Search Results (16)

Background: Gingival inflammation is highly prevalent and may impact systemic health. While professional mechanical plaque removal (PMPR) is the standard treatment, dietary interventions may provide additional benefits. The French maritime pine bark extract Pycnogenol^® has anti-inflammatory and antioxidant properties, but its impact on inflammatory biomarkers in saliva and serum has not been studied in a controlled clinical trial. Methods: In this randomized, double-blind, placebo-controlled clinical trial, 91 participants received Pycnogenol^® (100 mg twice daily; n = 46) or a placebo (n = 45) following PMPR. Saliva and serum samples were collected at baseline, and after two and three months. Inflammatory biomarkers (IL-1β, IL-6, MMP-8, and MMP-9) and polyphenol concentrations were analyzed using ELISA and LC-MS/MS. Results: Pycnogenol^® supplementation significantly reduced salivary MMP-8 levels (p = 0.0261), and serum IL-6 levels compared to placebo (p = 0.0409). Additionally, ferulic acid, caffeic acid, and the gut microbial metabolite 5-(3,4-dihydroxyphenyl)-γ-valerolactone (M1) significantly increased in saliva following Pycnogenol^® intake. A correlation analysis revealed a significant inverse association between bleeding on probing and M1 concentration in saliva (r = −0.3476, p = 0.0167). Conclusions: Dietary supplementation with Pycnogenol^® significantly reduced key inflammatory biomarkers and increased polyphenol concentrations in saliva, suggesting a potential anti-inflammatory effect of Pycnogenol^® on gingival inflammation. Trial registration: ClinicalTrials.gov (NCT05786820). Full article

Background/Objectives: 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone (γ-VL), recently identified as a predominant microbial metabolite derived from proanthocyanidins, offers benefits such as reducing inflammation, oxidative stress, and supporting brain health. Its effects on neuroinflammation and microglial activation remain largely unexplored. Curcumin, a bioactive component isolated from Curcuma longa L., is well known for its ability to reduce microglial activation and pro-inflammatory mediator production and release. While the individual effects of γ-VL and curcumin are well documented, their potential combined effects remain unexplored. This research sought to investigate the possible synergistic effects of γ-VL and curcumin in reducing microglial activation. Methods: Primary rat cortical microglia were pre-treated with γ-VL and curcumin, alone or in combination, before stimulation with LPS. An MTT assay was used to evaluate cell viability, while pro-inflammatory mediators were assessed by real-time PCR and ELISA. Nitric oxide production was evaluated with the Griess assay. SynergyFinder Plus software analyzed potential synergistic effects. Results: The combination of low micromolar concentrations of γ-VL and curcumin synergistically reduced LPS-induced microglial activation. Specifically, the combination exhibited a significantly greater ability to inhibit the production and release of pro-inflammatory factors (such as IL-1β, TNF-α, and NO) compared to each compound individually. Mechanistically, the anti-inflammatory activity was attributed to the downregulation of NLRP3 expression, and the reduction in microglial activation was linked to the modulation of the NOX2/Nrf2 signaling pathway. Conclusions: The combination of low micromolar concentrations of γ-VL and curcumin produces synergistic anti-inflammatory effects in microglia by targeting key inflammatory pathways, indicating its potential utility as a treatment strategy for neurodegenerative diseases involving microglial activation. Full article

The anti-oxidative and anti-inflammatory properties of high-density lipoprotein (HDL) are thought to be mediated by paraoxonase 1 (PON1), a calcium-dependent hydrolytic enzyme carried on a subfraction of HDL that also carries other anti-oxidative and anti-inflammatory proteins. In humans and mice, low PON1 activity is associated with elevated oxidized lipids and homocysteine (Hcy)-thiolactone, as well as proteins that are modified by these metabolites, which can cause oxidative stress and inflammation. PON1-dependent metabolic changes can lead to atherothrombotic cardiovascular disease, Alzheimer’s disease, and cancer. The molecular bases underlying these associations are not fully understood. Biochemical, proteomic, and metabolic studies have significantly expanded our understanding of the mechanisms by which low PON1 leads to disease and high PON1 is protective. The studies discussed in this review highlight the changes in gene expression affecting proteostasis as a cause of the pro-oxidative and pro-inflammatory phenotypes associated with attenuated PON1 activity. Accumulating evidence supports the conclusion that PON1 regulates the expression of anti-oxidative and anti-inflammatory proteins, and that the disruption of these processes leads to disease. Full article

