Probiotic Mixture Ameliorates a Diet-Induced MASLD/MASH Murine Model through the Regulation of Hepatic Lipid Metabolism and the Gut Microbiome.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disease that has no effective treatment. Our proprietary probiotic mixture, Prohep, has been proven in a previous study to be helpful in reducing hepatocellular carcinoma (HCC) in vivo. However, its prospective benefits on the treatment of other liver diseases such as MASLD, which is one of the major risk factors in the development of HCC, are unclear. To investigate the potential of Prohep in modulating the development and progression of MASLD, we first explored the effect of Prohep supplementation via voluntary intake in a high-fat diet (HFD)-induced MASLD/metabolic dysfunction-associated steatohepatitis (MASH) murine model. Our results indicated that Prohep alleviated HFD-induced liver steatosis and reduced excessive hepatic lipid accumulation and improved the plasma lipid profile when compared with HFD-fed control mice through suppressing hepatic de novo lipogenesis and cholesterol biosynthesis gene expressions. In addition, Prohep was able to modulate the gut microbiome, modify the bile acid (BA) profile, and elevate fecal short-chain fatty acid (SCFA) levels. Next, in a prolonged HFD-feeding MASLD/MASH model, we observed the effectiveness of Prohep in preventing the transition from MASLD to MASH via amelioration in hepatic steatosis, inflammation, and fibrosis. Taken together, Prohep could ameliorate HFD-induced MASLD and control the MASLD-to-MASH progression in mice. Our findings provide distinctive insights into the development of novel microbial therapy for the management of MASLD and MASH.

Dual functional roles of nutritional additives in nutritional fortification and safety of thermally processed food: Potential, limitations, and perspectives.

The Maillard reaction (MR) has been established to be a paramount contributor to the characteristic sensory property of thermally processed food products. Meanwhile, MR also gives rise to myriads of harmful byproducts (HMPs) (e.g., advanced glycation end products (AGEs) and acrylamide). Nutritional additives have attracted increasing attention in recent years owing to their potential to simultaneously improve nutritional quality and attenuate HMP formation. In this manuscript, a brief overview of various nutritional additives (vitamins, minerals, fatty acids, amino acids, dietary fibers, and miscellaneous micronutrients) in heat-processed food is provided, followed by a summary of the formation mechanisms of AGEs and acrylamide highlighting the potential crosstalk between them. The main body of the manuscript is on the capability of nutritional additives to modulate AGE and acrylamide formation besides their traditional roles as nutritional enhancers. Finally, limitations/concerns associated with their use to attenuate dietary exposure to HMPs and future perspectives are discussed. Literature data support that through careful control of the addition levels, certain nutritional additives possess promising potential for simultaneous improvement of nutritional value and reduction of AGE and acrylamide content via multiple action mechanisms. Nonetheless, there are some major concerns that may limit their wide applications for achieving such dual functions, including influence on sensory properties of food products, potential overestimation of nutrition enhancement, and introduction of hazardous alternative reaction products or derivatives. These could be overcome through comprehensive assay of dose-response relationships and systematic evaluation of the diverse combinations from the same and/or different categories of nutritional additives to establish synergistic mixtures.

A review of using Traditional Chinese Medicine in the management of glaucoma and cataract.

Traditional Chinese Medicine has a long history in ophthalmology in China. Over 250 kinds of Traditional Chinese Medicine have been recorded in ancient books for the management of eye diseases, which may provide an alternative or supplement to current ocular therapies. However, the core holistic philosophy of Traditional Chinese Medicine that makes it attractive can also hinder its understanding from a scientific perspective - in particular, determining true cause and effect. This review focused on how Traditional Chinese Medicine could be applied to two prevalent ocular diseases, glaucoma, and cataract. The literature on preclinical and clinical studies in both English and Chinese on the use of Traditional Chinese Medicine to treat these two diseases was reviewed. The pharmacological effects, safety profile, and drug-herb interaction of selected herbal formulas were also investigated. Finally, key considerations for conducting future Traditional Chinese Medicine studies are discussed.

