Identification of Anti-Neuroinflammatory Bioactive Compounds in Essential Oils and Aqueous Distillation Residues Obtained from Commercial Varieties of Cannabis sativa L.

Neuroinflammation, which is mainly triggered by microglia, is a key contributor to multiple neurodegenerative diseases. Natural products, and in particular Cannabis sativa L., due to its richness in phytochemical components, represent ideal candidates to counteract neuroinflammation. We previously characterized different C. sativa commercial varieties which showed significantly different chemical profiles. On these bases, the aim of this study was to evaluate essential oils and aqueous distillation residues from the inflorescences of three different hemp varieties for their anti-neuroinflammatory activity in BV-2 microglial cells. Cells were pretreated with aqueous residues or essential oils and then activated with LPS. Unlike essential oils, aqueous residues showed negligible effects in terms of anti-inflammatory activity. Among the essential oils, the one obtained from 'Gorilla Glue' was the most effective in inhibiting pro-inflammatory mediators and in upregulating anti-inflammatory ones through the modulation of the p38 MAPK/NF-κB pathway. Moreover, the sesquiterpenes (E)-caryophyllene, α-humulene, and caryophyllene oxide were identified as the main contributors to the essential oils' anti-inflammatory activity. To our knowledge, the anti-neuroinflammatory activity of α-humulene has not been previously described. In conclusion, our work shows that C. sativa essential oils characterized by high levels of sesquiterpenes can be promising candidates in the prevention/counteraction of neuroinflammation.

Autoimmune Thyroid Disorders: The Mediterranean Diet as a Protective Choice.

Autoimmune thyroid diseases are on the rise worldwide, and such a rapid increase is mainly driven by environmental factors related to changed lifestyles in "modern" societies. In this context, diet seems to play a crucial role. An unhealthy high-energy diet, rich in animal fat and proteins, salt and refined sugars (the so-called "Western diet") negatively influences the risk of autoimmunity by altering the immune balance and the gut microbiota composition, enhancing oxidative stress and promoting inflammation. In contrast, the Mediterranean diet represents a unique model of healthy eating, characterized by a high intake of food from vegetable sources, a low consumption of saturated fats in favor of unsaturated fats (mainly, olive oil), a moderate consumption of fish (typically, the small oily fishes) and dairy products, as well as a moderate consumption of wine at meals, and a low intake of meat. Thanks to its nutritional components, the Mediterranean Diet positively influences immune system function, gut microbiota composition, and redox homeostasis, exerting anti-oxidants, anti-inflammatory, and immunomodulatory effects. The present review was aimed at exploring the existing knowledge on the correlations between dietary habits and thyroid autoimmunity, to evaluate the role of the Mediterranean diet as a protective model.

By-Product Extracts from Castanea sativa Counteract Hallmarks of Neuroinflammation in a Microglial Model.

Castanea sativa is very common in Italy, and the large amount of waste material generated during chestnut processing has a high environmental impact. Several studies demonstrated that chestnut by-products are a good source of bioactive compounds, mainly endowed with antioxidant properties. This study further investigates the anti-neuroinflammatory effect of chestnut leaf and spiny bur extracts, together with the deepest phytochemical characterisation (by NMR and MS) of active biomolecules contained in leaf extracts, which resulted in being more effective than spiny bur ones. BV-2 microglial cells stimulated with lipopolysaccharide (LPS) were used as a model of neuroinflammation. In BV-2 cells pre-treated with chestnut extracts, LPS signalling is partially blocked via the reduced expression of TLR4 and CD14 as well as the expression of LPS-induced inflammatory markers. Leaf extract fractions revealed the presence of specific flavonoids, such as isorhamnetin glucoside, astragalin, myricitrin, kaempferol 3-rhamnosyl (1-6)(2″-trans-p-coumaroyl)hexoside, tiliroside and unsaturated fatty acids, all of which could be responsible for the observed anti-neuroinflammatory effects. Interestingly, the kaempferol derivative has been identified in chestnut for the first time. In conclusion, the exploitation of chestnut by-products is suitable for the achievement of two goals: satisfaction of consumers' demand for new, natural bio-active compounds and valorisation of by-products.

