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.

DRDs and Brain-Derived Neurotrophic Factor Share a Common Therapeutic Ground: A Novel Bioinformatic Approach Sheds New Light Toward Pharmacological Treatment of Cognitive and Behavioral Disorders.

Cognitive and behavioral disorders are subgroups of mental health disorders. Both cognitive and behavioral disorders can occur in people of different ages, genders, and social backgrounds, and they can cause serious physical, mental, or social problems. The risk factors for these diseases are numerous, with a range from genetic and epigenetic factors to physical factors. In most cases, the appearance of such a disorder in an individual is a combination of his genetic profile and environmental stimuli. To date, researchers have not been able to identify the specific causes of these disorders, and as such, there is urgent need for innovative study approaches. The aim of the present study was to identify the genetic factors which seem to be more directly responsible for the occurrence of a cognitive and/or behavioral disorder. More specifically, through bioinformatics tools and software as well as analytical methods such as systemic data and text mining, semantic analysis, and scoring functions, we extracted the most relevant single nucleotide polymorphisms (SNPs) and genes connected to these disorders. All the extracted SNPs were filtered, annotated, classified, and evaluated in order to create the "genomic grammar" of these diseases. The identified SNPs guided the search for top suspected genetic factors, dopamine receptors D and neurotrophic factor BDNF, for which regulatory networks were built. The identification of the "genomic grammar" and underlying factors connected to cognitive and behavioral disorders can aid in the successful disease profiling and the establishment of novel pharmacological targets and provide the basis for personalized medicine, which takes into account the patient's genetic background as well as epigenetic factors.

An Updated Evolutionary and Structural Study of TBK1 Reveals Highly Conserved Motifs as Potential Pharmacological Targets in Neurodegenerative Diseases.

TANK-binding kinase 1 protein (TBK1) is a kinase that belongs to the IκB (IKK) family. TBK1, also known as T2K, FTDALS4, NAK, IIAE8, and NF-κB, is responsible for the phosphorylation of the amino acid residues, serine and threonine. This enzyme is involved in various key biological processes, including interferon activation and production, homeostasis, cell growth, autophagy, insulin production, and the regulation of TNF-α, IFN-ß, and IL-6. Mutations in the TBK1 gene alter the protein's normal function and may lead to an array of pathological conditions, including disorders of the central nervous system. The present study sought to elucidate the role of the TBK1 protein in amyotrophic lateral sclerosis (ALS), a human neurodegenerative disorder. A broad evolutionary and phylogenetic analysis of TBK1 was performed across numerous organisms to distinguish conserved regions important for the protein's function. Subsequently, mutations and SNPs were explored, and their potential effect on the enzyme's function was investigated. These analytical steps, in combination with the study of the secondary, tertiary, and quaternary structure of TBK1, enabled the identification of conserved motifs, which can function as novel pharmacological targets and inform therapeutic strategies for amyotrophic lateral sclerosis.

Semantic and Population Analysis of the Genetic Targets Related to COVID-19 and Its Association with Genes and Diseases.

SARS-CoV-2 is a coronavirus responsible for one of the most serious, modern worldwide pandemics, with lasting and multifaceted effects. By late 2021, SARS-CoV-2 has infected more than 180 million people and has killed more than 3 million. The virus gains entrance to human cells through binding to ACE2 via its surface spike protein and causes a complex disease of the respiratory system, termed COVID-19. Vaccination efforts are being made to hinder the viral spread, and therapeutics are currently under development. Toward this goal, scientific attention is shifting toward variants and SNPs that affect factors of the disease such as susceptibility and severity. This genomic grammar, tightly related to the dark part of our genome, can be explored through the use of modern methods such as natural language processing. We present a semantic analysis of SARS-CoV-2-related publications, which yielded a repertoire of SNPs, genes, and disease ontologies. Population data from the 1000 Genomes Project were subsequently integrated into the pipeline. Data mining approaches of this scale have the potential to elucidate the complex interaction between COVID-19 pathogenesis and host genetic variation; the resulting knowledge can facilitate the management of high-risk groups and aid the efforts toward precision medicine.

