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Pharmacological Reviews Oct 2020RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various...
RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.
Topics: Aptamers, Nucleotide; Betacoronavirus; COVID-19; Chemistry Techniques, Analytical; Clustered Regularly Interspaced Short Palindromic Repeats; Coronavirus Infections; Drug Delivery Systems; Drug Development; Drug Discovery; Humans; MicroRNAs; Oligonucleotides, Antisense; Pandemics; Pneumonia, Viral; RNA; RNA, Antisense; RNA, Messenger; RNA, Ribosomal; RNA, Small Interfering; RNA, Viral; Ribonucleases; Riboswitch; SARS-CoV-2
PubMed: 32929000
DOI: 10.1124/pr.120.019554 -
Clinical Microbiology and Infection :... Sep 2021Bacteria colonizing the upper respiratory tract (URT) of young children play a key role in the pathogenesis of lower respiratory tract infection (LRTI). (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Bacteria colonizing the upper respiratory tract (URT) of young children play a key role in the pathogenesis of lower respiratory tract infection (LRTI).
OBJECTIVES
To systematically review the literature on the association between bacteria colonizing the URT and LRTI among young children.
DATA SOURCES
MEDLINE, Academic Search Premier, Africa-Wide Information and CINAHL, Scopus and Web of Science.
STUDY ELIGIBILITY CRITERIA
Studies published between 1923 and 2020, investigating URT bacteria from LRTI cases and controls.
PARTICIPANTS
Children under 5 years with and without acute LRTI.
METHODS
Three reviewers independently screened titles, abstracts and full texts. Meta-analysis was done using Mantel-Haenszel fixed- or random-effects models.
RESULTS
Most eligible studies (41/50) tested nasopharyngeal specimens when investigating URT bacteria. Most studies were of cross-sectional design (44/50). Twenty-four studies were performed in children in lower- or lower-middle-income countries (LMICs). There was higher prevalence of Haemophilus influenzae (pooled OR 1.60; 95% CI 1.23-2.07) and Klebsiella spp. (pooled OR 2.04; 95% CI 1.17-3.55) from URT specimens of cases versus controls. We observed a positive association between the detection of Streptococcus pneumoniae from URT specimens and LRTI after excluding studies where there was more antibiotic treatment prior to sampling in cases vs. controls (pooled OR 1.41; 95% CI 1.04-1.90). High density colonization with S. pneumoniae (>6.9 log copies/mL) was associated with an increased risk for LRTI. The associations between both Streptococcus and Haemophilus URT detection and LRTI were supported, at genus level, by 16S rRNA sequencing. Evidence for the role of Moraxella catarrhalis and Staphylococcus aureus was inconclusive.
CONCLUSIONS
Detection of H. influenzae or Klebsiella spp. in the URT was associated with LRTI, while evidence for association with S. pneumoniae was less conclusive. Longitudinal studies assessing URT microbial communities, together with environmental and host factors are needed to better understand pathogenesis of childhood LRTI.
Topics: Bacteria; Child; Child, Preschool; Cross-Sectional Studies; Humans; RNA, Ribosomal, 16S; Respiratory Tract Infections
PubMed: 34111578
DOI: 10.1016/j.cmi.2021.05.034 -
The Lancet. Microbe Nov 2022Data from animal models suggest a role of early-life gut microbiota in lung immune development, and in establishing susceptibility to respiratory infections and asthma... (Review)
Review
Data from animal models suggest a role of early-life gut microbiota in lung immune development, and in establishing susceptibility to respiratory infections and asthma in humans. This systematic review summarises the association between infant (ages 0-12 months) gut microbiota composition measured by genomic sequencing, and childhood (ages 0-18 years) respiratory diseases (ie, respiratory infections, wheezing, or asthma). Overall, there was evidence that low α-diversity and relative abundance of particular gut-commensal bacteria genera (Bifidobacterium, Faecalibacterium, Ruminococcus, and Roseburia) are associated with childhood respiratory diseases. However, results were inconsistent and studies had important limitations, including insufficient characterisation of bacterial taxa to species level, heterogeneous outcome definitions, residual confounding, and small sample sizes. Large longitudinal studies with stool sampling during the first month of life and shotgun metagenomic approaches to improve bacterial and fungal taxa resolution are needed. Standardising follow-up times and respiratory disease definitions and optimising causal statistical approaches might identify targets for primary prevention of childhood respiratory diseases.
