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Frontiers in Immunology 2020Clotting and inflammation are effective danger response patterns positively selected by evolution to limit fatal bleeding and pathogen invasion upon traumatic injuries.... (Review)
Review
Clotting and inflammation are effective danger response patterns positively selected by evolution to limit fatal bleeding and pathogen invasion upon traumatic injuries. As a trade-off, thrombotic, and thromboembolic events complicate severe forms of infectious and non-infectious states of acute and chronic inflammation, i.e., immunothrombosis. Factors linked to thrombosis and inflammation include mediators released by platelet granules, complement, and lipid mediators and certain integrins. Extracellular deoxyribonucleic acid (DNA) was a previously unrecognized cellular component in the blood, which elicits profound proinflammatory and prothrombotic effects. Pathogens trigger the release of extracellular DNA together with other pathogen-associated molecular patterns. Dying cells in the inflamed or infected tissue release extracellular DNA together with other danger associated molecular pattern (DAMPs). Neutrophils release DNA by forming neutrophil extracellular traps (NETs) during infection, trauma or other forms of vascular injury. Fluorescence tissue imaging localized extracellular DNA to sites of injury and to intravascular thrombi. Functional studies using deoxyribonuclease (DNase)-deficient mouse strains or recombinant DNase show that extracellular DNA contributes to the process of immunothrombosis. Here, we review rodent models of immunothrombosis and the evolving evidence for extracellular DNA as a driver of immunothrombosis and discuss challenges and prospects for extracellular DNA as a potential therapeutic target.
Topics: Animals; DNA; Humans; Inflammation; Thrombosis
PubMed: 33117353
DOI: 10.3389/fimmu.2020.568513 -
Seminars in Liver Disease Nov 2019There is a clear and unmet need for biomarkers in hepatocellular carcinoma (HCC). Circulating cell free deoxyribonucleic acid (cfDNA) is a fragmented DNA subtype, found... (Review)
Review
There is a clear and unmet need for biomarkers in hepatocellular carcinoma (HCC). Circulating cell free deoxyribonucleic acid (cfDNA) is a fragmented DNA subtype, found in the blood circulation. Circulating tumor DNA (ctDNA) is the fraction of total cfDNA, which originates from the primary tumor or metastases in patients with cancer. Earlier studies reported that quantitative measurement cfDNA has diagnostic and prognostic role for HCC. More recently, improvement in next-generation sequencing technology and better understanding of genetic or epigenetic alteration of HCC have allowed comprehensive analysis of mutational and methylation landscape of ctDNA. Hotspot mutation panels and methylation panels have both shown promising performance. None of these tests have yet been validated in longitudinal cohorts for preclinical detection of HCC. In this article, the authors discuss the currently available ctDNA detection technologies, their diagnostic and prognostic performance in HCC, and future research directions.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Circulating Tumor DNA; DNA Methylation; Humans; Liver Neoplasms; Mutation; Prognosis
PubMed: 31226727
DOI: 10.1055/s-0039-1688503 -
Essays in Biochemistry Apr 2021Deoxyribonucleic acid (DNA) hybridisation plays a key role in many biological processes and nucleic acid biotechnologies, yet surprisingly there are many aspects about... (Review)
Review
Deoxyribonucleic acid (DNA) hybridisation plays a key role in many biological processes and nucleic acid biotechnologies, yet surprisingly there are many aspects about the process which are still unknown. Prior to the invention of single-molecule microscopy, DNA hybridisation experiments were conducted at the ensemble level, and thus it was impossible to directly observe individual hybridisation events and understand fully the kinetics of DNA hybridisation. In this mini-review, recent single-molecule fluorescence-based studies of DNA hybridisation are discussed, particularly for short nucleic acids, to gain more insight into the kinetics of DNA hybridisation. As well as looking at single-molecule studies of intrinsic and extrinsic factors affecting DNA hybridisation kinetics, the influence of the methods used to detect hybridisation of single DNAs is considered. Understanding the kinetics of DNA hybridisation not only gives insight into an important biological process but also allows for further advancements in the growing field of nucleic acid biotechnology.
Topics: DNA; Kinetics; Nucleic Acid Hybridization; Optical Imaging; Single Molecule Imaging
PubMed: 33491734
DOI: 10.1042/EBC20200040 -
Clinical and Translational Medicine Apr 2022Extrachromosomal circular deoxyribonucleic acid (eccDNA) is evolving as a valuable biomarker, while little is known about its presence in urine.
BACKGROUND
Extrachromosomal circular deoxyribonucleic acid (eccDNA) is evolving as a valuable biomarker, while little is known about its presence in urine.
METHODS
Here, we report the discovery and analysis of urinary cell-free eccDNAs (ucf-eccDNAs) in healthy controls and patients with advanced chronic kidney disease (CKD) by Circle-Seq.
