Influence of Metabolic, Transporter, and Pathogenic Genes on Pharmacogenetics and DNA Methylation in Neurological Disorders.

Pharmacogenetics and DNA methylation influence therapeutic outcomes and provide insights into potential therapeutic targets for brain-related disorders. To understand the effect of genetic polymorphisms on drug response and disease risk, we analyzed the relationship between global DNA methylation, drug-metabolizing enzymes, transport genes, and pathogenic gene phenotypes in serum samples from two groups of patients: Group A, which showed increased 5-methylcytosine (5mC) levels during clinical follow-up, and Group B, which exhibited no discernible change in 5mC levels. We identified specific SNPs in several metabolizing genes, including CYP1A2, CYP2C9, CYP4F2, GSTP1, and NAT2, that were associated with differential drug responses. Specific SNPs in CYP had a significant impact on enzyme activity, leading to changes in phenotypic distribution between the two patient groups. Group B, which contained a lower frequency of normal metabolizers and a higher frequency of ultra-rapid metabolizers compared to patients in Group A, did not show an improvement in 5mC levels during follow-up. Furthermore, there were significant differences in phenotype distribution between patient Groups A and B for several SNPs associated with transporter genes (ABCB1, ABCC2, SLC2A9, SLC39A8, and SLCO1B1) and pathogenic genes (APOE, NBEA, and PTGS2). These findings appear to suggest that the interplay between pharmacogenomics and DNA methylation has important implications for improving treatment outcomes in patients with brain-related disorders.

Neuroprotective Effect of Nosustrophine in a 3xTg Mouse Model of Alzheimer's Disease.

Neurodegeneration, characterized by the progressive deterioration of neurons and glial cells, is a feature of Alzheimer's disease (AD). The present study aims to demonstrate that the onset and early progression of neurodegenerative processes in transgenic mice models of AD can be delayed by a cocktail of neurotrophic factors and derived peptides named Nosustrophine, a nootropic supplement made by a peptide complex extracted from the young porcine brain, ensuring neuroprotection and improving neuro-functional recovery. Experimental 3xTg-APP/Bin1/COPS5 transgenic mice models of AD were treated with Nosustrophine at two different early ages, and their neuropathological hallmark and behavior response were analyzed. Results showed that Nosustrophine increased the activity of the immune system and reduced pathological changes in the hippocampus and cortex by halting the development of amyloid plaques, mainly seen in mice of 3-4 months of age, indicating that its effect is more preventive than therapeutic. Taken together, the results indicate the potent neuroprotective activity of Nosustrophine and its stimulating effects on neuronal plasticity. This study shows for the first time an effective therapy using nootropic supplements against degenerative diseases, although further investigation is needed to understand their molecular pathways.

Natural Bioactive Products as Epigenetic Modulators for Treating Neurodegenerative Disorders.

Neurodegenerative disorders (NDDs) are major health issues in Western countries. Despite significant efforts, no effective therapeutics for NDDs exist. Several drugs that target epigenetic mechanisms (epidrugs) have been recently developed for the treatment of NDDs, and several of these are currently being tested in clinical trials. Furthermore, various bioproducts have shown important biological effects for the potential prevention and treatment of these disorders. Here, we review the use of natural products as epidrugs to treat NDDs in order to explore the epigenetic effects and benefits of functional foods and natural bioproducts on neurodegeneration.

Proteomic and Global DNA Methylation Modulation in Lipid Metabolism Disorders with a Marine-Derived Bioproduct.

