Nutraceuticals in the Prevention of Neonatal Hypoxia-Ischemia: A Comprehensive Review of their Neuroprotective Properties, Mechanisms of Action and Future Directions.

Neonatal hypoxia-ischemia (HI) is a brain injury caused by oxygen deprivation to the brain due to birth asphyxia or reduced cerebral blood perfusion, and it often leads to lifelong limiting sequelae such as cerebral palsy, seizures, or mental retardation. HI remains one of the leading causes of neonatal mortality and morbidity worldwide, and current therapies are limited. Hypothermia has been successful in reducing mortality and some disabilities, but it is only applied to a subset of newborns that meet strict inclusion criteria. Given the unpredictable nature of the obstetric complications that contribute to neonatal HI, prophylactic treatments that prevent, rather than rescue, HI brain injury are emerging as a therapeutic alternative. Nutraceuticals are natural compounds present in the diet or used as dietary supplements that have antioxidant, anti-inflammatory, or antiapoptotic properties. This review summarizes the preclinical in vivo studies, mostly conducted on rodent models, that have investigated the neuroprotective properties of nutraceuticals in preventing and reducing HI-induced brain damage and cognitive impairments. The natural products reviewed include polyphenols, omega-3 fatty acids, vitamins, plant-derived compounds (tanshinones, sulforaphane, and capsaicin), and endogenous compounds (melatonin, carnitine, creatine, and lactate). These nutraceuticals were administered before the damage occurred, either to the mothers as a dietary supplement during pregnancy and/or lactation or to the pups prior to HI induction. To date, very few of these nutritional interventions have been investigated in humans, but we refer to those that have been successful in reducing ischemic stroke in adults. Overall, there is a robust body of preclinical evidence that supports the neuroprotective properties of nutraceuticals, and these may represent a safe and inexpensive nutritional strategy for the prevention of neonatal HI encephalopathy.

Hydroxycinnamic acid derivatives isolated from hempseed and their effects on central nervous system enzymes.

New neuroprotective treatments of natural origin are being investigated. Both, plant extracts and isolated compounds have shown bioactive effects. Hempseed is known for its composition of fatty acids, proteins, fibre, vitamins, as well as a large number of phytochemical compounds. After a defatting process of the seeds, hydroxycinnamic acids and its amine derivatives are the majoritarian compounds in an ethyl acetate fraction (EAF). In the present study, we investigated in vitro effect on neuronal enzymes: MAO-A, MAO-B, tyrosinase and acetylcholinesterase. Besides, the effect of EAF on striatal biogenic amines in mice was evaluated. Both, EAF and isolated compounds (N-trans-caffeoyltyramine and N-trans-coumaroyltyramine), showed inhibitory action on MAO-A, MAO-B and tyrosinase. Furthermore, an increasing of biogenic amines was observed in the corpus striatum of the mice, after administration of EAF. These findings show that EAF and the hydroxycinnamic acid derivatives may represent a potential treatment in degenerative neuronal diseases.

Characterization of bioactive compounds in defatted hempseed (Cannabis sativa L.) by UHPLC-HRMS/MS and anti-inflammatory activity in primary human monocytes.

Hempseed (Cannabis sativa L.) has beneficial impact on human health mainly because of its wide variability of bioactive compounds. However, many of them are not fully characterized yet. In this work, hempseed was defatted and through a bio-guided studied, two fractions (F03 and F05) with the highest content of phenols, flavonoids and antioxidant capacity were selected. Fractions were chemically analyzed by UHPLC HRMS/MS. The anti-inflammatory capacities of these compounds were evaluated on human monocytes using flow cytometry, RT-qPCR and Elisa procedures. A high amount of phenolic compounds were identified, with the major compound being: N-trans-caffeoyltyramine (6.36 mg g-1 in F05 and 1.28 mg g-1 in F03). Both, F03 and F05 significantly reduced the inflammatory competence of LPS-treated human primary monocytes, decreasing TNF-α and IL-6 gene expression and secretion. These findings indicate that in the defatted fraction of the hempseed there are a wide number of compounds with beneficial potential to prevent and treat inflammatory disorders, as well as other processes caused by oxidative stress.

