Biomarkers for personalised prevention of chronic diseases: a common protocol for three rapid scoping reviews.

INTRODUCTION: Personalised prevention aims to delay or avoid disease occurrence, progression, and recurrence of disease through the adoption of targeted interventions that consider the individual biological, including genetic data, environmental and behavioural characteristics, as well as the socio-cultural context. This protocol summarises the main features of a rapid scoping review to show the research landscape on biomarkers or a combination of biomarkers that may help to better identify subgroups of individuals with different risks of developing specific diseases in which specific preventive strategies could have an impact on clinical outcomes. This review is part of the "Personalised Prevention Roadmap for the future HEalThcare" (PROPHET) project, which seeks to highlight the gaps in current personalised preventive approaches, in order to develop a Strategic Research and Innovation Agenda for the European Union. OBJECTIVE: To systematically map and review the evidence of biomarkers that are available or under development in cancer, cardiovascular and neurodegenerative diseases that are or can be used for personalised prevention in the general population, in clinical or public health settings. METHODS: Three rapid scoping reviews are being conducted in parallel (February-June 2023), based on a common framework with some adjustments to suit each specific condition (cancer, cardiovascular or neurodegenerative diseases). Medline and Embase will be searched to identify publications between 2020 and 2023. To shorten the time frames, 10% of the papers will undergo screening by two reviewers and only English-language papers will be considered. The following information will be extracted by two reviewers from all the publications selected for inclusion: source type, citation details, country, inclusion/exclusion criteria (population, concept, context, type of evidence source), study methods, and key findings relevant to the review question/s. The selection criteria and the extraction sheet will be pre-tested. Relevant biomarkers for risk prediction and stratification will be recorded. Results will be presented graphically using an evidence map. INCLUSION CRITERIA: Population: general adult populations or adults from specific pre-defined high-risk subgroups; concept: all studies focusing on molecular, cellular, physiological, or imaging biomarkers used for individualised primary or secondary prevention of the diseases of interest; context: clinical or public health settings. SYSTEMATIC REVIEW REGISTRATION: https://doi.org/10.17605/OSF.IO/7JRWD (OSF registration DOI).

Indole-Based Compounds in the Development of Anti-Neurodegenerative Agents.

Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023.

Autophagy in Its (Proper) Context: Molecular Basis, Biological Relevance, Pharmacological Modulation, and Lifestyle Medicine.

Autophagy plays a critical role in maintaining cellular homeostasis and responding to various stress conditions by the degradation of intracellular components. In this narrative review, we provide a comprehensive overview of autophagy's cellular and molecular basis, biological significance, pharmacological modulation, and its relevance in lifestyle medicine. We delve into the intricate molecular mechanisms that govern autophagy, including macroautophagy, microautophagy and chaperone-mediated autophagy. Moreover, we highlight the biological significance of autophagy in aging, immunity, metabolism, apoptosis, tissue differentiation and systemic diseases, such as neurodegenerative or cardiovascular diseases and cancer. We also discuss the latest advancements in pharmacological modulation of autophagy and their potential implications in clinical settings. Finally, we explore the intimate connection between lifestyle factors and autophagy, emphasizing how nutrition, exercise, sleep patterns and environmental factors can significantly impact the autophagic process. The integration of lifestyle medicine into autophagy research opens new avenues for promoting health and longevity through personalized interventions.

Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation.

The unique prolyl isomerase Pin1 binds to and catalyzes cis-trans conformational changes of specific Ser/Thr-Pro motifs after phosphorylation, thereby playing a pivotal role in regulating the structure and function of its protein substrates. In particular, Pin1 activity regulates the affinity of a substrate for E3 ubiquitin ligases, thereby modulating the turnover of a subset of proteins and coordinating their activities after phosphorylation in both physiological and disease states. In this review, we highlight recent advancements in Pin1-regulated ubiquitination in the context of cancer and neurodegenerative disease. Specifically, Pin1 promotes cancer progression by increasing the stabilities of numerous oncoproteins and decreasing the stabilities of many tumor suppressors. Meanwhile, Pin1 plays a critical role in different neurodegenerative disorders via the regulation of protein turnover. Finally, we propose a novel therapeutic approach wherein the ubiquitin-proteasome system can be leveraged for therapy by targeting pathogenic intracellular targets for TRIM21-dependent degradation using stereospecific antibodies.

Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies.

This review delves into the groundbreaking impact of induced pluripotent stem cells (iPSCs) and three-dimensional organoid models in propelling forward neuropathology research. With a focus on neurodegenerative diseases, neuromotor disorders, and related conditions, iPSCs provide a platform for personalized disease modeling, holding significant potential for regenerative therapy and drug discovery. The adaptability of iPSCs, along with associated methodologies, enables the generation of various types of neural cell differentiations and their integration into three-dimensional organoid models, effectively replicating complex tissue structures in vitro. Key advancements in organoid and iPSC generation protocols, alongside the careful selection of donor cell types, are emphasized as critical steps in harnessing these technologies to mitigate tumorigenic risks and other hurdles. Encouragingly, iPSCs show promising outcomes in regenerative therapies, as evidenced by their successful application in animal models.

Exploiting Natural Niches with Neuroprotective Properties: A Comprehensive Review.

Natural products from mushrooms, plants, microalgae, and cyanobacteria have been intensively explored and studied for their preventive or therapeutic potential. Among age-related pathologies, neurodegenerative diseases (such as Alzheimer's and Parkinson's diseases) represent a worldwide health and social problem. Since several pathological mechanisms are associated with neurodegeneration, promising strategies against neurodegenerative diseases are aimed to target multiple processes. These approaches usually avoid premature cell death and the loss of function of damaged neurons. This review focuses attention on the preventive and therapeutic potential of several compounds derived from natural sources, which could be exploited for their neuroprotective effect. Curcumin, resveratrol, ergothioneine, and phycocyanin are presented as examples of successful approaches, with a special focus on possible strategies to improve their delivery to the brain.

A mathematical model on the propagation of tau pathology in neurodegenerative diseases.

A system of partial differential equations is developed to study the spreading of tau pathology in the brain for Alzheimer's and other neurodegenerative diseases. Two cases are considered with one assuming intracellular diffusion through synaptic activities or the nanotubes that connect the adjacent cells. The other, in addition to intracellular spreading, takes into account of the secretion of the tau species which are able to diffuse, move with the interstitial fluid flow and subsequently taken up by the surrounding cells providing an alternative pathway for disease spreading. Cross membrane transport of the tau species are considered enabling us to examine the role of extracellular clearance of tau protein on the disease status. Bifurcation analysis is carried out for the steady states of the spatially homogeneous system yielding the results that fast cross-membrane transport combined with effective extracellular clearance is key to maintain the brain's healthy status. Numerical simulations of the first case exhibit solutions of travelling wave form describing the gradual outward spreading of the pathology; whereas the second case shows faster spreading with the buildup of neurofibrillary tangles quickly elevated throughout. Our investigation thus indicates that the gradual progression of the intracellular spreading case is more consistent with the clinical observations of the development of Alzheimer's disease.

Naringenin mitigates aluminum toxicity-induced learning memory impairments and neurodegeneration through amelioration of oxidative stress.

