Is Dna Read 5 Prime to 3 Prime

miRNAs equally Nutritional Targets in Aging

Robin A. McGregor , Dae Y. Seo , in Molecular Basis of Nutrition and Crumbling, 2016

Lexicon of Terms

•: three'UTR – The three prime untranslated region is the part of messenger RNA that procedes the translation termination codon. The three'UTR of mRNA is transcribed from DNA, only is not translated into protein.
•: Exosomes – are large vesicles between 30–100 nm which are released by cells and found in many biological fluids such as blood, urine, salvia. Exosomes can contain Deoxyribonucleic acid, mRNA, miRNA and proteins.
•: microRNAs (miRNAs) – are a novel form of minor non-coding RNAs which are function of the non-coding genome, which do not lawmaking for protein. miRNAs postal service-transcriptionally regulate poly peptide-coding genes.
•: myomiR – refers to a miRNA which is highly expressed in skeletal musculus tissue.
•: RISC – the RISC is a ribosomal induced silencing complex which contains multiple proteins and can bind to different types of double-stranded RNA including small interfering RNA and miRNA.
•: Seed sequence – the miRNA seed sequence or seed region refers to positions 2–7 from the five' prime end of the miRNA, which binds the complementary nucleotides in the iii'UTR target mRNAs.
•: Target gene – refers to a poly peptide-coding cistron which harbors a complementary miRNA target site in the 3'UTR of transcribed mRNA.
•: qPCR – refers to quantitative polymerase concatenation reaction and is a technique to measure the level of mRNA or miRNA in different cells, tissues or biological fluids. qPCR requires opposite transcription of RNA into cDNA, earlier distension and quantification of the template cDNA.

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Sirtuins as NAD+-dependent deacetylases and their potential in medical therapy

Ashok Kumar , Mona Dvir-Ginzberg , in Medical Epigenetics (Second Edition), 2021

Breast cancer

SIRT1 expression was almost frequently reported and significantly associated with the appearance of distant metastasis and, as a result, a poor prognosis [138, 139]. Ane possible machinery involving SIRT1 prometastatic effects is through the action of hypermethylated in cancer ane (HIC1), which represses the transcription of SIRT1, rendering P53 hyperacetylated and thereby promoting cancer cell apoptosis after accumulated DNA impairment [140] . SIRT1 upregulation promotes cell survival after Dna damage through inactivation of the p53 pathway. The upregulation of SIRT1 likewise overcomes the upshot of miR-200a, which targets the three prime number untranslated regions of SIRT1 messenger RNA (mRNA) and promotes epithelial-mesenchymal transition (EMT)-similar transformation in mammary epithelial cells [141]. The activation of miR-22 inactivated SIRT1 and induced cellular senescence to ultimately bestowed tumor suppression [142]. SIRT1 is involved in oncogenic signaling of estrogen receptor α (ERα) in breast cancer. In fact, SIRT1 inactivation suppresses estrogen/ERα-induced jail cell growth and tumor evolution and induces apoptosis [143]. Studies with SRT1720 show that SRT1720 promotes the migration and pulmonary metastasis of subcutaneously implanted chest cancer cells in mice and supports the involvement of SIRT1 in breast cancer [144]. On the other hand, reduced SIRT1 levels in human mammary epithelial cells (HMLER) breast cancer cells led to increased metastases in nude mice. SIRT1 was shown to suppress EMT by deacetylating Smad4 downstream to transforming growth cistron-beta (TGF-β) signaling resulting in reduced expression of MMP7. Reduced MMP7 results in less cleavage of surface E-cadherin, leaving β-catenin bound to E-cadherin at the cell-cell junctions, ultimately repressing EMT [145]. Recent studies show that increased nicotinamide N-methyltransferase (NNMT) is associated with poor prognosis and chemoresistance and thereby may exist a prognostic mensurate for predicting treatment outcomes of the clinical chemotherapy in breast cancer [146].

