Background With aging population, the prevalence of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), is on the rise. Numerous studies have found that blueberries, rich in polyphenols, have promising neuroprotective effects, but the underlying mechanisms remain unclear. Objective This review summarizes the neuroprotective mechanisms and potential effects of blueberry polyphenols in AD and PD based on in vitro , in vivo , preclinical, and clinical studies. Key findings Blueberries exert multi-targeted effects by reducing oxidative stress (activation of the Nrf2/MAPK pathway), suppressing neuroinflammation (inhibiting microglial activity), and enhancing neuroplasticity (upregulation of the ERK/CREB/BDNF pathway). In preclinical studies, these mechanisms reduce Aβ deposition and tau tangles in AD models and protect dopaminergic neurons in PD models. Limited clinical trials have found that blueberry supplementation can improve executive function, memory, and processing speed in older adults with cognitive decline. Conclusion Blueberries show potential as an early dietary intervention strategy for AD and PD. However, current clinical trials lack sufficient understanding of the bioavailability of blueberry's active components, interindividual metabolic differences, and specific targets of action. Future research should include larger-scale, long-term early intervention trials.

BACKGROUND:Periodontitis is a prevalent chronic inflammatory disease in older adults, often linked to systemic conditions and metabolic alterations. Standardized plant extracts may provide consistent adjunctive therapeutic benefits. PURPOSE AND STUDY DESIGN:This double-blind, randomized, placebo-controlled clinical trial (OLIVAGING; ClinicalTrials.gov: NCT05482373) evaluated whether a standardized olive leaf extract enriched to 40 % oleuropein, given in addition to non-surgical periodontal therapy, improves clinical outcomes and modulates systemic metabolism. Sixty participants aged ≥50 years were randomized to receive either supplement or placebo for 120 days. Primary and secondary outcomes were probing pocket depth (PPD) and clinical attachment level (CAL). Plasma metabolomics was performed using untargeted UHPLC-QTOF-MS. RESULTS:Forty-three participants completed the study (23 treatment, 20 placebo). Compared with placebo, the treatment group achieved greater reductions in ΔPPD and gains in ΔCAL across multiple tooth categories and surfaces. Metabolomic profiling revealed distinct Δ patterns, with 17 metabolites differing between groups. Several, including tentatively identified valine, cinnamic acid, 10‑hydroxy-2-decenoic acid, and cortisol, correlated with periodontal improvements, suggesting modulation of biological pathways related to inflammation, oxidative stress, and tissue homeostasis consistent with the know pharmacological effects of oleuropein. CONCLUSIONS:Adjunctive use of an oleuropein-enriched leaf extract improved clinical periodontal outcomes and modulated systemic metabolic signatures in older adults. The standardized extract ensured therapeutic consistency, while metabolomics provided mechanistic insights into host inflammatory and metabolic responses. Findings support further evaluation of plant-derived bioactives as safe, multi-target adjunctive strategies for periodontitis management.

Background/Objectives: Conventional pharmacotherapy for the most prevalent human diseases still has limited efficacy. Natural medicines are recognized for their therapeutic efficacy and low side effects. Tamarindus indica is a tropical tree of the Fabaceae family, valued for its multiple uses and the nutritional properties of its fruits. The purpose of this review is to provide an overview of the nutraceutical value of T. indica, focusing on its phytochemical composition and main health benefits. Methods: For this purpose, a bibliography search was performed in PubMed, Scopus, and ScienceDirect databases, including all articles published between 2000 and December 2025. Results: The T. indica fruit contains different phytochemical compounds, such as flavonoids, tannins, alkaloids, and saponins, with therapeutic potential. These compounds exert free radical scavenging activity, improve antioxidant and detoxification enzyme activities, exert antimicrobial effects, attenuate the activation of pro-inflammatory mediators, and regulate the expression of lipid metabolism genes. Conclusions: This article presents an integrated analysis summarizing the phytochemical characteristics, mode of action, medical utility, and safe use of T. indica, thereby contributing to a greater understanding of its potential health benefits.