Aluminum chloride (AlCl3) is a potent neurotoxic substance known to cause memory impairment and oxidative stress-dependent neurodegeneration. Naringenin (NAR) is a dietary flavonoid with potent antioxidant and anti-inflammatory properties which was implemented against AlCl3-induced neurotoxicity to ascertain its neuroprotective efficacy. Experimental neurotoxicity in mice was induced by exposure of AlCl3 (10 mg/kg, p.o.) followed by treatment with NAR (10 mg/kg, p.o.) for a total of 63 days. Assessed the morphometric, learning memory dysfunction (novel object recognition, T- and Y-maze tests), neuronal oxidative stress, and histopathological alteration in different regions of the brain, mainly cortex, hippocampus, thalamus, and cerebellum. AlCl3 significantly suppressed the spatial learning and memory power which were notably improved by administration of NAR. The levels of oxidative stress parameters nitric oxide, advanced oxidation of protein products, protein carbonylation, lipid peroxidation, superoxide dismutase, catalase, glutathione reductase, reduced glutathione, and the activity of acetylcholine esterase were altered 1.5-3 folds by AlCl3 significantly. Treatment of NAR remarkably restored the level of oxidative stress parameters and maintained the antioxidant defense system. AlCl3 suppressed the expression of neuronal proliferation marker NeuN that was restored by NAR treatment which may be a plausible mechanism. NAR showed therapeutic efficacy as a natural supplement against aluminum-intoxicated memory impairments and histopathological alteration through a mechanism involving an antioxidant defense system and neuronal proliferation.

CD4+ T-Cell Senescence in Neurodegenerative Disease: Pathogenesis and Potential Therapeutic Targets.

With the increasing proportion of the aging population, neurodegenerative diseases have become one of the major health issues in society. Neurodegenerative diseases (NDs), including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neurodegeneration associated with aging, leading to a gradual decline in cognitive, emotional, and motor functions in patients. The process of aging is a normal physiological process in human life and is accompanied by the aging of the immune system, which is known as immunosenescence. T-cells are an important part of the immune system, and their senescence is the main feature of immunosenescence. The appearance of senescent T-cells has been shown to potentially lead to chronic inflammation and tissue damage, with some studies indicating a direct link between T-cell senescence, inflammation, and neuronal damage. The role of these subsets with different functions in NDs is still under debate. A growing body of evidence suggests that in people with a ND, there is a prevalence of CD4+ T-cell subsets exhibiting characteristics that are linked to senescence. This underscores the significance of CD4+ T-cells in NDs. In this review, we summarize the classification and function of CD4+ T-cell subpopulations, the characteristics of CD4+ T-cell senescence, the potential roles of these cells in animal models and human studies of NDs, and therapeutic strategies targeting CD4+ T-cell senescence.

Mesenchymal Stem Cells and Their Role in Neurodegenerative Diseases.

Mesenchymal stem cells (MSCs) have garnered significant interest in the field of regenerative medicine for their ability to potentially treat various diseases, especially neurodegenerative disorders [...].

Tau- and α-synuclein-targeted gold nanoparticles: applications, opportunities, and future outlooks in the diagnosis and therapy of neurodegenerative diseases.

The use of nanomaterials in medicine offers multiple opportunities to address neurodegenerative disorders such as Alzheimer's and Parkinson's disease. These diseases are a significant burden for society and the health system, affecting millions of people worldwide without sensitive and selective diagnostic methodologies or effective treatments to stop their progression. In this sense, the use of gold nanoparticles is a promising tool due to their unique properties at the nanometric level. They can be functionalized with specific molecules to selectively target pathological proteins such as Tau and α-synuclein for Alzheimer's and Parkinson's disease, respectively. Additionally, these proteins are used as diagnostic biomarkers, wherein gold nanoparticles play a key role in enhancing their signal, even at the low concentrations present in biological samples such as blood or cerebrospinal fluid, thus enabling an early and accurate diagnosis. On the other hand, gold nanoparticles act as drug delivery platforms, bringing therapeutic agents directly into the brain, improving treatment efficiency and precision, and reducing side effects in healthy tissues. However, despite the exciting potential of gold nanoparticles, it is crucial to address the challenges and issues associated with their use in the medical field before they can be widely applied in clinical settings. It is critical to ensure the safety and biocompatibility of these nanomaterials in the context of the central nervous system. Therefore, rigorous preclinical and clinical studies are needed to assess the efficacy and feasibility of these strategies in patients. Since there is scarce and sometimes contradictory literature about their use in this context, the main aim of this review is to discuss and analyze the current state-of-the-art of gold nanoparticles in relation to delivery, diagnosis, and therapy for Alzheimer's and Parkinson's disease, as well as recent research about their use in preclinical, clinical, and emerging research areas.

