The high polyphenols content of cranberry accounts for its strong antioxidant activity underlying the beneficial health effects of this fruit. Rotenone (ROT) is a specific inhibitor of mitochondrial complex I in the brain which leads to the generation of oxidative stress. To date, there are few data indicating that toxicity of ROT is not limited to the brain but can also affect other tissues. We aimed to examine whether ROT-induced oxidative stress could be counteracted by cranberry juice not only in the brain but also in the liver and kidney. Wistar rats were given the combined treatment with ROT and cranberry juice (CJ) for 35 days. Parameters of antioxidant status were determined in the organs. ROT enhanced lipid peroxidation solely in the brain. The increase in the DNA damage was noticed in all organs examined and in leukocytes. The beneficial effect of CJ on these parameters appeared only in the brain. Additionally, CJ decreased the activity of serum hepatic enzymes. The effect of CJ on antioxidant enzymes was not consistent, however, in some organs, CJ reversed changes evoked by ROT. Summing up, ROT can cause oxidative damage not only in the brain but also in other organs. CJ demonstrated a protective effect against ROT-induced toxicity

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.

In this paper, an A-type procyanidin (PAC)-rich cranberry extract (CB-B) was obtained mixing different extracts and was formulated with D-mannose and ascorbic acid to obtain a novel nutraceutical (URO-F) aimed at preventing non-complicated bacterial urinary tract infections (UTIs). To assess the bioactivity of CB-B and URO-F, urine samples collected from six healthy volunteers undergoing a 2-days oral consumption of 0.41 g/day of CB-B or 10 g/day of URO-F (corresponding to 72 mg/day of PACs) were tested against uropathogenic E. coli (UPEC) incubated on urinary bladder epithelial cells (T24). Urinary markers of CB-B and URO-F consumption were assessed in the same urine output by UPLC-QTOF-based untargeted metabolomics approach. CB-B and URO-F were evaluated for their ability to promote the intestinal barrier function by restoring the trans-epithelial electrical resistance (TEER) and to inhibit the production of inflammatory cytokines in intestinal epithelial Caco2 cells. CB-B was characterized by a high PAC-A content (70% of total PACs) and a broad distribution of different PACs polymers (dimers-hexamers). Urine from subjects consuming CB-B and URO-F showed a significant effect in reducing the adhesion of UPEC to urothelium in vitro, supporting their efficacy as anti-adhesive agents after oral intake. CB-B inhibited the release of cytokine IL-8, and both products were effective in restoring the TEER. Overall, our results show that the beneficial effects of CB-B and URO-F on UTIs are not only due to the antiadhesive activity of cranberry on UPEC in the urothelium, but also to a multi-target activity involving anti-inflammatory and permeability-enhancing effects on intestinal epithelium.

The efficacy of cranberry (Vaccinium spp.) as adjuvant therapy in preventing urinary tract infections (UTIs) remains controversial. This study aims to update and determine cranberry effects as adjuvant therapy on the recurrence rate of UTIs in susceptible groups. According to PRISMA guidelines, we conducted a literature search in Web of Science, PubMed, Embase, Scopus, and the Cochrane Library from their inception dates to June 2021. We included articles with data on the incidence of UTIs in susceptible populations using cranberry-containing products. We then conducted a trial sequential analysis to control the risk of type I and type II errors. This meta-analysis included 23 trials with 3979 participants. We found that cranberry-based products intake can significantly reduce the incidence of UTIs in susceptible populations (risk ratio (RR) = 0.70; 95% confidence interval(CI): 0.59 ~ 0.83; P < 0.01). We identified a relative risk reduction of 32%, 45% and 51% in women with recurrent UTIs (RR = 0.68; 95% CI: 0.56 ~ 0.81), children (RR = 0.55; 95% CI: 0.31 ~ 0.97) and patients using indwelling catheters (RR = 0.49; 95% CI: 0.33 ~ 0.73). Meanwhile, a relative risk reduction of 35% in people who use cranberry juice compared with those who use cranberry capsule or tablet was observed in the subgroup analysis (RR = 0.65; 95% CI: 0.54 ~ 0.77). The TSA result for the effects of cranberry intake and the decreased risk of UTIs in susceptible groups indicated that the effects were conclusive. In conclusion, our meta-analysis demonstrates that cranberry supplementation significantly reduced the risk of developing UTIs in susceptible populations. Cranberry can be considered as adjuvant therapy for preventing UTIs in susceptible populations. However, given the limitations of the included studies in this meta-analysis, the conclusion should be interpreted with caution.