The oral microbiota represents a complex and dynamic microbial ecosystem that plays a critical role in preserving both oral and systemic homeostasis. Emerging evidence suggests that alterations in oral microbial milieu (dysbiosis) may contribute to the pathogenesis of neurodegenerative disorders, especially Alzheimer's disease (AD), through the oral-brain axis. This review synthesizes current evidence on the pathways linking oral microbiota to cognitive decline, integrating microbial, immunological, and vascular perspectives. Oral pathogens may access the central nervous system via hematogenous dissemination or neural routes, including the trigeminal nerve, while simultaneously promoting systemic inflammation, immune activation, and blood-brain barrier disruption. These processes converge on key neurodegenerative mechanisms, including chronic neuroinflammation, amyloid-β accumulation, and tau pathology. In parallel, alterations in oral microbial composition have been linked to disease severity, supporting a potential role of dysbiosis in both initiation and progression of cognitive impairment. Diet emerges as a critical modifiable determinant of oral microbial ecology. Diets rich in refined sugars may promote dysbiosis and inflammatory signaling, whereas (poly)phenols, probiotics, and prebiotics may support microbial eubiosis and exert neuroprotective effects through modulation of host-microbe interactions. Although current evidence remains largely observational and mechanistic, the diet-oral microbiota-brain axis represents a promising target for preventive and therapeutic strategies aimed at mitigating cognitive decline and promoting healthy aging. Future longitudinal and interventional studies are required to establish causality and translate these insights into clinical practice.

This review provides a mechanistic synthesis of extracellular vesicles (EVs) in fermented foods, highlighting their emerging role as key bioactive mediators beyond traditional metabolites. EVs originate from both fermentative microorganisms and raw materials, carrying diverse cargos that enable intercellular and cross-kingdom communication. During fermentation, EV characteristics are dynamically modified through microbial-raw material interactions and environmental factors, which regulate EV biogenesis, cargo composition, and functional activity. Mechanistically, fermented food-derived EVs modulate host signaling pathways, thereby influencing immune responses and intestinal barrier function.

Obesity is recognised to be a risk factor for breast cancer since adipose tissue influences the tumour microenvironment. This study aims to investigate the effect of the secretome of 3T3-L1 adipocytes untreated or treated with liquorice root extract (LRE), containing flavonoids, phenolic acids, and saponins on MCF-7 breast cancer cells. By treating adipocytes with LRE, the secretion of certain pro-tumorigenic factors like IGFBP-6, resistin, and VEGF was reduced. MCF-7 cells exposed to conditioned medium from LRE-treated adipocytes exhibited an increase in reactive oxygen species levels, downregulation of the Nrf2 antioxidant pathway, and increased autophagy. Those conditions reduced cell viability, migration, and colony formation. Additionally, there was downregulation of genes associated with oestrogen signalling and tumour-related processes, including CYP19A1 (aromatase), ERα, Her2, and components of the renin-angiotensin system (RAS). These findings suggest that LRE can modulate the adipocyte secretome to influence breast cancer cell behaviour under obesity-related in vitro conditions.

Opuntia ficus-indica peel is known to possess antioxidant, anti-inflammatory, and anticancer activities and currently is discarded or used for animal feeding. Within this context, the aim of this work was to evaluate the antiproliferative and pro-apoptotic effect of purple prickly pear peel extract (PPE) on the human colon adenocarcinoma cancer cell line (HTC116). The methanolic extract of PPE was characterized in terms of betalain and polyphenols as well as total antioxidant capacity. Cell viability, apoptosis induction, cell cycle arrest, and reactive oxygen species (ROS) production assays were performed. Important proteins and genes related to proliferation and apoptosis were determined. PPE represents a good source of bioactive compounds with a high antioxidant capacity. Cell viability was reduced gradually by PPE treatments, with lower effects in nontumorigenic cells. Compared to the control group, a significant induction of apoptosis as well as cell cycle arrest in the sub-G1 phase and ROS production was observed in PPE-treated cells. Furthermore, the treatment induced the overexpression of p53 at protein levels and upregulated the mRNA expression of pro-apoptotic BAX, CASP9, BID, and CYCS, along with the significant decrease of anti-apoptotic BCL2 gene expression. Simultaneously, cyclin D1 and CDK4 gene expression were significantly decreased, while p21 increased considerably. The treatment also induced the downregulation of Her2 and PI3K at protein levels and caused the suppression of PI3KCA and mTOR expression at gene levels. Overall, these findings suggested that PPE has potential anticancer effects against human colon adenocarcinoma progression.

