MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

The rapid expansion of the available genomic data continues to greatly impact biomedical science and medicine. Fulfilling the clinical potential of genetic discoveries requires the development of therapeutics that can specifically modulate the expression of disease-relevant genes. RNA-based drugs, including short interfering RNAs and antisense oligonucleotides, are particularly promising examples of this newer class of biologics. For over two decades, researchers have been trying to overcome major challenges for utilizing such RNAs in a therapeutic context, including intracellular delivery, stability, and immune response activation. This research is finally beginning to bear fruit as the first RNA drugs gain FDA approval and more advance to the final phases of clinical trials. Furthermore, the recent advent of CRISPR, an RNA-guided gene-editing technology, as well as new strides in the delivery of messenger RNA transcribed in vitro, have triggered a major expansion of the RNA-therapeutics field. In this review, we discuss the challenges for clinical translation of RNA-based therapeutics, with an emphasis on recent advances in delivery technologies, and present an overview of the applications of RNA-based drugs for modulation of gene/protein expression and genome editing that are currently being investigated both in the laboratory as well as in the clinic.

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Advances in the delivery of RNA therapeutics: from concept to clinical reality.

Inflammasome Priming in Sterile Inflammatory Disease.

MicroRNAs (miRNAs) are small noncoding RNAs that broadly affect cellular and physiological function in all multicellular organisms. Here, the role of miRNAs in neuroinflammation is considered. miRNAs are 21- to 23-oligonucleotide RNAs that regulate translation of specific RNAs by binding to complementary regulatory RNA sequences, thereby causing mRNA degradation or sequestration. More than 5000 miRNAs likely exist in humans, and each miRNA binds an average of 200 RNAs. Specific immunomodulatory miRNAs can regulate a set of RNAs in a coordinated manner, suggesting that effective miRNA-based therapeutic manipulations for neuroinflammatory conditions may be revealed. For instance, miRNAs that preferentially inhibit translation of many cellular anti-inflammatory proteins could drive a pro-inflammatory response. Key pro-inflammatory ( miR-155, miR-27b, miR-326), anti-inflammatory ( miR-124, miR-146a, miR-21, miR-223), and mixed immunomodulatory ( let-7 family) miRNAs regulate neuroinflammation in various pathologies, including spinal cord injury, multiple sclerosis, ischemic stroke, and Alzheimer's disease. miRNAs represent a newly revealed layer of physiological complexity, the therapeutic benefits of which remain to be fully explored and exploited. In this review, we discuss the role of miRNAs in neuroinflammatory regulation and discuss how controlling miRNAs could alter cellular machinery to improve neuroinflammatory dynamics.

https://journals.sagepub.com/doi/pdf/10.1177/1073858417721150

MicroRNAs: Roles in Regulating Neuroinflammation:

The decline of oxygen tension in the tissues below the physiological demand leads to the hypoxic adaptive response. This physiological consequence enables cells to recover from this cellular insult. Understanding the cellular pathways that mediate recovery from hypoxia is therefore critical for developing novel therapeutic approaches for cardiovascular diseases and cancer. The master regulators of oxygen homeostasis that control angiogenesis during hypoxia are hypoxia-inducible factors (HIFs). HIF-1 and HIF-2 function as transcriptional regulators and have both unique and overlapping target genes, whereas the role of HIF-3 is less clear. HIF-1 governs the acute adaptation to hypoxia, whereas HIF-2 and HIF-3 expressions begin during chronic hypoxia in human endothelium. When HIF-1 levels decline, HIF-2 and HIF-3 increase. This switch from HIF-1 to HIF-2 and HIF-3 signaling is required in order to adapt the endothelium to prolonged hypoxia. During prolonged hypoxia, the HIF-1 levels and activity are reduced, despite the lack of oxygen-dependent protein degradation. Although numerous protein factors have been proposed to modulate the HIF pathways, their application for HIF-targeted therapy is rather limited. Recently, the miRNAs that endogenously regulate gene expression via the RNA interference (RNAi) pathway have been shown to play critical roles in the hypoxia response pathways. Furthermore, these classes of RNAs provide therapeutic possibilities to selectively target HIFs and thus modulate the HIF switch. Here, we review the significance of the microRNAs on the relationship between the HIFs under both physiological and pathophysiological conditions.