Liquiritin apioside alleviates colonic inflammation and accompanying depression-like symptoms in colitis by gut metabolites and the balance of Th17/Treg.

BACKGROUND: Inflammatory bowel disease (IBD) is a significant global health concern that can lead to depression in affected patients. Liquiritin apioside (LA) possesses anti-oxidative and anti-inflammatory properties. However, its anti-inflammatory mechanism in IBD has not been extensively studied. PURPOSE: This study elucidates the pivotal role of LA in alleviating inflammation by regulating gut metabiota-derived metabolites and evaluating its regulative effects on promoting a balance of Th17/Treg cells in colitis mice. METHODS: To evaluate the effect of LA on IBD,16S rRNA gene sequencing and UPLC-QTOF-MS analysis were used to identify the changes of intestinal bacteria and their metabolites. Cytokines levels were determined by ELISA and qPCR, while immune cell ratios were evaluated via flow cytometry. RESULTS: Our findings revealed that LA treatment ameliorated general states of DSS-induced colitis mice and their accompanying depressive behaviors. Moreover, LA restricted the expression of pro-inflammatory cytokines and revised the imbalanced Treg/Th17 differentiation, while promoting SCFAs production in inflamed colon tissues. Fecal microbiota transplantation from LA-fed mice also corrected the imbalanced Treg/Th17 differentiation, indicating that LA-mediated restoration of the colonic Treg/Th17 balance mainly depends on the changes in gut metabolites. CONCLUSION: These results provide scientific evidence explaining the apparent paradox of low bioavailability and high bioactivity in polyphenols, and suggesting that LA could be used as a potential dietary supplement for the prevention and improvement of IBD.

Biological Activities of p-Hydroxycinnamic Acids in Maintaining Gut Barrier Integrity and Function.

It is well established that p-Hydroxycinnamic acids (HCAs), including ferulic, caffeic, sinapic, and p-coumaric acids, possess a characteristic phenylpropanoid C6-C3 backbone and account for about one-third of the phenolic compounds in our diet. HCAs are typically associated with various plant cell wall components, including mono-, di-, and polysaccharides, sterols, polyamines, glycoproteins, and lignins. Interestingly, enzymes produced by intestinal microbes liberate HCAs from these associations. HCAs are completely absorbed in their free form upon ingestion and undergo specific reactions upon absorption in the small intestine or liver. The gut epithelium, composed of intestinal epithelial cells (IECs), acts as a physical barrier against harmful bacteria and a site for regulated interactions between bacteria and the gut lumen. Thus, maintaining the integrity of the epithelial barrier is essential for establishing a physiochemical environment conducive to homeostasis. This review summarizes the protective effects of HCAs on the intestinal barrier, achieved through four mechanisms: preserving tight junction proteins (TJPs), modulating pro-inflammatory cytokines, exerting antioxidant activity, and regulating the intestinal microbiota.

Mechanistic insights into zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches.

Zearalenone (ZEA), a secondary metabolite of Fusarium fungi found in cereal-based foods, promotes the growth of colon, breast, and prostate cancer cells in vitro. However, the lack of animal studies hinders a deeper mechanistic understanding of the cancer-promoting effects of ZEA. This study aimed to determine the effect of ZEA on colon cancer progression and its underlying mechanisms. Through integrative analyses of transcriptomics, metabolomics, metagenomics, and host phenotypes, we investigated the impact of a 4-week ZEA intervention on colorectal cancer in xenograft mice. Our results showed a twofold increase in tumor weight with the 4-week ZEA intervention. ZEA exposure significantly increased the mRNA and protein levels of BEST4, DGKB, and Ki67 and the phosphorylation levels of ERK1/2 and AKT. Serum metabolomic analysis revealed that the levels of amino acids, including histidine, arginine, citrulline, and glycine, decreased significantly in the ZEA group. Furthermore, ZEA lowered the alpha diversity of the gut microbiota and reduced the abundance of nine genera, including Tuzzerella and Rikenella. Further association analysis indicated that Tuzzerella was negatively associated with the expression of BEST4 and DGKB genes, serum uric acid levels, and tumor weight. Additionally, circulatory hippuric acid levels positively correlated with tumor weight and the expression of oncogenic genes, including ROBO3, JAK3, and BEST4. Altogether, our results indicated that ZEA promotes colon cancer progression by enhancing the BEST4/AKT/ERK1/2 pathway, lowering circulatory amino acid concentrations, altering gut microbiota composition, and suppressing short chain fatty acids production.