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MicroRNAs and inflammation biomarkers in obesity

Bruna Jardim Quintanilha , ... Marcelo Macedo Rogero , in Precision Medicine for Investigators, Practitioners and Providers, 2020

Biogenesis

Biogenesis of miRNAs is a sequential process involving a diverseness of enzymes and proteins [16] . MicroRNAs are usually transcribed by RNA polymerase II from miRNA genes, first forming the primary miRNA transcript (pri-miRNA). This transcript is then cleaved by the DROSHA-DiGeorge syndrome disquisitional region gene 8 (DGCR8) microprocessor complex, creating a shorter sequence called the miRNA forerunner (pre-miRNA) that displays a hairpinlike secondary structure. The pre-miRNA is exported to the cytoplasm and processed by DICER, a ribonuclease Iii enzyme that produces mature miRNA, which is incorporated into an RNA-protein circuitous (i.e., the RNA-induced silencing complex, RISC). Under most conditions, mature RISC represses factor expression posttranscriptionally, by bounden the iii prime untranslated regions (iii′-UTRs) of specific mRNAs, and mediating mRNA degradation, destabilization, or translational inhibition, according to sequence complementarity to the target [3,17–19].

Evidence shows that, besides intracellular function, miRNAs are nowadays in extracellular fluids in the human trunk, including plasma, serum, urine, and saliva; recently, they have also been associated with diseases such as obesity, cancer, and cardiovascular affliction (CVD) [20–22]. MicroRNAs as well play an of import role in cell-to-cell communication in peripheral blood, either through membrane-enclosed vesicles such as exosomes (extracellular vesicles of endosomal origin), or by binding to lipoproteins (LDL or HDL), proteins, apoptotic bodies, and ribonucleoprotein complexes (linked to Argonaut) [21,22]. In add-on to their stability, it should be noted that circulating miRNAs are conserved across species, accept expression patterns that are tissue- and biological-stage specific, and are hands determined through real-time polymerase chain reaction (RT-PCR) [sixteen]. Thus, these molecules are promising noninvasive biomarkers of certain diseases, and even of nutritional status [23].

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Genetic Take chances Factors Link Autism to Many Other Disorders

Lynn Waterhouse , in Rethinking Autism, 2013

The OXTR Gene Creature Model Brain Deficits

Yrigollen et al. (2008) reported testify for polymorphisms of PRL, PRLR, and OXTR genes in 177 individuals diagnosed with ASD. Oxytocin (OT) is a peptide involved in affiliative behavior. Autistic children have been shown to have abnormal levels of plasma OT (Dark-green et al., 2001; Modahl et al., 1998). Prolactin (PRL) is a pituitary hormonal peptide as well establish to exist of import for affiliative behaviors.

Campbell et al. (2011) conducted a large family study of the association of common oxytocin receptor (OXTR) factor variants with risk for autism. They reported a link for autism and 2 regions of the OXTR gene: intron 3 (an intron is a nucleotide sequence removed in the creation of protein) and the 3′ UTR (three prime untranslated region of mRNA that may modify poly peptide product), where markers in intron three implicated the OXTR gene specifically in autism. The researchers noted that their findings were consonant with before reports linking OXTR with autism, including a CNV involving the deletion of a chromosome region including the OXTR gene, testify for altered methylation in the OXTR gene promoter in autism, and the decreased expression of OXTR in postmortem brains of individuals with autism.

Sala et al. (2011) created a mouse line in which oxytocin neurotransmission was eliminated past knocking out OXTR. The researchers reported that the oxytocin receptor knockout mice pups expressed reduced vocalization at separation from the female parent, and stayed with a foreign mouse equally long equally with the familiar mouse, indicating a failure in social memory. Knockout mice showed impaired cognitive flexibility in a maze-switching task. Knockout mice likewise had neuronal hyperexcitability and a reduced threshold for seizures. Investigation of hippocampal brain cells showed the oxytocin receptor knockout mice had a lower ratio of inhibitory synapses to excitatory synapses, and the researchers concluded that the hippocampal functioning of the OXTR knockout mice was set up to an abnormally high level of excitation. Sala et al. (2011) reported that administration of oxytocin or arginine vasopressin to 3-calendar month-former knockout mice normalized the animals' social beliefs.