Topics: Infant; Humans; Infant, Newborn; Child, Preschool; Child; Adolescent; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Feces; Bacteria; Asthma; Respiration Disorders; Respiratory Tract Infections
PubMed: 35988549
DOI: 10.1016/S2666-5247(22)00184-7 -
Microbiome Mar 2017Necrotizing enterocolitis (NEC) is a catastrophic disease of preterm infants, and microbial dysbiosis has been implicated in its pathogenesis. Studies evaluating the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Necrotizing enterocolitis (NEC) is a catastrophic disease of preterm infants, and microbial dysbiosis has been implicated in its pathogenesis. Studies evaluating the microbiome in NEC and preterm infants lack power and have reported inconsistent results.
METHODS AND RESULTS
Our objectives were to perform a systematic review and meta-analyses of stool microbiome profiles in preterm infants to discern and describe microbial dysbiosis prior to the onset of NEC and to explore heterogeneity among studies. We searched MEDLINE, PubMed, CINAHL, and conference abstracts from the proceedings of Pediatric Academic Societies and reference lists of relevant identified articles in April 2016. Studies comparing the intestinal microbiome in preterm infants who developed NEC to those of controls, using culture-independent molecular techniques and reported α and β-diversity metrics, and microbial profiles were included. In addition, 16S ribosomal ribonucleic acid (rRNA) sequence data with clinical meta-data were requested from the authors of included studies or searched in public data repositories. We reprocessed the 16S rRNA sequence data through a uniform analysis pipeline, which were then synthesized by meta-analysis. We included 14 studies in this review, and data from eight studies were available for quantitative synthesis (106 NEC cases, 278 controls, 2944 samples). The age of NEC onset was at a mean ± SD of 30.1 ± 2.4 weeks post-conception (n = 61). Fecal microbiome from preterm infants with NEC had increased relative abundances of Proteobacteria and decreased relative abundances of Firmicutes and Bacteroidetes prior to NEC onset. Alpha- or beta-diversity indices in preterm infants with NEC were not consistently different from controls, but we found differences in taxonomic profiles related to antibiotic exposure, formula feeding, and mode of delivery. Exploring heterogeneity revealed differences in microbial profiles by study and the target region of the 16S rRNA gene (V1-V3 or V3-V5).
CONCLUSIONS
Microbial dysbiosis preceding NEC in preterm infants is characterized by increased relative abundances of Proteobacteria and decreased relative abundances of Firmicutes and Bacteroidetes. Microbiome optimization may provide a novel strategy for preventing NEC.
Topics: Bacteria; Bacteroides; Dysbiosis; Enterocolitis, Necrotizing; Feces; Firmicutes; Gastrointestinal Microbiome; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intestines; Proteobacteria; RNA, Ribosomal, 16S
PubMed: 28274256
DOI: 10.1186/s40168-017-0248-8 -
Ageing Research Reviews Nov 2022Modifications of RNA, collectively called the "epitranscriptome", might provide novel biomarkers and innovative targets for interventions in geroscience but are just... (Review)
Review
Modifications of RNA, collectively called the "epitranscriptome", might provide novel biomarkers and innovative targets for interventions in geroscience but are just beginning to be studied in the context of ageing and stress resistance. RNA modifications modulate gene expression by affecting translation initiation and speed, miRNA binding, RNA stability, and RNA degradation. Nonetheless, the precise underlying molecular mechanisms and physiological consequences of most alterations of the epitranscriptome are still only poorly understood. We here systematically review different types of modifications of rRNA, tRNA and mRNA, the methodology to analyze them, current challenges in the field, and human disease associations. Furthermore, we compiled evidence for a connection between individual enzymes, which install RNA modifications, and lifespan in yeast, worm and fly. We also included resistance to different stressors and competitive fitness as search criteria for genes potentially relevant to ageing. Promising candidates identified by this approach include RCM1/NSUN5, RRP8, and F33A8.4/ZCCHC4 that introduce base methylations in rRNA, the methyltransferases DNMT2 and TRM9/ALKBH8, as well as factors involved in the thiolation or A to I editing in tRNA, and finally the mA machinery for mRNA.
Topics: Aging; AlkB Homolog 8, tRNA Methyltransferase; Animals; Humans; Methyltransferases; MicroRNAs; RNA, Messenger; RNA, Ribosomal; RNA, Transfer; Saccharomyces cerevisiae
PubMed: 35908668
DOI: 10.1016/j.arr.2022.101700 -
Asian Pacific Journal of Tropical... Sep 2017To verify phylogeography and genetic structure of Acanthamoeba populations among the Iranian clinical isolates and natural/artificial environments distributed in various... (Review)
Review
OBJECTIVE
To verify phylogeography and genetic structure of Acanthamoeba populations among the Iranian clinical isolates and natural/artificial environments distributed in various regions of the country.