FERREG: ferroptosis-based regulation of disease occurrence, progression and therapeutic response.

Ferroptosis is a non-apoptotic, iron-dependent regulatory form of cell death characterized by the accumulation of intracellular reactive oxygen species. In recent years, a large and growing body of literature has investigated ferroptosis. Since ferroptosis is associated with various physiological activities and regulated by a variety of cellular metabolism and mitochondrial activity, ferroptosis has been closely related to the occurrence and development of many diseases, including cancer, aging, neurodegenerative diseases, ischemia-reperfusion injury and other pathological cell death. The regulation of ferroptosis mainly focuses on three pathways: system Xc-/GPX4 axis, lipid peroxidation and iron metabolism. The genes involved in these processes were divided into driver, suppressor and marker. Importantly, small molecules or drugs that mediate the expression of these genes are often good treatments in the clinic. Herein, a newly developed database, named 'FERREG', is documented to (i) providing the data of ferroptosis-related regulation of diseases occurrence, progression and drug response; (ii) explicitly describing the molecular mechanisms underlying each regulation; and (iii) fully referencing the collected data by cross-linking them to available databases. Collectively, FERREG contains 51 targets, 718 regulators, 445 ferroptosis-related drugs and 158 ferroptosis-related disease responses. FERREG can be accessed at https://idrblab.org/ferreg/.

Implications of environmental nanoparticles on neurodegeneration.

The ubiquity of nanoparticles, sourced from both natural environments and human activities, presents critical challenges for public health. While offering significant potential for innovative biomedical applications-especially in enhancing drug transport across the blood-brain barrier-these particles also introduce possible hazards due to inadvertent exposure. This concise review explores the paradoxical nature of nanoparticles, emphasizing their promising applications in healthcare juxtaposed with their potential neurotoxic consequences. Through a detailed examination, we delineate the pathways through which nanoparticles can reach the brain and the subsequent health implications. There is growing evidence of a disturbing association between nanoparticle exposure and the onset of neurodegenerative conditions, highlighting the imperative for comprehensive research and strategic interventions. Gaining a deep understanding of these mechanisms and enacting protective policies are crucial steps toward reducing the health threats of nanoparticles, thereby maximizing their therapeutic advantages.

Potential Effects of Traditional Chinese Medicine in Anti-Aging and Aging-Related Diseases: Current Evidence and Perspectives.

Aging and aging-related diseases present a global public health problem. Therefore, the development of efficient anti-aging drugs has become an important area of research. Traditional Chinese medicine is an important complementary and alternative branch of aging-related diseases therapy. Recently, a growing number of studies have revealed that traditional Chinese medicine has a certain delaying effect on the progression of aging and aging-related diseases. Here, we review the progress in research into using traditional Chinese medicine for aging and aging-related diseases (including neurodegenerative diseases, cardiovascular diseases, diabetes, and cancer). Furthermore, we summarize the potential mechanisms of action of traditional Chinese medicine and provide references for further studies on aging and aging-related diseases.

Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19.