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Small non-coding RNAs as epigenetic regulators

Tong Zhou , in Nutritional Epigenomics, 2019

2.one Micro RNAs (miRNAs)

miRNAs are a family unit of small non-coding RNAs (nearly 22 nucleotides in length) found in almost all metazoan and some viruses [four–6]. To date, more than 1900 miRNAs accept been identified experimentally or computationally in humans co-ordinate to the miRBase (www.mirbase.org ) definition. miRNAs take been found to play regulatory roles in cistron expression via base-pairing with complementary sequences within mRNAs. Plant miRNAs are commonly complementary to coding sequences, while in animals, miRNAs are more often than not complementary to 3 prime untranslated regions (iii′-UTRs) [vii]. Plant miRNAs unremarkably have perfect or most-perfect base-pairing with target mRNAs, which results in gene silencing through cleavage of the mRNA strands [8]. In animals, the miRNA-mRNA base-pairing is unremarkably imperfect, which means miRNAs and their target mRNAs are but partially complementary by using as picayune as 6–8 nucleotides located at the five′ end of the miRNA (so called "seed region") [nine–xi]. Commonly, this kind of imperfect lucifer-ups are not enough to trigger cleavage of the target mRNAs [12] and miRNA-induced translational repression is thought to be more than prevalent in animals than in plants [5]. A given miRNA may target hundreds of different mRNAs, meanwhile a given mRNA may exist targeted by unlike miRNAs [12,13]. The seed regions within miRNAs are the most disquisitional factor determining the target mRNAs and most mammalian mRNAs have conserved targets of miRNAs [14]. For example, in humans, more than 45,000 miRNA target regions within 3′-UTRs are conserved to a higher place background levels and more than than 60% of protein-coding genes take undergone negative pick to maintain base of operations-pairing with miRNAs [xiv]. Mutations within miRNA seed regions potentially pb to inherited diseases. For example, mutations in the seed region of human being miR-96 are reported to induce nonsyndromic progressive hearing loss [15]; mutations in the seed region of human miR-184 may cause familial keratoconus with cataract [16]. Dysregulation of miRNA is besides implicated in human diseases, including cancers [17], cardiovascular diseases [18], neurological diseases [xix], pulmonary diseases [20], and so on. For example, a set of up- and downwardly-regulated miRNAs, which disrupt suppression of the oncogene PLAG1, was found to be associated with chronic lymphocytic leukemia [21]. Even so, most current studies on the relationships between miRNAs and human diseases have heavily relied on animal models. No doubt, the knowledge gained from animal studies tin guide future translational inquiry and clinical investigations, the interpretation of animal data, however, needs to be cautious as not all observations from fauna models are relevant to humans. Therefore, translating the current animal studies to homo subjects would provide directly show to the regulatory part of miRNAs in the development of human diseases.

Epigenetic modify is divers equally the heritable alterations in gene expression that do non represent changes in Dna sequence. Co-ordinate to this generalized definition, miRNA-induced mRNA degradation and translational repression should be considered as 1 type of epigenetic machinery at the post-transcriptional level. However, how miRNAs are directly involved in epigenetic regulation in terms of DNA methylation and histone modification is still controversial. Fortunately, several lines of testify may help the states understand the epigenetic role of miRNAs regarding this specialized definition of "epigenetics". Firstly, miRNAs are key players in regulating DNA methylation machinery [22]. Fabbri et al. found that up-regulation of the miR-29 family unit in human being lung triggered down-regulation of global Dna methylation and DNA methyltransferases (DNMTs), including DNA methyltransferase-3A (DNMT3A) and DNA methyltransferase-3B (DNMT3B) [23]. Similar results were observed by Garzon et al. in acute myeloid leukemia cancer cell lines [24]. Secondly, miRNAs may contribute to aberrant histone modification [25]. For instance, miR-10a could impact trimethylation of histone 3 lysine 27 (H3K27me3) in both MCF7 and MDA-MB-231 cells [26]. It was too observed that histone deacetylase four (HDAC4) was a target of miR-140 in mouse embryonic cartilage [27]. Despite these findings, we are nevertheless at the offset step to proceeds a clear picture regarding the epigenetic roles of miRNAs.