ADRA2B and HTR1A: An Updated Study of the Biogenic Amine Receptors Reveals Novel Conserved Motifs Which Play Key Role in Mental Disorders.

Mental disorders are strongly connected with several psychiatric conditions including depression, bipolar disorder, schizophrenia, eating disorder, and suicides. There are many biological conditions and pathways that define these complicated illnesses. For example, eating disorders are complex mental health conditions that require the intervention of geneticists, psychiatrists, and medical experts in order to alleviate their symptoms. A patient with suicidal ideation should first be identified and consequently monitored by a similar team of specialists. Both genetics and epigenetics can shed light on eating disorders and suicides as they are found in the main core of such investigations. In the present study, an analysis has been performed on two specific members of the GPCR family toward drawing conclusions regarding their functionality and implementation in mental disorders. Specifically, evolutionary and structural studies on the adrenoceptor alpha 2b (ADRA2B) and the 5-hydroxytryptamine receptor 1A (HTR1A) have been carried out. Both receptors are classified in the biogenic amine receptors sub-cluster of the GPCRs and have been connected in many studies with mental diseases and malnutrition conditions. The major goal of this study is the investigation of conserved motifs among biogenic amine receptors that play an important role in this family signaling pathway, through an updated evolutionary analysis and the correlation of this information with the structural features of the HTR1A and ADRA2B. Furthermore, the structural comparison of ADRA2B, HTR1A, and other members of GPCRs related to mental disorders is performed.

A Genomic Study of the Japanese Population Focusing on the Glucocorticoid Receptor Interactome Highlights Distinct Genetic Characteristics Associated with Stress Response.

All living organisms have been programmed to maintain a complex inner equilibrium called homeostasis, despite numerous adversities during their lifespan. Any threatening or perceived as such stimuli for homeostasis is termed a stressor, and a highly conserved response system called the stress response system has been developed to cope with these stimuli and maintain or reinstate homeostasis. The glucocorticoid receptor, a transcription factor belonging to the nuclear receptors protein superfamily, has a major role in the stress response system, and research on its interactome may provide novel information regarding the mechanisms underlying homeostasis maintenance. A list of 149 autosomal genes that have an essential role in GR function or are prime examples of GRE-containing genes was composed in order to gain a comprehensive view of the GR interactome. A search for SNPs on those particular genes was conducted on a dataset of 3554 Japanese individuals, with mentioned polymorphisms being annotated with relevant information from the ClinVar, LitVar, and dbSNP databases. Forty-two SNPs of interest and their genomic locations were identified. These SNPs have been associated with drug metabolism and neuropsychiatric, metabolic, and immune system disorders, while most of them were located in intronic regions. The frequencies of those SNPs were later compared with a dataset consisting of 1465 Korean individuals in order to find population-specific characteristics based on some of the identified SNPs of interest. The results highlighted.that rs1043618 frequencies were different in the two populations, with mentioned polymorphism having a potential role in chronic obstructive pulmonary disease in response to environmental stressors. This SNP is located in the HSPA1A gene, which codes for an essential GR co-chaperone, and such information showcases that similar gene may be novel genomic targets for managing or combatting stress-related pathologies.

Genetic factors involved in the co­occurrence of endometriosis with ankylosing spondylitis (Review).

