Elderberry Extracts: Characterization of the Polyphenolic Chemical Composition, Quality Consistency, Safety, Adulteration, and Attenuation of Oxidative Stress- and Inflammation-Induced Health Disorders.

Elderberry is highly reputed for its health-improving effects. Multiple pieces of evidence indicate that the consumption of berries is linked to enhancing human health and preventing or delaying the onset of chronic medical conditions. Compared with other fruit, elderberry is a very rich source of anthocyanins (approximately 80% of the polyphenol content). These polyphenols are the principals that essentially contribute to the high antioxidant and anti-inflammatory capacities and the health benefits of elderberry fruit extract. These health effects include attenuation of cardiovascular, neurodegenerative, and inflammatory disorders, as well as anti-diabetic, anticancer, antiviral, and immuno-stimulatory effects. Sales of elderberry supplements skyrocketed to $320 million over the year 2020, according to an American Botanical Council (ABC) report, which is attributable to the purported immune-enhancing effects of elderberry. In the current review, the chemical composition of the polyphenolic content of the European elderberry (Sambucus nigra) and the American elderberry (Sambucus canadensis), as well as the analytical techniques employed to analyze, characterize, and ascertain the chemical consistency will be addressed. Further, the factors that influence the consistency of the polyphenolic chemical composition, and hence, the consistency of the health benefits of elderberry extracts will be presented. Additionally, adulteration and safety as factors contributing to consistency will be covered. The role of elderberry in enhancing human health alone with the pharmacological basis, the cellular pathways, and the molecular mechanisms underlying the observed health benefits of elderberry fruit extracts will be also reviewed.

Potential Benefits of Black Chokeberry (Aronia melanocarpa) Fruits and Their Constituents in Improving Human Health.

Aronia berry (black chokeberry) is a shrub native to North America, of which the fresh fruits are used in the food industry to produce different types of dietary products. The fruits of Aronia melanocarpa (Aronia berries) have been found to show multiple bioactivities potentially beneficial to human health, including antidiabetic, anti-infective, antineoplastic, antiobesity, and antioxidant activities, as well as heart-, liver-, and neuroprotective effects. Thus far, phenolic compounds, such as anthocyanins, cyanidins, phenolic acids, proanthocyanidins, triterpenoids, and their analogues have been identified as the major active components of Aronia berries. These natural products possess potent antioxidant activity, which contributes to the majority of the other bioactivities observed for Aronia berries. The chemical components and the potential pharmaceutical or health-promoting effects of Aronia berries have been summarized previously. The present review article focuses on the molecular targets of extracts of Aronia berries and the examples of promising lead compounds isolated from these berries, including cyanidin-3-O-galactoside, chlorogenic acid, quercetin, and ursolic acid. In addition, presented herein are clinical trial investigations for Aronia berries and their major components, including cancer clinical trials for chlorogenic acid and COVID-19 trial studies for quercetin. Additionally, the possible development of Aronia berries and their secondary metabolites as potential therapeutic agents is discussed. It is hoped that this contribution will help stimulate future investigations on Aronia berries for the continual improvement of human health.

Enzyme-assisted extraction of anthocyanins and other phenolic compounds from blackcurrant (Ribes nigrum L.) press cake: From processing to bioactivities.

The effects of commercial enzymes (pectinases, cellulases, beta-1-3-glucanases, and pectin lyases) on the recovery of anthocyanins and polyphenols from blackcurrant press cake were studied considering two solid:solvent ratios (1:10 and 1:4 w/v). ß-glucanase enabled the recovery of the highest total phenolic content - 1142 mg/100 g, and the extraction of anthocyanins was similar using all enzymes (∼400 mg/100 g). The use of cellulases and pectinases enhanced the extraction of antioxidants (DPPH - 1080 mg/100 g; CUPRAC - 3697 mg/100 g). The freeze-dried extracts presented antioxidant potential (CUPRAC, DPPH), which was associated with their biological effects in different systems: antiviral activity against both non-enveloped viruses (enterovirus coxsackievirus A-9) and enveloped coronaviruses (HCoV-OC43), and cytotoxicity towards cancer cells (A549 and HCT8). No cytotoxic effects on normal human lung fibroblast (IMR90) were observed, and no anti-inflammatory activity was detected in lipopolysaccharides-treated murine immortalised microglial cells.

Polyphenols as Potential Inhibitors of SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp).

An increasing number of studies have demonstrated the antiviral nature of polyphenols, and many polyphenols have been proposed to inhibit SARS-CoV or SARS-CoV-2. Our previous study revealed the inhibitory mechanisms of polyphenols against DNA polymerase α and HIV reverse transcriptase to show that polyphenols can block DNA elongation by competing with the incoming NTPs. Here we applied computational approaches to examine if some polyphenols can also inhibit RNA polymerase (RdRp) in SARS-CoV-2, and we identified some better candidates than remdesivir, the FDA-approved drug against RdRp, in terms of estimated binding affinities. The proposed compounds will be further examined to develop new treatments for COVID-19.

Discovery of a AHR pelargonidin agonist that counter-regulates Ace2 expression and attenuates ACE2-SARS-CoV-2 interaction.