METHODS
We searched electronic databases including Medline, PubMed, Science Direct, Scopus and Google Scholar from 2005 to 2016. To explore the genetic variability of Acanthamoeba sp, 205 sequences were retrieved from keratitis patients, immunosuppressed cases and environmental sources as of various geographies of Iran.
RESULTS
T4 genotype was the predominant strain in Iran, and the rare genotypes belonged to T2, T3, T5 (Acanthamoeba lenticulata), T6, T9, T11, T13 and T15 (Acanthamoeba jacobsi). A total of 47 unique haplotypes of T4 were identified. A parsimonious network of the sequence haplotypes demonstrated star-like feature containing haplogroups IR6 (34.1%) and IR7 (31.2%) as the most common haplotypes. In accordance with the analysis of molecular variance, the high value of haplotype diversity (0.612-0.848) of Acanthamoeba T4 represented genetic variability within populations. Neutrality indices of the 18S ribosomal RNA demonstrated negative values in all populations which represented a considerable divergence from neutrality. The majority of genetic diversity belonged to the infected contact lens and dust samples in immunodeficiency and ophthalmology wards, which indicated potential routes for exposure to a pathogenic Acanthamoeba sp. in at-risk individuals. A pairwise fixation index (F) was from low to high values (0.02433-0.41892). The statistically F points out that T4 is genetically differentiated between north-west, north-south and central-south metapopulations, but not differentiated between west-central, west-south, central-south, and north-central isolates.
CONCLUSIONS
An occurrence of IR6 and IR7 displays that possibly a gene flow of Acanthamoeba T4 occurred after the founder effect or bottleneck experience through ecological changes or host mobility. This is the first systematic review and meta-analysis providing new approaches into gene migration and transmission patterns of Acanthamoeba sp, and targeting at the high-risk individuals/sources among the various regions of Iran.
PubMed: 29080613
DOI: 10.1016/j.apjtm.2017.08.011 -
Experimental Dermatology Oct 2021Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory skin disease with still largely unknown pathogenesis. While infectious organisms...
Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory skin disease with still largely unknown pathogenesis. While infectious organisms have been identified in lesions of the disease since the 1980s, questions remain over the role that bacteria and microbiome play. Recent studies using 16S ribosomal RNA gene sequencing and larger culture-based studies have begun to paint a clearer picture of the microbial world of HS. With this systematic review, we summarize all the work that has been done to date in HS bacteriology, analyse potential pitfalls and limitations of the current studies, and address future directions of investigation. This systematic review attempted to collate and analyse all bacteriology studies done to date. This review was prospectively registered with PROSPERO (1670769) performed in line with the PRISMA checklist. Twenty two studies were identified comprising 862 individual HS patients for culture studies and 206 HS patients for 16S rRNA gene sequencing studies. Methodology tended to be varied, with different sampling, culturing and sequencing methods as well as amount of analysis and stratification of patients. Bacteria identified as elevated in HS lesions in sequencing studies as well as grown from HS lesions in culture studies are identified and discussed. These primarily included the anerobic Gram-negative bacilli Prevotella, Porphyromonas and Fusibacterium, the Gram-positive bacilli Corynebacterium, and the Gram-positive cocci Staphylococcus, Streptococcus and Parvimonas. Potential interactions, as well as work in other disease models with related bacteria are also discussed. Areas of further investigation include in vitro studies of interactions between bacteria and keratinocytes, gut and oral microbiome studies and deep sequencing studies for virulence and phage factors.
Topics: Hidradenitis Suppurativa; Humans; Metagenomics; Microbiota; Skin
PubMed: 32614993
DOI: 10.1111/exd.14141 -
Clinical and Experimental Dental... Dec 2022Diet is one of the main factors influencing the diversity and interactions of the oral microbiota. The purpose of this study is to determine the impact of sugar intake... (Review)
Review
OBJECTIVES
Diet is one of the main factors influencing the diversity and interactions of the oral microbiota. The purpose of this study is to determine the impact of sugar intake on the microbial diversity and bacteria that predominate under these conditions.
MATERIAL AND METHODS
A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guide, using the PubMed, Scopus, and Science Direct databases and combinations of the words "microbiota," "microbiology," "bacteria," "sugars," "dysbiosis," "caries," "microbiome," "oral microbial," and "oral microbiota profile pattern." The selection criteria included year, language, type of publication, comparison of microbiota during low and high sugar intake, and bacterial identification by molecular sequencing of the 16S subunit of ribosomal RNA.