Previous research has revealed an association between endometriosis and various autoimmune diseases, while recent data suggest, for the first time, an association between endometriosis and the risk of developing ankylosing spondylitis (AS). AS, the prototype of spondyloarthritides diseases, is a systemic, chronic, immune­mediated inflammatory arthritis, which primarily affects the spine and sacroiliac joints, as well as the axial skeleton with or without extraspinal manifestations. AS is of polygenic inheritance and numerous immunologically relevant genes contribute to its development. Endometriosis is an enigmatic, relatively common, benign, estrogen­dependent, heterogeneous gynecological disease, influenced by multiple genetic, epigenetic and environmental factors. It is characterized by the growth of endometrial tissue occurring in sites other than the uterine cavity, most commonly in the pelvic cavity, including the ovaries and the uterosacral ligaments, affecting up to 10% of the female population of childbearing age, causing pain and infertility. The present review discusses whether a partially shared genetic background may explain the co­occurrence of these disorders, as well as potential similarities regarding the underlying pathogenetic mechanisms and specific molecular and cellular pathways.

Association of endometriosis with cardiovascular disease: Genetic aspects (Review).

Cardiovascular disease (CVD) comprises a broad spectrum of pathological conditions that affect the heart or blood vessels, including sequelae that arise from damaged vasculature in other organs of the body, such as the brain, kidneys or eyes. Atherosclerosis is a chronic inflammatory disease of the arterial intima and is the primary cause of coronary artery disease, peripheral vascular disease, heart attack, stroke and renal pathology. It represents a leading cause of mortality worldwide and the loss of human productivity that is marked by an altered immune response. Endometriosis is a heritable, heterogeneous, common gynecological condition influenced by multiple genetic, epigenetic and environmental factors, affecting up to 10% of the female population of childbearing age, causing pain and infertility; it is characterized by the ectopic growth of endometrial tissue outside the uterine cavity. Of note, epidemiological data obtained thus far have suggested a link between endometriosis and the risk of developing CVD. The similarities observed in specific molecular and cellular pathways of endometriosis and CVD may be partially explained by a shared genetic background. The present review presents and discusses the shared genetic factors which have been reported to be associated with the development of both disorders.

Role of non­coding RNAs as biomarkers and the application of omics technologies in Alzheimer's disease (Review).

Alzheimer's disease (AD) is a neurodegenerative disorder that has a significant association with age. Despite its increasing incidence in the population, the etiology of the disease remains poorly understood, and there are currently no effective treatments readily available. The main genes that are associated with AD are the amyloid precursor protein, presenilin­1 and presenilin­2, as well as the apolipoprotein E gene. In addition to genetic factors, a wide range of environmental and lifestyle factors are equally characterized as risk factors for the development of AD, while non­coding RNAs (ncRNAs) and other epigenetic mechanisms play a key role in their detrimental effects. Multiple types of ncRNAs, such as microRNAs, circular RNAs, Piwi­interacting RNAs and long non­coding RNAs are being increasingly implicated in AD. Alterations in ncRNAs can be detected in cerebrospinal fluid, as well in as the brain, highlighting these as promising biomarkers for the detection and treatment of AD. Developments in high­throughput technologies have led to the so­called 'omics' era, which involves the collection of big data and information at both molecular and protein levels, while combining the development of novel computational and statistical tools capable of analyzing and filtering such data. The present review discusses the role of ncRNAs and their use as biomarkers for AD, and summarizes the findings from the application of omics technologies in AD.

Recent approaches on Huntington's disease (Review).

Huntington's disease (HD) is a neurodegenerative disorder characterized by severe motor, cognitive and psychiatric symptoms. Patients of all ages can present with a dysfunction of the nervous system, which leads to the progressive loss of movement control and disabilities in speech, swallowing, communications, etc. The molecular basis of the disease is well-known, as HD is related to a mutated gene, a trinucleotide expansion, which encodes to the huntingtin protein. This protein is linked to neurogenesis and the loss of its function leads to neurodegenerative disorders. Although the genetic cause of the disorder has been known for decades, no effective treatment is yet available to prevent onset or to eliminate the progression of symptoms. Thus, the present review focused on the development of novel methods for the timely and accurate diagnosis of HD in an aim to aid the development of therapies which may reduce the severity of the symptoms and control their progression. The majority of the therapies include gene-silencing mechanisms of the mutated huntingtin gene aiming to suppress its expression, and the use of various substances as drugs with highly promising results. In the present review, the latest approaches on the diagnosis of HD are discussed along with the need for genetic counseling and an up-to-date presentation of the applied treatments.

