The natural polyphenol resveratrol (RV) has garnered fame for its extensive pharmacological properties. Although clinical studies have shown some positive results, many contradictory outcomes remain. An important obstacle to the development of therapeutic applications for RV is its low bioavailability in vivo. This may be partially attributed to biotransformation mediated by phase I and II enzymes, such as cytochrome P450s, UDP-glucuronosyltransferases, and sulfotransferases. To date, more than 20 different types of metabolites have been detected after catalysis by these enzymes. Notably, RV and some of its metabolites serve as substrates for these enzymes. Conversely, RV can directly regulate the expression or activity of these enzymes. Given the increasing number of studies investigating the bioactivity of RV, this review summarizes its physicochemical and pharmacokinetic characteristics and describes the metabolism of RV and the bioactivities of its metabolites, with emphasis on the interaction between RV and its related metabolic enzymes. In addition to hepatic metabolism, the crucial roles of RV metabolism in multiple other tissues and organs cannot be overlooked, and they reveal the relationship between RV metabolism and its biological potential.

Annually, a growing body of studies substantiates the health advantages of polyphenolic compounds, yet their practical application is constrained by swift metabolism and low bioavailability. Resveratrol, a stilbene derivative showcasing typical polyphenolic traits, is particularly noteworthy. Despite abundant bioavailability data from in vitro and animal studies, applying these findings to humans demands nuanced consideration. The objective of this article is to conduct a meta-analysis on clinical trial data, systematically assessing the oral bioavailability of resveratrol and deriving meaningful insights into its efficacy in humans. To achieve this goal, we thoroughly examined publications across five major global databases: PubMed, Cochrane Library, Scopus, Embase, and Science Direct. The study exclusively included clinical trials involving healthy adults, where pharmacokinetic parameters were measured following the oral administration of at least one dose of resveratrol as a single preparation. For the meta-analysis data extraction, the mean score and standard deviation (SD) were included. Heterogeneity, degree of inconsistency between studies, and meta-regression were assessed. From these searches, we scrutinized data from 84 oral administrations encompassing nine resveratrol doses ranging from 25 to 5000 mg. Our findings indicate a linear increase in the amount of free resveratrol entering the bloodstream with the administered dose, while T max values remain unaffected. The mean maximum plasma concentration of resveratrol (31.07 ng/mL) closely mirrors the mean C max observed in the group administered a medium resveratrol dose ranging from 100 to 500 mg (33.59 ng/mL). This similarity implies the appropriateness of employing these specific doses of resveratrol, taking into consideration both its bioavailability and very low risk of potential side effects. However, the analysis of available human oral bioavailability data is constrained by methodological inconsistencies prevalent in existing studies. The meta-analysis underscores substantial heterogeneity, underscoring the imperative for multiple studies to rectify this prevailing trend.

Resveratrol and extra virgin olive oil are both recognized for their potential protective effects against age-related diseases. This overview highlights their mechanisms of action, health benefits, and the scientific evidence supporting their roles in promoting longevity and cognitive health. A literature search was conducted. Important findings related to the health benefits, mechanisms of action, and clinical implications of resveratrol and EVOO were summarized. Both resveratrol and EVOO have complementary mechanisms that may enhance their anti-aging effects. Resveratrol and EVOO are promising age-related disease-protective agents. Their antioxidant, anti-inflammatory, and neuroprotective properties contribute to improved health outcomes and longevity. Incorporating these compounds into a balanced diet may offer significant benefits for aging populations, supporting cognitive health and reducing the risk of chronic diseases. Continued research is essential to fully understand their mechanisms and optimize their use in clinical settings. Future research should focus on investigating the synergistic effects of resveratrol and EVOO when consumed together, as they may enhance each other's bioavailability and efficacy in promoting health; conducting extensive clinical trials to confirm the long-term benefits of these compounds in various populations, particularly in aging individuals; further exploring the molecular pathways through which resveratrol and EVOO exert their effects, including their interactions with gut microbiota and metabolic pathways.

The brain's response to cognitive demands hinges on sufficient blood flow, with changes in brain hemodynamics serving as a reflection of this process. Certain bioactive compounds found in our diet, such as caffeine, polyphenols, and nitrate, can acutely impact brain hemodynamics through diverse neural, vasoactive, and metabolic mechanisms. Functional Near-Infrared Spectroscopy (fNIRS) offers a non-invasive and real-time method to investigate these effects. Despite their potential, fNIRS studies investigating the acute impacts of bioactive compounds on cognition face methodological gaps, especially in controlling confounding factors. Given the impact of these confounding effects, which can be significant due to the relatively limited sample size of such studies, there is a need to refine the methodologies employed. This review proposes recommendations to enhance current methodologies in the research field, focusing on key aspects of the data collection phase, including research design, experimental paradigms, and participant demographics, and their integration into the analysis phase. Ultimately, it seeks to advance our understanding of the effects of bioactive compounds on cognitive functions to contribute to the development of targeted nutritional interventions for improved brain health.

Numerous experimental studies suggest the potential for resveratrol (RVT) to be useful in the Alzheimer's disease treatment, but its low bioavailability limits its application. This study aimed to assess the potential of resveratrol-loaded micelles as a neuronal delivery platform to protect rats from scopolamine-induced memory impairment. Resveratrol was incorporated into Pluronic micelles, and the effects of micellar (mRVT) and pure resveratrol (RVT) were compared in the model of scopolamine-induced dementia in male Wistar rats. Memory performance was assessed by a T maze test. The effect of the treatment on specific neurotransmitter levels and protein expression in the cortex and the hippocampus were evaluated biochemically. Our results revealed that the polymeric micelles were in nanoscale (approximately 33 nm) and reached 79% encapsulation efficiency. The treatment with mRVT demonstrated better spatial memory protective effect. The biochemical assays showed that mRVT in a dose of 10 mg/kg enhanced the effects of the pure drug in regard to noradrenalin neurotransmission and acetylcholinesterase inhibitory activity in the hippocampus. Furthermore, micellar resveratrol increased the cAMP-response element-binding protein expression in the cortex and hippocampus of rats as well as the Bcl2/BAX ratio, which indicated an anti-apoptotic effect in the experimental dementia model. In conclusion, our results indicated the potential of a micellar system loaded with resveratrol for neurodegenerative diseases treatment.