/pdf/mirnas-regulate-the-hif-switch-during-hypoxia-a-novel-7emhz52dg2.pdf

miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression in diverse biological process. They act as intracellular mediators that are necessary for various biological processes. MicroRNAs targeting pathways of human disease provide a new and potential powerful candidate for therapeutic intervention against various pathological conditions. Even though, the information about miRNA biology has significantly enriched but we still do not completely understand the mechanism of miRNA gene regulation. Various groups across the globe and pharmaceutical companies are conducting research and developments to explore miRNA based therapy and build a whole new area of miroRNA therapeutics. Consequently, few miRNAs have entered the preclinical and clinical stage and soon might be available in the market for use in humans.

MicroRNA therapeutics: Discovering novel targets and developing specific therapy.

Background: Escherichia coli is well known as noninvasive commensal and has been established as etiological agent of various human infections. E. coli also contributes to high rate of resistance to several antibiotics due to multiresistant antibiotic plasmid genes e.g., extended spectrum β-lactamases (ESBL). Material and Methods: To analyse the situation of antibiotic resistance, a total of 77 E.coli isolates from urine, pus, sputum and endotracheal aspirate were screened for their antibiograms for antibiotic resistance, multiple antibiotic resistance (MAR) index for evaluating the spread of resistance and plasmid profiles for the presence and characterization of plasmids. Results: Very high resistance level (> 90%) was detected against ampicillin, amoxycillin, ceftazidime, norfloxacin, tetracycline while imipenem and amikacin recorded the least resistance levels of 2.3% and 13.9%, respectively, among the isolates. An increased resistance to amoxycillin, tetracycline, cotrimoxazole and norfloxacin were observed in this geographical area which however displayed a lower resistance in other countries. The MAR index varied considerably, the lowest was 0.18 and the highest was 0.89. Plasmids of 10 size ranges were detected in the isolates. Some isolates possessed single-sized plasmid while other possessed multiple plasmids. Isolates with high MAR profiles were found to possess multiple plasmids. Conclusion: Regular antimicrobial sensitivity surveillance is necessary and acquisition of plasmid could greatly contribute in the antibiotic resistance and poses a significant risk of the spread of microbial resistance in this community. Also, it was observed that route of administration of antibiotics perhaps reduced its misuse and hence led to the reduction in the emergence of resistant bacterial strains.

Investigation of plasmid profile, antibiotic susceptibility pattern multiple antibiotic resistance index calculation of Escherichia coli isolates obtained from different human clinical specimens at tertiary care hospital in Bareilly-India

Clinical research is making toiling efforts for promotion and wellbeing of the health status of the people. There is a rapid increase in number and severity of diseases like cancer, hepatitis, HIV etc, resulting in high morbidity and mortality. Clinical research involves drug discovery and development whereas clinical trials are performed to establish safety and efficacy of drugs. Drug discovery is a long process starting with the target identification, validation and lead optimization. This is followed by the preclinical trials, intensive clinical trials and eventually post marketing vigilance for drug safety. Softwares and the bioinformatics tools play a great role not only in the drug discovery but also in drug development. It involves the use of informatics in the development of new knowledge pertaining to health and disease, data management during clinical trials and to use clinical data for secondary research. In addition, new technology likes molecular docking, molecular dynamics simulation, proteomics and quantitative structure activity relationship in clinical research results in faster and easier drug discovery process. During the preclinical trials, the software is used for randomization to remove bias and to plan study design. In clinical trials software like electronic data capture, Remote data capture and electronic case report form (eCRF) is used to store the data. eClinical, Oracle clinical are software used for clinical data management and for statistical analysis of the data. After the drug is marketed the safety of a drug could be monitored by drug safety software like Oracle Argus or ARISg. Therefore, softwares are used from the very early stages of drug designing, to drug development, clinical trials and during pharmacovigilance. This review describes different aspects related to application of computers and bioinformatics in drug designing, discovery and development, formulation designing and clinical research.

Ajay Francis Christopher

Papers

MicroRNA therapeutics: Discovering novel targets and developing specific therapy.

Investigation of plasmid profile, antibiotic susceptibility pattern multiple antibiotic resistance index calculation of Escherichia coli isolates obtained from different human clinical specimens at tertiary care hospital in Bareilly-India

Emerging role of bioinformatics tools and software in evolution of clinical research

Potential pathways of pesticide action on erectile function – A contributory factor in male infertility

Micronome revealed miR-19a/b as key regulator of SOCS3 during cancer related inflammation of oral squamous cell carcinoma.