Dark DNA and stress (Review).

Over the past few decades, research at the molecular level has focused on the part of the genome that does not encode protein sequences. Since the discovery of transcriptional evidence from the hitherto considered 'junk' DNA, this region of the genome, which is currently termed dark DNA, is constantly gaining interest. The term borrows an analogy from the corresponding eminent fields of dark matter and dark energy in physics and cosmology. In fact, an increasing number of attempts are being made to enhance the current understanding of the non­coding RNA (ncRNA) transcripts produced by such regions. Although the base­pair length and gene number appear to be very diverse between species, it appears that the amount of the non­coding regions of the genome of an organism is a sign of evolutional superiority. ncRNA molecules are able to orchestrate the expression of genetic information in the most complex, rapid and reversible manner, participating in almost every major biological process. A prime example of such a process is the maintenance of homeostasis, the internal physiological balance, despite internal and external stressful stimuli. These molecules have been shown to be excellent regulators of gene expression, with marked spatiotemporal specificity, rendering them ideal tools for regulating stress responses. Herein, an attempt is made to extract and fuse information from a repertoire of studies, which have demonstrated that the expression of a number of these molecules was modified following exposure to acute and chronic stress, as well as in patients with anxiety disorders and their respective animal models. All in all, ncRNAs have the potential to be used either as biomarkers or as therapeutic targets for disorders resulting from the loss of equilibrium, the disruption of homeostasis and the destabilization of the hypothalamic­pituitary­adrenal axis.

Multiple sclerosis and computational biology (Review).

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease whose prevalence has increased worldwide. The resultant symptoms may be debilitating and can substantially reduce the of patients. Computational biology, which involves the use of computational tools to answer biomedical questions, may provide the basis for novel healthcare approaches in the context of MS. The rapid accumulation of health data, and the ever-increasing computational power and evolving technology have helped to modernize and refine MS research. From the discovery of novel biomarkers to the optimization of treatment and a number of quality-of-life enhancements for patients, computational biology methods and tools are shaping the field of MS diagnosis, management and treatment. The final goal in such a complex disease would be personalized medicine, i.e., providing healthcare services that are tailored to the individual patient, in accordance to the particular biology of their disease and the environmental factors to which they are subjected. The present review article summarizes the current knowledge on MS, modern computational biology and the impact of modern computational approaches of MS.

Novel computational pipelines in antiviral structure­based drug design (Review).

Viral infections constitute a fundamental and continuous challenge for the global scientific and medical community, as highlighted by the ongoing COVID-19 pandemic. In combination with prophylactic vaccines, the development of safe and effective antiviral drugs remains a pressing need for the effective management of rare and common pathogenic viruses. The design of potent antivirals can be informed by the study of the three-dimensional structure of viral protein targets. Structure-based design of antivirals in silico provides a solution to the arduous and costly process of conventional drug development pipelines. Furthermore, rapid advances in high-throughput computing, along with the growth of available biomolecular and biochemical data, enable the development of novel computational pipelines in the hunt of antivirals. The incorporation of modern methods, such as deep-learning and artificial intelligence, has the potential to revolutionize the structure-based design and repurposing of antiviral compounds, with minimal side effects and high efficacy. The present review aims to provide an outline of both traditional computational drug design and emerging, high-level computing strategies.

Role of microRNAs and long non­coding RNAs in glucocorticoid signaling (Review).

The synthesis and release of glucocorticoids in living organisms are related to their response to unfavorable stressful conditions in order to maintain homeostatic functions and survive. One such hormone in humans is cortisol, which is produced by the hypothalamic­pituitary­adrenal cortex axis and binds with the glucocorticoid receptor (GR) following its secretion. GR controls a number of distinct gene networks. Non­coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non­coding RNAs (lncRNAs), regulate the expression and function of GR, having a considerable impact on various biological processes and treatment approaches for numerous disorders. In the present review, the GR pathways and signaling as part of the stress response system are discussed. A detailed report on the role of miRNAs and lncRNAs in glucocorticoid signaling is also presented.