Reaction kinetics have been theoretically examined to ascertain the potency of quercetin (Q) and flavonoid catecholic metabolites 1–5 in the inactivation of HOO^•, CH₃OO^•, and O₂^•− under physiological conditions. In lipidic media, the $k_{\mathrm{overall}}^{\mathrm{TST}/\mathrm{Eck}}$ rate constants for the proton-coupled electron transfer (PCET) mechanism indicate the catecholic moiety of Q and 1–5 as the most important in HOO^• and CH₃OO^• scavenging. 5-(3,4-Dihydroxyphenyl)-γ-valerolactone (1) and alphitonin (5) are the most potent scavengers of HOO^• and CH₃OO^•, respectively. The $k_{\mathrm{overall}}^{\mathrm{Mf}}$ rate constants, representing actual behavior in aqueous media, reveal Q as more potent in the inactivation of HOO^• and CH₃OO^• via single electron transfer (SET). SET from 3-O⁻ phenoxide anion of Q, a structural motif absent in 1–5, represents the most contributing reaction path to overall activity. All studied polyphenolics have a potency of O₂^•− inactivation via a concerted two-proton–coupled electron transfer (2PCET) mechanism. The obtained results indicate that metabolites with notable radical scavenging potency, and more bioavailability than ingested flavonoids, may contribute to human health-promoting effects ascribed to parent molecules. Full article

Obesity-related cardiometabolic disorders are driven by inflammation, oxidative stress, and gut dysbiosis. Green tea catechins protect against cardiometabolic disorders by anti-inflammatory, antioxidant, and prebiotic activities. However, whether obesity alters catechin bioavailability remains unknown. We hypothesized that obesity would decrease catechin bioavailability due to altered gut microbiota composition. Obese and healthy persons completed a pharmacokinetics trial in which a confection formulated with green tea extract (GTE; 58% epigallocatechin gallate, 17% epigallocatechin, 8% epicatechin, 6% epicatechin gallate) was ingested before collecting plasma and urine at timed intervals for up to 24 h. Stool samples were collected prior to confection ingestion. Catechins and γ-valerolactones were assessed by LC-MS. Obesity reduced plasma area under the curve (AUC_0-12h) by 24–27% and maximum plasma concentrations by 18–36% for all catechins. Plasma AUC_0-12h for 5′-(3′,4′-dihydroxyphenyl)-γ-valerolactone and 5′-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone, as well as total urinary elimination of all catechins and valerolactones, were unaffected. ⍺-Diversity in obese persons was lower, while Slackia was the only catechin-metabolizing bacteria that was altered by obesity. Ascorbic acid and diversity metrics were correlated with catechin/valerolactone bioavailability. These findings indicate that obesity reduces catechin bioavailability without affecting valerolactone generation, urinary catechin elimination, or substantially altered gut microbiota populations, suggesting a gut-level mechanism that limits catechin absorption. Full article

Oxidative stress and chronic inflammation contribute to some chronic diseases. Aronia berries are rich in polyphenols. The aim of the present study was to characterize the cellular antioxidant effect of an aronia extract to reflect the potential physiological in vivo effect. Cellular in vitro assays in three cell lines (Caco-2, HepG2, and SH-SY5Y) were used to measure the antioxidant effect of AE, in three enriched polyphenolic fractions (A1: anthocyanins and phenolic acids; A2: oligomeric proanthocyanidins; A3: polymeric proanthocyanidins), pure polyphenols and microbial metabolites. Both direct (intracellular and membrane radical scavenging, catalase-like effect) and indirect (NRF2/ARE) antioxidant effects were assessed. AE exerted an intracellular free radical scavenging activity in the three cell lines, and A2 and A3 fractions showed a higher effect in HepG2 and Caco-2 cells. AE also exhibited a catalase-like activity, with the A3 fraction having a significant higher activity. Only A1 fraction activated the NRF2/ARE pathway. Quercetin and caffeic acid are the most potent antioxidant polyphenols, whereas cyanidin and 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone showed the highest antioxidant effect among polyphenol metabolites. AE rich in polyphenols possesses broad cellular antioxidant effects, and proanthocyanidins are major contributors. Polyphenol metabolites may contribute to the overall antioxidant effect of such extract in vivo. Full article