The severe acute respiratory syndrome (SARS)-CoV-2 is the pathogenetic agent of Corona Virus Induced Disease (COVID)19. The virus enters the human cells after binding to the angiotensin converting enzyme (ACE)2 receptor in target tissues. ACE2 expression is induced in response to inflammation. The colon expression of ACE2 is upregulated in patients with inflammatory bowel disease (IBD), highlighting a potential risk of intestinal inflammation in promoting viral entry in the human body. Because mechanisms that regulate ACE2 expression in the intestine are poorly understood and there is a need of anti-SARS-CoV-2 therapies, we have settled to investigate whether natural flavonoids might regulate the expression of Ace2 in intestinal models of inflammation. The results of these studies demonstrated that pelargonidin activates the Aryl hydrocarbon Receptor (AHR) in vitro and reverses intestinal inflammation caused by chronic exposure to high fat diet or to the intestinal braking-barrier agent TNBS in a AhR-dependent manner. In these two models, development of colon inflammation associated with upregulation of Ace2 mRNA expression. Colon levels of Ace2 mRNA were directly correlated with Tnf-α mRNA levels. Molecular docking studies suggested that pelargonidin binds a fatty acid binding pocket on the receptor binding domain of SARS-CoV-2 Spike protein. In vitro studies demonstrated that pelargonidin significantly reduces the binding of SARS-CoV-2 Spike protein to ACE2 and reduces the SARS-CoV-2 replication in a concentration-dependent manner. In summary, we have provided evidence that a natural flavonoid might hold potential in reducing intestinal inflammation and ACE2 induction in the inflamed colon in a AhR-dependent manner.

Interaction of small molecules with the SARS-CoV-2 papain-like protease: In silico studies and in vitro validation of protease activity inhibition using an enzymatic inhibition assay.

The SARS-CoV-2 virus is causing COVID-19, an ongoing pandemic, with extraordinary global health, social, and political implications. Currently, extensive research and development efforts are aimed at producing a safe and effective vaccine. In the interim, small molecules are being widely investigated for antiviral effects. With respect to viral replication, the papain-like (PLpro) and main proteases (Mpro), are critical for processing viral replicase polypeptides. Further, the PLpro possesses deubiquitinating activity affecting key signalling pathways, including inhibition of interferon and innate immune antagonism. Therefore, inhibition of PLpro activity with small molecules is an important research direction. Our aim was to focus on identification of potential inhibitors of the protease activity of SARS-CoV-2 PLpro. We investigated 300 small compounds derived predominantly from our OliveNet™ library (222 phenolics) and supplemented with synthetic and dietary compounds with reported antiviral activities. An initial docking screen, using the potent and selective noncovalent PLpro inhibitor, GRL-0617 as a control, enabled a selection of 30 compounds for further analyses. From further in silico analyses, including docking to scenes derived from a publicly available molecular dynamics simulation trajectory (100 µs PDB 6WX4; DESRES-ANTON-11441075), we identified lead compounds for further in vitro evaluation using an enzymatic inhibition assay measuring SARS-CoV-2 PLpro protease activity. Our findings indicate that hypericin possessed inhibition activity, and both rutin and cyanidin-3-O-glucoside resulted in a concentration-dependent inhibition of the PLpro, with activity in the micromolar range. Overall, hypericin, rutin, and cyanidin-3-O-glucoside can be considered lead compounds requiring further characterisation for potential antiviral effects in appropriate model systems.

Recovery and Stabilization of Anthocyanins and Phenolic Antioxidants of Roselle (Hibiscus sabdariffa L.) with Hydrophilic Deep Eutectic Solvents.

Deep eutectic solvents (DESs) have got huge interest as new green and sustainable solvents for the extraction of bioactive compounds from plants in recent decades. In the present study, we aimed to investigate the effectiveness of hydrophilic DES for the extraction of anthocyanin and polyphenol antioxidants from Roselle. A natural hydrophilic DES constituted of sodium acetate (hydrogen bond acceptor) and formic acid (hydrogen bond donor) designed to evaluate the total phenolic compound (TPC), total flavonoid (TFC), total anthocyanin (TACN), 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and ferric reducing antioxidant power (FRAP) values of Roselle. Distilled water, 70% ethanol, and 80% methanol used as conventional solvents for comparison. The results indicated that the DES prepared in molarity ratio (SAFAm) was the most efficient. Subsequently, this prominent DES selected for the optimization and the optimum extraction conditions were 1:3.6 molarity ratio, 0% additional water, and 10 mL solvent. TPC, TFC, TACN, FRAP, and DPPH radical scavenging at the optimum point were 233.26 mg GAE/g, 10.14 mg ECE/g, 10.62 mg D3S/g, 493.45 mmol ISE/g, and 343.41 mmol TE/g, respectively. The stability tests showed that anthocyanins were more stable in SAFAm. These findings revealed that SAFAm is an effective green solvent for the extraction of polyphenols from various plants.

Polyacylated anthocyanins constructively network with catalytic dyad residues of 3CLpro of 2019-nCoV than monomeric anthocyanins: A structural-relationship activity study with 10 anthocyanins using in-silico approaches.

Coronavirus epidemic 2019 (COVID-19), caused by novel coronavirus (2019-nCoV), is newly increasing worldwide and elevating global health concerns. Similar to SARS-CoV and MERS-CoV, the viral key 3-chymotrypsin-like cysteine protease enzyme (3CLPro), which controls 2019-nCoV duplications and manages its life cycle, could be pointed as a drug discovery target. Herein, we theoretically studied the binding ability of 10 structurally different anthocyanins with the catalytic dyad residues of 3CLpro of 2019-nCoV using molecular docking modelling. The results revealed that the polyacylated anthocyanins, including phacelianin, gentiodelphin, cyanodelphin, and tecophilin, were found to authentically bind with the receptor binding site and catalytic dyad (Cys145 and His41) of 2019-nCoV-3CLpro. Our analyses revealed that the top four hits might serve as potential anti-2019-nCoV leading molecules for further optimization and drug development process to combat COVID-19. This study unleashed that anthocyanins with specific structure could be used as effective anti-COVID-19 natural components.