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.

Epione application: An integrated web­toolkit of clinical genomics and personalized medicine in systemic lupus erythematosus.

Genome wide association studies (GWAS) have identified autoimmune disease­associated loci, a number of which are involved in numerous disease­associated pathways. However, much of the underlying genetic and pathophysiological mechanisms remain to be elucidated. Systemic lupus erythematosus (SLE) is a chronic, highly heterogeneous autoimmune disease, characterized by differences in autoantibody profile, serum cytokines and a multi­system involvement. This study presents the Epione application, an integrated bioinformatics web­toolkit, designed to assist medical experts and researchers in more accurately diagnosing SLE. The application aims to identify the most credible gene variants and single nucleotide polymorphisms (SNPs) associated with SLE susceptibility, by using patient's genomic data to aid the medical expert in SLE diagnosis. The application contains useful knowledge of >70,000 SLE­related publications that have been analyzed, using data mining and semantic techniques, towards extracting the SLE­related genes and the corresponding SNPs. Probable genes associated with the patient's genomic profile are visualized with several graphs, including chromosome ideograms, statistic bars and regulatory networks through data mining studies with relative publications, to obtain a representative number of the most credible candidate genes and biological pathways associated with the SLE. Furthermore, an evaluation study was performed on a patient diagnosed with SLE and is presented herein. Epione has also been expanded in family­related candidate patients to evaluate its predictive power. All the recognized gene variants that were previously considered to be associated with SLE were accurately identified in the output profile of the patient, and by comparing the results, novel findings have emerged. The Epione application may assist and facilitate in early stage diagnosis by using the patients' genomic profile to compare against the list of the most predictable candidate gene variants related to SLE. Its diagnosis­oriented output presents the user with a structured set of results on variant association, position in genome and links to specific bibliography and gene network associations. The overall aim of the present study was to provide a reliable tool for the most effective study of SLE. This novel and accessible webserver tool of SLE is available at http://geneticslab.aua.gr/epione/.

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.

Demetra Application: An integrated genotype analysis web server for clinical genomics in endometriosis.

Demetra Application is a holistic integrated and scalable bioinformatics web­based tool designed to assist medical experts and researchers in the process of diagnosing endometriosis. The application identifies the most prominent gene variants and single nucleotide polymorphisms (SNPs) causing endometriosis using the genomic data provided for the patient by a medical expert. The present study analyzed >28.000 endometriosis­related publications using data mining and semantic techniques aimed towards extracting the endometriosis­related genes and SNPs. The extracted knowledge was filtered, evaluated, annotated, classified, and stored in the Demetra Application Database (DAD). Moreover, an updated gene regulatory network with the genes implements in endometriosis was established. This was followed by the design and development of the Demetra Application, in which the generated datasets and results were included. The application was tested and presented herein with whole­exome sequencing data from seven related patients with endometriosis. Endometriosis­related SNPs and variants identified in genome­wide association studies (GWAS), whole­genome (WGS), whole­exome (WES), or targeted sequencing information were classified, annotated and analyzed in a consolidated patient profile with clinical significance information. Probable genes associated with the patient's genomic profile were visualized using several graphs, including chromosome ideograms, statistic bars and regulatory networks through data mining studies with relative publications, in an effort to obtain a representative number of the most credible candidate genes and biological pathways associated with endometriosis. An evaluation analysis was performed on seven patients from a three­generation family with endometriosis. All the recognized gene variants that were previously considered to be associated with endometriosis were properly identified in the output profile per patient, and by comparing the results, novel findings emerged. This novel and accessible webserver tool of endometriosis to assist medical experts in the clinical genomics and precision medicine procedure is available at http://geneticslab.aua.gr/.

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.