The intestinal absorption of dietary catechins is quite low, resulting in most of them being metabolized by gut microbiota in the colon. It has been hypothesized that microbiota-derived metabolites may be partly responsible for the association between catechin consumption and beneficial cardiometabolic effects. Given the profound differences in gut microbiota composition and microbial load between individuals and across different colon regions, this study examined how microbial (+)-catechin metabolite profiles differ between colon regions and individuals. Batch exploration of the interindividual variability in (+)-catechin microbial metabolism resulted in a stratification based on metabolic efficiency: from the 12 tested donor microbiota, we identified a fast- and a slow-converting microbiota that was subsequently inoculated to SHIME, a dynamic model of the human gut. Monitoring of microbial (+)-catechin metabolites from proximal and distal colon compartments with UHPLC-MS and UPLC-IMS-Q-TOF-MS revealed profound donor-dependent and colon-region-dependent metabolite profiles with 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone being the largest contributor to differences between the fast- and slow-converting microbiota and the distal colon being a more important region for (+)-catechin metabolism than the proximal colon. Our findings may contribute to further understanding the role of the gut microbiota as a determinant of interindividual variation in pharmacokinetics upon (+)-catechin ingestion. Full article

Jaboticaba is a Brazilian native berry described as a rich source of phenolic compounds (PC) with health promoting effects. PC from jaboticaba peel powder (JPP) have low intestinal bio-accessibility and are catabolized by gut microbiota. However, the biological implication of PC-derived metabolites produced during JPP digestion remains unclear. This study aimed to evaluate the antiproliferative effects of colonic fermented JPP (FJPP) in a 3D model of colorectal cancer (CRC) composed by HT29 spheroids. JPP samples fermented with human feces during 0, 2, 8, 24 or 48 h were incubated (10,000 µg mL⁻¹) with spheroids, and cell viability was assessed after 72 h. Chemometric analyses (cluster and principal component analyses) were used to identify the main compounds responsible for the bioactive effect. The antiproliferative effect of FJPP in the CRC 3D model was increased between 8 h and 24 h of incubation, and this effect was associated with HHDP-digalloylglucose isomer and dihydroxyphenyl-γ-valerolactone. At 48 h of fermentation, the antiproliferative effect of FJPP was negligible, indicating that the presence of urolithins did not improve the bioactivity of JPP. These findings provide relevant knowledge on the role of colonic microbiota fermentation to generate active phenolic metabolites from JPP with positive impact on CRC. Full article

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)-γ-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. Full article

Despite numerous reports on the beneficial effects of catechin or epicatechin contained in tea and cacao extract on human health, a conclusive and precise molecular mechanism has not been elucidated. Metabolism of chemical compounds in gut microbiota recently gained significant attention, and extensive studies have been devoted in this field. In conjunction with these results, our group focused on the anti-inflammatory effects of both enantiomers of DHPV (5-(3′,4′-dihydroxyphenyl)-γ-valerolactone), produced in the intestine by microbiota metabolism, on IEC-6 cells. Divergent and efficient enantioselective synthesis of (S)- and (R)-DHPV was efficiently achieved by cross-metathesis and Sharpless asymmetric dihydroxylation as a key reaction for four steps in 16% and 14% overall yields, respectively. The anti-inflammatory effects of two enantiomers were tested on IEC-6 cells, and we found that (S)-DHPV was more active than (R)-DHPV. This result implicates that the metabolite produced in the gut has beneficial effects on IEC-6 cells of rat intestines, and the chirality of the metabolite is important for its anti-inflammatory activity. This also provided information for the future discovery of novel small molecular therapeutics for the treatment of inflammatory bowel disease. Full article

A concise and scalable synthetic route for optically pure (4S) and (4R)-5-(3′,4′-dihydroxyphenyl)-γ-valerolactones (DHPVs), catechin metabolites, has been developed via the efficient construction of a γ-valerolactone moiety from hexenol. Noticeably, the different skin wrinkle-reducing activities of each metabolite were revealed via our unique syntheses of DHPVs in an enantiomerically pure form. Full article