Ginger rhizome enhances the anti-inflammatory and anti-nociceptive effects of paracetamol in an experimental mouse model of fibromyalgia.

BACKGROUND: The dried rhizome of ginger has been widely used for more than 2500 years in folk medicine for the treatment of various diseases that involve inflammation or are caused by oxidative stress. AIMS: This study was designed to compare the anti-nociceptive and anti-inflammatory effect of dried powdered ginger rhizome (GR) and paracetamol (APAP) on an experimental mouse model of fibromyalgia syndrome (FMS) induced by intermittent cold stress (ICS). METHODS: Forty-eight female C57BL/6 J mice were used for the experiments. The animals were allocated in six groups (n = 8). Each group received one of the following treatments for 8 weeks: healthy control, ICS group, ICS + APAP (40 mg/Kg/day), ICS + GR (0.5%); ICS + GR (1%), and ICS + GR (0.5%) + APAP (40 mg/Kg/day). After treatment, symptoms of FMS were induced by intermittent cold stress (ICS). RESULTS AND CONCLUSIONS: GR consumption improved mechanical and thermal allodynia and mechanical hyperalgesia and improved behavioural changes related to cognitive disturbances, anxiety, and depression. In addition, GR also significantly decreased the inflammatory response of proinflammatory mediators such as NO, PGE2, TXB2, and IL-1ß in LPS-stimulated macrophages. The effects of APAP were significantly enhanced by co-administration with GR. These findings provide evidence that the daily consumption of GR enhances the anti-nociceptive effect of APAP in mice, improves other cognitive disturbances associated with chronic pain, and reduces the inflammatory state generated in an experimental FMS model.

Mitraphylline inhibits lipopolysaccharide-mediated activation of primary human neutrophils.

BACKGROUND: Mitraphylline (MTP) is the major pentacyclic oxindolic alkaloid presented in Uncaria tomentosa. It has traditionally been used to treat disorders including arthritis, heart disease, cancer, and other inflammatory diseases. However, the specific role of MTP is still not clear, with more comprehensivestudies, our understanding of this ancient herbal medicine will continue growing. HYPOTHESIS/PURPOSE: Some studies provided its ability to inhibit proinflamatory cytokines, such as TNF-α, through NF-κB-dependent mechanism. TNF-α primes neutrophils and modulates phagocytic and oxidative burst activities in inflammatory processes. Since, neutrophils represent the most abundant pool of leukocytes in human blood and play a crucial role in inflammation, we aimed to determine the ability of MTP to modulate neutrophil activation and differentially regulate inflammatory-related cytokines. METHODS: To determine the mechanism of action of MTP, we investigated the effects on LPS-activated human primary neutrophils responses including activation surface markers by FACS and the expression of inflammatory cytokines, measured by real time PCR and ELISA. RESULTS: Treatment with MTP reduced the LPS-dependent activation effects. Activated neutrophils (CD16(+)CD62L(-)) diminished after MTP administration. Moreover, proinflamatory cytokines (TNF-α, IL-6 or IL-8) expression and secretion were concomitantly reduced, similar to basal control conditions. CONCLUSION: Taken together, our results demonstrate that MTP is able to elicit an anti-inflammatory response that modulates neutrophil activation contributing to the attenuation of inflammatory episodes. Further studies are need to characterize the mechanism by which MTP can affect this pathway that could provide a means to develop MTP as new candidate for inflammatory disease therapies.

Self-care Improvement After a Pharmaceutical Intervention in Elderly Type 2 Diabetic Patients.