Agri-Food Waste from Apple, Pear, and Sugar Beet as a Source of Protective Bioactive Molecules for Endothelial Dysfunction and Its Major Complications.

Endothelial damage is recognized as the initial step that precedes several cardiovascular diseases (CVD), such as atherosclerosis, hypertension, and coronary artery disease. It has been demonstrated that the best treatment for CVD is prevention, and, in the frame of a healthy lifestyle, the consumption of vegetables, rich in bioactive molecules, appears effective at reducing the risk of CVD. In this context, the large amount of agri-food industry waste, considered a global problem due to its environmental and economic impact, represents an unexplored source of bioactive compounds. This review provides a summary regarding the possible exploitation of waste or by-products derived by the processing of three traditional Italian crops-apple, pear, and sugar beet-as a source of bioactive molecules to protect endothelial function. Particular attention has been given to the bioactive chemical profile of these pomaces and their efficacy in various pathological conditions related to endothelial dysfunction. The waste matrices of apple, pear, and sugar beet crops can represent promising starting material for producing "upcycled" products with functional applications, such as the prevention of endothelial dysfunction linked to cardiovascular diseases.

Microalgae biomass concentration and reuse of water as new cultivation medium using ceramic membrane filtration.

The aim of this study is to advance means for microalgae dewatering with the simultaneous reuse of water as new cultivation medium, specifically through ceramic membrane filtration. Three algae, namely, Spirulina platensis, Scenedesmus obliquus, and Chlorella sorokiniana were tested by filtering suspensions with four ceramic membranes having nominal pore sizes of 0.8 µm, 0.14 µm, 300 kDa, 15 kDa. The observed flux values and organic matter removal rates were related to the membrane pore size and cake layer properties, with some differences in productivity between algae types, likely due to cell size and shape. Interestingly, similar near steady-state fluxes (70-120 L m-2h-1) were measured using membranes with nominal pore size above 15 kDa, suggesting the dominance of cake layer filtration independently of the initial flux. Virtually complete algae cells rejections and high nutrient passage (>75%) were observed in all combinations. When the permeate streams were used as media for new growth cycles of the various algae, no or little growth was observed with Spirulina p., while Chlorella s. (permeate from 300 kDa membrane) and especially Scenedesmus o. (permeate from 0.14 µm membrane) showed the fastest growth rates, almost comparable to those observed with ideal fresh media.

Mechanisms Underlying Neurodegenerative Disorders and Potential Neuroprotective Activity of Agrifood By-Products.

Neurodegenerative diseases, characterized by progressive loss in selected areas of the nervous system, are becoming increasingly prevalent worldwide due to an aging population. Despite their diverse clinical manifestations, neurodegenerative diseases are multifactorial disorders with standard features and mechanisms such as abnormal protein aggregation, mitochondrial dysfunction, oxidative stress and inflammation. As there are no effective treatments to counteract neurodegenerative diseases, increasing interest has been directed to the potential neuroprotective activities of plant-derived compounds found abundantly in food and in agrifood by-products. Food waste has an extremely negative impact on the environment, and recycling is needed to promote their disposal and overcome this problem. Many studies have been carried out to develop green and effective strategies to extract bioactive compounds from food by-products, such as peel, leaves, seeds, bran, kernel, pomace, and oil cake, and to investigate their biological activity. In this review, we focused on the potential neuroprotective activity of agrifood wastes obtained by common products widely produced and consumed in Italy, such as grapes, coffee, tomatoes, olives, chestnuts, onions, apples, and pomegranates.

Moderate Wine Consumption and Health: A Narrative Review.

