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Cardiovascular Health and Anti-inflammatory Benefits: In-Vitro

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Anti-inflammatory Effects of Proanthocyanidin-rich Cranberry Extract through the Suppression of NF-kB Pathway and Histone Acetylase in RAW 264.7 and Mouse Bone Marrow-derived Macrophages

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Authors
Seok-Yeong Yu, Jungbae Oh, Justin S. Kim, Young-In Kwon, Emmanouil Apostolidis, Young-Cheul Kim
Journal
Journal of Food and Nutrition Research, 2021, Vol. 9, No. 2, 79-86
Abstract

Obesity-mediated chronic inflammation promotes the progression of obesity to metabolic anti-inflammatory effect of cranberries by decreasing plasma inflammatory cytokines. However, its specific mechanisms of action remain unclear. The nuclear factor-κB (NF-κB) pathway in macrophages plays a critical role in regulating the expression of many inflammatory genes, and histone acetylation has been identified as a key epigenetic modification for the NF-κB p65-mediated inflammatory responses. The objective of the study was to investigate if proanthocyanidin (PAC)-rich cranberry extract (CBE) suppresses histone acetylation and NF-κB p65 activation in RAW 264.7 macrophages and mouse bone marrow-derived macrophages (BMDMs). Treatment with 5% and 15% PAC-containing CBEs markedly suppressed the expression of pro-inflammatory mediators (iNos, Cox-2, Tnfα, Mcp-1 and Il-6) in both RAW 264.7 macrophages and BMDMs stimulated with lipopolysaccharides (LPS). CBE significantly reduced LPS-induced phosphorylation of p65 in both cell types without changing total p65 expression levels. Moreover, 15% PAC-CBE increased the expression levels of histone deacetylase 3 (HDAC3) with a concomitant decrease in histone H4 acetylation levels. These results suggest that CBE increases HDAC3 protein expression with the subsequent inhibition of p65 phosphorylation to mediate anti-inflammatory effects in macrophages. Cranberries may serve as a dietary agent to attenuate chronic inflammation in patients with obesity and related complications.

 

Candida albicans biofilm inhibition by two Vaccinium macrocarpon (cranberry) urinary metabolites: 5-(3',4'-dihydroxyphenyl)-P-valerolactone and 4-hydroxybenzoic acid.

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Authors
Ottaviano, E., Baron, G., Fumagalli, L., Leite, J., Colombo, E. A., Artasensi, A., Aldini, G., Borghi, E.
Journal
Microorganisms 2021. 9(7).
Abstract

Candida spp. are pathobionts, as they can switch from commensals to pathogens, responsible for a variety of pathological processes. Adhesion to surfaces, morphological switch and biofilm-forming ability are the recognized virulence factors promoting yeast virulence. Sessile lifestyle also favors fungal persistence and antifungal tolerance. In this study, we investigated, in vitro, the efficacy of two urinary cranberry metabolites, 5-(3',4'-dihydroxy phenyl)-P-valerolactone (VAL) and 4-hydroxybenzoic acid (4-HBA), in inhibiting C. albicans adhesion and biofilm formation. Both the reference strain SC5314 and clinical isolates were used. We evaluated biomass reduction, by confocal microscopy and crystal violet assay, and the possible mechanisms mediating their inhibitory effects. Both VAL and 4-HBA were able to interfere with the yeast adhesion, by modulating the expression of key genes, HWP1 and ALS3. A significant dose-dependent reduction in biofilm biomass and metabolic activity was also recorded. Our data showed that the two cranberry metabolites VAL and 4-HBA could pave the way for drug development, for targeting the very early phases of biofilm formation and for preventing genitourinary Candida infections.

 

Cranberry (Vaccinium macrocarpon) Extract Impairs Nairovirus Infection by Inhibiting the Attachment to Target Cells.

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Authors
Mirandola M, Salvati MV, Rodigari C, Appelberg KS, Mirazimi A, Maffei ME, Gribaudo G, Salata C
Journal
Pathogens. 10(8), 2021 Aug 13.
Abstract