5-Heptadecylresorcinol (AR-C17), a homologue of alkylresorcinols (ARs) and mainly observed in cereal brans, has stronger physiological functions compared with its homologues. However, not only is its content rare but also the purification low. Besides, few researches on its digestion characteristics and bioavailability limits its maximum applications. Here, we mainly relied on solid-state fermentation, embedment, in vitro models to systematically evaluate processing technologies, digestion and absorption characteristics of AR-C17. We showed that the highest content of AR-C17 was 57.6 μg/g extracted from triticale bran fermented by Saccharomyces cerevisiae relying on ultrasound-assistance. Additionally, AR-C17 was chiefly absorbed in duodenum and jejunum, and its apparent absorption increased by around 2.1 times when quercetin was added as the synergistic agent, which was higher than other phenolics in bran extract. Furthermore, AR-C17 embedded by β-cyclodextrin avoided the decomposition of in strong acidic environment, enhancing the retention rate to 96 % in in vitro digestion. According to the results above, we mixed AR-C17 with the quercetin, and embedded the mixture by β-cyclodextrin, which maximized the apparent absorption of AR-C17, reaching 19.8 % when the ratio of quercetin and AR-C17 was 1:1.

Resveratrol is a potent phytochemical known for its potential in treating cardiometabolic multimorbidity. However, its underlying mechanisms remain unclear. Our study systematically investigates the effects of resveratrol on cardiometabolic multimorbidity and elucidates its mechanisms using network pharmacology and molecular docking techniques.

We screened cardiometabolic multimorbidity-related targets using the OMIM, GeneCards, and DisGeNET databases, and utilized the DSigDB drug characterization database to predict resveratrol's effects on cardiometabolic multimorbidity. Target identification for resveratrol was conducted using the TCMSP, SymMap, DrugBank, Swiss Target Prediction, CTD, and UniProt databases. SwissADME and ADMETlab 2.0 simulations were used to predict drug similarity and toxicity profiles of resveratrol. Protein-protein interaction (PPI) networks were constructed using Cytoscape 3.9.1 software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed via the DAVID online platform, and target-pathway networks were established. Molecular docking validated interactions between core targets and resveratrol, followed by molecular dynamics simulations on the optimal core proteins identified through docking. Differential analysis using the GEO dataset validated resveratrol as a core target in cardiometabolic multimorbidity.

A total of 585 cardiometabolic multimorbidity target genes were identified, and the predicted results indicated that the phytochemical resveratrol could be a major therapeutic agent for cardiometabolic multimorbidity. SwissADME simulations showed that resveratrol has potential drug-like activity with minimal toxicity. Additionally, 6703 targets of resveratrol were screened. GO and KEGG analyses revealed that the main biological processes involved included positive regulation of cell proliferation, positive regulation of gene expression, and response to estradiol. Significant pathways related to MAPK and PI3K-Akt signaling pathways were also identified. Molecular docking and molecular dynamics simulations demonstrated strong interactions between resveratrol and core targets such as MAPK and EGFR.

This study predicts potential targets and pathways of resveratrol in treating cardiometabolic multimorbidity, offering a new research direction for understanding its molecular mechanisms. Additionally, it establishes a theoretical foundation for the clinical application of resveratrol.

With neurodegenerative disorders being on the rise, a great deal of research from multiple fields is being conducted in order to further knowledge and propose novel therapeutic interventions. Among these investigations, research on the role of antioxidants in contrasting cognitive decline is putting forward interesting and promising results. In this review, we aim to collect evidence that focused on the role of a variety of antioxidants and antioxidant-rich foods in improving or stabilizing cognitive functions, memory, and Alzheimer's disease, the most common neurodegenerative disorder. Specifically, we considered evidence collected on humans, either through longitudinal studies or randomized, placebo-controlled ones, which evaluated cognitive performance, memory abilities, or the progression level of neurodegeneration. Overall, despite a great deal of variety between study protocols, cohorts of participants involved, neuropsychological tests used, and investigated antioxidants, there is a solid trend that suggests that the properties of antioxidants may be helpful in hampering cognitive decline in older people. Thus, the help of future research that will further elucidate the role of antioxidants in neuroprotection will lead to the development of novel interventions that will take into account such findings to provide a more global approach to treating neurodegenerative disorders.

Circadian clocks regulate metabolic homeostasis. Disruption to our circadian clocks, by lifestyle behaviors such as timing of eating and sleeping, has been linked to increased rates of metabolic disorders. There is now considerable evidence that selected dietary (poly)phenols, including flavonoids, phenolic acids and tannins, may modulate metabolic and circadian processes. This review evaluates the effects of (poly)phenols on circadian clock genes and linked metabolic homeostasis in vitro, and potential mechanisms of action, by critically evaluating the literature on mammalian cells. A systematic search was conducted to ensure full coverage of the literature and identified 43 relevant studies addressing the effects of (poly)phenols on cellular circadian processes. Nobiletin and tangeretin, found in citrus, (-)-epigallocatechin-3-gallate from green tea, urolithin A, a gut microbial metabolite from ellagitannins in fruit, curcumin, bavachalcone, cinnamic acid, and resveratrol at low micromolar concentrations all affect circadian molecular processes in multiple types of synchronized cells. Nobiletin emerges as a putative retinoic acid-related orphan receptor (RORα/γ) agonist, leading to induction of the circadian regulator brain and muscle ARNT-like 1 (BMAL1), and increased period circadian regulator 2 (PER2) amplitude and period. These effects are clear despite substantial variations in the protocols employed, and this review suggests a methodological framework to help future study design in this emerging area of research.

