1,720,981 research outputs found
Overview of the First 6 Months of Clinical Trials for COVID-19 Pharmacotherapy: The Most Studied Drugs
No full textSARS-CoV-2 rapidly spread from China until it was defined a pandemic by WHO in March 2020. Related scientific papers have rapidly extended information regarding the diagnosis, treatment and epidemiology of COVID-19 infection. To date, no vaccine or definitive treatment is available to defeat the virus and therapies are mainly based on existing drugs used to treat other conditions. Existing therapies used in several clinical trials work by affecting the biology of COVID-19 and/or counteracting the harmful host excessive immune response. Here, we have reviewed 526 ongoing clinical trials for COVID-19 to provide a perspective on the first 6 months of global efforts to identify an effective therapy. The drugs most actively tested in various centers include hydroxychloroquine, ritonavir, azithromycin, tocilizumab, lopinavir chloroquine and ivermectin. Our analysis shows that most clinical trials focus on a small number of candidate drugs (namely hydroxychloroquine and chloroquine representing 25% of total clinical trials) while underestimating the potential of other promising drugs. A global coordination in clinical trial management could avoid duplications and increase the effectiveness of the response to the global challenge
Circular RNAs in Immune-Related Diseases
No full textCircRNAs are a novel class of noncoding RNAs characterized by a covalently closed loop structure lacking both a 3' polyadenylation tail and a 5' cap. Increasing evidence demonstrated that circRNAs can participate in several biological processes including immune system physiology and immune-related diseases. CircRNAs act on immune pathways through several molecular mechanisms including miRNAs and RBP sponges, protein scaffolds, and mRNA stability modulation via diverse signaling pathways including MAPK, JAK-STAT, and Wnt signaling pathway. Recently, circRNAs have also been studied as biomarkers for immune diseases as well as new potential therapeutic targets. Effects of dysregulated circRNA levels correlate, among others, with alterations in immune cell behavior, cytokines production, and immune response in general.In this chapter, we describe new experimental progress in circRNAs that participates in the regulation of the immune system and in the pathogenesis of autoimmune diseases and infectious diseases
Genetic variants in mRNA untranslated regions
No full textGenome Wide Association Studies (GWAS) have mapped thousands of genetic variants associated with complex disease risk and regulating quantitative traits, thus exploiting an unprecedented high-resolution genetic characterization of the human genome. A small fraction (3.7%) of the identified associations is located in untranslated regions (UTRs), and the molecular mechanism has been elucidated for few of them. Genetic variations at UTRs may modify regulatory elements affecting the interaction of the UTRs with proteins and microRNAs. The overall functional consequences include modulation of messenger RNA (mRNA) transcription, secondary structure, stability, localization, translation, and access to regulators like microRNAs (miRNAs) and RNA-binding proteins (RBPs). Alterations of these regulatory mechanisms are known to modify molecular pathways and cellular processes, potentially leading to disease processes. Here, we analyze some examples of genetic risk variants mapping in the UTR regulatory elements. We describe a recently identified genetic variant localized in the 3'UTR of the TNFSF13B gene, associated with autoimmunity risk and responsible of an increased stability and translation of TNFSF13B mRNA. We discuss how the correct use and interpretation of public GWAS repositories could lead to a better understanding of etiopathogenetic mechanisms and the generation of robust biological hypothesis as starting point for further functional studies.This article is categorized under:RNA Structure and Dynamics > RNA Structure, Dynamics and ChemistryRNA Evolution and Genomics > Computational Analyses of RNARNA in Disease and Development > RNA in Diseas
Noncoding RNAs in Alzheimer's disease
No full textAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia among the elderly worldwide. Despite intense efforts to develop drugs for preventing and treating AD, no effective therapies are available as yet, posing a growing burden at the personal, medical, and socioeconomic levels. AD is characterized by the production and aggregation of amyloid beta (A beta) peptides derived from amyloid precursor protein (APP), the presence of hyperphosphorylated microtubule-associated protein Tau (MAPT), and chronic inflammation leading to neuronal loss. A beta accumulation and hyperphosphorylated Tau are responsible for the main histopathological features of AD, A beta plaques, and neurofibrillary tangles (NFTs), respectively. However, the full spectrum of molecular factors that contribute to AD pathogenesis is not known. Noncoding (nc)RNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), regulate gene expression at the transcriptional and posttranscriptional levels in various diseases, serving as biomarkers and potential therapeutic targets. There is rising recognition that ncRNAs have been implicated in both the onset and pathogenesis of AD. Here, we review the ncRNAs implicated posttranscriptionally in the main AD pathways and discuss the growing interest in targeting regulatory ncRNAs therapeutically to combat AD pathology.This article is categorized under:RNA in Disease and Development > RNA in Diseas