Alzheimer’s disease (AD) is the most prevalent form of dementia and a major global health challenge, characterized by progressive cognitive decline and neurodegeneration. Despite decades of research, there is currently no cure, and available treatments provide only limited symptomatic relief without halting disease progression. In this context, natural compounds with multi-targeted biological activities are being explored as potential complementary therapeutic strategies. Honey, a complex natural substance rich in bioactive phytochemicals, has emerged as a promising candidate due to its antioxidant, anti-inflammatory, anti-apoptotic, and enzyme-inhibitory properties. This review summarizes the molecular mechanisms underlying the neuroprotective effects of honey in the context of AD, with a particular focus on its ability to modulate oxidative stress, mitochondrial dysfunction, inflammation, apoptosis, β-amyloid accumulation, tau hyperphosphorylation, and neurotransmission-related enzymes. Notably, the botanical origin of honey significantly influences its composition and biological activity, as evidenced by studies on avocado, manuka, acacia, kelulut, chestnut, coffee, or tualang honeys. While preclinical findings are encouraging, especially in vitro and in invertebrate and rodent models, clinical validation is still lacking. Therefore, further research, including well-designed in vivo and human studies, is needed to clarify the therapeutic relevance of honey in AD. Overall, honey may represent a promising natural adjunct in the prevention or management of AD, but current evidence remains preliminary.

Background: The gut-brain axis is a complex communication network that connects the gastrointestinal system with the central nervous system, significantly influencing various health outcomes, such as mental health, cognitive function, metabolic regulation, and immune responses. While traditional research models, particularly animal studies, have provided valuable insights, they often overlook the intricate and human-specific interactions within this axis. Consequently, translating findings from these models into clinical applications has been challenging. However, recent advancements in human-based Novel Approach Methodologies (NAMs), like organoids, organs-on-chip, and omic sciences, present innovative tools for investigating the gut-brain axis with improved accuracy and relevance to human physiology. These methodologies facilitate a deeper understanding of the molecular and cellular mechanisms by which nutritional interventions affect not only mental health but also a wider range of gut-brain-related health outcomes. Scope and approach: Scope and approach: This paper explores how NAMs are revolutionizing gut-brain axis research by providing more accurate models that replicate human physiology, thereby replacing less effective traditional approaches. Key findings and conclusion: By using these advanced methods, researchers can produce detailed data that better mirror human responses to dietary components, resulting in more effective and personalized strategies for managing and enhancing gut-brain health. Future research should concentrate on utilizing NAMs to deepen our understanding of the gut-brain axis in nutritional science, which will ultimately lead to more targeted and effective health interventions for various conditions.

Understanding how dietary compounds affect human health is challenged by their molecular complexity and cell-type-specific effects. Conventional multi-cell type (bulk) analyses obscure cellular heterogeneity, while animal and standard in vitro models often fail to replicate human physiology. Single-cell omics technologies-such as single-cell RNA sequencing, as well as single-cell-resolved proteomic and metabolomic approaches-enable high-resolution investigation of nutrient-cell interactions and reveal mechanisms at a single-cell resolution. When combined with advanced human-derived in vitro systems like organoids and organ-on-chip platforms, they support mechanistic studies in physiologically relevant contexts. This review outlines emerging applications of single-cell omics in nutrition research, emphasizing their potential to uncover cell-specific dietary responses, identify nutrient-sensitive pathways, and capture interindividual variability. It also discusses key challenges-including technical limitations, model selection, and institutional biases-and identifies strategic directions to facilitate broader adoption in the field. Collectively, single-cell omics offer a transformative framework to advance human-centric nutrition research.