Alzheimer's disease (AD) is a very common neurodegenerative disorder associated with memory loss and a progressive decline in cognitive activity. The two major pathophysiological factors responsible for AD are amyloid plaques (comprising amyloid-beta aggregates) and neurofibrillary tangles (consisting of hyperphosphorylated tau protein). Polyphenols, a class of naturally occurring compounds, are immensely beneficial for the treatment or management of various disorders and illnesses. Naturally occurring sources of polyphenols include plants and plant-based foods, such as fruits, herbs, tea, vegetables, coffee, red wine, and dark chocolate. Polyphenols have unique properties, such as being the major source of anti-oxidants and possessing anti-aging and anti-cancerous properties. Currently, dietary polyphenols have become a potential therapeutic approach for the management of AD, depending on various research findings. Dietary polyphenols can be an effective strategy to tackle multifactorial events that occur with AD. For instance, naturally occurring polyphenols have been reported to exhibit neuroprotection by modulating the Aβ biogenesis pathway in AD. Many nanoformulations have been established to enhance the bioavailability of polyphenols, with nanonization being the most promising. This review comprehensively provides mechanistic insights into the neuroprotective potential of dietary polyphenols in treating AD. It also reviews the usability of dietary polyphenol as nanoformulation for AD treatment.

Components that comprise our brain parenchymal and cerebrovascular structures provide a homeostatic environment for proper neuronal function to ensure normal cognition. Cerebral insults (e.g. ischaemia, microbleeds and infection) alter cellular structures and physiologic processes within the neurovascular unit and contribute to cognitive dysfunction. COVID-19 has posed significant complications during acute and convalescent stages in multiple organ systems, including the brain. Cognitive impairment is a prevalent complication in COVID-19 patients, irrespective of severity of acute SARS-CoV-2 infection. Moreover, overwhelming evidence from in vitro, preclinical and clinical studies has reported SARS-CoV-2-induced pathologies in components of the neurovascular unit that are associated with cognitive impairment. Neurovascular unit disruption alters the neurovascular coupling response, a critical mechanism that regulates cerebromicrovascular blood flow to meet the energetic demands of locally active neurons. Normal cognitive processing is achieved through the neurovascular coupling response and involves the coordinated action of brain parenchymal cells (i.e. neurons and glia) and cerebrovascular cell types (i.e. endothelia, smooth muscle cells and pericytes). However, current work on COVID-19-induced cognitive impairment has yet to investigate disruption of neurovascular coupling as a causal factor. Hence, in this review, we aim to describe SARS-CoV-2's effects on the neurovascular unit and how they can impact neurovascular coupling and contribute to cognitive decline in acute and convalescent stages of the disease. Additionally, we explore potential therapeutic interventions to mitigate COVID-19-induced cognitive impairment. Given the great impact of cognitive impairment associated with COVID-19 on both individuals and public health, the necessity for a coordinated effort from fundamental scientific research to clinical application becomes imperative. This integrated endeavour is crucial for mitigating the cognitive deficits induced by COVID-19 and its subsequent burden in this especially vulnerable population.

Neuropsychiatric disorders are anticipated to be a leading health concern in the near future, emphasizing an outstanding need for the development of new effective therapeutics to treat them. Stilbenes, with resveratrol attracting the most attention, are an example of multi-target compounds with promising therapeutic potential for a broad array of neuropsychiatric and neurological conditions. This review is a comprehensive summary of the current state of research on stilbenes in several neuropsychiatric and neurological disorders such as depression, anxiety, schizophrenia, autism spectrum disorders, epilepsy, traumatic brain injury, and neurodegenerative disorders. We describe and discuss the results of both in vitro and in vivo studies. The majority of studies concentrate on resveratrol, with limited findings exploring other stilbenes such as pterostilbene, piceatannol, polydatin, tetrahydroxystilbene glucoside, or synthetic resveratrol derivatives. Overall, although extensive preclinical studies show the potential benefits of stilbenes in various central nervous system disorders, clinical evidence on their therapeutic efficacy is largely missing.

Alzheimer's diseases (AD) and dementia are among the highly prevalent neurological disorders characterized by deposition of beta amyloid (Aβ) plaques, dense deposits of highly phosphorylated tau proteins, insufficiency of acetylcholine (ACh) and imbalance in glutamatergic system. Patients typically experience cognitive, behavioral alterations and are unable to perform their routine activities. Evidence also suggests that inflammatory processes including excessive microglia activation, high expression of inflammatory cytokines and release of free radicals. Thus, targeting inflammatory pathways beside other targets might be the key factors to control- disease symptoms and progression.

This review is aimed to highlight the mechanisms and pathways involved in the neuroprotective potentials of lead phytochemicals. Further to provide updates regarding challenges associated with their use and their progress into clinical trials as potential lead compounds.

Most recent scientific literature on pre-clinical and clinical data published in quality journals especially on the lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin was collected using SciFinder, PubMed, Google Scholar, Web of Science, JSTOR, EBSCO, Scopus and other related web sources.

Literature review indicated that the drug discovery against AD is insufficient and only few drugs are clinically approved which have limited efficacy. Among the therapeutic options, natural products have got tremendous attraction owing to their molecular diversity, their safety and efficacy. Research suggest that natural products can delay the disease onset, reduce its progression and regenerate the damage via their anti-amyloid, anti-inflammatory and antioxidant potentials. These agents regulate the pathways involved in the release of neurotrophins which are implicated in neuronal survival and function. Highly potential lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin regulate neuroprotective signaling pathways implicated in neurotrophins-mediated activation of tropomyosin receptor kinase (Trk) and p75 neurotrophins receptor (p75NTR) family receptors.

Phytochemicals especially phenolic compounds were identified as highly potential molecules which ameliorate oxidative stress induced neurodegeneration, reduce Aβ load and inhibit vital enzymes. Yet their clinical efficacy and bioavailability are the major challenges which need further interventions for more effective therapeutic outcomes.