Although it is clearly established that the abuse of alcohol is seriously harmful to health, much epidemiological and clinical evidence seem to underline the protective role of moderate quantities of alcohol and in particular of wine on health. This narrative review aims to re-evaluate the relationship between the type and dose of alcoholic drink and reduced or increased risk of various diseases, in the light of the most current scientific evidence. In particular, in vitro studies on the modulation of biochemical pathways and gene expression of wine bioactive components were evaluated. Twenty-four studies were selected after PubMed, Scopus and Google Scholar searches for the evaluation of moderate alcohol/wine consumption and health effects: eight studies concerned cardiovascular diseases, three concerned type 2 diabetes, four concerned neurodegenerative diseases, five concerned cancer and four were related to longevity. A brief discussion on viticultural and enological practices potentially affecting the content of bioactive components in wine is included. The analysis clearly indicates that wine differs from other alcoholic beverages and its moderate consumption not only does not increase the risk of chronic degenerative diseases but is also associated with health benefits particularly when included in a Mediterranean diet model. Obviously, every effort must be made to promote behavioral education to prevent abuse, especially among young people.

Acid Sphingomyelinase Controls Early Phases of Skeletal Muscle Regeneration by Shaping the Macrophage Phenotype.

Skeletal muscle regeneration is a complex process involving crosstalk between immune cells and myogenic precursor cells, i.e., satellite cells. In this scenario, macrophage recruitment in damaged muscles is a mandatory step for tissue repair since pro-inflammatory M1 macrophages promote the activation of satellite cells, stimulating their proliferation and then, after switching into anti-inflammatory M2 macrophages, they prompt satellite cells' differentiation into myotubes and resolve inflammation. Here, we show that acid sphingomyelinase (ASMase), a key enzyme in sphingolipid metabolism, is activated after skeletal muscle injury induced in vivo by the injection of cardiotoxin. ASMase ablation shortens the early phases of skeletal muscle regeneration without affecting satellite cell behavior. Of interest, ASMase regulates the balance between M1 and M2 macrophages in the injured muscles so that the absence of the enzyme reduces inflammation. The analysis of macrophage populations indicates that these events depend on the altered polarization of M1 macrophages towards an M2 phenotype. Our results unravel a novel role of ASMase in regulating immune response during muscle regeneration/repair and suggest ASMase as a supplemental therapeutic target in conditions of redundant inflammation that impairs muscle recovery.

Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease.

The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 µM), confirming the design rationale.

Influence of Dietary Habits on Oxidative Stress Markers in Hashimoto's Thyroiditis.

Background: There is a growing awareness that nutritional habits may influence risk of several inflammatory and immune-mediated disorders, including autoimmune diseases, through various mechanisms. The aim of the present study was to investigate dietary habits and their relationship with redox homeostasis in the setting of thyroid autoimmunity. Materials and Methods: Two hundred subjects (173 females and 27 males; median age, 37 years) were enrolled. None were under any pharmacological treatment. Exclusion criteria were any infectious/inflammatory/autoimmune comorbidity, kidney failure, diabetes, and cancer. In each subject, serum thyrotropin (TSH), free thyroxine, antithyroid antibodies, and circulating oxidative stress markers were measured. A questionnaire on dietary habits, evaluating the intake frequencies of food groups and adherence to the Mediterranean diet, was submitted to each participant. Results: Among the 200 recruited subjects, 81 (71 females and 10 males) were diagnosed with euthyroid Hashimoto's thyroiditis (HT); the remaining 119 (102 females and 17 males) served as controls. In questionnaires, HT subjects reported higher intake frequencies of animal foods (meat, p = 0.0001; fish, p = 0.0001; dairy products, p = 0.004) compared with controls, who reported higher intake frequencies of plant foods (legumes, p = 0.001; fruits and vegetables, p = 0.030; nuts, p = 0.0005). The number of subjects who preferentially consumed poultry instead of red/processed meat was lower in HT subjects than in controls (p = 0.0141). In logistic regression analysis, meat consumption was associated with increased odds ratio of developing thyroid autoimmunity, while the Mediterranean diet traits were protective. In HT subjects, serum advanced glycation end products (markers of oxidative stress) were significantly higher (p = 0.0001) than in controls, while the activity of glutathione peroxidase and thioredoxin reductase, as well as total plasma antioxidant activity, were lower (p = 0.020, p = 0.023, and p = 0.002, respectively), indicating a condition of oxidative stress. Stepwise regression models demonstrated a significant dependence of oxidative stress parameters on consumption of animal foods, mainly meat. Conclusions: The present study suggests a protective effect of low intake of animal foods toward thyroid autoimmunity and a positive influence of such nutritional patterns on redox balance and potentially on oxidative stress-related disorders.