Hazara virus (HAZV) belongs to the Nairoviridae family and is included in the same serogroup of the Crimean-Congo hemorrhagic fever virus (CCHFV). CCHFV is the most widespread tick-borne arbovirus. It is responsible for a serious hemorrhagic disease, for which specific and effective treatment and preventive systems are missing. Bioactive compounds derived from several natural products may provide a natural source of broad-spectrum antiviral agents, characterized by good tolerability and minimal side effects. Previous in vitro studies have shown that a cranberry (Vaccinium macrocarpon Ait.) extract containing a high content of A-type proanthocyanidins (PAC-A) inhibits the replication of herpes simplex and influenza viruses by hampering their attachment to target cells. Given the broad-spectrum antimicrobial activity of polyphenols and the urgency to develop therapies for the treatment of CCHF, we investigated the antiviral activity of cranberry extract against HAZV, a surrogate nairovirus model of CCHFV that can be handled in Level 2 Biosafety Laboratories (BSL-2). The results indicate that the cranberry extract exerts an antiviral activity against HAZV by targeting early stages of the viral replication cycle, including the initial adsorption to target cells. Although the details of the molecular mechanism of action remain to be clarified, the cranberry extract exerts a virucidal effect through a direct interaction with HAZV particles that leads to the subsequent impairment of virus attachment to cell-surface receptors. Finally, the antiviral activity of the cranberry extract was also confirmed for CCHFV. As a whole, the evidence obtained suggests that cranberry extract is a valuable candidate to be considered for the development of therapeutic strategies for CCHFV infections.

 

Cranberry (Vacinium macrocarpon) phytochemicals inhibit hepatic stellate cell activation and liver fibrosis

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Authors
L Shi, X Zhang, X Liu, Y Jiang, Y Deng, J Liu
Journal
Food Bioscience 42 (2021) 101176
Abstract

Excessive activation and proliferation of hepatic stellate cells (HSCs) is the most critical factor in liver fibrosis.Cranberry (Vaccinium macrocarpon) is berry-bearing with potential health benefits. Here, we reported the inhibitory effects of cranberry phytochemicals (CPS) on HSC activation and liver fibrogenesis. The results showed that CPS reduced cell viability and inhibited the TGFβ/Smad signaling pathway of HSCs in vitro. The therapeutic effects of CPS on HSC activation were further linked to the amelioration of CCl4-induced liver fibrosis in rats. CPS treatment reduced liver fibrosis, revived liver function (HYP, MDA, ALB, ALP, ALT, AST, and TBIL), and decreased inflammatory cytokines (IL-1, IL-6, and TNF-α) in a dose-dependent manner. Moreover, the expression levels of the TGFβ/Smad signaling pathway related genes, including TGF-β1, Smad2/3, p-Smad2/3, Col1α1, and α-SMA, were down-regulated by CPS. It is suggested that CPS may inhibit HSC activation and liver fibrosis by reducing the expression of inflammatory cytokines and inhibiting the TGFβ/Smad signaling pathway.

Cranberry extract-based formulations for preventing bacterial biofilms.

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Authors
Greene AC, Acharya AP, Lee SB, Gottardi R, Zaleski E, Little SR
Journal
Drug Delivery & Translational Research. 11(3):1144-1155, 2021 06.
Abstract

Generating formulations for the delivery of a mixture of natural compounds extracted from natural sources is a challenge because of unknown active and inactive ingredients and possible interactions between them. As one example, natural cranberry extracts have been proposed for the prevention of biofilm formation on dental pellicle or teeth. However, such extracts may contain phenolic acids, flavonol glycosides along with other constituents like coumaroyl iridoid glycosides, flavonoids, alpha-linolenic acid, n-6 (or n-3) fatty acids, and crude fiber. Due to the presence of a variety of compounds, determining which molecules (and how many molecules) are essential for preventing biofilm growth is nontrivial to ascertain. Therefore, a formulation that could contain natural, unrefined, cranberry extract (with all its constituent compounds) at high loading would be ideal. Accordingly, we have generated several candidate formulations including poly(lactic-co-glycolic) acid (PLGA)-based microencapsulation of cranberry extract (CE15) as well as formulations including stearic acid along with polyvinylpyrrolidone (PVP) or Ethyl lauroyl arginate (LAE) complexed with cranberry extracts (CE15). We found that stearic acid in combination with PVP or LAE as excipients led to higher loading of the active and inactive compounds in CE15 as compared with a PLGA microencapsulation and also sustained release of CE15 in a tunable manner. Using this method, we have been able to generate two successful formulations (one preventative based, one treatment based) that effectively inhibit biofilm growth when incubated with saliva. In addition to cranberry extract, this technique could also be a promising candidate for other natural extracts to form controlled release systems.

 

Cranberry Proanthocyanidins-PANI Nanocomposite for the Detection of Bacteria Associated with Urinary Tract Infections.