Resveratrol has long been proposed as being beneficial to human health across multiple morbidities, yet there is currently no conclusive clinical evidence to advocate its recommendation in any healthcare setting. A large cohort with high-quality clinical data and clearly defined biomarkers or endpoints are required to draw meaningful conclusions. This systematic review compiles every clinical trial conducted using a defined dose of resveratrol in a purified form across multiple morbidities to highlight the current 'state-of-play' and knowledge gaps, informing future trial designs to facilitate the realisation of resveratrol's potential benefits to human health. Over the last 20 years, there have been almost 200 studies evaluating resveratrol across at least 24 indications, including cancer, menopause symptoms, diabetes, metabolic syndrome, and cardiovascular disease. There are currently no consensus treatment regimens for any given condition or endpoint, beyond the fact that resveratrol is generally well-tolerated at a dose of up to 1 g/day. Additionally, resveratrol consistently reduces inflammatory markers and improves aspects of a dysregulated metabolism. In conclusion, over the last 20 years, the increasing weight of clinical evidence suggests resveratrol can benefit human health, but more large, high-quality clinical trials are required to transition this intriguing compound from health food shops to the clinic.

Resveratrol (3, 5, 4'-trihydroxystilbene) is a polyphenolic derivative with herbal origin. It has attracted considerable attention in recent decades. Many studies have revealed the benefits of Resveratrol over several human disease models, including heart and neurological diseases, nephroprotective, immune regulation, antidiabetic, anti-obesity, age-related diseases, antiviral, and anticancer in experimental and clinical conditions. Recently, the antioxidant and anti-inflammatory activities of Resveratrol have been observed, and it has been shown that Resveratrol reduces inflammatory biomarkers, such as tissue degradation factor, cyclooxygenase 2, nitric oxide synthase, and interleukins. All of these activities appear to be dependent on its structural properties, such as the number and position of the hydroxyl group, which regulates oxidative stress, cell death, and inflammation. Resveratrol is well tolerated and safe even at higher pharmacological doses and desirably affects cardiovascular, neurological, and diabetic diseases. Consequently, it is plausible that Resveratrol can be regarded as a beneficial nutritional additive and a complementary drug, particularly for therapeutic applications. The present review provides an overview of currently available investigations on preventive and therapeutic characteristics and the main molecular mechanisms of Resveratrol and its potent derivatives in various diseases. Thus, this review would enhance knowledge and information about Resveratrol and encourage researchers worldwide to consider it as a pharmaceutical drug to struggle with future health crises against different human disorders.

Introduction: resveratrol has multiple beneficial effects on different body systems, including the central nervous system, however, the results reported on the effect on cognitive functions in older adults are inconsistent. Therefore, the purpose of this systematic review is to present a synthesis of knowledge about the effect of resveratrol on cognitive functions in older adults. Method: a systematic review was carried out according to the PRISMA-2009 criteria. The search for articles was carried out until September 7, 2021 in PubMed, Scopus, Web of Science, PsycINFO, SciELO, and TESIUNAM. The outcome variables were delayed, immediate, and working memory, and processing speed. The standardized mean difference (SMD) was estimated to assess the effect. Results: one thousand sixty-five studies were found, of which six met the eligibility criteria for the systematic review and meta-analysis. No significant effect was found on delayed memory (SMD = 0.69, 95 % CI: 0.85-2.23, p = 0.38), immediate memory (SMD = 0.56, 95 % CI: -0.20-1.31, p = 0.15), working memory (SMD = -0.21, 95 % CI: -0.74-0.32, p = 0.43) and processing speed (SMD = 0.25, 95 % CI: -0.58-1.07, p = 0.55). Conclusion: our results suggest that resveratrol does not have an effect on cognitive functions in older adults, however, it is necessary to carry out more studies with different doses, type of nutraceutical formulation and treatment time.

Metabolic syndrome (MetS) is a growing global health problem. Evidence suggests that diets rich in phytochemical-containing herbs and spices can contribute to reducing the risk of chronic diseases. This review assesses the scope of evidence supporting the use of herbs and spices in the diet for the prevention or treatment of MetS and its associated health conditions. A search of the PubMed, Scopus and Google Scholar databases was carried out to assess the available clinical evidence for culinary doses of commonly used herbs and spices. Trials that were measuring health factors related to metabolic disorders in healthy individuals, or the health of individuals with MetS or associated diseases, were included. Out of a total of 1738 papers identified, there were 142 relevant studies on black pepper, chilli, cardamom, cinnamon, coriander, cumin, fennel, fenugreek, garlic, ginger, nigella seed, rosemary, sage and turmeric. No relevant research was found for cloves, mint, oregano, parsley or thyme. Cinnamon, fenugreek and ginger were the herbs/spices with the most published trials on them and that showed promise for glycaemic control. Cardamom appears to have potential to reduce inflammatory markers, and cinnamon, ginger and turmeric to reduce blood lipids. Patients with type 2 diabetes were the population most likely to be included in studies, but the preventative benefits of herbs/spices in healthy populations were also investigated, particularly for chilli, ginger and cinnamon. There is evidence for the beneficial effect of culinary doses of many common herbs/spices in the prevention and treatment of MetS and associated disorders.

In recent years, growing awareness of the role of oxidative stress in brain health has prompted antioxidants, especially dietary antioxidants, to receive growing attention as possible treatments strategies for patients with neurodegenerative diseases (NDs). The most widely studied dietary antioxidants include active substances such as vitamins, carotenoids, flavonoids and polyphenols. Dietary antioxidants are found in usually consumed foods such as fresh fruits, vegetables, nuts and oils and are gaining popularity due to recently growing awareness of their potential for preventive and protective agents against NDs, as well as their abundant natural sources, generally non-toxic nature, and ease of long-term consumption. This review article examines the role of oxidative stress in the development of NDs, explores the 'two-sidedness' of the blood-brain barrier (BBB) as a protective barrier to the nervous system and an impeding barrier to the use of antioxidants as drug medicinal products and/or dietary antioxidants supplements for prevention and therapy and reviews the BBB permeability of common dietary antioxidant suplements and their potential efficacy in the prevention and treatment of NDs. Finally, current challenges and future directions for the prevention and treatment of NDs using dietary antioxidants are discussed, and useful information on the prevention and treatment of NDs is provided.