Metabolic fate of black raspberry polyphenols in association with gut microbiota of different origins in vitro.

Polyphenols, ubiquitous in plant-originated foods, exhibit multifarious health benefits but are notorious for their low bioavailability. As the majority of polyphenols enter the colon where they are metabolized into the more bioavailable metabolites with multifarious bioactivities, gut microbiota composition is critical for realizing the health benefits of polyphenols. Black raspberries (BRB) are highly abundant in health-promoting but poorly absorbable polyphenols, primarily ellagitannins and anthocyanins. This study aimed to dissect the bilateral interactions between polyphenols and gut microbiotas of diverse origins. Using an optimized extraction procedure, BRB polyphenols were first comprehensively characterized by UHPLC-QTOF-MS/MS. Next, in vitro anaerobic fermentations with microbiota from human adults, infants, rats, and mice were conducted for comparison of phenolic profile (by metabolomics) and microbiota composition (by 16S rDNA sequencing) before and after fermentation. Bioinformatics analysis further revealed unique polyphenol-microbiota interactions and identified several bacterial species that could potentially produce bioactive and bioavailable phenolic metabolites following BRB consumption.

Origin and Fate of Acrolein in Foods.

Acrolein is a highly toxic agent that may promote the occurrence and development of various diseases. Acrolein is pervasive in all kinds of foods, and dietary intake is one of the main routes of human exposure to acrolein. Considering that acrolein is substantially eliminated after its formation during food processing and re-exposed in the human body after ingestion and metabolism, the origin and fate of acrolein must be traced in food. Focusing on molecular mechanisms, this review introduces the formation of acrolein in food and summarises both in vitro and in vivo fates of acrolein based on its interactions with small molecules and biomacromolecules. Future investigation of acrolein from different perspectives is also discussed.

Carotenoids and Vitamin A in Breastmilk of Hong Kong Lactating Mothers and Their Relationships with Maternal Diet.

Carotenoids and vitamin A are nutrients crucial to infants' development. To date, there is limited data on their availability in breastmilk and the associated dietary factors, especially in Hong Kong, where people follow a westernized Chinese diet. This study determined the selected breastmilk's carotenoid and vitamin A (retinol) contents by ultraperformance liquid chromatography with photodiode detection (UPLC-PDA) and the dietary intakes by three-day food records in 87 Hong Kong lactating mothers, who were grouped into tertiles based on their daily carotenoid intake. Low vitamin A intake (530.2 ± 34.2 µg RAE/day) and breastmilk retinol level (1013.4 ± 36.8 nmol/L) were reported in our participants, suggesting a poor vitamin A status of the lactating participants having relatively higher socioeconomic status in Hong Kong. Mothers in the highest tertile (T3) had higher breastmilk carotenoid levels than those in the lowest (T1) (p < 0.05). There were significant associations between maternal carotenoid intakes and breastmilk lutein levels in the linear regression models (p < 0.05) regardless of dietary supplement intake. Furthermore, maternal dark green vegetable intakes were associated with breastmilk retinol, lutein, and ß-carotene levels. These findings can serve as dietary references for lactating mothers to enhance breastmilk carotenoid and vitamin A contents for the benefits of child growth and development.

Changes in polyphenol serum levels and cognitive performance after dietary supplementation with Concord grape juice in veterans with Gulf War Illness.