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Authors
Urena-Saborio H, Udayan APM, Alfaro-Viquez E, Madrigal-Carballo S, Reed JD, Gunasekaran S
Journal
Biosensors. 11(6), 2021 Jun 19
Abstract

Consumption of cranberries is associated with the putative effects of preventing urinary tract infections (UTIs). Cranberry proanthocyanidins (PAC) contain unusual double A-type linkages, which are associated with strong interactions with surface virulence factors found on UTI-causing bacteria such as extra-intestinal pathogenic Escherichia coli (ExPEC), depicting in bacterial agglutination processes. In this work, we demonstrated the efficacy of cranberry PAC (200 mug/mL) to agglutinate ExPEC (5.0 x 108 CFU/mL) in vitro as a selective interaction for the design of functionalized biosensors for potential detection of UTIs. We fabricated functionalized screen-printed electrodes (SPEs) by modifying with PAC-polyaniline (PANI) nanocomposites and tested the effectiveness of the PAC-PANI/SPE biosensor for detecting the presence of ExPEC in aqueous suspensions. Results indicated that the PAC-PANI/SPE was highly sensitive (limit of quantification of 1 CFU/mL of ExPEC), and its response was linear over the concentration range of 1-70,000 CFU/mL, suggesting cranberry PAC-functionalized biosensors are an innovative alternative for the detection and diagnosis of ExPEC-associated UTIs. The biosensor was also highly selective, reproducible, and stable.

 

Cranberry-derived proanthocyanidins potentiate beta-lactam antibiotics against resistant bacteria.

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Authors
Gallique, M., Wei, K., Maisuria, V. B., Okshevsky, M., McKay, G., Nguyen, D., Tufenkji, N
Journal
Applied and Environmental Microbiology 2021. 87(10).
Abstract

The emergence and spread of extended-spectrum beta-lactamases (ESBLs), metallo-beta-lactamases (MBLs), or variant low-affinity penicillin-binding proteins (PBPs) pose a major threat to our ability to treat bacterial infection using beta-lactam antibiotics. Although combinations of beta-lactamase inhibitors with beta-lactam agents have been clinically successful, there are no MBL inhibitors in current therapeutic use. Furthermore, recent clinical use of new-generation cephalosporins targeting PBP2a, an altered PBP, has led to the emergence of resistance to these antimicrobial agents. Previous work shows that natural polyphenols such as cranberry-extracted proanthocyanidins (cPAC) can potentiate non-beta-lactam antibiotics against Gram-negative bacteria. This study extends beyond previous work by investigating the in vitro effect of cPAC in overcoming ESBL-, MBL-, and PBP2a-mediated beta-lactam resistance. The results show that cPAC exhibit variable potentiation of different beta-lactams against beta-lactam-resistant Enterobacteriaceae clinical isolates as well as ESBL- and MBL-producing E. coli. We also discovered that cPAC have broad-spectrum inhibitory properties in vitro on the activity of different classes of beta-lactamases, including CTX-M3 ESBL and IMP-1 MBL. Furthermore, we observe that cPAC selectively potentiate oxacillin and carbenicillin against methicillin-resistant but not methicillin-sensitive staphylococci, suggesting that cPAC also interfere with PBP2a-mediated resistance. This study motivates the need for future work to identify the most bioactive compounds in cPAC and to evaluate their antibiotic-potentiating efficacy in vivo.

Deacidification of cranberry juice reduces its antibacterial properties against oral streptococci but preserves barrier function and attenuates the inflammatory response of oral epithelial cells.

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Authors
Pellerin, G., Bazinet, L., Grenier, D.
Journal
Foods 2021. 10(7).
Abstract

Cranberry (Vaccinium macrocarpon) may be a potent natural adjuvant for the prevention of oral diseases due to its anti-adherence, anti-cariogenic, and anti-inflammatory properties. However, the high titrable acidity of cranberry juice (CJ) has been reported to cause gastrointestinal discomfort, leading consumers to restrict their intake of this beverage. Electrodialysis with a bipolar membrane (EDBM) can reduce the organic acid content of CJ while retaining the flavonoids associated with potential health benefits. This study aimed to assess how the deacidification of CJ by EDBM impacts the antibacterial properties of the beverage against cariogenic (Streptococcus mutans, Streptococcus sobrinus) and commensal (Streptococcus gordonii, Streptococcus oralis, Streptococcus salivarius) streptococci, and how it affects oral epithelial barrier function and inflammatory response in an in vitro model. The removal of organic acids from CJ (deacidification rate 42%) reduced the bactericidal activity of the beverage against planktonic S. mutans and S. gordonii after a 15-min exposure, whereas only the viability of S. gordonii was significantly impacted by CJ deacidification rate when the bacteria were embedded in a biofilm. Moreover, conditioning saliva-coated hydroxyapatite with undiluted CJ samples significantly lowered the adherence of S. mutans, S. sobrinus, and S. oralis. With respect to epithelial barrier function, exposure to CJ deacidified at a rate of 19% maintained the integrity of a keratinocyte monolayer over the course of 24 h compared to raw CJ, as assessed by the determination of transepithelial electrical resistance (TER) and fluorescein isothiocyanate-conjugated dextran paracellular transport. These results can be in part attributed to the inability of the deacidified CJ to disrupt two tight junction proteins, zonula occludens-1 and occludin, following exposure, unlike raw CJ. Deacidification of CJ impacted the secretion of IL-6, but not of IL-8, by oral epithelial cells. In conclusion, deacidification of CJ appears to provide benefits with respect to the maintenance of oral health.