Diabetes mellitus involves long-term complications that affect diabetic patients' quality of life. The best way to prevent these complications is that patients achieve good metabolic control. In order to reach this goal, patients are requested to acquire daily behaviours (self-care). Such behaviours are sometimes hard to adhere, because they require changes in habits acquired over time. The aim of the present study is to evaluate the improvement on self-care after a pharmaceutical intervention on home regime patients. We performed a controlled experimental comparative study with a follow up of 6 months, on 87 patients, randomized in control group (n=43) and intervention group (n=44). We accessed sociodemographic and clinical data (glycaemic profile), as well as adherence to drug therapy and self-assessed care (before/after). In the intervention group, mean age was 74.2±5.4 years, and the median time of T2DM diagnosis was 14.7±8.5 years. At the end of study, the decrease in fasting blood glucose was higher in the intervention group patients than that observed in the control group (50.2mg/dL), with statistically significant difference (p<0.05), as well as the decrease verified in HbA1c. In self-care adherence, alterations in the levels of adherence of the general nutrition and physical exercise dimensions became evident, with an increase in the number of days of adherence. On medication adherence statistically significant alterations (p<0.05) were also recorded. We can conclude that an individualized pharmaceutical intervention can improve self-care behaviours, as well as medication adherence, contributing to better metabolic control.

Sucrose esters from Physalis peruviana calyces with anti-inflammatory activity.

Physalis peruviana is a native plant from the South American Andes and is widely used in traditional Colombian medicine of as an anti-inflammatory medicinal plant, specifically the leaves, calyces, and small stems in poultice form. Previous studies performed by our group on P. peruviana calyces showed potent anti-inflammatory activity in an enriched fraction obtained from an ether total extract. The objective of the present study was to obtain and elucidate the active compounds from this fraction and evaluate their anti-inflammatory activity in vivo and in vitro. The enriched fraction of P. peruviana was purified by several chromatographic methods to obtain an inseparable mixture of two new sucrose esters named peruviose A (1) and peruviose B (2). Structures of the new compounds were elucidated using spectroscopic methods and chemical transformations. The anti-inflammatory activity of the peruvioses mixture was evaluated using λ-carrageenan-induced paw edema in rats and lipopolysaccharide-activated peritoneal macrophages. Results showed that the peruvioses did not produce side effects on the liver and kidneys and significantly attenuated the inflammation induced by λ-carrageenan in a dosage-dependent manner, probably due to an inhibition of nitric oxide and prostaglandin E2, which was demonstrated in vitro. To our knowledge, this is the first report of the presence of sucrose esters in P. peruviana that showed a potent anti-inflammatory effect. These results suggest the potential of sucrose esters from the Physalis genus as a novel natural alternative to treat inflammatory diseases.

Bioactive constituents from "triguero" asparagus improve the plasma lipid profile and liver antioxidant status in hypercholesterolemic rats.

We have previously shown that the Andalusian-cultivated Asparagus officinalis L. "triguero" variety produces hypocholesterolemic and hepatoprotective effects on rats. This asparagus is a rich source of phytochemicals although we hypothesized there would be some of them more involved in these functional properties. Thus, we aimed to study the effects of asparagus (500 mg/kg body weight (bw)/day) and their partially purified fractions in flavonoids (50 mg/kg bw/day), saponins (5 mg/kg bw/day) and dietary fiber (500 mg/kg bw/day) on oxidative status and on lipid profile in rats fed a cholesterol-rich diet. After 5 weeks treatment, plasma lipid values, hepatic enzyme activities and liver malondialdehyde (MDA) concentrations were measured. With the exception of the saponin fraction (SF), the administration of lyophilized asparagus (LA), fiber fraction (FF), and flavonoid fraction (FVF) to hypercholesterolemic rats produced a significant hypolipidemic effect compare to a high-cholesterol diet (HCD). In addition, the LA and FVF groups exhibited a significant increase in enzyme activity from multiple hepatic antioxidant systems including: superoxide dismutase, catalase, and gluthatione reductase/peroxidase as well as a decrease in MDA concentrations compared to HCD group. These results demonstrate that "triguero" asparagus possesses bioactive constituents, especially dietary fiber and flavonoids, that improve the plasma lipid profile and prevent hepatic oxidative damage under conditions of hypercholesterolemia.

Cytotoxic effect of the pentacyclic oxindole alkaloid mitraphylline isolated from Uncaria tomentosa bark on human Ewing's sarcoma and breast cancer cell lines.