Non-coding RNAs in malaria infection
No full textAbstract Malaria is one of the most severe infectious diseases affecting humans and it is caused by protozoan pathogens of the species Plasmodium (spp.). The malaria parasite Plasmodium is characterized by a complex, multistage life cycle that requires tight gene regulation which allows for host invasion and defense against host immune responses. Unfortunately, the mechanisms regulating gene expression during Plasmodium infection remain largely elusive, though several lines of evidence implicate a major involvement of non-coding RNAs (ncRNAs). The ncRNAs have been found to play a key role in regulating transcriptional and post-transcriptional events in a broad range of organisms including Plasmodium. In Plasmodium ncRNAs have been shown to regulate key events in the multistage life cycle and virulence ability. Here we review recent progress involving ncRNAs (microRNAs, long non-coding RNAs, and circular RNAs) and their role as regulators of gene expression during Plasmodium infection in human hosts with focus on the possibility of using these molecules as biomarkers for monitoring disease status. We also discuss the surprising function of ncRNAs in mediating the complex interplay between parasite and human host and future perspectives of the field. This article is categorized under: RNA in Disease and Development > RNA in Diseas
Substituted 2-pyrrolinone compounds as inhibitors of B-cell activating factor (BAFF) for autoimmune diseases treatment
No full textB-cell activating factor (BAFF) is a cytokine that plays a critical role in the proliferation and differentiation of B cells. We have previously demonstrated that its inherited overexpression is associated with increased circulating B cell and immunoglobulin levels, correlating with increased risk of multiple sclerosis and systemic lupus erythematosus. These findings suggest that enhanced BAFF expression may be involved in the causal biology of these disorders, thus supporting the rationale for therapeutic inhibition of this cytokine. However, to date, no small-molecule modulator capable of inhibiting BAFF is available. We therefore employed a virtual screening approach to analyze a library of 275,561 small molecules, followed by in vitro validation of 218 selected compounds with potential to disrupt the interaction between BAFF and its receptor BAFFR. Our results identified two promising small molecules, C45 and C145, belonging to the substituted 2-pyrrolinone family, which effectively inhibited BAFF activity. These compounds warrant further investigation as potential therapeutic agents for BAFF-driven autoimmune diseases
GRSF1 suppresses cell senescence
No full textA prominent phenotype triggered by the loss of mitochondrial homeostasis is cellular senescence, characterized by cessation of growth and a senescence-associated secretory phenotype (SASP). We identified the G-rich RNA sequence-binding factor 1 (GRSF1) as a major mitochondrial protein implicated in this response. GRSF1 levels declined in senescent cells through reduced protein stability, and lowering GRSF1 abundance caused mitochondrial stress leading to elevated production of superoxide, increased DNA damage foci, and diminished cell proliferation. In addition, reducing GRSF1 increased the activity of a senescence-associated beta-galactosidase (SA-beta-gal) and the production and secretion of the SASP factor interleukin 6 (IL6). Together, our findings indicate that the decline in GRSF1 levels during cellular senescence contributes to impairing mitochondrial function, elevating ROS and DNA damage, suppressing growth, and implementing a pro-inflammatory program
Long Noncoding RNAs and Circular RNAs in Autoimmune Diseases
No full textImmune responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled, autoimmune diseases can occur. Autoimmune diseases (ADs) are a family of disorders characterized by the body’s immune response being directed against its own tissues, with consequent chronic inflammation and tissue damage. Despite enormous efforts to identify new drug targets and develop new therapies to prevent and ameliorate AD symptoms, no definitive solutions are available today. Additionally, while substantial progress has been made in drug development for some ADs, most treatments only ameliorate symptoms and, in general, ADs are still incurable. Hundreds of genetic loci have been identified and associated with ADs by genome-wide association studies. However, the whole list of molecular factors that contribute to AD pathogenesis is still unknown. Noncoding (nc)RNAs, such as microRNAs, circular (circ)RNAs, and long noncoding (lnc)RNAs, regulate gene expression at different levels in various diseases, including ADs, and serve as potential drug targets as well as biomarkers for disease progression and response to therapy. In this review, we will focus on the potential roles and genetic regulation of ncRNA in four autoimmune diseases—systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes mellitus
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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