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Plant Epigenetics

Nelson R. Cabej , in Epigenetic Principles of Evolution (2d Edition), 2019

Plant Growth and Development

The Vegetative Phase

In the meaning used herein, the vegetative phase comprises both the juvenile and adult stages. Post-obit germination, plants laissez passer through a vegetative phase, which is very long in perennial woody plants, and is characterized by increased trunk mass and photosynthetic capacity, changes in morphology (e.g., size and shape of leaves, branching patterns, and accidental root product) and physiology, including changes in cistron expression (Poethig, 2010).

Plant growth results from both the cell proliferation and growth of the cell size. The cellulose wall of establish cells restraints the prison cell growth, only cell wall in plants expands under the action of jail cell loosening enzymes, such as expansins, which disrupt hydrogen bonds between cellulose microfibrils, leading to cell wall loosening and remodeling. The well-nigh important hormone related to the plant cell wall modification is auxin. Compared with the wild type, in the axr3-1 mutants are identified 108 repressed genes, of which 28 are involved in the cell wall biosynthesis (Murray et al., 2012). The expansion of the plant cell volume requires biosynthesis of various types of macromolecules and organelles to fill the enlarged cell book. While the cell wall modification may serve every bit a signal for increasing the metabolic and constructed activities in cells, experimental evidence suggests that auxin plays the most important function for increasing protein biosynthesis, including ribosomal proteins, too as for increasing the translation charge per unit and recruitment of ribosomal complexes (Murray et al., 2012).

It is observed that high miR156 level in Arabidopsis was reached at the seedling stage (Axtell and Bartel, 2005). The targets of miR156 include transcripts of eleven of the 17 SPL genes (Huijser and Schmid, 2011). The most of import amongst them are the smallest of all and closely related SPL3, SPL4, and SPLfive genes. SPL3 contains a miRNA-responsive element (MRE) in the 3′ UTR (three prime number untranslated region) of the Arabidopsis SBP box gene, which is complementary to miR156 and miRNA157 (Gandikota et al., 2007). The about agile of the factors was SPL3 and its expression was epigenetically regulated posttranscriptionally by miR156. The temporal variation in the level of this miRNA contributes significantly to the temporal change in SPL3 activity during vegetative development (Wu and Poethig, 2006) and overexpression of miR156 in Arabidopsis extends the juvenile growth phase.

Later on the seedling phase, with the commencement of the vegetative phase, miR156 levels proceed to decline gradually and this process culminates in the initiation of transition to the flowering stage. Thus miR156 is both necessary and sufficient for expression of the juvenile phase (Huijser and Schmid, 2011). The decline in the miR156 levels during the vegetative phase is determined primarily by product by leaf primordia of a chemical signal that represses miR156 expression, hence the transition to flowering stage is time dependent (Yang et al., 2011). However, most recently it is demonstrated that increasing levels of H3K27me3 and declining levels of H3K27ac in genes MIR156A and MIR156C are related to the decreased levels of miRNA156 during the vegetative phase (Fig. fifteen.fourteen). Simply it is PICKLE (PKL), a chromatin remodeler (Zhang et al., 2008) that past binding to the promoters of the MIR156A/MIR156C genes promotes the addition of H3K27me3 and reduces the levels of H3K27ac. This increases the affinity of PRC2, a member of the chromatin modifying Polycomb group, for miR156 genes, as is suggested by the increase of amount of PRC2 bound to these genes (Xu et al., 2016).

The Reproductive Stage

The flowering initiation time is an inherited life history trait that is regulated past exogenous (environmental) and endogenous stimuli to maximize reproductive success in a range of environments (Amasino, 2010). Transition from the vegetative to reproductive phase in A. thaliana involves transition of the vegetative meristem into reproductive meristem. This results from activation of hormonal and epigenetic pathways involving changes in patterns of epigenetic marks and expression of miRNAs correlated with changes in photoperiod and environmental temperature.

In A. thaliana, FLC represses flowering by repressing FT and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS i (SOC1). And so, the temporary prevention of flowering requires switching off the FLC gene, which in nature is accomplished past wintertime temperatures in moderate climate areas. It is observed that during the cold period, decline in the FLC levels and vernalization-specific complex of PcG proteins, PHD-PRC2 (abbreviation for 'Establish Homeo Domain-Polycomb Repressive Complex two') (Fig. xv.14), which generates trimethylation of histone 3 lysine 27 (H3K27me3) (Müller-Xing and Goodrich, 2011; Hansen et al., 2008).