Preparations from Uncaria tomentosa, a South American Rubiaceae, have been used in the Peruvian traditional medicine for the treatment of infective, inflammatory and tumoral processes. In this study, the pentacyclic oxindole alkaloid mitraphylline was isolated from the dried inner bark of this plant species, and its structure elucidated by analysis of NMR spectroscopic data. Mitraphylline was differentially identified from its stereoisomeric pair isomitraphylline by (15)N-NMR. Its antiproliferative and cytotoxic effects have been tested on human Ewing's sarcoma MHH-ES-1 and breast cancer MT-3 cell lines, using cyclophosphamide and vincristine as reference controls. A Coulter counter was used to determine viable cell numbers, followed by the application of the tetrazolium compound MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium] an inner salt. A colorimetric method was employed to evaluate cell viability in this cytotoxic assay. Micromolar concentrations of mitraphylline (5 microM to 40 microM) inhibited the growth of both cell lines in a dose-dependent manner. The IC (50) +/- SE values were 17.15 +/- 0.82 microM for MHH-ES-1 and 11.80 +/- 1.03 microM for MT-3 for 30 hours, smaller than those obtained for the reference compounds. This action suggests that the pentacyclic oxindole alkaloid mitraphylline might be a new promising agent in the treatment of both human sarcoma and breast cancer.

Influence of dietary fat on oxidative stress and inflammation in murine macrophages.

OBJECTIVE: Many studies have shown that the nature of the lipid consumed in the diet significantly affects the development of inflammatory diseases. In this study, we compared the effect of diets supplemented with 15% by weight of fish oil (FO), refined olive oil (ROO), and pomace olive oil (POO) with that of a low-fat diet, 2% by weight of corn oil, considered as the basal diet (BD), on the ability to modify reactive oxidative species and proinflammatory mediator generation by stimulated murine macrophages. METHODS: Mice were fed the different oil-enriched diets for 8 wk. Peritoneal macrophages were isolated from these mice and subsequently stimulated. Reactive oxygen species and proinflammatory mediators were measured in the corresponding supernatants. Data were statistically treated by one-way analysis of variance and Tukey's multiple comparison post hoc test. RESULTS: The ROO and POO significantly reduced the hydrogen peroxide production compared with BD, whereas FO stimulated its production. Moreover, the generation of nitric oxide was significantly prevented in all the experimental oil-enriched dietary groups. The ROO and FO groups showed significantly reduced cytokine (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6) and prostaglandin E(2) production. CONCLUSION: These results confirm the prevention action on proinflammatory mediator generation exerted by FO and demonstrate the protective antioxidant properties not only of olive oil but also of POO. The consumption of these olive oils may help to prevent cellular oxidative stress and inflammation.

Modulation of cytokine secretion by pentacyclic triterpenes from olive pomace oil in human mononuclear cells.

Olive pomace oil, also known as "orujo" olive oil, is a blend of refined-pomace oil and virgin olive oil, fit for human consumption. Maslinic acid, oleanolic acid, erythrodiol, and uvaol are pentacyclic triterpenes, found in the non-glyceride fraction of orujo oil, which have previously been reported to have anti-inflammatory properties. In the present work, we investigated the effect of these minor components on pro-inflammatory cytokine production by human peripheral blood mononuclear cells in six different samples. Uvaol, erythrodiol, and oleanolic acid significantly decreased IL-1beta and IL-6 production in a dose-dependent manner. All three compounds significantly reduced TNF-alpha production at 100microM; however, at 10microM, uvaol and oleanolic acid enhanced the generation of TNF-alpha. In contrast, maslinic acid did not significantly alter the concentration of those cytokines, with the exception of a slight inhibitory effect at 100microM. All four triterpenes inhibited production of I-309, at 50microM and 100microM. However, uvaol enhanced I-309 production at 10microM. The triterpenic dialcohols had a similar effect on MIG production. In conclusion, this study demonstrates that pentacyclic triterpenes in orujo oil exhibit pro- and anti-inflammatory properties depending on chemical structure and dose, and may be useful in modulating the immune response.