Depression, a mood disorder characterized by persistent feelings of sadness and aversion to activity that can interfere with daily life, is a condition of great concern. Prebiotics, which are non-digestible substances selectively utilized by host microorganisms for health benefits, have gained attention for their potential to improve overall wellness and alleviate various disorders including depression. This study aims to review clinical trials utilizing carbohydrate-type prebiotics such as inulin-type fructans, galactooligosaccharides (GOS), human milk oligosaccharides, resistant starch, prebiotic phytochemicals including epigallocatechin gallate (EGCG), chlorogenic acids, resveratrol, and prebiotic lipids (n-3 polysaturated fatty acids) to determine their effects on depression. Our findings suggest that GOS at a daily dosage of 5 g and eicosapentaenoic acid at or less than 1 g can effectively mitigate depressive symptoms. While EGCG exhibits potential antidepressant properties, a higher dosage of 3 g/d may be necessary to elicit significant effects. The plausible mechanisms underlying the impact of prebiotics on depression include the synthesis of neurotransmitters, production of short-chain fatty acids, and regulation of inflammation.

Age-related neurological disorders (ANDs), including neurodegenerative diseases, are multifactorial disorders whose risk increases with age. The main pathological hallmarks of ANDs include behavioral changes, excessive oxidative stress, progressive functional declines, impaired mitochondrial function, protein misfolding, neuroinflammation, and neuronal cell death. Recently, efforts have been made to overcome ANDs because of their increased age-dependent prevalence. Black pepper, the fruit of Piper nigrum L. in the family Piperaceae, is an important food spice that has long been used in traditional medicine to treat various human diseases. Consumption of black pepper and black pepper-enriched products is associated with numerous health benefits due to its antioxidant, antidiabetic, anti-obesity, antihypertensive, anti-inflammatory, anticancer, hepatoprotective, and neuroprotective properties. This review shows that black pepper's major bioactive neuroprotective compounds, such as piperine, effectively prevent AND symptoms and pathological conditions by modulating cell survival signaling and death. Relevant molecular mechanisms are also discussed. In addition, we highlight how recently developed novel nanodelivery systems are vital for improving the efficacy, solubility, bioavailability, and neuroprotective properties of black pepper (and thus piperine) in different experimental AND models, including clinical trials. This extensive review shows that black pepper and its active ingredients have therapeutic potential for ANDs.

Phytochemicals, produced as secondary plant metabolites, have shown interesting potential therapeutic activities against neurodegenerative diseases and cancer. Unfortunately, poor bioavailability and rapid metabolic processes compromise their therapeutic use, and several strategies are currently proposed for overcoming these issues. The present review summarises strategies for enhancing the central nervous system's phytochemical efficacy. Particular attention has been paid to the use of phytochemicals in combination with other drugs (co-administrations) or administration of phytochemicals as prodrugs or conjugates, particularly when these approaches are supported by nanotechnologies exploiting conjugation strategies with appropriate targeting molecules. These aspects are described for polyphenols and essential oil components, which can improve their loading as prodrugs in nanocarriers, or be part of nanocarriers designed for targeted co-delivery to achieve synergistic anti-glioma or anti-neurodegenerative effects. The use of in vitro models, able to simulate the blood-brain barrier, neurodegeneration or glioma, and useful for optimizing innovative formulations before their in vivo administration via intravenous, oral, or nasal routes, is also summarised. Among the described compounds, quercetin, curcumin, resveratrol, ferulic acid, geraniol, and cinnamaldehyde can be efficaciously formulated to attain brain-targeting characteristics, and may therefore be therapeutically useful against glioma or neurodegenerative diseases.

With rising technological advancements, several factors influence the lifestyle of people and stimulate chronic inflammation that severely affects the human body. Chronic inflammation leads to a broad range of physical and pathophysiological distress. For many years, non-steroidal drugs and corticosteroids were most frequently used in treating inflammation and related ailments. However, long-term usage of these drugs aggravates the conditions of chronic diseases and is presented with morbid side effects, especially in old age. Hence, the quest for safe and less toxic anti-inflammatory compounds of high therapeutic potential with least adverse side effects has shifted researchers' attention to ancient medicinal system. Resveratrol (RSV) - 3,4,5^' trihydroxystilbene is one such naturally available polyphenolic stilbene derivative obtained from various plant sources. For over 2000 years, these plants have been used in Asian medicinal system for curing inflammation-associated disorders. There is a wealth of in vitro, in vivo and clinical evidence that shows RSV could induce anti-aging health benefits including, anti-cancer, anti-inflammatory, anti-oxidant, phytoesterogenic, and cardio protective properties. However, the issue of rapid elimination of RSV through the metabolic system and its low bio-availability is of paramount importance which is being studied extensively. Therefore, in this article, we scientifically reviewed the molecular targets, biological activities, beneficial and contradicting effects of RSV as evinced by clinical studies for the prevention and treatment of inflammation-mediated chronic disorders.

The gradual ageing of the world population has been accompanied by a dramatic increase in the prevalence of obesity and metabolic diseases, especially type 2 diabetes. The adipose tissue dysfunction associated with ageing and obesity shares many common physiological features, including increased oxidative stress and inflammation. Understanding the mechanisms responsible for adipose tissue dysfunction in obesity may help elucidate the processes that contribute to the metabolic disturbances that occur with ageing. This, in turn, may help identify therapeutic targets for the treatment of obesity and age-related metabolic disorders. Because oxidative stress plays a critical role in these pathological processes, antioxidant dietary interventions could be of therapeutic value for the prevention and/or treatment of age-related diseases and obesity and their complications. In this chapter, we review the molecular and cellular mechanisms by which obesity predisposes individuals to accelerated ageing. Additionally, we critically review the potential of antioxidant dietary interventions to counteract obesity and ageing.