Phenolic compounds have been recognized as promising compounds for the prevention of chronic diseases, including neurodegenerative ones. However, phenolics like flavan-3-ols (F3O) are poorly absorbed along the gastrointestinal tract and structurally rearranged by gut microbiota, yielding smaller and more polar metabolites like phenyl-γ-valerolactones, phenylvaleric acids and their conjugates. The present work investigated the ability of F3O-derived metabolites to cross the blood-brain barrier (BBB), by linking five experimental models with increasing realism. First, an in silico study examined the physical-chemical characteristics of F3O metabolites to predict those most likely to cross the BBB. Some of these metabolites were then tested at physiological concentrations to cross the luminal and abluminal membranes of brain microvascular endothelial cells, cultured in vitro. Finally, three different in vivo studies in rats injected with pure 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone, and rats and pigs fed grapes or a F3O-rich cocoa extract, respectively, confirmed the presence of 5-(hydroxyphenyl)-γ-valerolactone-sulfate (3′,4′ isomer) in the brain. This work highlighted, with different experimental models, the BBB permeability of one of the main F3O-derived metabolites. It may support the neuroprotective effects of phenolic-rich foods in the frame of the “gut-brain axis”. Full article

Flavan-3-ols are dietary bioactive molecules that have beneficial effects on human health and reduce the risk of various diseases. Monomeric flavan-3-ols are rapidly absorbed in the small intestine and released in the blood stream as phase II conjugates. Polymeric flavan-3-ols are extensively metabolized by colonic gut microbiota into phenyl-γ-valerolactones and their related phenylvaleric acids. These molecules are the main circulating metabolites in humans after the ingestion of flavan-3-ol rich-products; nevertheless, they have received less attention and their role is not understood yet. Here, we describe the quantification of 8 phenyl-γ-valerolactones and 3 phenylvaleric acids in the urine of 11 subjects on consumption of apples by using UHPLC-ESI-Triple Quad-MS with pure reference compounds. Phenyl-γ-valerolactones, mainly as sulfate and glucuronic acid conjugates, reached maximum excretion between 6 and 12 after apple consumption, with a decline thereafter. Significant differences were detected in the cumulative excretion rates within subjects and in the ratio of dihydroxyphenyl-γ-valerolactone sulfate to glucuronide conjugates. This work observed for the first time the presence of two distinct metabotypes with regards to the excretion of phenyl-γ-valerolactone phase II conjugates. Full article

Over the last three decades, green tea has been studied for its beneficial effects, including anti-cancer, anti-obesity, anti-diabetes, anti-inflammatory, and neuroprotective effects. At present, a number of studies that have employed animal, human and cell cultures support the potential neuroprotective effects of green tea catechins against neurological disorders. However, the concentration of (−)-epigallocatechin gallate (EGCG) in systemic circulation is very low and EGCG disappears within several hours. EGCG undergoes microbial degradation in the small intestine and later in the large intestine, resulting in the formation of various microbial ring-fission metabolites which are detectable in the plasma and urine as free and conjugated forms. Recently, in vitro experiments suggested that EGCG and its metabolites could reach the brain parenchyma through the blood–brain barrier and induce neuritogenesis. These results suggest that metabolites of EGCG may play an important role, alongside the beneficial activities of EGCG, in reducing neurodegenerative diseases. In this review, we discuss the function of EGCG and its microbial ring-fission metabolites in the brain in suppressing brain dysfunction. Other possible actions of EGCG metabolites will also be discussed. Full article

Several metabolomics of polymeric flavan-3-ols have reported that proanthocyanidins are extensively metabolized by gut microbiota. 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone (DHPV) has been reported to be the major microbial metabolite of proanthocyanidins. We demonstrated that DHPV has stronger prevention effect on tumor necrosis factor (TNF)-α-stimulated adhesion of THP-1 human monocytic cells to human umbilical vein endothelial cells compared to its potential precursors such as procyanidin A1, A2, B1 and B2, (+)catechin, (−)epicatechin and its microbial metabolites such as 3-(3,4-dihydroxyphenyl)propionic acid and 2-(3,4-dihydroxyphenyl)acetic acid. Mechanism study showed that DHPV prevents THP-1 monocyte-endothelial cell adhesion by downregulating TNF-α-stimulated expressions of the two biomarkers of atherosclerosis such as vascular cell adhesion molecule-1 and monocyte chemotactic protein-1, activation of nuclear factor kappa B transcription and phosphorylation of I kappa-B kinase and IκBα. We suggested that DHPV has higher potentiality in prevention of atherosclerosis among the proanthocyanidin metabolites. Full article