.

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