Both physiological and pathological aging processes induce brain alterations especially affecting the speed of processing, working memory, conceptual reasoning and executive functions. Many therapeutic approaches to reduce the impact of brain aging on cognitive functioning have been tested; unfortunately, there are no satisfactory results as a single therapy. As aging is partly contributed by free radical reactions, it has been proposed that exogenous antioxidants could have a positive impact on both aging and its associated manifestations. The aim of this report is to provide a summary and a subsequent review of the literature evidence on the role of antioxidants in preventing and improving cognition in the aging brain. Manipulation of endogenous cellular defense mechanisms through nutritional antioxidants or pharmacological compounds represents an innovative approach to therapeutic intervention in diseases causing brain tissue damage, such as neurodegeneration. Coherently with this notion, antioxidants, especially those derived from the Mediterranean diet such as hydroxytyrosol and resveratrol, seem to be able to delay and modulate the cognitive brain aging processes and decrease the occurrence of its effects on the brain. The potential preventive activity of antioxidants should be evaluated in long-term exposure clinical trials, using preparations with high bioavailability, able to bypass the blood-brain barrier limitation, and that are well standardized.

Currently, the nutraceutical approach to treat dyslipidaemia is increasing in use, and in many cases is used by physicians as the first choice in the treatment of patients with borderline values. Nutraceuticals represent an excellent opportunity to treat the preliminary conditions not yet showing the pathological signs of dyslipidaemia. Their general safety, the patient's confidence, the convincing proof of efficacy and the reasonable costs prompted the market of new preparations. Despite this premise, many nutraceutical products are poorly formulated and do not meet the minimum requirements to ensure efficacy in normalizing blood lipid profiles, promoting cardiovascular protection, and normalizing disorders of glycemic metabolism. In this context, bioaccessibility and bioavailability of the active compounds is a crucial issue. Little attention is paid to the proper formulations needed to improve the overall bioavailability of the active molecules. According to these data, many products prove to be insufficient to ensure full enteric absorption. The present review analysed the literature in the field of nutraceuticals for the treatment of dyslipidemia, focusing on resveratrol, red yeast rice, berberine, and plant sterols, which are among the nutraceuticals with the greatest formulation problems, highlighting bioavailability and the most suitable formulations.

High doses of paracetamol (APAP) can cause irreversible liver damage. Piperine (P) inhibits cytochrome P450, which is involved in the metabolism of various xenobiotics, including paracetamol. We evaluated the hepatoprotective effects of piperine with or without N-acetylcysteine (NAC) in APAP-induced hepatotoxicity. The mice were treated with two doses of piperine (P20 or P40) and/or NAC at 2 h after administration of APAP. The NAC+P20 and NAC+P40 groups showed a reduced area of necrosis, MMP-9 activity, and Casp-1 expression. Furthermore, the NAC+P20 group was the only treatment that reduced alanine aminotransferase (ALT) and increased the levels of sulfhydryl groups (-SH). In the NAC+P40 group, NLRP-3 expression was reduced. Aspartate aminotransferase (AST), thiobarbituric acid-reactive substances (TBARS), and IL-1β expression decreased in the NAC, NAC+P20, and NAC+P40 groups compared to the APAP group. The liver necrosis area, TNF levels, carbonylated protein, and IL-18 expression decreased in the P40, NAC, NAC+P20, and NAC+P40 groups compared to the APAP group. The cytokine IL-6 was reduced in all treatments. Piperine can be used in combination with NAC to treat APAP-induced hepatotoxicity.

Peripheral artery disease (PAD) is a vascular pathology with high prevalence among the aging population. PAD is associated with decreased cognitive performance, but the underlying mechanisms remain obscure. Normal brain function critically depends on an adequate adjustment of cerebral blood supply to match the needs of active brain regions via neurovascular coupling (NVC). NVC responses depend on healthy microvascular endothelial function. PAD is associated with significant endothelial dysfunction in peripheral arteries, but its effect on NVC responses has not been investigated. This study was designed to test the hypothesis that NVC and peripheral microvascular endothelial function are impaired in PAD. We enrolled 11 symptomatic patients with PAD and 11 age- and sex-matched controls. Participants were evaluated for cognitive performance using the Cambridge Neuropsychological Test Automated Battery and functional near-infrared spectroscopy to assess NVC responses during the cognitive n-back task. Peripheral microvascular endothelial function was evaluated using laser speckle contrast imaging. We found that cognitive performance was compromised in patients with PAD, evidenced by reduced visual memory, short-term memory, and sustained attention. We found that NVC responses and peripheral microvascular endothelial function were significantly impaired in patients with PAD. A positive correlation was observed between microvascular endothelial function, NVC responses, and cognitive performance in the study participants. Our findings support the concept that microvascular endothelial dysfunction and neurovascular uncoupling contribute to the genesis of cognitive impairment in older PAD patients with claudication. Longitudinal studies are warranted to test whether the targeted improvement of NVC responses can prevent or delay the onset of PAD-associated cognitive decline.NEW & NOTEWORTHY Peripheral artery disease (PAD) was associated with significantly decreased cognitive performance, impaired neurovascular coupling (NVC) responses in the prefrontal cortex (PFC), left and right dorsolateral prefrontal cortices (LDLPFC and RDLPFC), and impaired peripheral microvascular endothelial function. A positive correlation between microvascular endothelial function, NVC responses, and cognitive performance may suggest that PAD-related cognitive decrement is mechanistically linked, at least in part, to generalized microvascular endothelial dysfunction and subsequent impairment of NVC responses.

The poor oral bioavailability, rapid biotransformation to less active metabolites, and fast elimination from systemic circulation have been identified as the major limitations responsible for the clinical insignificance of many drug candidates and phytonutrients. Despite the technological advancements in the nanoformulations of synthetic drugs, there exist many challenges for nutritional therapy, due to the regulatory issues, use of high levels of synthetic emulsifiers and polymers, low stability, low loading levels, mainly liquid state, etc. Herein, we report the characterization and human pharmacokinetics of a natural self-emulsifying hybrid-hydrogel formulation of trans-resveratrol prepared by uniformly impregnating resveratrol micelles into the fenugreek galactomannan hydrogel scaffold to form a water-soluble micelle/hydrogel composite in powder form (RF-20). Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), particle size analysis by dynamic light scattering (DLS), and transmission electron microscopy (TEM) demonstrated the uniform impregnation of resveratrol micelles within the galactomannan hydrogel matrix to form a soluble (average particle size of 172.0 ± 10.4 nm and -21.0 ± 2.5 mV zeta potential) and amorphous powder form with smooth and translucent surface morphology for RF-20, with no chemical alterations. Upon pharmacokinetic studies on healthy human subjects (n = 16) following a randomized, double-blinded, placebo-controlled, 2-arm, 4-sequence crossover design and tandem mass spectrometry (UPLC-ESI-MS/MS), 80 mg of trans-resveratrol from RF-20 provided enhanced free resveratrol bioavailability and pharmacokinetic properties compared to the unformulated resveratrol with 98% purity. The enhancement in bioavailability was more when supplemented in sachet (12.98-fold) form than the capsule (10.48-fold) with improved absorption (C _max = 50.97 ± 15.82 ng/mL), circulation half-life (t _1/2 = 7.01 ± 1.44 h), and sustained delivery (T _max = 4.71 ± 0.73 h), as compared to the unformulated form (C _max = 15.07 ± 5.10 ng/mL; t _1/2 = 1.58 ± 0.65 h; T _max = 1.21 ± 0.42 h).

