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.

Long non­coding RNAs and microRNAs as regulators of stress in cancer (Review).

Resistance to stress is a feature of cancer cells. Cellular stress includes oxidative, metabolic and genotoxic stress conditions, which under normal conditions lead to cell death. However, in contrast to normal cells, cancer cells overcome the checkpoints that normally restrict growth, and are able to resist cellular stress and subsequent cell death through a variety of mechanisms, which include several non­coding RNAs (ncRNAs). Within this context, long ncRNAs (lncRNAs) and microRNAs (miRNAs/miRs) are the main categories of ncRNAs that have been shown in the literature to function as regulators of stress resistance pathways in cancer. miRNAs play a key role in the majority of biological pathways, as they regulate the expression of hundreds of target genes, including genes involved in stress response and cell death, oncogenes, or tumor suppressor genes, by inhibiting protein translation or promoting the degradation of mRNAs. Respectively, lncRNAs are epigenetic regulators, which are also involved in cancer progression, stress response and metabolic pathways by promoting or inhibiting the transcription, splicing, translation and modulation of protein function. Thus, the present review summarizes recent knowledge related to the role of these molecules in the cancer response to stress, highlighting the ability of these non­coding molecules to be effective drug targets and biomarkers in cancer treatment.

Increased risk of rheumatoid arthritis in patients with endometriosis: genetic aspects.

RA is an inflammatory joint disease of an autoimmune nature, with a complex mode of inheritance characterized by chronic and destructive inflammation in the peripheral joints of the hands and feet and irreversible disability. This disorder occurs more often in women, and reproductive and hormonal factors have been shown to be related to increased risk. Endometriosis is a chronic, complex, oestrogen-dependent and progressive gynaecological disorder characterized by the growth of endometrial tissue outside the uterine cavity. Thus far, substantial abnormalities in the immune system of women with endometriosis have been demonstrated. Epidemiological data have suggested a link between endometriosis and the risk of incident RA. The similarities between molecular and cellular pathways of endometriosis and RA may implicate a partially shared genetic background. In this review we present an overview of the shared genetic factors known thus far that are associated with the development of both disorders.

Clinical Genomic, phenotype and epigenetic insights into the pathology, autoimmunity and weight management of patients with Myasthenia Gravis (Review).

Myasthenia Gravis (MG) is an autoimmune disease that affects neuromuscular junctions and is characterized by muscle weakness as a result of autoantibodies against certain proteins. As a heterogeneous disorder, MG presents with different types, including neonatal, ocular and generalized in both juveniles and adults. Different types of antibodies serve a role in how MG presents. The main biological characteristic of MG is the production of antibodies against the muscular acetylcholine receptor; however, other types of antibody have been associated with the disorder. The role of the thymus gland has been established and thymectomy is a possible treatment of the disease, along with traditional medication such as pyridostigmine bromide (Mestinon) and immunosuppresants. In recent years, steps have been made towards developing more sensitive diagnostic methods. Additionally, novel treatments have demonstrated promising results. Developing new assays may lead to an increased understanding of the disease and to unravelling the genetic pathway that leads to the development of neuromuscular diseases.

An updated evolutionary study of the Notch family reveals a new ancient origin and novel invariable motifs as potential pharmacological targets.

Notch family proteins play a key role in a variety of developmental processes by controlling cell fate decisions and operating in a great number of biological processes in several organ systems, such as hematopoiesis, somatogenesis, vasculogenesis, neurogenesis and homeostasis. The Notch signaling pathway is crucial for the majority of developmental programs and regulates multiple pathogenic processes. Notch family receptors' activation has been largely related to its multiple effects in sustaining oncogenesis. The Notch signaling pathway constitutes an ancient and conserved mechanism for cell to cell communication. Much of what is known about Notch family proteins function comes from studies done in Caenorhabditis Elegans and Drosophila Melanogaster. Although, human Notch homologs had also been identified, the molecular mechanisms which modulate the Notch signaling pathway remained substantially unknown. In this study, an updated evolutionary analysis of the Notch family members among 603 different organisms of all kingdoms, from bacteria to humans, was performed in order to discover key regions that have been conserved throughout evolution and play a major role in the Notch signaling pathway. The major goal of this study is the presentation of a novel updated phylogenetic tree for the Notch family as a reliable phylogeny "map", in order to correlate information of the closely related members and identify new possible pharmacological targets that can be used in pathogenic cases, including cancer.

