Role of Phenolic Compounds in Human Disease: Current Knowledge and Future Prospects

Inflammation is a natural protective mechanism that occurs when the body’s tissue homeostatic mechanisms are disrupted by biotic, physical, or chemical agents. The immune response generates pro-inflammatory mediators, but excessive output, such as chronic inflammation, contributes to many persistent diseases. Some phenolic compounds work in tandem with nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit pro-inflammatory mediators’ activity or gene expression, including cyclooxygenase (COX). Various phenolic compounds can also act on transcription factors, such as nuclear factor-κB (NF-κB) or nuclear factor-erythroid factor 2-related factor 2 (Nrf-2), to up-or downregulate elements within the antioxidant response pathways. Phenolic compounds can inhibit enzymes associated with the development of human diseases and have been used to treat various common human ailments, including hypertension, metabolic problems, incendiary infections, and neurodegenerative diseases. The inhibition of the angiotensin-converting enzyme (ACE) by phenolic compounds has been used to treat hypertension. The inhibition of carbohydrate hydrolyzing enzyme represents a type 2 diabetes mellitus therapy, and cholinesterase inhibition has been applied to treat Alzheimer’s disease (AD). Phenolic compounds have also demonstrated anti-inflammatory properties to treat skin diseases, rheumatoid arthritis, and inflammatory bowel disease. Plant extracts and phenolic compounds exert protective effects against oxidative stress and inflammation caused by airborne particulate matter, in addition to a range of anti-inflammatory, anticancer, anti-aging, antibacterial, and antiviral activities. Dietary polyphenols have been used to prevent and treat allergy-related diseases. The chemical and biological contributions of phenolic compounds to cardiovascular disease have also been described. This review summarizes the recent progress delineating the multifunctional roles of phenolic compounds, including their anti-inflammatory properties and the molecular pathways through which they exert anti-inflammatory effects on metabolic disorders. This study also discusses current issues and potential prospects for the therapeutic application of phenolic compounds to various human diseases.

Chemical, Manufacturing, and Standardization Controls of Grape Polyphenol Dietary Supplements in Support of a Clinical Study: Mass Uniformity, Polyphenol Dosage, and Profiles

Bioactive dietary polyphenols in grape (Vitis vinifera) have been used in Dietary Supplements (DSs) with the aim to prevent numerous diseases, including cardiovascular and neurodegenerative diseases, and to reduce depression and anxiety. Given prior recognition that DSs can be quality challenged from the purity, authentication, adulteration, and actual concentration of targeted bioactives, to ensure consumer health protection as well as the quality and safety of grape polyphenol-based DSs, the present investigation was aimed at establishing a comprehensive quality control (QC) approach for grape polyphenol-based DSs in support of a human clinical study. In this study, the manufactured grape seed polyphenol extract (GSPE) and trans-resveratrol (RSV) capsules and Concord Grape Juice (CGJ) along with the corresponding original drug materials were analyzed using the developed different liquid chromatography/UV-visible spectroscopy/mass spectrometry (LC/UV-Vis/MS) methods. The weight variation of GSPE and RSV capsules was also evaluated according to the US Pharmacopeia (USP) tests. The results indicate that the total identified polyphenol content in each grape seed extract (GSE) capsule/CGJ is very similar and all GSE/RSV capsules pass the content/weight uniformity test. Given the complexity of these and many botanical products from the issues of purity, quality, adulteration, consistency, and their coupling to the complex chemistry in each grape-derived botanical, quality assurance and the steps needed to ensure grape-derived DSs being well homogeneous and stable and containing the known and expected bioactives at specific concentration ranges are fundamental to any research study and in particular to a clinical trial. Each of these issues is essential to provide a solid foundation upon which clinical trials with botanicals can be conducted with the goal of realizing measurable mental health outcomes such as reducing depression and anxiety as well as understanding of their underlying biological mechanisms.

Effects of Polyphenols on P-Glycoprotein (ABCB1) Activity

P-glycoprotein (Pgp, ABCB1) is a member of one of the largest families of active transporter proteins called ABC transporters. Thanks to its expression in tissues with barrier functions and its broad substrate spectrum, it is an important determinant of the absorption, metabolism and excretion of many drugs. Pgp and/or some other drug transporting ABC proteins (e.g., ABCG2, MRP1) are overexpressed in nearly all cancers and cancer stem cells by which cancer cells become resistant against many drugs. Thus, Pgp inhibition might be a strategy for fighting against drug-resistant cancer cells. Previous studies have shown that certain polyphenols interact with human Pgp. We tested the effect of 15 polyphenols of sour cherry origin on the basal and verapamil-stimulated ATPase activity of Pgp, calcein-AM and daunorubicin transport as well as on the conformation of Pgp using the conformation sensitive UIC2 mAb. We found that quercetin, quercetin-3-glucoside, narcissoside and ellagic acid inhibited the ATPase activity of Pgp and increased the accumulation of calcein and daunorubicin by Pgp-positive cells. Cyanidin-3O-sophoroside, catechin, naringenin, kuromanin and caffeic acid increased the ATPase activity of Pgp, while they had only a weaker effect on the intracellular accumulation of fluorescent Pgp substrates. Several tested polyphenols including epicatechin, trans-ferulic acid, oenin, malvin and chlorogenic acid were ineffective in all assays applied. Interestingly, catechin and epicatechin behave differently, although they are stereoisomers. We also investigated the effect of quercetin, naringenin and ellagic acid added in combination with verapamil on the transport activity of Pgp. In these experiments, we found that the transport inhibitory effect of the tested polyphenols and verapamil was additive or synergistic. Generally, our data demonstrate diverse interactions of the tested polyphenols with Pgp. Our results also call attention to the potential risks of drug–drug interactions (DDIs) associated with the consumption of dietary polyphenols concurrently with chemotherapy treatment involving Pgp substrate/inhibitor drugs.