Dyslipidemia is a significant risk factor for cardiovascular disease and stroke. Our recent findings showed that RCI-1502, a bioproduct derived from the muscle of the European S. pilchardus, has lipid-lowering effects in the liver and heart in high-fat diet (HFD) fed mice. In the present follow-up study, we investigated the therapeutic potential of RCI-1502 on gene expression and DNA methylation in HFD-fed mice and in patients with dyslipidemia. Using LC-MS/MS, we identified 75 proteins in RCI-1502 that are primarily involved in binding and catalytic activity and which regulate pathways implicated in cardiovascular diseases. In HFD-fed mice, RCI-1502 treatment significantly reduced the expression of cardiovascular disease-related genes, including vascular cell adhesion molecule and angiotensin. RCI-1502 also decreased DNA methylation levels, which were elevated in HFD-fed mice, to levels similar to those in control animals. Furthermore, peripheral blood leukocyte DNA from dyslipidemic patients exhibited higher DNA methylation levels than healthy individuals, suggesting a potential association with cardiovascular risk. Serum analysis also revealed that RCI-1502 treatment regulated cholesterol and triglyceride levels in patients with dyslipidemia. Our findings appear to suggest that RCI-1502 is an epigenetic modulator for the treatment of cardiovascular diseases, specifically in individuals with dyslipidemia.

Cardiovascular and lipid-lowering effects of a marine lipoprotein extract in a high-fat diet-induced obesity mouse model.

Obesity is a major health challenge worldwide, with implications for diabetes, hypertension and cardiovascular disease (CVD). Regular consumption of dark-meat fish is linked to a lower incidence of CVD and associated metabolic disorders due to the presence of long-chain omega-3 fatty acid ethyl esters in fish oils. The aim of the present study was to determine whether a marine compound like a sardine lipoprotein extract (RCI-1502), regulates fat accumulation in the heart of a high-fat diet-induced (HFD) mouse model of obesity. To investigate its effects in the heart and liver, we conducted a randomized, 12-week placebo-controlled study in which we analyzed the expression of vascular inflammation markers, obesity biochemical patterns and related CVD pathologies. Male HFD-fed mice treated with a RCI-1502-supplemented diet showed reduced body weight, abdominal fat tissue and pericardial fat pad mass density without systemic toxicity. RCI-1502 significantly reduced triacylglyceride, low-density lipoprotein and total-cholesterol concentrations in serum, but increased HDL-cholesterol levels. Our data show that RCI-1502 is beneficial for reducing obesity associated with a long-term HFD, possibly by exerting a protective effect on lipidic homeostasis, indicated also by histopathological analysis. These results collectively indicate that RCI-1502 acts as a cardiovascular therapeutic nutraceutical agent, which modulates fat-induced inflammation and improves metabolic health.

Nosustrophine: An Epinutraceutical Bioproduct with Effects on DNA Methylation, Histone Acetylation and Sirtuin Expression in Alzheimer's Disease.

Alzheimer's disease (AD), the most common cause of dementia, causes irreversible memory loss and cognitive deficits. Current AD drugs do not significantly improve cognitive function or cure the disease. Novel bioproducts are promising options for treating a variety of diseases, including neurodegenerative disorders. Targeting the epigenetic apparatus with bioactive compounds (epidrugs) may aid AD prevention treatment. The aims of this study were to determine the composition of a porcine brain-derived extract Nosustrophine, and whether treating young and older trigenic AD mice produced targeted epigenetic and neuroprotective effects against neurodegeneration. Nosustrophine regulated AD-related APOE and PSEN2 gene expression in young and older APP/BIN1/COPS5 mice, inflammation-related (NOS3 and COX-2) gene expression in 3-4-month-old mice only, global (5mC)- and de novo DNA methylation (DNMT3a), HDAC3 expression and HDAC activity in 3-4-month-old mice; and SIRT1 expression and acetylated histone H3 protein levels in 8-9-month-old mice. Mass spectrometric analysis of Nosustrophine extracts revealed the presence of adenosylhomocysteinase, an enzyme implicated in DNA methylation, and nicotinamide phosphoribosyltransferase, which produces the NAD+ precursor, enhancing SIRT1 activity. Our findings show that Nosustrophine exerts substantial epigenetic effects against AD-related neurodegeneration and establishes Nosustrophine as a novel nutraceutical bioproduct with epigenetic properties (epinutraceutical) that may be therapeutically effective for prevention and early treatment for AD-related neurodegeneration.