RESULTS
Out of a total of 374 papers that came up after the initial search, 8 met the criteria for this review. The papers included research on populations comprising children, young adults, and adults, with most of the studies reporting selection criteria for the participants and using validated instruments to determine sugar intake. Apart from one study, all others reported for high sugar intake conditions a significant decrease in microbial diversity of the oral microbiome and the predominance of several bacterial genera or species, including Streptococcus, Scardovia, Veillonella, Rothia, Actinomyces, and Lactobacillus.
CONCLUSIONS
Sugar-rich diets have a significantly unfavorable effect on the diversity and balance of oral microbiota; however, further studies are required to determine the exact role of sugar in microbial interactions.
Topics: Child; Young Adult; Humans; Microbiota; Bacteria; Dental Caries; Dysbiosis; Sugars
PubMed: 35946056
DOI: 10.1002/cre2.640 -
Clinics (Sao Paulo, Brazil) 2022The increase in the incidence of pancreatic and biliary cancers has attracted the search for methods of early detection of diseases and biomarkers. The authors propose... (Review)
Review
INTRODUCTION
The increase in the incidence of pancreatic and biliary cancers has attracted the search for methods of early detection of diseases and biomarkers. The authors propose to analyze new findings on the association between microbiota and Pancreatic Ductal Adenocarcinoma (PDAC) or Cholangiocarcinoma (CCA).
METHODS
This systematic review was carried out according to the items of Preferred Reports for Systematic Reviews and Protocol Meta-Analysis (PRISMA-P). This study was registered by the Prospective Register of Systematic Reviews (PROSPERO), identification code CRD42020192748 before the review was carried out. Articles were selected from the PUBMED, EMBASE, and Cochrane databases.
RESULTS
Most studies (86.67%) used 16s rRNA as a sequencing method. The main comorbidities found were diabetes mellitus, systemic arterial hypertension, and dyslipidemia. Many studies were limited by the small number of participants, but the biases were mostly low. There was very little concordance about the composition of the microbiome of different sites, for both case and control groups when compared to other studies' results. Bile sample analysis was the one with a greater agreement between studies, as three out of four studies found Escherichia in cases of CCA.
CONCLUSION
There was great disagreement in the characterization of both the microbiota of cases and control groups. Studies are still scarce, making it difficult to adequately assess the data in this regard. It was not possible to specify any marker or to associate any genus of microbiota bacteria with PDAC or CCA.
Topics: Carcinoma, Pancreatic Ductal; Humans; Microbiota; Pancreatic Neoplasms; RNA, Ribosomal, 16S; Syndrome
PubMed: 36122499
DOI: 10.1016/j.clinsp.2022.100101 -
Journal of Zhejiang University.... Dec 2022: Osteoporosis (OP) has become a major public health issue, threatening the bone health of middle-aged and elderly people from all around the world. Changes in the gut... (Meta-Analysis)
Meta-Analysis
: Osteoporosis (OP) has become a major public health issue, threatening the bone health of middle-aged and elderly people from all around the world. Changes in the gut microbiota (GM) are correlated with the maintenance of bone mass and bone quality. However, research results in this field remain highly controversial, and no systematic review or meta-analysis of the relationship between GM and OP has been conducted. This paper addresses this shortcoming, focusing on the difference in the GM abundance between OP patients and healthy controls based on previous 16S ribosomal RNA (rRNA) gene sequencing results, in order to provide new clinical reference information for future customized prevention and treatment options of OP. : According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), we comprehensively searched the databases of PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI). In addition, we applied the R programming language version 4.0.3 and Stata 15.1 software for data analysis. We also implemented the Newcastle-Ottawa Scale (NOS), funnel plot analysis, sensitivity analysis, Egger's test, and Begg's test to assess the risk of bias. : This research ultimately considered 12 studies, which included the fecal GM data of 2033 people (604 with OP and 1429 healthy controls). In the included research papers, it was observed that the relative abundance of and increased in the OP group, while the relative abundance for of Bacteroidetes increased (except for Ireland). Meanwhile, Firmicutes, , , , and showed reduced relative abundance in Chinese studies. In the linear discriminant analysis Effect Size (LEfSe) analysis, certain bacteria showed statistically significant results consistently across different studies. : This observational meta-analysis revealed that changes in the GM were correlated with OP, and variations in some advantageous GM might involve regional differences.
Topics: Aged; Humans; Middle Aged; Feces; Gastrointestinal Microbiome; Genes, rRNA; Osteoporosis; RNA, Ribosomal, 16S
PubMed: 36518053
DOI: 10.1631/jzus.B2200344