Olive Oil Polyphenols in Neurodegenerative Pathologies.

Neurodegenerative diseases lead to the death of nerve cells in the brain or the spinal cord. A wide range of diseases are included within the group of neurodegenerative disorders, with the most common ones being dementia, Alzheimer's, and Parkinson's diseases. Millions of older people are suffering from such pathologies. The global increase of life expectancy unavoidably leads to a consequent increase in the number of people who will be at some degree affected by neurodegenerative-related diseases. At this moment, there is no effective therapy or treatment that can reverse the loss of neurons. A growing number of studies highlight the value of the consumption of medical foods, and in particular olive oil, as one of the most important components of the Mediterranean diet. A diet based on extra virgin olive oil seems to contribute toward the lowering of risk of age-related pathologies due to high phenol concentration. The link of a polyphenol found in extra virgin olive oil, namely, tyrosol, with the protein tyrosinase, associated to Parkinson's disease is underlined as a paradigm of affiliation between polyphenols and neurodegenerative disorders.

Drugena: A Fully Automated Immunoinformatics Platform for the Design of Antibody-Drug Conjugates Against Neurodegenerative Diseases.

Antibodies are proteins that are the first line of defense in the adaptive immune response of vertebrates. Thereby, they are involved in a multitude of biochemical mechanisms and clinical manifestations with significant medical interest, such as autoimmunity, the regulation of infection, and cancer. An emerging field in antibody science that is of huge medicinal interest is the development of novel antibody-interacting drugs. Such entities are the antibody-drug conjugates (ADCs), which are a new type of targeted therapy, which consist of an antibody linked to a payload drug. Overall, the underlying principle of ADCs is the discerning delivery of a drug to a target, hoping to increase the potency of the original drug. Drugena suite is a pioneering platform that employs state-of-the-art computational biology methods in the fight against neurodegenerative diseases using ADCs. Drugena encompasses an up-to-date structural database of specialized antibodies for neurological disorders and the NCI database with over 96 million entities for the in silico development of ADCs. The pipeline of the Drugena suite has been divided into several steps and modules that are closely related with a synergistic fashion under a user-friendly graphical user interface.

Carcinogenic Pesticide Control via Hijacking Endosymbiosis; The Paradigm of DSB-A from Wolbachia pipientis for the Management of Otiorhynchus singularis.

BACKGROUND/AIM: Pesticides have little, if any specificity, to the pathogen they target in most cases. Wide spectrum toxic chemicals are being used to remove pestcides and salvage crops and economies linked to agriculture. The burden on the environment, public health and economy is huge. Traditional pestcide control is based on administering heavy loads of highly toxic compounds and elements that essentially strip all life from the field. Those chemicals are a leading cause of increased cancer related deaths in countryside. Herein, the Trojan horse of endosymbiosis was used, in an effort to control pests using high specificity compounds in reduced quantities. MATERIALS AND METHODS: Our pipeline has been applied on the case of Otiorhynchus singularis, which is a very widespread pest, whose impact is devastating on a repertoire of crops. To date, there is no specific pesticide nor agent to control it. The deployed strategy involves the inhibition of the key DSB-A enzyme of its endosymbiotic Wolbachia pipientis bacterial strain. RESULTS: Our methodology, provides the means to design, test and identify highly specific pestcide control substances that minimize the impact of toxic chemicals on health, economy and the environment. CONCLUSION: All in all, in this study a radical computer-based pipeline is proposed that could be adopted under many other similar scenarios and pave the way for precision agriculture via optimized pest control.

Antibodies as stratagems against cancer.

Antibodies have been in the frontline of anticancer research during the last few decades, since a number of different ways have been discovered to utilize them as parts or main components of anticancer drugs. Antibodies are used as the only component of some anticancer drugs, but they can also be conjugated with a variety of substances. Antibody engineering methods such as humanization, chimerization and Fc engineering are applied in order to modify their properties according to the requirements of anticancer drug application. Given the continuous advances in biology and informatics, the role of antibodies in anticancer treatment is expected to be prominent.