Besides mulberry fruit, mulberry ( Morus alba L. ) has many byproducts, including leaves, branches, and roots. Although these byproducts have long been used as traditional Chinese medicine, their use is limited mainly to rheumatism, diabetes, arthritis. These natural products have a variety of bioactive ingredients, including flavonoids, alkaloids, polysaccharides, with antioxidant, anti-inflammatory, lipid-lowering and other biological functions. This review introduces the bioactive ingredients of mulberry leaves, branches, and roots and discusses their potential in alleviating cardiovascular diseases from antioxidant, anti-inflammatory, lipid regulation, blood glucose regulation, vascular protection and other aspects.

This systematic review included 31 clinical trial articles examining the effects of natural compounds on Alzheimer’s disease (AD) and mild cognitive impairment (MCI), involving 3582 participants aged 50–90. Treatment durations ranged from 8 weeks to 2 years, with an average of 12.5 months. Notably, 11 studies focused on herbal extracts highlighting their prominence in current research. These extracts showed potential cognitive and neuroprotective benefits, although results varied across compounds and study designs. Other natural compounds—including flavonoids, polyphenols, omega-3 fatty acids, Aloe vera, Spirulina, and citrus phytochemicals—may provide cognitive and neuroprotective benefits, with ginseng and Ginkgo biloba combinations also showing promise. Curcumin and Melissa officinalis had limited effects, resveratrol showed mixed outcomes with some side effects, and matcha green tea may improve cognition and sleep quality. Despite generally favorable results, the studies varied considerably in design and quality; nonetheless, herbal extracts represent a prominent category of natural interventions in AD and MCI, underscoring the need for further large-scale, high-quality clinical trials to confirm their therapeutic potential.

Polyphenols are naturally occurring compounds that can be found in plant-based foods, including fruits, vegetables, nuts, seeds, herbs, spices, and beverages, the use of which has been linked to enhanced brain health and cognitive function. These natural molecules are broadly classified into two main groups: flavonoids and non-flavonoid polyphenols, the latter including phenolic acids, stilbenes, and tannins. Flavonoids are primarily known for their potent antioxidant properties, which help neutralize harmful reactive oxygen species (ROS) in the brain, thereby reducing oxidative stress, a key contributor to neurodegenerative diseases. In addition to their antioxidant effects, flavonoids have been shown to modulate inflammation, enhance neuronal survival, and support neurogenesis, all of which are critical for maintaining cognitive function. Phenolic acids possess strong antioxidant properties and are believed to protect brain cells from oxidative damage. Neuroprotective effects of these molecules can also depend on their ability to modulate signaling pathways associated with inflammation and neuronal apoptosis. Among polyphenols, hydroxycinnamic acids such as caffeic acid have been shown to enhance blood-brain barrier permeability, which may increase the delivery of other protective compounds to the brain. Another compound of interest is represented by resveratrol, a stilbene extensively studied for its potential neuroprotective properties related to its ability to activate the sirtuin pathway, a molecular signaling pathway involved in cellular stress response and aging. Lignans, on the other hand, have shown promise in reducing neuroinflammation and oxidative stress, which could help slow the progression of neurodegenerative diseases and cognitive decline. Polyphenols belonging to different subclasses, such as flavonoids, phenolic acids, stilbenes, and lignans, exert neuroprotective effects by regulating microglial activation, suppressing pro-inflammatory cytokines, and mitigating oxidative stress. These compounds act through multiple signaling pathways, including NF-κB, MAPK, and Nrf2, and they may also influence genetic regulation of inflammation and immune responses at brain level. Despite their potential for brain health and cognitive function, polyphenols are often characterized by low bioavailability, something that deserves attention when considering their therapeutic potential. Future translational studies are needed to better understand the right dosage, the overall diet, the correct target population, as well as ideal formulations allowing to overcome bioavailability limitations. See also the graphical abstract(Fig. 1).