The Mediterranean Athlete's Nutrition: Are Protein Supplements Necessary?

(1) Background: It is recommended that an athlete, in order to ensure correct nutrition and performance, should consume between 1.2 and 2.0 g/kg/day of protein, while the daily recommended protein intake for a non-athlete is 0.8and 0.9 mg/kg/day. It is unclear if athletes living in Mediterranean countries are able to meet protein requirements without supplementation, since Mediterranean diet de-emphasizes meat and meat products. (2) Methods: 166 athletes (125 males) enrolled between 2017 and 2019 were required to keep a dietary journal for three consecutive days (2 workdays and 1 weekend day). Athletes had to be >18 years old, train in a particular sport activity more than 3 h a week and compete at least at an amateur level. Journal data were collected and then translated into macro-nutrient content (grams of protein, carbohydrates, and lipids) by a nutritionist. (3) Results: The protein intake reported by this specific population vary slightly from the Academy of Nutrition and Dietetics (AND), Dietitians of Canada (DC), and the American College of Sports Medicine (ACSM) joint statement recommendation level. Average protein levels without protein supplementation fell within the protein guidelines. Counterintuitively, the intake among those who supplemented their diet with protein was higher compared with those who did not, even when excluding the contribution of supplements. Although the majority of subjects participating in the study were able to meet protein intake recommended for athletes without protein supplementation, 27% of athletes were below the guideline range. (4) Conclusions: these data suggest that athletes' nutrition should be more often evaluated by a nutritionist and that they will benefit from increasing their nutritional knowledge in order to make better food choices, resorting to protein supplementation only when effectively needed.

Leaves and Spiny Burs of Castanea Sativa from an Experimental Chestnut Grove: Metabolomic Analysis and Anti-Neuroinflammatory Activity.

Castanea sativa cultivation has been present in Mediterranean regions since ancient times. In order to promote a circular economy, it is of great importance to valorize chestnut groves' by-products. In this study, leaves and spiny burs from twenty-four Castanea trees were analyzed by 1H NMR metabolomics to provide an overview of their phytochemical profile. The Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) performed on these data allowed us to distinguish 'Marrone' from 'Castagna', since the latter were generally more enriched with secondary metabolites, in particular, flavonoids (astragalin, isorhamnetin glucoside, and myricitrin) were dominant. Knowing that microglia are involved in mediating the oxidative and inflammatory response of the central nervous system, the potential anti-inflammatory effects of extracts derived from leaves and spiny burs were evaluated in a neuroinflammatory cell model: BV-2 microglia cells. The tested extracts showed cytoprotective activity (at 0.1 and 0.5 mg/mL) after inflammation induction by 5 µg/mL lipopolysaccharide (LPS). In addition, the transcriptional levels of IL-1ß, TNF-α, and NF-kB expression induced by LPS were significantly decreased by cell incubation with spiny burs and leaves extracts. Taken together, the obtained results are promising and represent an important step to encourage recycling and valorization of chestnut byproducts, usually considered "waste".

The "Elderly" Lesson in a "Stressful" Life: Italian Holistic Approach to Increase COVID-19 Prevention and Awareness.

It's a frightening time due to COVID-19, but the great elderly/centenarians, apparently with more frailty, seem to have a better response to the pandemic. "The South Italy" lifestyle seems an "effective strategy" promoting the well-being embedded in a holistic solution: healthy diet, less exposure to PM10 pollution, protected environment, and moderate physical activity. The European FP7 Project RISTOMED results, since 2010, have shown that dietary intervention improved a heathy status in the elderly people. Based on the RISTOMED results, in addition to sociocultural and environmental factors, the authors suggest an integrated approach for resilience to COVID-19. Such an approach during the next months could make the difference for the success of any government progress policy to fight COVID-19, finalizing long-term well-being and successful aging.