AIMS: We investigated whether the consumption of Concord grape juice (CGJ) was associated with increased bioavailability of serum metabolites and their potential impact on cognitive performance in Veterans with Gulf War Illness (GWI). MAIN METHODS: Twenty-six veterans were selected from a cohort of 36 enrolled in a 24-week randomized, double-blind, Phase I/IIA clinical trial exploring whether the consumption of Concord grape juice (CGJ) was tolerable and safe in Veterans with GWI and improved cognitive function and fatigue. These 26 veterans were selected based on their completion of the entire 24-week protocol and documented adherence to the study beverage ≥80%. Differences in serum metabolite levels between CGJ and placebo at midpoint and endpoint were evaluated using two-way repeated measures ANOVA with post hoc Sidak's multiple comparison test. Bivariate correlations to assess for possible relationships between change in serum metabolite levels and change in cognitive function as measured by the Halstead Category Test-Russell Revised Version (RCAT) were also conducted. KEY FINDINGS: Seventy-six metabolites were identified and quantified in this study, with three (cyanidin-glucuronide, me-cyanidin-glucuronide, and me-malvidin-glucuronide) found to be significantly higher (p < 0.05) in the CGJ group compared to placebo at 24 weeks. Significant associations between changes in cognitive function and changes in serum levels of epicatechin-sulphate (r = 0.48, p = 0.01) and petunidin-glucuronide (r = 0.53, p < 0.01) from baseline to 24 weeks were also observed. SIGNIFICANCE: Our data suggest that dietary supplementation with CGJ is associated with increased bioavailability of specific phenolic metabolites, some of which may be correlated with cognitive performance.

Levels of polyphenols and phenolic metabolites in breast milk and their association with plant-based food intake in Hong Kong lactating women.

Dietary polyphenols are phytonutrients exhibiting multiple health benefits in humans including those in infants. However, data on breast milk (poly)phenolic composition are limited, especially among Asian populations. This study aimed to assess the levels of dietary polyphenols and their microbial-derived metabolites in the breast milk of Hong Kong lactating women, and how maternal diet correlated with the phenolic composition in breast milk. Breast milk samples from 89 healthy Hong Kong lactating women (aged 19-40 years) were collected. Maternal intake of plant-based foods and polyphenols was estimated through 3-day dietary records and the Phenol-Explorer database. Twelve commonly consumed polyphenols including their microbial-derived metabolites in breast milk were quantified using an optimized and validated UHPLC-MS/MS method. The effect of maternal intake on breast milk phenolic levels was then examined via the Pearson correlation test. The mean concentrations of individual phenolic compounds ranged from 5.1 nmol L-1 (chlorogenic acid) to 731.5 nmol L-1 (3,4-dihydroxybenzoic acid). Despite suboptimal intake of fruits and vegetables among our participants, breast milk phenolic levels were comparable to those of foreign populations. Significant correlations were found between dietary intake and multiple phenolics, particularly legume and daidzein (r = 0.33, P = 0.001), and tea and epicatechin (r = 0.30, P = 0.03). Regarding phenolic metabolites, 3,4-dihydroxyphenylacetic acid was significantly correlated with several polyphenols, particularly quercetin (r = 0.34, P = 0.002), and equol was exclusively correlated with daidzein (r = 0.46, P < 0.001). Our findings support that intake of plant-based foods significantly affects breast milk phenolic composition. Future investigation on the bioavailability and health outcomes in infants is warranted to substantiate the transferability of these bioactive phytonutrients from mother to child through lactation, and to promote maternal intake of polyphenol-rich foods.

Development and validation of a micro-QuEChERS method with high-throughput enhanced matrix removal followed with UHPLC-QqQ-MS/MS for analysis of raspberry ketone-related phenolic compounds in adipose tissues.