Epigenetic Studies in the Male APP/BIN1/COPS5 Triple-Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's Disease (AD) is a major health problem worldwide. The lack of efficacy of existing therapies for AD is because of diagnosis at late stages of the disease, limited knowledge of biomarkers, and molecular mechanisms of AD pathology, as well as conventional drugs that are focused on symptomatic rather than mechanistic features of the disease. The connection between epigenetics and AD, however, may be useful for the development of novel therapeutics or diagnostic biomarkers for AD. The aim of this study was to investigate a pathogenic role for epigenetics and other biomarkers in the male APP/BIN1/COPS5 triple-transgenic (3xTg) mouse model of AD. In the APP/BIN1/COPS5 3xTg-AD mouse hippocampus, sirtuin expression and activity decreased, HDAC3 expression and activity increased, PSEN1 mRNA levels were unchanged, PSEN2 and APOE expression was reduced, and levels of the pro-inflammatory marker IL-6 increased; levels of pro-inflammatory COX-2 and TNFα and apoptotic (NOS3) markers increased slightly, but these were non-significant. In fixed mouse-brain slices, immunoreactivity for CD11b and ß-amyloid immunostaining increased. APP/BIN1/COPS5 3xTg-AD mice are a suitable model for evaluating epigenetic changes in AD, the discovery of new epigenetic-related biomarkers for AD diagnosis, and new epidrugs for the treatment of this neurodegenerative disease.

AntiGan: An Epinutraceutical Bioproduct with Antitumor Properties in Cultured Cell Lines.

Novel and effective chemotherapeutic agents are needed to improve cancer treatment. Epidrugs are currently used for cancer therapy but also exhibit toxicity. Targeting the epigenetic apparatus with bioproducts may aid cancer prevention and treatment. To determine whether the lipoprotein marine extract AntiGan shows epigenetic and antitumor effects, cultured HepG2 (hepatocellular carcinoma) and HCT116 (colorectal carcinoma) cell lines were treated with AntiGan (10, 50, 100, and to 500 µg/mL) for 24 h, 48 h, and 72 h. AntiGan (10 µg/mL) reduced cell viability after 48 h and increased Bax expression; AntiGan (10 and 50 µg/mL) increased caspase-3 immunoreactivity in HepG2 and HCT116 cells. AntiGan (10 and 50 µg/mL) attenuated COX-2 and IL-17 expression in both cell lines. AntiGan (10 µg/mL) increased 5mC levels in both cell types and reduced DNMT1 and DNMT3a expression in these cells. AntiGan (10 and 50 µg/mL) promoted DNMT3a immunoreactivity and reduced SIRT1 mRNA expression in both cell types. In HCT116 cells treated with AntiGan (10 µg/mL), SIRT1 immunoreactivity localized to nuclei and the cytoplasm; AntiGan (50 µg/mL) increased cytoplasmic SIRT1 localization in HCT116 cells. AntiGan is a novel antitumoral bioproduct with epigenetic properties (epinutraceutical) for treating liver and colorectal cancer.

What is the gold standard model for Alzheimer's disease drug discovery and development?

Introduction: Alzheimer's disease models (ADMs) are currently used for drug development (DD). More than 20,000 molecules were screened for AD treatment over decades, with only one drug (Aducanumab)FDA-approved over the past 18 years. A revision of pathogenic concepts and ADMs are needed.Areas covered: The authors discuss herein preclinical models including: (i) in vitro models (cell lines, primary neuron cell cultures, iPSC-derived brain cells), (ii) ex vivo models, and (iii) in vivo models (artificial, transgenic, non-transgenic and induced).Expert opinion: The following types of ADMs have been reported: Mouse models (45.08%), Rat models (15.04%), Non-human Primate models (0.76%), Rabbit models (0.46%), Cat models (0.53%), Pig models (0.30%), Guinea pig models (0.15%), Octodon degu models (0.02%), Dog models (0.54%), Drosophila melanogaster models (1.79%), Zebrafish models (0.50%), Caenorhabditis elegans (1.21%), Cell culture models (3.31%), Cholinergic models (8.26%), Neurotoxic models (6.79%), Neuroinflammation models (6.92%), Neurovascular models (7.88%), and Microbiome models (0.45%).No single ADM faithfully reproduces all the pathogenic events in the human AD phenotype spectrum. ADMs should be different for (i) pathogenic studies vs basic DD, and (ii) preventive interventions vs symptomatic treatments. There cannot be an ideal ADM for DD, because AD is a spectrum of syndromes. DD can integrate pathogenic, mechanistic, metabolic, transporter and pleiotropic genes in a multisystem model.

Atremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics.

Atremorine is a novel bioproduct obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba. Atremorine is a potent dopamine (DA) enhancer with powerful effects on the neuronal dopaminergic system, acting as a neuroprotective agent in Parkinson's disease (PD). Over 97% of PD patients respond to a single dose of Atremorine (5 g, p.o.) 1 h after administration. This response is gender-, time-, dose-, and genotype-dependent, with optimal doses ranging from 5 to 20 g/day, depending upon disease severity and concomitant medication. Drug-free patients show an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ml; and patients chronically treated with anti-PD drugs show an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effects of conventional anti-PD drugs. Atremorine also influences the levels of other neurotransmitters (adrenaline, noradrenaline) and hormones which are regulated by DA (e.g., prolactin, PRL), with no effect on serotonin or histamine. The variability in Atremorine-induced DA response is highly attributable to pharmacogenetic factors. Polymorphic variants in pathogenic (SNCA, NUCKS1, ITGA8, GPNMB, GCH1, BCKDK, APOE, LRRK2, ACMSD), mechanistic (DRD2), metabolic (CYP2D6, CYP2C9, CYP2C19, CYP3A4/5, NAT2), transporter (ABCB1, SLC6A2, SLC6A3, SLC6A4) and pleiotropic genes (APOE) influence the DA response to Atremorine and its psychomotor and brain effects. Atremorine enhances DNA methylation and displays epigenetic activity via modulation of the pharmacoepigenetic network. Atremorine is a novel neuroprotective agent for dopaminergic neurons with potential prophylactic and therapeutic activity in PD.

Influence of dopamine, noradrenaline, and serotonin transporters on the pharmacogenetics of Atremorine in Parkinson's disease.

Atremorine is a potent dopamine (DA) enhancer obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba. Atremorine affects the neuronal dopaminergic system by acting as a neuroprotective agent against Parkinson's disease (PD). PD patients (N = 127) responded to a single dose of Atremorine (5 g, p.o.) 1 h after administration in a sex-, time-, dose-, and genotype-dependent fashion. Drug-free patients (N = 81) showed an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ml; and patients chronically treated with anti-PD drugs (N = 46) showed an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effect of conventional anti-PD drugs. The variability in Atremorine-induced DA response is strongly attributable to pharmacogenetic factors. Polymorphic variants in pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes influence the DA response to Atremorine. Genetic variation in the DA (SLC6A3; rs460000), noradrenaline (NA) (SLC6A2; rs12708954, rs3785143, rs5569), and serotonin (5-HT) transporter (SLC6A4; rs2020934, rs2020936, rs4251417, rs6354) genes exert a genotype-dependent Atremorine-induced DA response in PD, with potential impact on the DA-related pharmacogenetic outcome and minimum effects on NA and 5-HT levels.

Effectiveness of Superior Hypogastric Plexus Neurolysis for Pelvic Cancer Pain.

