Massimo Cocchi

The use of artificial neural networks to study fatty acids in neuropsychiatric disorders

BackgroundThe range of the fatty acids has been largely investigated in the plasma and erythrocytes of patients suffering from neuropsychiatric disorders. In this paper we investigate, for the first time, whether the study of the platelet fatty acids from such patients may be facilitated by means of artificial neural networks.MethodsVenous blood samples were taken from 84 patients with a DSM-IV-TR diagnosis of major depressive disorder and from 60 normal control subjects without a history of clinical depression. Platelet levels of the following 11 fatty acids were analyzed using one-way analysis of variance: C14:0, C16:0, C16:1, C18:0, C18:1 n-9, C18:1 n-7, C18:2 n-6, C18:3 n-3, C20:3 n-3, C20:4 n-6 and C22:6 n-3. The results were then entered into a wide variety of different artificial neural networks.ResultsAll the artificial neural networks tested gave essentially the same result. However, one type of artificial neural network, the self-organizing map, gave superior information by allowing the results to be described in a two-dimensional plane with potentially informative border areas. A series of repeated and independent self-organizing map simulations, with the input parameters being changed each time, led to the finding that the best discriminant map was that obtained by inclusion of just three fatty acids.ConclusionOur results confirm that artificial neural networks may be used to analyze platelet fatty acids in neuropsychiatric disorder. Furthermore, they show that the self-organizing map, an unsupervised competitive-learning network algorithm which forms a nonlinear projection of a high-dimensional data manifold on a regular, low-dimensional grid, is an optimal type of artificial neural network to use for this task.

Bio Molecular Considerations in Major Depression and Ischemic Cardiovascular Disease

In our study we have evaluated the theme of the platelet fatty acid composition in subjects with a clinical diagnosis of Major Depression (MD), in subjects with a clinical diagnosis of Ischemic Heart Disease (IHD) according to the coronary angiography and in control subjects. We have analyzed all the groups without taking in account therapies, gender and age. As far as we know, the platelet fatty acid composition has never been analyzed before, in MD. The results obtained with the Self Organizing Map (SOM) show the evidence of three fatty acids, Arachidonic Acid (AA), Linoleic Acid (LA), and Palmitic Acid (PA) in a peculiar position with respect to the biochemical characterization of MD and three fatty acids, Arachidonic Acid (AA), Linoleic Acid (LA) and Oleic Acid (OA) in a peculiar position with respect to the biochemical characterization of the IHD. Bio molecular considerations are made about the possibility of controlling positive changes in platelet viscosity, in both pathologies.

A comparison of oxidative stress in smokers and non-smokers: an in vivo human quantitative study of n-3 lipid peroxidation

BackgroundCigarette smoking is believed to cause oxidative stress by several mechanisms, including direct damage by radical species and the inflammatory response induced by smoking, and would therefore be expected to cause increased lipid peroxidation. The aim was to carry out the first study of the relationship of smoking in humans to the level of n-3 lipid peroxidation indexed by the level of ethane in exhaled breath.MethodsSamples of alveolar air were obtained from 11 smokers and 18 non-smokers. The air samples were analyzed for ethane using mass spectrometry.ResultsThe two groups of subjects were matched with respect to age and gender. The mean cumulative smoking status of the smokers was 11.8 (standard error 2.5) pack-years. The mean level of ethane in the alveolar breath of the group of smokers (2.53 (0.55) ppb) was not significantly different from that of the group of non-smokers (2.59 (0.29) ppb; p = 0.92). With all 29 subjects included, the Spearman rank correlation coefficient between ethane levels and cumulative smoking status was -0.11 (p = 0.58), while an analysis including only the smokers yielded a corresponding correlation coefficient of 0.11 (p = 0.75).ConclusionOur results show no evidence that cigarette smoking is related to increased n-3 lipid peroxidation as measured by expired ethane.