The majority of patients with Parkinson disease (PD) experience a loss in their sense of smell and accumulate insoluble α-synuclein aggregates in their olfactory bulbs (OB). Subjects affected by a SARS-CoV-2-linked illness (COVID-19) also frequently experience hyposmia. We previously postulated that microglial activation as well as α-synuclein and tau misprocessing can occur during host responses following microbial encounters. Using semiquantitative measurements of immunohistochemical signals, we examined OB and olfactory tract specimens collected serially at autopsies between 2020 and 2023. Deceased subjects comprised 50 adults, which included COVID19 + patients (n = 22), individuals with Lewy body disease (e.g., PD; dementia with Lewy bodies (n = 6)), Alzheimer disease (AD; n = 3), and other neurodegenerative disorders (e.g., progressive supranuclear palsy (n = 2); multisystem atrophy (n = 1)). Further, we included neurologically healthy controls (n = 9), and added subjects with an inflammation-rich brain disorder as neurological controls (NCO; n = 7). When probing for microglial and histiocytic reactivity in the anterior olfactory nuclei (AON) by anti-CD68 immunostaining, scores were consistently elevated in NCO and AD cases. In contrast, microglial signals on average were not significantly altered in COVID19 + patients relative to healthy controls, although anti-CD68 reactivity in their OB and tracts declined with progression in age. Mild-to-moderate increases in phospho-α-synuclein and phospho-tau signals were detected in the AON of tauopathy- and synucleinopathy-afflicted brains, respectively, consistent with mixed pathology, as described by others. Lastly, when both sides were available for comparison in our case series, we saw no asymmetry in the degree of pathology of the left versus right OB and tracts. We concluded from our autopsy series that after a fatal course of COVID-19, microscopic changes in the rostral, intracranial portion of the olfactory circuitry -when present- reflected neurodegenerative processes seen elsewhere in the brain. In general, microglial reactivity correlated best with the degree of Alzheimer's-linked tauopathy and declined with progression of age in COVID19 + patients.

Proteostasis in neurodegenerative diseases.

Proteostasis is essential for normal function of proteins and vital for cellular health and survival. Proteostasis encompasses all stages in the "life" of a protein, that is, from translation to functional performance and, ultimately, to degradation. Proteins need native conformations for function and in the presence of multiple types of stress, their misfolding and aggregation can occur. A coordinated network of proteins is at the core of proteostasis in cells. Among these, chaperones are required for maintaining the integrity of protein conformations by preventing misfolding and aggregation and guide those with abnormal conformation to degradation. The ubiquitin-proteasome system (UPS) and autophagy are major cellular pathways for degrading proteins. Although failure or decreased functioning of components of this network can lead to proteotoxicity and disease, like neuron degenerative diseases, underlying factors are not completely understood. Accumulating misfolded and aggregated proteins are considered major pathomechanisms of neurodegeneration. In this chapter, we have described the components of three major branches required for proteostasis-chaperones, UPS and autophagy, the mechanistic basis of their function, and their potential for protection against various neurodegenerative conditions, like Alzheimer's, Parkinson's, and Huntington's disease. The modulation of various proteostasis network proteins, like chaperones, E3 ubiquitin ligases, proteasome, and autophagy-associated proteins as therapeutic targets by small molecules as well as new and unconventional approaches, shows promise.

The effect of epigenetic aging on neurodegenerative diseases: a Mendelian randomization study.

Background: Aging has always been considered as a risk factor for neurodegenerative diseases, but there are individual differences and its mechanism is not yet clear. Epigenetics may unveil the relationship between aging and neurodegenerative diseases. Methods: Our study employed a bidirectional two-sample Mendelian randomization (MR) design to assess the potential causal association between epigenetic aging and neurodegenerative diseases. We utilized publicly available summary datasets from several genome-wide association studies (GWAS). Our investigation focused on multiple measures of epigenetic age as potential exposures and outcomes, while the occurrence of neurodegenerative diseases served as potential exposures and outcomes. Sensitivity analyses confirmed the accuracy of the results. Results: The results show a significant decrease in risk of Parkinson's disease with GrimAge (OR = 0.8862, 95% CI 0.7914-0.9924, p = 0.03638). Additionally, we identified that HannumAge was linked to an increased risk of Multiple Sclerosis (OR = 1.0707, 95% CI 1.0056-1.1401, p = 0.03295). Furthermore, we also found that estimated plasminogen activator inhibitor-1(PAI-1) levels demonstrated an increased risk for Alzheimer's disease (OR = 1.0001, 95% CI 1.0000-1.0002, p = 0.04425). Beyond that, we did not observe any causal associations between epigenetic age and neurodegenerative diseases risk. Conclusion: The findings firstly provide evidence for causal association of epigenetic aging and neurodegenerative diseases. Exploring neurodegenerative diseases from an epigenetic perspective may contribute to diagnosis, prognosis, and treatment of neurodegenerative diseases.