BACKGROUND: The superior hypogastric plexus block has been indicated for visceral pelvic pain treatment associated with malignancy. The first international report of this technique was published by Plancarte et al, in which a posterior percutaneous approach guided by fluoroscopy was described by applying neurolytic agents. The considerable variability in the data reported gave rise to 2 clinical approaches to those who performed the blockade early and those who executed it at a later stage of cancer. OBJECTIVES: The present study aims to provide more evidence regarding the effectiveness of this procedure. STUDY DESIGN: This is a retrospective, longitudinal, descriptive study. SETTING: The study was held at the pain unit service of the National Cancer Institute, Mexico City. METHODS: A nonprobabilistic sample was selected; the data collection took place from January 2006 to December 2016 with patients diagnosed with pelvic pain, confirmed by imaging and biopsy studies. Patients who received any other type of intervention of the sympathetic axis, patients with a different approach than the classic or paravertebral technique, and patients with low survival rate were excluded. The Student t test was used to measure the significant difference between Visual Analog Scale (VAS) and morphine equivalent daily dose. The Cochran-Mantel-Haenszel test and the Gamma test were used to measure the association between the initial Karnofsky and blockade success. RESULTS: The study included a total of 180 patients. The success rate was 59.4% at 1 month, 55.5% at 3 months, and 48.8% at 6 months. There was a sustained and significant VAS reduction that was 49.55% at 3 months. A significant reduction in opioid consumption of 12.55% was found at 3 months. There was no significant statistical evidence related to either opioid consumption or the functionality of the patient before the blockade as an influential variable in the success of the procedure. LIMITATIONS: Retrospective study, developed in a single center. CONCLUSIONS: Although opioids remain the cornerstone of cancer pain treatment, they produce many deleterious side effects. The superior hypogastric plexus neurolysis represents a reproducible and effective alternative in the management of pain in this group of patients. KEY WORDS: Pelvic pain, neoplasms, chemical neurolysis, pain management, cancer pain, palliative care, analgesia, nerve block.

DNA Methylation in Neurodegenerative and Cerebrovascular Disorders.

DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer's, Parkinson's or Cerebrovascular diseases. We also analyze methylation status of a transgenic Alzheimer's disease mouse model (3xTg-AD). Our results show that both global methylation (n = 141) and hydroxymethylation (n = 131) levels are reduced in DNA samples from buffy coats of patients with neurodegenerative disorders and age-related cerebrovascular disease. The importance of methylation and hydroxymethylation reduction is stressed by the finding that DNMT3a mRNA levels are also downregulated in buffy coats of patients with Dementia (n = 25). Global methylation is also reduced in brain, liver and serum samples of 3xTg-AD vs. wild type mice, such as DNMT3a mRNA levels that are also decreased in the brain of 3xTg-AD (n = 10). These results suggest that the use of global methylation and hydroxymethylation levels, together with the study of DNMT3a expression, could be useful as a new diagnostic biomarker for these prevalent disorders.

Risk of New Fractures in Vertebroplasty for Multiple Myeloma. A Retrospective Study.

OBJECTIVE: Vertebroplasty is a percutaneous minimally invasive procedure indicated for vertebral collapse pain treatment. Among the known complications of the procedure is the augmented risk of new vertebral fractures. There are no specific studies in this patient population describing the risk of new vertebral fractures after vertebroplasty. This study analyzed risk factors associated with new vertebral fractures after vertebroplasty in patients with multiple myeloma. METHODS: Observational retrospective study in patients with multiple myeloma. The data collection took place from January 1, 2010, to December 30, 2017, at the National Cancer Institute. Clinical data and procedural variables such as cement volume, cement leaks, fracture level, number of treated vertebrae, pedicular disease, and cement distribution pattern, with two years follow-up, were analyzed with the Wilcoxon test, and a logistic regression model was used to identify risk factors related to new vertebral fractures. A confidence interval of 95% was used for analysis. RESULTS: At one-year follow-up, 30% of fractures were reported after vertebroplasty, most of them at low thoracic and lumbar level (50% adjacent level). Vertebroplasty was most commonly performed at the thoracolumbar and lumbar area. We demonstrated a 70.7% median numerical rating scale reduction at one-year follow-up; a significant decrease in opioid consumption occurred only during the first month. CONCLUSIONS: Pedicle involvement, disc leakage, cement volume, thoracolumbar and lumbar level, and number of treated vertebrae by intervention are important risk factors when performing vertebroplasty. Prospective randomized studies are needed to evaluate these factors in this specific population.

Nutrition, Health, and Disease: Role of Selected Marine and Vegetal Nutraceuticals.