 

Effect of a berry polyphenolic fraction on biofilm formation, adherence properties and gene expression of Streptococcus mutans and its biocompatibility with oral epithelial cells.

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Authors
Souissi, M., Lagha, A. B., Chaieb, K., Grenier, D
Journal
Antibiotics 2021. 10(1).
Abstract

The ability of Streptococcus mutans to adhere to oral surfaces and form biofilm is a key step in the tooth decay process. The aim of this study was to investigate a berry (wild blueberry, cranberry, and strawberry) polyphenolic fraction, commercialized as OrophenolR, for its antibacterial, anti-biofilm, and anti-adhesion properties on S. mutans. Moreover, the biocompatibility of the fraction with human oral epithelial cells was assessed. Phenolic acids, flavonoids (flavonols, anthocyanins, flavan-3-ols), and procyanidins made up 10.71%, 19.76%, and 5.29% of the berry polyphenolic fraction, respectively, as determined by chromatography and mass spectrometry. The berry polyphenolic preparation dose-dependently inhibited S. mutans biofilm formation while not reducing bacterial growth. At concentrations ranging from 250 to 1000 micro g/mL, the fraction inhibited the adhesion of S. mutans to both saliva-coated hydroxyapatite and saliva-coated nickel-chrome alloy. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis showed that incubating S. mutans with the berry polyphenolic fraction was associated with a reduced expression of luxS gene, which regulates quorum sensing in S. mutans. The berry fraction did not show any significant cytotoxicity in an oral epithelial cell model. In conclusion, OrophenolR, which is a mixture of polyphenols from wild blueberry, cranberry and strawberry, possesses interesting anti-caries properties while being compatible with oral epithelial cells.

Effect of cranberry juice deacidification on its antibacterial activity against periodontal pathogens and its anti-inflammatory properties in an oral epithelial cell model.

Posted
Authors
Pellerin, G., Bazinet, L., Grenier, D.
Journal
Food and Function 2021. 12(21):10470-10483.
Abstract

Cranberries are widely recognized as a functional food that can promote oral health. However, the high concentration of organic acids in cranberry juice can cause tooth enamel erosion. Electrodialysis with bipolar membrane (EDBM) is a process used for the deacidification of cranberry juice. The present study investigated whether the removal of organic acids (0%, 19%, 42%, 60%, and 79%) from cranberry juice by EDBM affects its antibacterial activity against major periodontopathogens as well as its anti-inflammatory properties in an oral epithelial cell model. A deacidification rate 60% attenuated the bactericidal effect against planktonic and biofilm-embedded Aggregatibacter actinomycetemcomitans but had no impact on Porphyromonas gingivalis and Fusobacterium nucleatum. Cranberry juice increased the adherence of A. actinomycetemcomitans and P. gingivalis to oral epithelial cells, but reduced the adherence of F. nucleatum by half regardless of the deacidification rate. F. nucleatum produced more hydrogen sulfide when it was exposed to deacidified cranberry juice with a deacidification rate 42% compared to the raw beverage. Interestingly, the removal of organic acids from cranberry juice lowered the cytotoxicity of the beverage for oral epithelial cells. Deacidification attenuated the anti-inflammatory effect of cranberry juice in an in vitro oral epithelial cell model. The secretion of IL-6 by lipopolysaccharide (LPS)-stimulated oral epithelial cells exposed to cranberry juice increased proportionally with the deacidification rate. No such effect was observed with respect to the production of IL-8. This study provided evidence that organic acids, just like phenolic compounds, might contribute to the health benefits of cranberry juice against periodontitis.