Raspberry ketone (RK) is a major flavor compound in red raspberries, and it has been marketed as a popular weight-loss dietary supplement with high potential in accumulating in fatty tissues. However, challenges in extracting and characterizing RK and its associated phenolic compounds in fatty tissues persist due to the complex matrix effect. In this work, we reported a high-throughput sample preparation method for RK and 25 related phenolic compounds in white adipose tissues using an improved micro-scale QuEChERS (quick, efficient, cheap, easy, rugged and safe) approach with enhanced matrix removal (EMR)-lipid cleanup in 96-well plates, followed by UHPLC-QqQ-MS/MS analysis. The absolute recovery was 73-105% at the extraction step, and achieved 71-96% at the EMR cleanup step. The EMR cleanup removed around 66% of total lipids in the acetonitrile extract as profiled by UHPLC-QTOF-MS/MS. The innovative introduction of a reversed-phase C18 sorbent into the extract significantly improved the analytes' recovery during SpeedVac drying. The final accuracy achieved 80-120% for most analytes. Overall, this newly developed and validated method could serve as a powerful tool for analyzing RK and related phenolic compounds in fatty tissues.

Optimization of probiotic therapeutics using machine learning in an artificial human gastrointestinal tract.

The gut microbiota's metabolome is composed of bioactive metabolites that confer disease resilience. Probiotics' therapeutic potential hinges on their metabolome altering ability; however, characterizing probiotics' metabolic activity remains a formidable task. In order to solve this problem, an artificial model of the human gastrointestinal tract is introduced coined the ABIOME (A Bioreactor Imitation of the Microbiota Environment) and used to predict probiotic formulations' metabolic activity and hence therapeutic potential with machine learning tools. The ABIOME is a modular yet dynamic system with real-time monitoring of gastrointestinal conditions that support complex cultures representative of the human microbiota and its metabolome. The fecal-inoculated ABIOME was supplemented with a polyphenol-rich prebiotic and combinations of novel probiotics that altered the output of bioactive metabolites previously shown to invoke anti-inflammatory effects. To dissect the synergistic interactions between exogenous probiotics and the autochthonous microbiota a multivariate adaptive regression splines (MARS) model was implemented towards the development of optimized probiotic combinations with therapeutic benefits. Using this algorithm, several probiotic combinations were identified that stimulated synergistic production of bioavailable metabolites, each with a different therapeutic capacity. Based on these results, the ABIOME in combination with the MARS algorithm could be used to create probiotic formulations with specific therapeutic applications based on their signature metabolic activity.

Microbiota metabolites modulate the T helper 17 to regulatory T cell (Th17/Treg) imbalance promoting resilience to stress-induced anxiety- and depressive-like behaviors.

Chronic stress disrupts immune homeostasis while gut microbiota-derived metabolites attenuate inflammation, thus promoting resilience to stress-induced immune and behavioral abnormalities. There are both peripheral and brain region-specific maladaptations of the immune response to chronic stress that produce interrelated mechanistic considerations required for the design of novel therapeutic strategies for prevention of stress-induced psychological impairment. This study shows that a combination of probiotics and polyphenol-rich prebiotics, a synbiotic, attenuates the chronic-stress induced inflammatory responses in the ileum and the prefrontal cortex promoting resilience to the consequent depressive- and anxiety-like behaviors in male mice. Pharmacokinetic studies revealed that this effect may be attributed to specific synbiotic-produced metabolites including 4-hydroxyphenylpropionic, 4-hydroxyphenylacetic acid and caffeic acid. Using a model of chronic unpredictable stress, behavioral abnormalities were associated to strong immune cell activation and recruitment in the ileum while inflammasome pathways were implicated in the prefrontal cortex and hippocampus. Chronic stress also upregulated the ratio of activated proinflammatory T helper 17 (Th17) to regulatory T cells (Treg) in the liver and ileum and it was predicted with ingenuity pathway analysis that the aryl hydrocarbon receptor (AHR) could be driving the synbiotic's effect on the ileum's inflammatory response to stress. Synbiotic treatment indiscriminately attenuated the stress-induced immune and behavioral aberrations in both the ileum and the brain while in a gut-immune co-culture model, the synbiotic-specific metabolites promoted anti-inflammatory activity through the AHR. Overall, this study characterizes a novel synbiotic treatment for chronic-stress induced behavioral impairments while defining a putative mechanism of gut-microbiota host interaction for modulating the peripheral and brain immune systems.

Prophylactic effect of flavanol rich preparation metabolites in promoting resilience to a mouse model of social stress.