ABSTRACT Alzheimer's disease (AD) involves β‐amyloid plaques and tau hyperphosphorylation, driven by oxidative stress and neuroinflammation. Cyclooxygenase‐2 (COX‐2) and acetylcholinesterase (AChE) activities exacerbate AD pathology. Olive leaf (OL) extracts, rich in bioactive compounds, offer potential therapeutic benefits. This study aimed to assess the anti‐inflammatory, anti‐cholinergic, and antioxidant effects of three OL extracts (low, mid, and high bioactive content) in vitro and their protective effects against AD‐related proteinopathies in Caenorhabditis elegans models. OL extracts were characterized for phenolic composition, AChE and COX‐2 inhibition, as well as antioxidant capacity. Their effects on intracellular and mitochondrial reactive oxygen species (ROS) were tested in C. elegans models expressing human Aβ and tau proteins. Gene expression analyses examined transcription factors (DAF‐16, skinhead [SKN]‐1) and their targets (superoxide dismutase [SOD]‐2, SOD‐3, GST‐4, and heat shock protein [HSP]‐16.2). High‐OL extract demonstrated superior AChE and COX‐2 inhibition and antioxidant capacity. Low‐ and high‐OL extracts reduced Aβ aggregation, ROS levels, and proteotoxicity via SKN‐1/NRF‐2 and DAF‐16/FOXO pathways, whereas mid‐OL showed moderate effects through proteostasis modulation. In tau models, low‐ and high‐OL extracts mitigated mitochondrial ROS levels via SOD‐2 but had limited effects on intracellular ROS levels. High‐OL extract also increased GST‐4 levels, whereas low and mid extracts enhanced GST‐4 levels. OL extracts protect against AD‐related proteinopathies by modulating oxidative stress, inflammation, and proteostasis. High‐OL extract showed the most promise for nutraceutical development due to its robust phenolic profile and activation of key antioxidant pathways. Further research is needed to confirm long‐term efficacy.

ABSTRACT Garlic is a horticultural product highly valued for its culinary and medicinal attributes. The aim of this study was to evaluate the composition of a garlic hydrophilic extract as well as the influence on redox biology, Alzheimer's Disease (AD) markers and aging, using Caenorhabditis elegans as experimental model. The extract was rich in sulfur compounds, highlighting the presence of other compounds like phenolics, and the antioxidant property was corroborated. Regarding AD markers, the acetylcholinesterase inhibitory capacity was demonstrated in vitro. Although the extract did not modify the amyloid β‐induced paralysis degree, it was able to improve, in a dose‐dependent manner, some locomotive parameters affected by the hyperphosphorylated tau protein in C. elegans. It could be related to the effect found on GFP‐transgenic stains, mainly regarding to the increase in the gene expression of HSP‐16.2. Moreover, an initial investigation into the aging process revealed that the extract successfully inhibited the accumulation of intracellular and mitochondrial reactive oxygen species in aged worms. These results provide valuable insights into the multifaceted impact of garlic extract, particularly in the context of aging and neurodegenerative processes. This study lays a foundation for further research avenues exploring the intricate molecular mechanisms underlying garlic effects and its translation into potential therapeutic interventions for age‐related neurodegenerative conditions.

Background/Objectives: Bioactive compounds possess the ability to maintain health and improve diseases by regulating inflammation and cell death processes. Pyroptosis is programmed cell death related to inflammation and exerts a critical role in the development and progression of different types of diseases. This narrative review aims to investigate and discuss the effects of dietary bioactive compounds on pyroptosis in different common human pathologies, such as inflammatory disease, bacterial infection, injury disease, cancer, diabetes and heart disease, etc. Method: Studies published in the major databases until December 2024 in English were considered, for a total of 50 papers. Results: The current evidence demonstrated that the bioactive compounds are able to regulate the pyroptosis process by modulating different inflammasome sensors (NLRP1, NLRP3, and AIM2), caspase family proteins (caspase-1, caspase-3, and caspase-11), and gasdermins (GSDMD and GSDME) in many pathological conditions related to inflammation, including cancer and cardiovascular diseases. Conclusions: Bioactive compounds have powerful potential to be the candidate drug for pyroptosis modulation in inflammatory diseases, even if more clinical studies are needed to confirm the effects and establish efficient doses for humans.