The investigation of new alternatives for disease prevention through the application of findings from dietary and food biotechnology is an ongoing challenge for the scientific community. New nutritional trends and the need to meet social and health demands have inspired the concept of functional foods and nutraceuticals which, in addition to their overall nutritional value, present certain properties for the maintenance of health. However, these effects are not universal. Nutrigenetics describes how the genetic profile has an impact on the response of the body to bioactive food components by influencing their absorption, metabolism, and site of action. The EbioSea Program, for biomarine prospection, and the Blue Butterfly Program, for the screening of vegetable-derived bioproducts, have identified a new series of nutraceuticals, devoid of side effects at conventional doses, with genotype-dependent preventive and therapeutic activity. Nutrigenomics and nutrigenetics provide the opportunity to explore the inter-individual differences in the metabolism of and response to nutrients, achieving optimal results. This fact leads to the concept of personalized nutrition as opposed to public health nutrition. Consequently, the development and prescription of nutraceuticals according to the individual genetic profile is essential to improve their effectiveness in the prevention and natural treatment of prevalent diseases.

Neuroprotection with Natural Antioxidants and Nutraceuticals in the Context of Brain Cell Degeneration: The Epigenetic Connection.

Bioactive antioxidant agents present in selected plants are known to provide the first line of biological defense against oxidative stress. In particular, soluble vitamin C, E, carotenoids and phenolic compounds have demonstrated crucial biological effects in cells against oxidative damage, preventing prevalent chronic diseases, such as diabetes, cancer and cardiovascular disease. The reported wide range of effects that included anti-aging, anti-atherosclerosis, anti-inflammatory and anticancer activity were studied against degenerative pathologies of the brain. Vitamins and different phytochemicals are important epigenetic modifiers that prevent neurodegeneration. In order to explore the potential antioxidant sources in functional foods and nutraceuticals against neurodegeneration, the present paper aims to show a comprehensive assessment of antioxidant activity at chemical and cellular levels. The effects of the different bioactive compounds available and their antioxidant activity through an epigenetic point of view are also discussed.

Pharmacogenetics of Atremorine-Induced Neuroprotection and Dopamine Response in Parkinson's Disease.

Atremorine is a novel bioproduct with neuroprotective effects on dopaminergic neurons and a natural L-DOPA donor in Parkinson's disease (PD). In the present study, we show the effects of a single dose of Atremorine (5 g, p. o.) on plasma dopamine (DA) response and brain function in PD (n = 183) and the influence that pathogenic (LRRK2), metabolic (CYP2D5, CYP2C9, CYP2C19, CYP3A5, NAT2), transporter (ABCB1), pleiotropic (APOE), and detoxifying genes (CYP1B1, GSTT1, GSTP1, GSTM1, SOD2) involved in the pharmacogenetic network exerts on Atremorine-induced DA response. Over 90% of PD patients at diagnosis show plasma DA levels below 20 pg/mL. Atremorine induces DA synthesis causing a significant increase in plasma DA levels 1 h after administration in practically 100% of patients. Females tend to show lower basal DA levels than males and the response of DA to Atremorine is stronger in males than in females. Atremorine-induced DA response is pharmacogenotype-specific and lasts from 6 - 12 h depending upon the pharmacogenetic profile of each patient. Genetic variants in pathogenic genes, metabolic genes, and genes involved in the detoxification processes affect the response of DA to Atremorine in a genotype-specific manner. Atremorine or any of its bioactive components can cross the blood-brain barrier and improve brain function and motor function, as revealed by the reduction in slow wave activity in brain mapping and psychometric assessment, respectively. Atremorine is a selective neuroprotective agent for dopaminergic neurons with prophylactic and therapeutic potential in PD.

Role of bioactive lipofishins in prevention of inflammation and colon cancer.