Cranberry (Vaccinium macrocarpon) dietary supplementation can help prevention of urinary tract infections through the supply of proanthocyanidin-type polyphenols (PAC). The main uropathogenic bacteria are members of the intestinal microbiota. A randomized cross-over experiment was done to investigate whether cranberry dietary supplementation affects concentrations of thermotolerant coliforms, Enterococcus spp. and Lactobacillus spp. in rat faeces. Thirteen rats, housed in individual cages, received successively two diets as pellets during 7 days each: a standard diet without polyphenols and the standard diet supplemented with cranberry powder containing 10.9 mg/100 g of PAC. There was a 7 days wash-out period in between with standard diet without polyphenols. Body weight and feed intake were recorded. Faeces were collected on the last day of treatment, and crushed to count the different bacterial populations using the most probable number method. Thermotolerant coliforms were grown in BGBLB tubes and on MacConkey agar. Enterococcus spp. were grown in Rothe and Litsky broths and on KF Streptococcus agar. Lactobacillus spp. were grown in Man Rogosa Sharpe broth. Body mass gains were not affected by cranberry supplementation. This is consistent with equal food intake, cranberry powder not providing significant energy supplement. Cranberry dietary supplementation was associated with changes in fecal concentrations of thermotolerant coliforms, and Enterococcus spp. in some rats, but did not induce significant changes in bacterial fecal concentrations in a global population of 13 rats. In conclusion, we did not observe any significant effect of dietary cranberry supplementation on the fecal microbiota of Wistars rats for a 7-day diet.

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.

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.

Background/Aim: Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive type of primary brain tumor and a cornerstone in its treatment is radiotherapy (RT). However, RT for GBM is largely ineffective at clinically safe doses, thus, the study of radiosensitizers is of great significance.Materials and Methods: With accumulating evidence for the anticancer effect of compounds from cranberry, this study was designed to investigate if cranberry extract (CE) sensitizes GBM to RT in the widely used human glioblastoma cell line U87. We utilized clonogenic survival assays, cell proliferation assays, and caspase-3 activity kits. Potential proliferative and apoptotic molecular mechanisms were evaluated by reverse transcription-polymerase chain reaction.Results: We found that CE alone had little effect on the survival of U87 cells. However, RT supplemented by CE significantly inhibited proliferation and promoted apoptosis of U87 cells when compared with RT alone. The proliferation-inhibitory effect of RT/CE might be attributable to the up-regulation of p21, along with the down-regulation of cyclin B and cyclin-dependent kinase 4. This pro-apoptotic effect might additionally be attributable to the down-regulation of surviving.Conclusion: These results warrant further study of the potential radiosensitizing capacity of CE in glioblastoma and other cancer types.

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.

Improving the longevity of composite restorations has proven to be difficult when they are bonded to dentin. Dentin demineralization leaves collagen fibrils susceptible to enzymatic digestion, which causes breakdown of the resin-dentin interface. Therefore, measures for counteracting the enzymatic environment by enhancing dentin collagen's resistance to degradation have the potential to improve the durability of dental composite restorations. This study aimed to evaluate the effects of polyphenol-rich extracts and a chemical cross-linker on the cross-linking interaction, resistance to digestion, and endogenous matrix metalloproteinase (MMP) activities of dentin collagen under clinically relevant conditions. Ten-microm-thick films were cut from dentin slabs of non-carious extracted human third molars. Following demineralization, polyphenol-rich extracts-including grape seed (GSE), green tea (GTE), and cranberry juice (CJE)-or chemical cross-linker carbodiimide with n-hydroxysuccinimide (EDC/NHS) were applied to the demineralized dentin surfaces for 30 s. The collagen cross-linking, bio-stabilization, and gelatinolytic activities of MMPs 2 and 9 were studied by using Fourier-transform infrared spectroscopy, weight loss, hydroxyproline release, scanning/transmission electron microscopy, and in situ zymography. All treatments significantly increased resistance to collagenase degradation and reduced the gelatinolytic MMP activity of dentin collagen compared to the untreated control. The CJE- and GSE-treated groups were more resistant to digestion than the GTE- or EDC/NHS-treated ones (p < 0.05), which was consistent with the cross-linking interaction found with FTIR and the in situ performance on the acid-etched dentin surface found with SEM/TEM. The collagen films treated with CJE showed the lowest MMP activity, followed by GSE, GTE, and, finally, EDC/NHS. The CJE-treated dentin collagen rapidly increased its resistance to digestion and MMP inhibition. An application of CJE as short as 30 s may be a clinically feasible approach to improving the longevity of dentin bonding in composite restorations.