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are characterized by the progressive degeneration of neurons. Although the etiology and pathogenesis of neurodegenerative diseases have been studied intensively, the mechanism is still in its infancy. In general, most neurodegenerative diseases share common molecular mechanisms, and multiple risks interact and promote the pathologic process of neurogenerative diseases. At present, most of the approved drugs only alleviate the clinical symptoms but fail to cure neurodegenerative diseases. Numerous studies indicate that dietary plant polyphenols are safe and exhibit potent neuroprotective effects in various neurodegenerative diseases. However, low bioavailability is the biggest obstacle for polyphenol that largely limits its adoption from evidence into clinical practice. In this review, we summarized the widely recognized mechanisms associated with neurodegenerative diseases, such as misfolded proteins, mitochondrial dysfunction, oxidative damage, and neuroinflammatory responses. In addition, we summarized the research advances about the neuroprotective effect of the most widely reported dietary plant polyphenols. Moreover, we discussed the current clinical study and application of polyphenols and the factors that result in low bioavailability, such as poor stability and low permeability across the blood-brain barrier (BBB). In the future, the improvement of absorption and stability, modification of structure and formulation, and the combination therapy will provide more opportunities from the laboratory into the clinic for polyphenols. Lastly, we hope that the present review will encourage further researches on natural dietary polyphenols in the treatment of neurodegenerative diseases.

Translation of traditional knowledge of herbs into a viable product for clinical use is still an uphill task. Piperine, a pungent alkaloid molecule derived from Piper nigrum and Piper longum possesses diverse pharmacological effects. Traditionally, pepper is used for arthritis, bronchitis, gastritis, diarrhea, snake bite, menstrual pain, fever, and bacterial infections, etc. The anti-inflammatory, antioxidant and immunomodulatory actions of piperine are the possible mechanisms behind its therapeutic potential. Various in-silico and experimental studies have shown piperine as a possible promising molecule in coronavirus disease (COVID-19), ebola, and dengue due to its immunomodulatory and antiviral activities. The other important clinical applications of piperine are due to its bio enhancing effect on drugs, by modulating, absorption in the gastrointestinal tract, altering activities of transporters like p-glycoprotein substrates, and modulating drug metabolism by altering the expression of cytochrome P450 or UDP-glucuronosyltransferase enzymes. Piperine attracted clinicians in treating patients with arthritis, metabolic syndrome, diabetes, skin infections, gastric and liver disorders. This review focused on systematic, evidence-based insight into the use of piperine in clinical settings and mechanistic details behind its therapeutic actions. Also, highlights a number of clinical trials of piperine at various stages exploring its clinical application in cancer, neurological, respiratory, and viral disease, etc.

Polyphenols are a wide group of plant components that include a high number of individual compounds and are present in foods, dietary supplements and drugs. Many of them have shown pharmacological effects, are used in cardiovascular disease prevention, and not as many have been assayed in cancer treatment or co-treatment. In the last few years, however, the research on polyphenols implications in a healthy aging and especially in neurodegeneration and cognition improvement has increased dramatically. Most of the results found in this sense are again related with the capacity of some specific polyphenols to regulate the blood flow, but this time at the cerebral level, and to protect the endothelium at this same level. In this thorough review, we want to concentrate precisely on the effect of polyphenols on the cerebrovascular homeostasis, reviewing the mechanisms that underline this effect and the radiological methods and endogenous biomarkers that are used in human trials aimed at showing the beneficial effect of polyphenols or polyphenols rich foods on neuroprotection and cognition function.

Peanuts are rich in bioactive compounds that may have a positive impact on memory and stress response.

To evaluate the effect of regular consumption of peanut products on cognitive functions and stress response in healthy young adults.

A three-arm parallel-group randomized controlled trial was conducted in 63 healthy young adults that consumed 25 g/day of skin roasted peanuts (SRP, n = 21), 32 g/d of peanut butter (PB, n = 23) or 32 g/d of a control butter made from peanut oil (free of phenolic compounds and fiber) (CB, n = 19) for six months. Polyphenol intake, cognitive functions, and anxiety and depression scores were evaluated using validated tests. Fecal short-chain fatty acids (SCFAs) and plasma and fecal fatty acids were assessed by chromatographic methods. Urinary cortisol was quantified by an enzymatic method.

Comparing the two interventions with the control, a significant reduction in anxiety scores was observed in the SRP compared to the CB group. After the intervention, consumers of SRP and PB had an improved immediate memory (p = 0.046 and p = 0.011). Lower anxiety scores were associated with SRP and PB (p < 0.001 and p = 0.002, respectively) and lower depression scores with SRP, PB and CB (p = 0.007, p = 0.003 and p = 0.032, respectively). Memory functions and stress response were significantly correlated with polyphenol intake, fecal SCFAs, plasma and fecal very long chain saturated fatty acids (VLCSFAs).

Regular peanut and peanut butter consumption may enhance memory function and stress response in a healthy young population. These effects seem to be associated with the intake of peanut polyphenols, increased levels of fecal SCFAs, and unexpectedly, VLCSFAs, which were also present in the control product.