Major depressive disorder (MDD) is a leading cause of disability, and there is an urgent need for new therapeutics. Stress-mediated induction of pro-inflammation in the periphery contributes to depression-like behaviors both in humans and in experimental models. Inflammatory cytokine interleukin-6 (IL-6) has emerged as a potential therapeutic target. Our studies demonstrated that metabolism of flavanol rich cocoa preparation (FRP) led to the accumulation of select phenolic acids that may contribute to its anti-inflammatory activity. Using a repeated social defeat stress (RSDS) model of depression, we showed that oral administration of FRP attenuates susceptibility to RSDS-mediated depression, supporting the further development of FRP as a novel therapeutic for the treatment of stress disorders and anxiety in humans.

UHPLC-QqQ-MS/MS method development and validation with statistical analysis: Determination of raspberry ketone metabolites in mice plasma and brain.

Raspberry ketone (RK) (4-(4-hydroxyphenyl)-2-butanone) is the major compound responsible for the characteristic aroma of red raspberries, and has long been used commercially as a flavoring agent and recently as a weight loss supplement. A targeted UHPLC-QqQ-MS/MS method was developed and validated for analysis of RK and 25 associated metabolites in mouse plasma and brain. Dispersion and projection analysis and central composite design were used for method optimization. Random effect analysis of variance was applied for validation inference and variation partition. Within this framework, repeatability, a broader sense of precision, was calculated as fraction of accuracy variance, reflecting instrumental imprecision, compound degradation and carry-over effects. Multivariate correlation analysis and principle component analysis were conducted, revealing underlying association among the manifold of method traits. R programming was engaged in streamlined statistical analysis and data visualization. Two particular phenomena, the analytes' background existence in the enzyme solution used for phase II metabolites deconjugation, and the noted lability of analytes in pure solvent at 4 ℃ vs. elevated stability in biomatrices, were found critical to method development and validation. The approach for the method development and validation provided a foundation for experiments that examine RK metabolism and bioavailability.

Influence of Diet-Induced Obesity on the Bioavailability and Metabolism of Raspberry Ketone (4-(4-Hydroxyphenyl)-2-Butanone) in Mice.

OBJECTIVES: Raspberry ketone (RK) is the primary aroma compound in red raspberries and a dietary supplement for weight loss. This work aims to 1) compare RK bioavailability in male versus female, normal-weight versus obese mice; 2) characterize RK metabolic pathways. METHODS: Study 1: C57BL/6J male and female mice fed a low-fat diet (LFD; 10% fat) receive a single oral gavage dose of RK (200 mg kg-1 ). Blood, brain, and white adipose tissue (WAT) are collected over 12 h. Study 2: Male mice are fed a LFD or high-fat diet (45% fat) for 8 weeks before RK dosing. Samples collected are analyzed by UPLC-MS/MS for RK and its metabolites. RESULTS: RK is rapidly absorbed (Tmax  ≈ 15 min), and bioconverted into diverse metabolites in mice. Total bioavailability (AUC0-12 h ) is slightly lower in females than males (566 vs 675 nmol mL-1 min-1 ). Total bioavailability in obese mice is almost doubled that of control mice (1197 vs 679 nmol mL-1 min-1 ), while peaking times and elimination half-lives are delayed. Higher levels of RK and major metabolites are found in WAT of the obese than normal-weight animals. CONCLUSIONS: RK is highly bioavailable, rapidly metabolized, and exhibits significantly different pharmacokinetic behaviors between obese and control mice. Lipid-rich tissues, especially WAT, can be a direct target of RK.

Pine Bark Polyphenolic Extract Attenuates Amyloid-ß and Tau Misfolding in a Model System of Alzheimer's Disease Neuropathology.