Many clinical conditions exist in which it is desirable to stimulate or suppress the immune system, and many different drugs are able to do this. It is also well known that nutrition may affect human health and immune responses. Nutritional factors are crucial components of the diet and essential for normal growth and development of both vertebrate and invertebrate organisms. Many of these components have been shown to play different roles in the immune response and, under different circumstances, they can significantly modulate the immune system to create an effective response. Diet and its components are known to play an important factor in the process of inflammation and in turn on the health effects related to inflammation, such as cancer and cardiovascular diseases. Previous research so far has mainly looked at the effect of specific food stuffs or nutrients on inflammation and health outcomes. The aims of the present review was a) to underline the fact that diet as a whole plays an important role in modifying inflammation and health outcomes related to inflammation, aging, and colon cancer; b) to show the in vitro cytotoxic effect of LipoFishins (E-Congerine 10423®; AntiGan™) obtained from the Atlantic Conger conger marine organism present on the Galician coast, against different human tumor cell lines; c) to show the in vivo effect of E-Congerine-10423® on colonic inflammation induced in mice by seven weeks' exposure to 2% of dextran sulfate sodium (DSS); and d) to show the effect of E-Congerine-10423® (AntiGan™) on tumor markers (TMs) in healthy subjects and in patients with different types of cancer at the time of diagnosis. Preliminary data in a limited number of cases indicate that about 50% of the patients show a reduction in the levels of tumor markers (TM), and this response was much more evident in patients with cancer, when TM values are above normal range. Finally, all the above mentioned results suggest that diet has a major role in controlling inflammation and thereby plays an important role in the development or prevention of various chronic diseases, hence public health steps should be taken to modify the individual's whole diet and to promote the intake of specific natural compounds.

Current Drugs and Potential Future Neuroprotective Compounds for Parkinson's Disease.

The research progress of understanding the etiology and pathogenesis of Parkinson's disease (PD) has yet lead to the development of some clinical approaches intended to treat cognitive and behavioral symptoms, such as memory and perception disorders. Despite the major advances in different genetic causes and risk factors for PD, which share common pathways to cell dysfunction and death, there is not yet a complete model of PD that can be used to accurately predict the effect of drugs on disease progression. Clinical trials are also important to test any novel neuro-protective agent, and recently there have been great advances in the use of anti-inflammatory drugs and plant flavonoid antioxidants to protect against specific neuronal degeneration and its interference with lipid and cholesterol metabolism. The increasing knowledge of the molecular events underlying the degenerative process of PD has stimulated research to identify natural compounds capable of halting or slowing the progress of neural deterioration. Polyphenols and flavonoids, which play a neuroprotective role in a wide array of in vitro and in vivo models of neurological disorders, emerged from among the multi-target bio-agents found mainly in plants and microorganisms. This review presents a detailed overview of the multimodal activities of neuroprotective bio-agents tested so far, emphasizing their neurorescue/neuroregenerative activity. The brain-penetrating property of bioagents may make these compounds an important class of natural drugs for the treatment of neurodegenerative diseases. Although there are numerous studies demonstrating beneficial effects in the laboratory by identifying critical molecular targets, the clinical efficacy of these neuroprotective treatments remains to be proven accurately.

Dopaminergic Neuroprotection with Atremorine in Parkinson´s Disease.

Patients with Parkinson's disease (PD) are looking forward to new therapeutic strategies that may gradually decelerate the rate of neurodegenerative decline, associated with mobility restrictions and related morbidity. Its continuous neurodegenerative process, exacerbated by genetic mutations or environmental toxins, involves a progressive reduction in the dopamine neurotransmission levels, synaptic uptake density, oxidative glucose intake, deficient striatal lactate accumulation and chronic inflammation. Over the last decade, novel bioproducts have received considerable interest due to their unique potential of unifying nutritional, safety and therapeutic natural effects. Some nutraceuticals play a crucial role in the control of the signaling transduction pathways in neurotransmission and inflammation affected in PD, and some natural compounds can beneficially interact with each one of these biological mechanisms to slow down disease progression. Atremorine, a novel plant-derived nutraceutical, probably with a neuroprotective effect in the dopaminergic neurons of the substantia nigra (pars compacta), is a prototype of this new category of bioproducts with potential effects in PD. The major focus of this review will be on the current knowledge and biomedical investigation strategies through a plant-derived neuroprotective approach to improve life quality in PD patients, being of paramount importance for health providers, caregivers and the patients themselves.