Respiratory inflammation is caused by an air-mediated disease induced by polluted air, smoke, bacteria, and viruses. The COVID-19 pandemic is also a kind of respiratory disease, induced by a virus causing a serious effect on the lungs, bronchioles, and pharynges that results in oxygen deficiency. Extensive research has been conducted to find out the potent natural products that help to prevent, treat, and manage respiratory diseases. Traditionally, wider floras were reported to be used, such as Morus alba, Artemisia indica, Azadirachta indica, Calotropis gigantea, but only some of the potent compounds from some of the plants have been scientifically validated. Plant-derived natural products such as colchicine, zingerone, forsythiaside A, mangiferin, glycyrrhizin, curcumin, and many other compounds are found to have a promising effect on treating and managing respiratory inflammation. In this review, current clinically approved drugs along with the efficacy and side effects have been studied. The study also focuses on the traditional uses of medicinal plants on reducing respiratory complications and their bioactive phytoconstituents. The pharmacological evidence of lowering respiratory complications by plant-derived natural products has been critically studied with detailed mechanism and action. However, the scientific validation of such compounds requires clinical study and evidence on animal and human models to replace modern commercial medicine.

The pathophysiology of psychiatric and neurodegenerative disorders is complex and multifactorial. Polyphenols possess a range of potentially beneficial mechanisms of action that relate to the implicated pathways in psychiatric and neurodegenerative disorders. The aim of this review is to highlight the emerging clinical trial and preclinical efficacy data regarding the role of polyphenols in mental and brain health, elucidate novel mechanisms of action including the gut microbiome and gene expression, and discuss the factors that may be responsible for the mixed clinical results; namely, the role of interindividual differences in treatment response and the potentially pro-oxidant effects of some polyphenols. Further clarification as part of larger, well conducted randomized controlled trials that incorporate precision medicine methods are required to inform clinical efficacy and optimal dosing regimens.

The present demographic changes toward an aging society caused a rise in the number of senior citizens and the incidence and burden of age-related diseases (such as cardiovascular diseases [CVD], cancer, nonalcoholic fatty liver disease [NAFLD], diabetes mellitus, and dementia), of which nearly half is attributable to the population ≥60 years of age. Deficiencies in individual nutrients have been associated with increased risks for age-related diseases and high intakes and/or blood concentrations with risk reduction. Nutrition in general and the dietary intake of essential and nonessential biofactors is a major determinant of human health, the risk to develop age-related diseases, and ultimately of mortality in the older population. These biofactors can be a cost-effective strategy to prevent or, in some cases, even treat age-related diseases. Examples reviewed herein include omega-3 fatty acids and dietary fiber for the prevention of CVD, α-tocopherol (vitamin E) for the treatment of biopsy-proven nonalcoholic steatohepatitis, vitamin D for the prevention of neurodegenerative diseases, thiamine and α-lipoic acid for the treatment of diabetic neuropathy, and the role of folate in cancer epigenetics. This list of potentially helpful biofactors in the prevention and treatment of age-related diseases, however, is not exhaustive and many more examples exist. Furthermore, since there is currently no generally accepted definition of the term biofactors, we here propose a definition that, when adopted by scientists, will enable a harmonization and consistent use of the term in the scientific literature.

Background: The effects of polyphenols on cognitive functions have been extensively studied. Due to the large heterogeneity in the study designs, however, it is often difficult to interpret their efficacy. To address this issue, we conducted a systematic review and meta-analyses to examine whether acute polyphenol intake may have a beneficial effect on cognition and specifically on the accuracy and speed of attention. Methods: PubMed and Scopus databases were systematically searched for studies published up to end of August 2020 following PRISMA guidelines (PROSPERO registration number: CRD42021232109). Only placebo-controlled human intervention trials that assessed acute effects of polyphenols on accuracy and speed of attention were included in the meta-analyses. When cognitive tasks were repeated over time, pooled means and standard deviations for intervention and placebo over repetitions separately for each task for both speed and accuracy were calculated. We also conducted separate analyses focusing only on the last repetition. Furthermore, confounding effects of age and source of polyphenols were also considered. Results: Eighteen studies met the inclusion criteria. The pooled analysis of last task repetitions showed that the acute consumption of polyphenols improved rapid visual information processing speed in young participants (SMD = 0.26; 95%CI = [0.03-0.50]; I ²= 0%; p = 0.02; k = 5). All other analyses did not reach significance. Conclusion: The results of the current study indicate that acute polyphenol consumption might improve speed in rapid visual information processing task, a higher order task with elements of vigilance, working memory, and executive function, in young participants; however, as the current literature is inconsistent and limited, further acute intervention studies are warranted to achieve more conclusive results.

While the elderly segment of the population continues growing in importance, neurodegenerative diseases increase exponentially. Lifestyle factors such as nutrition, exercise, and education, among others, influence ageing progression, throughout life. Notably, the Central Nervous System (CNS) can benefit from nutritional strategies and dietary interventions that prevent signs of senescence, such as cognitive decline or neurodegenerative diseases such as Alzheimer's disease and Parkinson's Disease. The dietary polyphenol Resveratrol (RV) possesses antioxidant and cytoprotective effects, producing neuroprotection in several organisms. The oxidative stress (OS) occurs because of Reactive oxygen species (ROS) accumulation that has been proposed to explain the cause of the ageing. One of the most harmful effects of ROS in the cell is DNA damage. Nevertheless, there is also evidence demonstrating that OS can produce other molecular changes such as mitochondrial dysfunction, inflammation, apoptosis, and epigenetic modifications, among others. Interestingly, the dietary polyphenol RV is a potent antioxidant and possesses pleiotropic actions, exerting its activity through various molecular pathways. In addition, recent evidence has shown that RV mediates epigenetic changes involved in ageing and the function of the CNS that persists across generations. Furthermore, it has been demonstrated that RV interacts with gut microbiota, showing modifications in bacterial composition associated with beneficial effects. In this review, we give a comprehensive overview of the main mechanisms of action of RV in different experimental models, including clinical trials and discuss how the interconnection of these molecular events could explain the neuroprotective effects induced by RV.