Polyphenol utilization proteins in human gut microbiome

Dietary polyphenols can significantly benefit human health, but their bioavailability is metabolically controlled by human gut microbiota. To facilitate the study of polyphenol metabolism for human gut health, we have manually curated experimentally characterized polyphenol utilization proteins (PUPs) from published literature. This resulted in 60 experimentally characterized PUPs (named seeds) with various metadata, such as species and substrate. Further database search found 107,851 homologs of the seeds from UniProt and UHGP (Unified Human Gastrointestinal Protein) databases. All PUP seeds and homologs were classified into protein classes, families and subfamilies based on Enzyme Commission (EC) numbers, Pfam (protein family) domains and sequence similarity networks. By locating PUP homologs in the genomes of UHGP, we have identified 1,074 physically linked PUP gene clusters (PGCs), which are potentially involved in polyphenol metabolism in the human gut. The gut microbiome of Africans was consistently ranked the top in terms of the abundance and prevalence of PUP homologs and PGCs among all geographical continents. This reflects the fact that dietary polyphenols are more commonly consumed by African population than other populations such as Europeans and North Americans. A case study of the Hadza hunter-gatherer microbiome verified the feasibility of using dbPUP to profile metagenomic data for biologically meaningful discovery, suggesting an association between diet and PUP abundance. A Pfam domain enrichment analysis of PGCs identified a number of putatively novel PUP families. Lastly, a user-friendly web interface ( https://bcb.unl.edu/dbpup/ ) provides all the data online to facilitate the research of polyphenol metabolism for improved human health. Importance Long-term consumption of polyphenol-rich foods have been shown to lower the risk of various human diseases such as cardiovascular diseases, cancers, and metabolic diseases. Raw polyphenols are often enzymatically processed by gut microbiome, which encode various polyphenol utilization proteins (PUPs) to produce metabolites with much higher bioaccessibility to gastrointestinal cells. This study delivered dbPUP as an online database for experimentally characterized PUPs and their homologs in human gut microbiome. This work also performed a systematic classification of PUPs into enzyme classes, families, and subfamilies. The signature Pfam domains were identified for PUP families, enabling conserved domain-based PUP annotation. This standardized sequence similarity-based PUP classification system offered a guideline for the future inclusion of new experimentally characterized PUPs and the creation of new PUP families. An in-depth data analysis was further conducted on PUP homologs and physically linked PUP gene clusters (PGCs) in gut microbiomes of different human populations.

Characterization of Reactive Oxygen Species Signaling changes in a cell culture model of skeletal muscle ageing, and its application to screening pharmacokinetically-relevant exposures of dietary polyphenols for bioactivity.

Age-related frailty is a significant health and social care burden, however treatment options are limited. There is currently a lack of suitable cell culture model for screening large numbers of test compounds to identifying those which can potentially promote healthy skeletal muscle function. This paper describes the characterization of reactive oxygen and nitrogen species (RONS) signalling changes in young and aged myoblasts and myotubes using the C2C12 cell line, and the application of aged myoblast and myotube cultures to assess the effect of dietary polyphenols on RONS signalling. Aged myoblasts and myotubes were observed to have significantly increased reactive oxygen species levels (p<0.01 and p<0.001 respectively), increases in nitric oxide levels (p<0.05 for myoblasts and myotubes), and lipid peroxidation markers (p<0.05 for myoblasts and myotubes). A panel of nine polyphenols were assessed in aged myoblasts and myotubes using concentrations and incubation times consistent with known pharmacokinetic parameters for these compounds. Of these, although several polyphenols were seen to reduce single markers of RONS signalling, only kaempferol and resveratrol consistently reduced multiple markers of RONS signalling with statistical significance in both cell models. Overall, this research has shown the utility of the C2C12 model, as both myoblasts and myotubes, as a suitable cell model for screening compounds for modulating RONS signalling in aged muscle, and that resveratrol and kaempferol (using pharmacokinetically-informed exposures) can modulate RONS signalling in skeletal muscle cells after an acute exposure.

Polyphenols and Stem Cells for Neuroregeneration in Parkinson’s Disease and Amyotrophic Lateral Sclerosis

: Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS) are neurological disorders, pathologically characterized by chronic degeneration of dopaminergic neurons and motor neurons respectively. There is still no cure or effective treatment against the disease progression and most of the treatments are symptomatic. The present review offers an overview of the different factors involved in the pathogenesis of these diseases. Subsequently, we focused on the recent advanced studies of dietary polyphenols and stem cell therapies, which have made it possible to slow down the progression of neurodegeneration. To date, stem cells and different polyphenols have been used for the directional induction of neural stem cells into dopaminergic neurons and motor neurons. We have also discussed their involvement in the modulation of different signal transduction pathways and growth factor levels in various in vivo and in vitro studies. Likewise stem cells, polyphenols also exhibit the potential of neuroprotection by their anti-apoptotic, anti-inflammatory, anti-oxidant properties regulating the growth factors levels and molecular signaling events. Overall this review provides a detailed insight into recent strategies that promise the use of polyphenol with stem cell therapy for the possible treatment of PD and ALS.