RESULTS
Millions of unique ucf-eccDNAs were identified and comprehensively characterised. The ucf-eccDNAs are GC-rich. Most ucf-eccDNAs are less than 1000 bp and are enriched in four pronounced peaks at 207, 358, 553 and 732 bp. Analysis of the genomic distribution of ucf-eccDNAs shows that eccDNAs are found on all chromosomes but enriched on chromosomes 17, 19 and 20 with a high density of protein-coding genes, CpG islands, short interspersed transposable elements (SINEs) and simple repeat elements. Analysis of eccDNA junction sequences further suggests that microhomology and palindromic repeats might be involved in eccDNA formation. The ucf-eccDNAs in CKD patients are significantly higher than those in healthy controls. Moreover, eccDNA with miRNA genes is highly enriched in CKD ucf-eccDNA.
CONCLUSIONS
This work discovers and provides the first deep characterisation of ucf-eccDNAs and suggests ucf-eccDNA as a valuable noninnvasive biomarker for urogenital disorder diagnosis and monitoring.
Topics: Biomarkers; DNA; DNA, Circular; Female; Genomics; Humans; Male; Renal Insufficiency, Chronic
PubMed: 35474296
DOI: 10.1002/ctm2.817 -
Molecules (Basel, Switzerland) Jan 2023Despite structural differences between the right-handed conformations of A-RNA and B-DNA, both nucleic acids adopt very similar, left-handed Z-conformations. In contrast... (Review)
Review
Despite structural differences between the right-handed conformations of A-RNA and B-DNA, both nucleic acids adopt very similar, left-handed Z-conformations. In contrast to their structural similarities and sequence preferences, RNA and DNA exhibit differences in their ability to adopt the Z-conformation regarding their hydration shells, the chemical modifications that promote the Z-conformation, and the structure of junctions connecting them to right-handed segments. In this review, we highlight the structural and chemical properties of both Z-DNA and Z-RNA and delve into the potential factors that contribute to both their similarities and differences. While Z-DNA has been extensively studied, there is a gap of knowledge when it comes to Z-RNA. Where such information is lacking, we try and extend the principles of Z-DNA stability and formation to Z-RNA, considering the inherent differences of the nucleic acids.
Topics: DNA, Z-Form; RNA; Nucleic Acid Conformation; DNA; Nucleic Acids
PubMed: 36677900
DOI: 10.3390/molecules28020843 -
Molecules (Basel, Switzerland) Jan 2020Every cell in a living organism is constantly exposed to physical and chemical factors which damage the molecular structure of proteins, lipids, and nucleic acids.... (Review)
Review
Every cell in a living organism is constantly exposed to physical and chemical factors which damage the molecular structure of proteins, lipids, and nucleic acids. Cellular DNA lesions are the most dangerous because the genetic information, critical for the identity and function of each eukaryotic cell, is stored in the DNA. In this review, we describe spectroscopic markers of DNA damage, which can be detected by infrared, Raman, surface-enhanced Raman, and tip-enhanced Raman spectroscopies, using data acquired from DNA solutions and mammalian cells. Various physical and chemical DNA damaging factors are taken into consideration, including ionizing and non-ionizing radiation, chemicals, and chemotherapeutic compounds. All major spectral markers of DNA damage are presented in several tables, to give the reader a possibility of fast identification of the spectral signature related to a particular type of DNA damage.
Topics: DNA; DNA Damage; Humans; Models, Molecular; Molecular Conformation; Radiation; Spectrum Analysis, Raman
PubMed: 32012927
DOI: 10.3390/molecules25030561 -
International Journal of Molecular... Aug 2021Gestational diabetes mellitus (GDM) is the most common metabolic complication in pregnancy, which affects the future health of both the mother and the newborn. Its... (Review)
Review
Gestational diabetes mellitus (GDM) is the most common metabolic complication in pregnancy, which affects the future health of both the mother and the newborn. Its pathophysiology involves nutritional, hormonal, immunological, genetic and epigenetic factors. Among the latter, it has been observed that alterations in DNA (deoxyribonucleic acid) methylation patterns and in the levels of certain micro RNAs, whether in placenta or adipose tissue, are related to well-known characteristics of the disease, such as hyperglycemia, insulin resistance, inflammation and excessive placental growth. Furthermore, epigenetic alterations of gestational diabetes mellitus are observable in maternal blood, although their pathophysiological roles are completely unknown. Despite this, it has not been possible to determine the causes of the epigenetic characteristics of GDM, highlighting the need for integral and longitudinal studies. Based on this, this article summarizes the most relevant and recent studies on epigenetic alterations in placenta, adipose tissue and maternal blood associated with GDM in order to provide the reader with a general overview of the subject and indicate future research topics.