Effects of Chitosan on Plasma Lipids and Lipoproteins: A 4-Month Prospective Pilot Study

Chitosan can favorably modulate plasma lipids, but the available data are not conclusive. We evaluated the effect of chitosan on plasma lipids and lipoproteins in 28 patients with plasma triglyceride levels >150 mg/dL (mean age: 63 ± 12 years), not taking other lipid-lowering agents. All patients received a chitosan derived from fungal mycelium (Xantonet, Bromatech, Italy) at a fixed dose of 125 mg/d in addition to their current medications for 4 months. Polyacrylamide gel electrophoresis was used to measure low-density lipoprotein (LDL) subclasses. After treatment, total cholesterol reduced by 8%, LDL cholesterol by 2%, and triglycerides by 19%, with a concomitant 14% increase in high-density lipoprotein cholesterol. We also found a beneficial effect of chitosan on LDL subclasses, with a significant increase in LDL-2 particles (from 37 ± 8% to 47 ± 8%, P = .0001) and a decrease (although not significant) in atherogenic small, dense LDL. Whether these findings may affect cardiovascular risk remains to be established in future studies.

Gut microbiota imbalance and chaperoning system malfunction are central to ulcerative colitis pathogenesis and can be counteracted with specifically designed probiotics: a working hypothesis.

In this work, we propose that for further studies of the physiopathology and treatment for inflammatory bowel diseases, an integral view of the conditions, including the triad of microbiota–heat shock proteins (HSPs)–probiotics, ought to be considered. Microbiota is the complex microbial flora that resides in the gut, affecting not only gut functions but also the health status of the whole body. Alteration in the microbiota’s composition has been implicated in a variety of pathological conditions (e.g., ulcerative colitis, UC), involving both gut and extra-intestinal tissues and organs. Some of these pathologies are also associated with an altered expression of HSPs (chaperones) and this is the reason why they may be considered chaperonopathies. Probiotics, which are live microorganisms able to restore the correct, healthy equilibrium of microbiota composition, can ameliorate symptoms in patients suffering from UC and modulate expression levels of HSPs. However, currently probiotic therapy follows ex-adiuvantibus criteria, i.e., treatments with beneficial effects but whose mechanism of action is unknown, which should be changed so the probiotics needed in each case are predetermined on the basis of the patient’s microbiota. Consequently, efforts are necessary to develop diagnostic tools for elucidating levels and distribution of HSPs and the microbiota composition (microbiota fingerprint) of each subject and, thus, guide specific probiotic therapy, tailored to meet the needs of the patient. Microbiota fingerprinting ought to include molecular biology techniques for sequencing highly conserved DNA, e.g., genes encoding 16S RNA, for species identification and, in addition, quantification of each relevant microbe.

Human depression: A new approach in quantitative psychiatry

The biomolecular approach to major depression disorder is explained by the different steps that involve cell membrane viscosity, Gsα protein and tubulin. For the first time it is hypothesised that a biomolecular pathway exists, moving from cell membrane viscosity through Gsα protein and Tubulin, which can condition the conscious state and is measurable by electroencephalogram study of the brains γ wave synchrony.

Fatty acids, membrane viscosity, serotonin and ischemic heart disease

Novel markers for ischemic heart disease are under investigation by the scientific community at international level.This work focuses on a specific platelet membrane fatty acid condition of viscosity which is linked to molecular aspects such as serotonin and G proteins, factors involved in vascular biology.A suggestive hypothesis is considered about the possibility to use platelet membrane viscosity, in relation to serotonin or, indirectly, the fatty acid profile, as indicator of ischemic risk.

Depression, osteoporosis, serotonin and cell membrane viscosity between biology and philosophical anthropology

Due to the relationship between biology and culture, we believe that depression, understood as a cultural and existential phenomenon, has clear markers in molecular biology. We begin from an existential analysis of depression constituting the human condition and then shift to analysis of biological data confirming, according to our judgment, its original (ontological) structure. In this way philosophy is involved at the anthropological level, in as much as it detects the underlying meanings of depression in the original biological-cultural horizon of human life. Considering the integration of knowledge it is the task of molecular biology to identify the aforementioned markers, to which the existential aspects of depression are linked to. In particular, recent works show the existence of a link between serotonin and osteoporosis as a result of a modified expression of the low-density lipoprotein receptor-related protein 5 gene. Moreover, it is believed that the hereditary or acquired involvement of tryptophan hydroxylase 2 (Tph2) or 5-hydroxytryptamine transporter (5-HTT) is responsible for the reduced concentration of serotonin in the central nervous system, causing depression and affective disorders. This work studies the depression-osteoporosis relationship, with the aim of focusing on depressive disorders that concern the quantitative dynamic of platelet membrane viscosity and interactome cytoskeleton modifications (in particular Tubulin and Gsα protein) as a possible condition of the involvement of the serotonin axis (gut, brain and platelet), not only in depression but also in connection with osteoporosis.