Fruit Quality Characterization of New Sweet Cherry Cultivars as a Good Source of Bioactive Phenolic Compounds with Antioxidant and Neuroprotective Potential.

Sweet cherries (Prunus avium L.) are highly appreciated fruits for their taste, color, nutritional value, and beneficial health effects. In this work, seven new cultivars of sweet cherry were investigated for their main quality traits and nutraceutical value. The phytochemical profile of three classes of phenolic compounds and the antioxidant activity of the new cultivars were investigated through high-performance liquid chromatography with diode array detection (HPLC-DAD) and spectrophotometric assays, respectively, and compared with those of commonly commercialized cultivars. Cyanidine-3-O-rutinoside was the main anthocyanin in all genotypes, and its levels in some new cultivars were about three-fold higher than in commercial ones. The ORAC-assayed antioxidant capacity was positively correlated with the total anthocyanin index. The nutraceutical value of the new cultivars was investigated in terms of antioxidant/neuroprotective capacity in neuron-like SH-SY5Y cells. Results demonstrated that the new cultivars were more effective in counteracting oxidative stress and were also able to upregulate brain-derived neurotrophic factor (BDNF), a pro-survival neurotrophin, suggesting their potential pleiotropic role in counteracting neurodegenerations.

Common Protective Strategies in Neurodegenerative Disease: Focusing on Risk Factors to Target the Cellular Redox System.

Neurodegenerative disease is an umbrella term for different conditions which primarily affect the neurons in the human brain. In the last century, significant research has been focused on mechanisms and risk factors relevant to the multifaceted etiopathogenesis of neurodegenerative diseases. Currently, neurodegenerative diseases are incurable, and the treatments available only control the symptoms or delay the progression of the disease. This review is aimed at characterizing the complex network of molecular mechanisms underpinning acute and chronic neurodegeneration, focusing on the disturbance in redox homeostasis, as a common mechanism behind five pivotal risk factors: aging, oxidative stress, inflammation, glycation, and vascular injury. Considering the complex multifactorial nature of neurodegenerative diseases, a preventive strategy able to simultaneously target multiple risk factors and disease mechanisms at an early stage is most likely to be effective to slow/halt the progression of neurodegenerative diseases.

The Central Role of Iron in Human Nutrition: From Folk to Contemporary Medicine.

Iron is a fundamental element in human history, from the dawn of civilization to contemporary days. The ancients used the metal to shape tools, to forge weapons, and even as a dietary supplement. This last indication has been handed down until today, when martial therapy is considered fundamental to correct deficiency states of anemia. The improvement of the martial status is mainly targeted with dietary supplements that often couple diverse co-factors, but other methods are available, such as parenteral preparations, dietary interventions, or real-world approaches. The oral absorption of this metal occurs in the duodenum and is highly dependent upon its oxidation state, with many absorption influencers possibly interfering with the intestinal uptake. Bone marrow and spleen represent the initial and ultimate step of iron metabolism, respectively, and the most part of body iron circulates bound to specific proteins and mainly serves to synthesize hemoglobin for new red blood cells. Whatever the martial status is, today's knowledge about iron biochemistry allows us to embrace exceedingly personalized interventions, which however owe their success to the mythical and historical events that always accompanied this metal.

Oral Supplementation with Sucrosomial Ferric Pyrophosphate Plus L-Ascorbic Acid to Ameliorate the Martial Status: A Randomized Controlled Trial.