Topics: Adipose Tissue; DNA; DNA Methylation; Diabetes, Gestational; Epigenesis, Genetic; Epigenomics; Female; Humans; MicroRNAs; Placenta; Pregnancy; Pregnant Women
PubMed: 34502370
DOI: 10.3390/ijms22179462 -
Biochimie Nov 2023Non-canonical secondary structures (NCSs) are alternative nucleic acid structures that differ from the canonical B-DNA conformation. NCSs often occur in repetitive DNA... (Review)
Review
Non-canonical secondary structures (NCSs) are alternative nucleic acid structures that differ from the canonical B-DNA conformation. NCSs often occur in repetitive DNA sequences and can adopt different conformations depending on the sequence. The majority of these structures form in the context of physiological processes, such as transcription-associated R-loops, G4s, as well as hairpins and slipped-strand DNA, whose formation can be dependent on DNA replication. It is therefore not surprising that NCSs play important roles in the regulation of key biological processes. In the last years, increasing published data have supported their biological role thanks to genome-wide studies and the development of bioinformatic prediction tools. Data have also highlighted the pathological role of these secondary structures. Indeed, the alteration or stabilization of NCSs can cause the impairment of transcription and DNA replication, modification in chromatin structure and DNA damage. These events lead to a wide range of recombination events, deletions, mutations and chromosomal aberrations, well-known hallmarks of genome instability which are strongly associated with human diseases. In this review, we summarize molecular processes through which NCSs trigger genome instability, with a focus on G-quadruplex, i-motif, R-loop, Z-DNA, hairpin, cruciform and multi-stranded structures known as triplexes.
Topics: Humans; DNA; Nucleic Acid Conformation; DNA Damage; DNA Repair; DNA Replication; Genomic Instability
PubMed: 37429410
DOI: 10.1016/j.biochi.2023.07.002 -
Advanced Science (Weinheim,... May 2023Phase separation (PS) is a fundamental principle in diverse life processes including immunosurveillance. Despite numerous studies on PS, little is known about its...
Phase separation (PS) is a fundamental principle in diverse life processes including immunosurveillance. Despite numerous studies on PS, little is known about its dissolution. Here, it is shown that oleic acid (OA) dissolves the cyclic GMP-AMP synthase (cGAS)-deoxyribonucleic acid (DNA) PS and inhibits immune surveillance of DNA. As solvent components control PS and metabolites are abundant cellular components, it is speculated that some metabolite(s) may dissolve PS. Metabolite-screening reveals that the cGAS-DNA condensates formed via PS are markedly dissolved by long-chain fatty acids, including OA. OA revokes intracellular cGAS-PS and DNA-induced activation. OA attenuates cGAS-mediated antiviral and anticancer immunosurveillance. These results link metabolism and immunity by dissolving PS, which may be targeted for therapeutic interventions.
Topics: DNA; Nucleotidyltransferases; Oleic Acid
PubMed: 36950761
DOI: 10.1002/advs.202206820 -
Fertility and Sterility Aug 2022To reveal the relationship between mitochondrial function in cumulus cells (CCs) and the aging-related decline in ovarian function and reproductive capacity.
OBJECTIVE
To reveal the relationship between mitochondrial function in cumulus cells (CCs) and the aging-related decline in ovarian function and reproductive capacity.
DESIGN
Retrospective and transcriptome analysis of human tissue.
SETTING
University hospital.
PATIENT(S)
A total of 186 infertile women with normal weight and no other diseases, including 86 young women (aged <38 years) with normal ovarian reserve and 100 advanced-age women (aged ≥38 years) with diminished ovarian reserve.
INTERVENTION(S)
None.
MAIN OUTCOME MEASURE(S)
Embryo development data were analyzed. The mitochondrial ultrastructure of CCs was observed by transmission electron microscopy. Mitochondrial activity was detected by immunofluorescence. The per-CC mitochondrial deoxyribonucleic acid copy numbers and cellular adenosine triphosphate levels were quantified. Unbiased comprehensive genome-wide transcriptomics was performed. The functions of all annotated genes and biologic pathways were analyzed by the Kyoto Encyclopedia of Genes and Genomes.
RESULT(S)
Advanced-age women with diminished ovarian function had significantly fewer retrieved oocytes and lower embryo quality. The normal mitochondrial rate in CCs was significantly lower. In addition to mitochondrial morphology and structural changes, the fluorescence intensity of Fluo-3/AM was significantly higher, and that of MitoTracker was lower than that of young women with normal ovarian reserve, suggesting that age negatively affects the mitochondrial activity of CCs. The per-CC mitochondrial deoxyribonucleic acid copy number and adenosine triphosphate levels significantly decreased in the advanced-age group. The Kyoto Encyclopedia of Genes and Genomes analysis showed that differentially expressed genes were significantly enriched in the oxidative phosphorylation pathway. Additionally, most mitochondrially encoded genes related to oxidative phosphorylation were significantly down-regulated in the advanced-age group.
CONCLUSION(S)
We present current evidence that mitochondrial dysfunction in CCs may play a key role in the age-related decline in ovarian function and reproductive capacity.
Topics: Adenosine Triphosphate; Cumulus Cells; DNA, Mitochondrial; Female; Humans; Infertility, Female; Mitochondria; Oocytes; Retrospective Studies
PubMed: 35637023
DOI: 10.1016/j.fertnstert.2022.04.019