Running the hypothesis of a bio molecular approach to psychiatric disorder characterization and fatty acids therapeutical choices

Beyond the conviction that Major Depression can found its origin in genetics [1-3] a bio molecular mechanism could be hypothesized from what emerged from the studies on platelets fatty acid composition in human (normal and depressive subjects) which allowed classifying the depressive disorder [4] using an Artificial Neural Network (Self Organizing Map-SOM) [5], as mathematical tool, because of the complexity of the membrane dynamics. Rapid changes in membrane lipid composition or in the cytoskeleton could modify neuronal signalling. In the knowledge to have found something that could have implications in the understanding of some aspects of psychiatric disorders and a very suggestive hypothesis was build as summarized in Figure ​Figure1.1. In figure ​figure11 is described the molecular depression hypothesis made according to Cocchi and collegues [4], Donati and collegues [6], Hameroff and Penrose [7]. The membrane viscosity can modify the Gsα protein status. The Gsα protein is connected with Tubulin. Tubulin, depending on local membrane lipid fase concentration, may serve as a positive or negative regulator of phosphatidylinositol bisphosphate (PIP2) hydrolysis, such as Gsα protein does. Tubulin is known to form high-affinity complexes with certain G proteins. The formation of such complexes allows tubulin to activate Gsα, which, in turn, can activate the Protein Kinase C and fosters a system whereby elements of the cytoskeleton can influence G-protein signalling. Rapid changes in membrane lipid composition or in the cytoskeleton might modify neuronal signalling. We have hypothesized that through this mechanism is possible to modify the consciousness state and that it is mesurable through gamma syncrony EEG. Figure 1 The molecular depression hypothesis. There are strong reasons to think that each fatty acid combination of Palmitic Acid (PA), Linoleic Acid (LA) and Arachidonic Acid (AA), in platelet, is responsible of the membrane viscosity and, therefore, of the molecular conditioning of the cellular stuctures (Gsα and Tubulin) and that the main therapeutic target is the reduction of the Arachidonic Acid.

Alcoholic Liver Disease: A Mouse Model Reveals Protection by Lactobacillus fermentum

Objectives:Alcoholism is one of the most devastating diseases with high incidence, but knowledge of its pathology and treatment is still plagued with gaps mostly because of the inherent limitations of research with patients. We developed an animal model for studying liver histopathology, Hsp (heat-shock protein)-chaperones involvement, and response to treatment.Methods:The system was standardized using mice to which ethanol was orally administered alone or in combination with Lactobacillus fermentum following a precise schedule over time and applying, at predetermined intervals, a battery of techniques (histology, immunohistochemistry, western blotting, real-time PCR, immunoprecipitation, 3-nitrotyrosine labeling) to assess liver pathology (e.g., steatosis, fibrosis), and Hsp60 and iNOS (inducible form of nitric oxide synthase) gene expression and protein levels, and post-translational modifications.Results:Typical ethanol-induced liver pathology occurred and the effect of the probiotic could be reliably monitored. Steatosis score, iNOS levels, and nitrated proteins (e.g., Hsp60) decreased after probiotic intake.Conclusions:We describe a mouse model useful for studying liver disease induced by chronic ethanol intake and for testing pertinent therapeutic agents, e.g., probiotics. We tested L. fermentum, which reduced considerably ethanol-induced tissue damage and deleterious post-translational modifications of the chaperone Hsp60. The model is available to test other agents and probiotics with therapeutic potential in alcoholic liver disease.