SNP and Structural Study of the Notch Superfamily Provides Insights and Novel Pharmacological Targets against the CADASIL Syndrome and Neurodegenerative Diseases.

The evolutionary conserved Notch signaling pathway functions as a mediator of direct cell-cell communication between neighboring cells during development. Notch plays a crucial role in various fundamental biological processes in a wide range of tissues. Accordingly, the aberrant signaling of this pathway underlies multiple genetic pathologies such as developmental syndromes, congenital disorders, neurodegenerative diseases, and cancer. Over the last two decades, significant data have shown that the Notch signaling pathway displays a significant function in the mature brains of vertebrates and invertebrates beyond neuronal development and specification during embryonic development. Neuronal connection, synaptic plasticity, learning, and memory appear to be regulated by this pathway. Specific mutations in human Notch family proteins have been linked to several neurodegenerative diseases including Alzheimer's disease, CADASIL, and ischemic injury. Neurodegenerative diseases are incurable disorders of the central nervous system that cause the progressive degeneration and/or death of brain nerve cells, affecting both mental function and movement (ataxia). There is currently a lot of study being conducted to better understand the molecular mechanisms by which Notch plays an essential role in the mature brain. In this study, an in silico analysis of polymorphisms and mutations in human Notch family members that lead to neurodegenerative diseases was performed in order to investigate the correlations among Notch family proteins and neurodegenerative diseases. Particular emphasis was placed on the study of mutations in the Notch3 protein and the structure analysis of the mutant Notch3 protein that leads to the manifestation of the CADASIL syndrome in order to spot possible conserved mutations and interpret the effect of these mutations in the Notch3 protein structure. Conserved mutations of cysteine residues may be candidate pharmacological targets for the potential therapy of CADASIL syndrome.

The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging.

While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in the field of chronobiology. A plethora of new data demonstrates melatonin to be a very powerful molecule, being a potent ROS/RNS scavenger with anti-inflammatory, immunoregulatory, and oncostatic properties. Melatonin and its metabolites exert multiple beneficial effects in cutaneous and systemic aging. This review is focused on the neuroprotective role of melatonin during aging. Melatonin has an anti-aging capacity, retarding the rate of healthy brain aging and the development of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process. Melatonin could also be implicated in the treatment of neurodegenerative conditions, by modifying their characteristic low-grade neuroinflammation. It can either prevent the initiation of inflammatory responses or attenuate the ongoing inflammation. Drawing on the current knowledge, this review discusses the potential benefits of melatonin supplementation in preventing and managing cognitive impairment and neurodegenerative diseases.

DReAmocracy: A Method to Capitalise on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing.

In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have tested/are testing drugs in different phases. To the best of our knowledge, the aggregation of the proposed lists of drugs by previous studies has not been extensively exploited towards generating a dynamic reference matrix with enhanced resolution. To fill this knowledge gap, we performed weight-modulated majority voting of the modes of action, initial indications and targeted pathways of the drugs in a well-known repository, namely the Drug Repurposing Hub. Our method, DReAmocracy, exploits this pile of information and creates frequency tables and, finally, a disease suitability score for each drug from the selected library. As a testbed, we applied this method to a group of neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's disease and Multiple Sclerosis). A super-reference table with drug suitability scores has been created for all four neurodegenerative diseases and can be queried for any drug candidate against them. Top-scored drugs for Alzheimer's Disease include agomelatine, mirtazapine and vortioxetine; for Parkinson's Disease, they include apomorphine, pramipexole and lisuride; for Huntington's, they include chlorpromazine, fluphenazine and perphenazine; and for Multiple Sclerosis, they include zonisamide, disopyramide and priralfimide. Overall, DReAmocracy is a methodology that focuses on leveraging the existing drug-related experimental and/or computational knowledge rather than a predictive model for drug repurposing, offering a quantified aggregation of existing drug discovery results to (1) reveal trends in selected tracks of drug discovery research with increased resolution that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) score new candidate drugs for repurposing against a selected disease.