Plant-derived polyphenolic compounds possess diverse biological activities, including strong anti-oxidant, anti-inflammatory, anti-microbial, and anti-tumorigenic activities. There is a growing interest in the development of polyphenolic compounds for preventing and treating chronic and degenerative diseases, such as cardiovascular disorders, cancer, and neurological diseases including Alzheimer's disease (AD). Two neuropathological changes of AD are the appearance of neurofibrillary tangles containing tau and extracellular amyloid deposits containing amyloid-ß protein (Aß). Our laboratory and others have found that polyphenolic preparations rich in proanthocyanidins, such as grape seed extract, are capable of attenuating cognitive deterioration and reducing brain neuropathology in animal models of AD. Oligopin is a pine bark extract composed of low molecular weight proanthocyanidins oligomers (LMW-PAOs), including flavan-3-ol units such as catechin (C) and epicatechin (EC). Based on the ability of its various components to confer resilience to the onset of AD, we tested whether oligopin can specifically prevent or attenuate the progression of AD dementia preclinically. We also explored the underlying mechanism(s) through which oligopin may exert its biological activities. Oligopin inhibited oligomer formation of not only Aß1-40 and Aß1-42, but also tau in vitro. Our pharmacokinetics analysis of metabolite accumulation in vivo resulted in the identification of Me-EC-O-ß-Glucuronide, Me-(±)-C-O-ß-glucuronide, EC-O-ß-glucuronide, and (±)-C-O-ß-glucuronide in the plasma of mice. These metabolites are primarily methylated and glucuronidated C and EC conjugates. The studies conducted provide the necessary impetus to design future clinical trials with bioactive oligopin to prevent both prodromal and residual forms of AD.

A critical review on grape polyphenols for neuroprotection: Strategies to enhance bioefficacy.

The aging of populations worldwide is driving greater demands for dietary polyphenols which have been recognized as promising prophylactic and/or therapeutic agents in the context of neurodegeneration, and are ubiquitously present in plant-based diets. In particular, grape-derived products encompass a wide array of phenolic compounds purported with multiple health benefits including neuroprotective efficacy. Despite the increasing preclinical and clinical evidence demonstrating high potential of grape polyphenol (GPP)-rich botanicals in preventing and attenuating diverse neurodegenerative disorders, the limited bioavailability of GPPs, especially in the brain, generates questions as to their applications and effectiveness in neuroprotection. To address this issue, significant research efforts have been made to enhance oral bioavailability of GPPs via application of novel strategies. This review highlights some critical issues related to the bioavailability and neuroprotective efficacy of GPPs and GPP-rich botanicals. The representative bioavailability-enhancing strategies are critically reviewed to provide practical solutions for augmenting the bioefficacy of GPP-rich botanicals. Synergistic applications of encapsulation techniques (for physiochemical protection and bypassing xenobiotic metabolism) and dietary intervention strategies involving modulation of gut microbiota (for generating more bioavailable phenolic metabolites) appear promising, and may substantially enhance the bioefficacy, especially the neuroprotective efficacy, of orally consumed GPPs.

A highly sensitive ultra-high performance liquid chromatography/tandem mass spectrometry method with in-source fragmentation for rapid quantification of raspberry ketone.

Raspberry ketone (RK) is the characteristic aromatic compound in raspberry (Rubus idaeus L.) with wide applications as food additive and anti-obesity agent. However, quantification of RK has presented difficulties in MS detection and reliable LC-MS method for RK analysis in literature is in limit to date. In order to facilitate quality control of raspberry derived products and RK metabolomics study, this study aimed to develop a validated and sensitive UHPLC-MS/MS method. Strong in-source fragmentation was noted and the fragmental ion of 107 m/z produced was selected as the precursor ion for MRM detection, and as such the electrospray ionization performance was optimized by fractional factorial design to accommodate such ion-source dissociation behavior as well as its moderate volatility. A pathway involving the formation of quinone-like structure with strong conjugation was proposed to explain the intense in-source fragmentation. The MRM transition was optimized with product ion of 77 m/z selected as the quantifier ion. The method featured low limit of quantification of ∼2 ng/mL and allowed for rapid detection of RK in fresh raspberries following direct sample preparation. RK contents were found to be higher from locally grown and harvested farm sources compared to commercial products shipped into the state, and higher in those at late-stage compared with early-stage maturity. No correlations in RK content between organic and non-organic labels were noted.