Altered martial indices before orthopedic surgery are associated with higher rates of complications and greatly affect the patient's functional ability. Oral supplements can optimize the preoperative martial status, with clinical efficacy and the patient's tolerability being highly dependent on the pharmaceutical formula. Patients undergoing elective hip/knee arthroplasty were randomized to be supplemented with a 30-day oral therapy of sucrosomial ferric pyrophosphate plus L-ascorbic acid. The tolerability was 2.7% among treated patients. Adjustments for confounding factors, such as iron absorption influencers, showed a relevant response limited to older patients (≥ 65 years old), whose uncharacterized Hb loss was averted upon treatment with iron formula. Older patients with no support lost -2.8 ± 5.1%, while the intervention group gained +0.7 ± 4.6% of circulating hemoglobin from baseline (p = 0.019). Gastrointestinal diseases, medications, and possible dietary factors could affect the efficacy of iron supplements. Future opportunities may consider to couple ferric pyrophosphate with other nutrients, to pay attention in avoiding absorption disruptors, or to implement interventions to obtain an earlier martial status optimization at the population level.

Nutraceuticals and physical activity: Their role on oxysterols-mediated neurodegeneration.

Over the past few years, the contribution of oxysterols to the onset and development of some of the major neurodegenerative diseases (such as Alzheimer's and Parkinson's diseases) has been scientifically asserted, being mainly related to altered brain cholesterol homeostasis. To counteract oxysterol induced inflammation at neuronal level, one possible intervention approach is the administration of some nutrients and/or plant secondary metabolites. On the other hand, the pleiotropic beneficial effects of physical activity seem to play an important role on prevention and counteraction of neurodegenerative diseases, through the modulation of oxysterol homeostasis and the prevention of demyelination. The present review provides a picture of the promising role of nutraceuticals and physical activity on oxysterol-mediated neurodegeneration, pointing out also the different in vitro and in vivo aspects that need to be further investigated for a better understanding of the association of these three counterparts and their overall effect on people at increased risk for neurodegenerative diseases.

Anti-Inflammatory Activities of Marine Algae in Neurodegenerative Diseases.

Neuroinflammation is one of the main contributors to the onset and progression of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Microglial and astrocyte activation is a brain defense mechanism to counteract harmful pathogens and damaged tissues, while their prolonged activation induces neuroinflammation that can trigger or exacerbate neurodegeneration. Unfortunately, to date there are no pharmacological therapies able to slow down or stop the progression of neurodegeneration. For this reason, research is turning to the identification of natural compounds with protective action against these diseases. Considering the important role of neuroinflammation in the onset and development of neurodegenerative pathologies, natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Marine organisms represent a huge source of natural compounds, and among them, algae are appreciated sources of important bioactive components such as antioxidants, proteins, vitamins, minerals, soluble dietary fibers, polyunsaturated fatty acids, polysaccharides, sterols, carotenoids, tocopherols, terpenes, phycobilins, phycocolloids, and phycocyanins. Recently, numerous anti-inflammatory compounds have been isolated from marine algae with potential protective efficacy against neuroinflammation. This review highlights the key inflammatory processes involved in neurodegeneration and the potential of specific compounds from marine algae to counteract neuroinflammation in the CNS.

Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles.

Preclinical and clinical studies suggest that many food molecules could interact with drug transporters and metabolizing enzymes through different mechanisms, which are predictive of what would be observed clinically. Given the recent incorporation of dietary modifications or supplements in traditional medicine, an increase in potential food-drug interactions has also appeared. The objective of this article is to review data regarding the influence of food on drug efficacy. Data from Google Scholar, PubMed, and Scopus databases was reviewed for publications on pharmaceutical, pharmacokinetic, and pharmacodynamic mechanisms. The following online resources were used to integrate functional and bioinformatic results: FooDB, Phenol-Explorer, Dr. Duke's Phytochemical and Ethnobotanical Databases, DrugBank, UniProt, and IUPHAR/BPS Guide to Pharmacology. A wide range of food compounds were shown to interact with proteins involved in drug pharmacokinetic/pharmacodynamic profiles, starting from drug oral bioavailability to enteric/hepatic transport and metabolism, blood transport, and systemic transport/metabolism. Knowledge of any food components that may interfere with drug efficacy is essential, and would provide a link for obtaining a holistic view for cancer, cardiovascular, musculoskeletal, or neurological therapies. However, preclinical interaction may be irrelevant to clinical interaction, and health professionals should be aware of the limitations if they intend to optimize the therapeutic effects of drugs.