Background Clinical trials are essential for assessing the efficacy and safety of new therapeutic strategies. This study describes the design and baseline characteristics of the OLIVAGING trial, which evaluates the effects of an olive leaf extract (OLE) enriched in oleuropein in older adults with periodontitis.Methods OLIVAGING is a randomized, double-blind, parallel-group, multicenter clinical trial. Sixty participants with age-related periodontitis were randomized 1:1 to receive either OLE or placebo for 16 weeks. All participants underwent comprehensive periodontal treatment and received standardized oral hygiene instructions. Measurements and biological samples were collected at baseline and after follow-up.Results A total of 46 participants completed the intervention. The mean age was 61.7 +/- 9.2 years. Most participants presented overweight or central obesity and elevated blood pressure. Men showed more severe periodontal involvement compared to women. These baseline data indicate a metabolically vulnerable cohort.Conclusions The baseline characteristics support the relevance of evaluating OLE as a nutritional strategy in older adults with periodontitis. The results of this trial may contribute to improving current therapeutic approaches to this prevalent inflammatory condition. Trial registration: ClinicalTrials.gov Identifier: NCT05482373. Registered at: https://clinicaltrials.gov/ct2/show/NCT05482373.Conclusions The baseline characteristics support the relevance of evaluating OLE as a nutritional strategy in older adults with periodontitis. The results of this trial may contribute to improving current therapeutic approaches to this prevalent inflammatory condition. Trial registration: ClinicalTrials.gov Identifier: NCT05482373. Registered at: https://clinicaltrials.gov/ct2/show/NCT05482373.

Over the last decades, the Mediterranean diet gained enormous scientific, social, and commercial attention due to proven positive effects on health and undeniable taste that facilitated a widespread popularity. Researchers have investigated the role of Mediterranean-type dietary patterns on human health all around the world, reporting consistent findings concerning its benefits. However, what does truly define the Mediterranean diet? The myriad of dietary scores synthesizes the nutritional content of a Mediterranean-type diet, but a variety of aspects are generally unexplored when studying the adherence to this dietary pattern. Among dietary factors, the main characteristics of the Mediterranean diet, such as consumption of fruit and vegetables, olive oil, and cereals should be accompanied by other underrated features, such as the following: (i) specific reference to whole-grain consumption; (ii) considering the consumption of legumes, nuts, seeds, herbs and spices often untested when exploring the adherence to the Mediterranean diet; (iii) consumption of eggs and dairy products as common foods consumed in the Mediterranean region (irrespectively of the modern demonization of dietary fat intake). Another main feature of the Mediterranean diet includes (red) wine consumption, but more general patterns of alcohol intake are generally unmeasured, lacking specificity concerning the drinking occasion and intensity (i.e., alcohol drinking during meals). Among other underrated aspects, cooking methods are rather simple and yet extremely varied. Several underrated aspects are related to the quality of food consumed when the Mediterranean diet was first investigated: foods are locally produced, minimally processed, and preserved with more natural methods (i.e., fermentation), strongly connected with the territory with limited and controlled impact on the environment. Dietary habits are also associated with lifestyle behaviors, such as sleeping patterns, and social and cultural values, favoring commensality and frugality. In conclusion, it is rather reductive to consider the Mediterranean diet as just a pattern of food groups to be consumed decontextualized from the social and geographical background of Mediterranean culture. While the methodologies to study the Mediterranean diet have demonstrated to be useful up to date, a more holistic approach should be considered in future studies by considering the aforementioned underrated features and values to be potentially applied globally through the concept of a “Planeterranean” diet.