PRC2 acts as a histone methyltransferase, specifically catalyzing trimethylation of lysine 27 on the histone H3 tail (H3K27me3). PHD-PRC2 contains several constitute-specific components that are probably required to boost the histone methyltransferase activity of the circuitous (Müller-Xing and Goodrich, 2011) (Fig. fifteen.15). The components are fertilization-independent endosperm (FIE), a PcG protein, the histone methyltransferase subunit, SWINGER (SWN); histone-bounden poly peptide MSI1 (MULTICOPY SUPPRESSOR OF IRA 1); the PcG protein FIE; VRN2 and VRN5 vernalization genes; VEL1, a vernalization-like protein, and VIN3 (VERNALIZATION INSENSITIVE3), a fellow member of the VIN3 family unit of proteins. H3K27me3 recruits PRC2 to maintain the marking at the site of DNA replication and in the course of cell divisions propagates the epigenetic modification (Hansen et al., 2008)

During flowering, in Chrysanthemum leaves Dna methylation percentage is reduced under the influence of lengthening of the photoperiod. The DNA hypomethylation may promote expression of the FT cistron, which, from leaves, reaches the meristem to induce expression of meristem flowering genes, leading to showtime of flowering from buds (Li et al., 2016).

A generalized view of the transcriptional and epigenetic factors involved in phase transition in Arabidopsis is presented in Fig. 15.16.

Vernalization

Many temperate-zone plants need to experience winter colds in order to increase seed product or accelerate constitute flowering. This phenomenon is known as vernalization (from Latin vernus-leap) and it was experimentally used to produce ii crops within a year.

Physiological need for vernalization is the cause why many institute species prevent flowering until the spring. In nature, plants sense when bound is budgeted by perceiving the lengthening of the photoperiod, elapsing of the cold (in chill hours), and a rise in the environmental temperature.

Cold sensing in A. thaliana stimulates expression of VERNALIZATION INSENSITIVE 3 (VIN3) gene (Sung and Amasino, 2004), which codes for a PHD (Constitute Homeo Domain) finger-containing protein, and often is office of chromatin-remodeling complexes. Vernalization is accomplished via epigenetic regulation of the flowering repressor FLC, which encodes a MADS-box transcription cistron that represses flower initiation SOC1 and FT genes (Sung and Amasino, 2005; Oliver et al., 2009). Some other vernalization factor, VRN2, is required for maintaining FLC in repressed state. Before vernalization, the FLC chromatin is enriched in trimethylated histone H3K4 (H3 Lys 4). During vernalization the level of both H3K9 and H3K27 increases. Vernalization modifies the FLC chromatin country from actively transcribed to stably repressed (Oliver et al., 2009). The vernalized state is lost when FLC chromatin is activated (Sung and Amasino, 2006).

On the Control System in Plants

Animals utilise the nervous organization to integrate and procedure environmental stimuli for generating an adequate output in the form of an adaptive beliefs, morphology, or life history. Unlike animals, plants have neither a brain, or a brain-similar construction, nor a nervous system or neuron-like cells for processing and integrating ecology changes to adaptively reply to changed conditions of life. All the same, it is well known that more often than not many plant behavioral responses are adaptive, plastic, and flexible, as opposed to the All-or-nothing principle related to animate being instincts.

However, plants, nether normal or changed conditions, display measurable electric pulses suggesting the presence of electrical wirings in their tissues and organs. An action potential (AP) arises when an insect tilts the mechanosensors of the trap of the carnivorous Venus flytrap (Dionaea muscipula). On a second AP, elicited by insect touch within ~ 20–thirty due south of the start touch, the trap closes chop-chop, in 0.3 s, catching the insect and digesting it in the green tummy. The plant ignores the get-go affect as a subthreshold signal only two touches within a short time period are taken as a stimulus to elicit the trap-endmost response. It was found that "by counting and integrating the mechanoelectric signals elicited past the trapped casualty, Dionaea muscipula triggers biosynthesis of the bear upon hormone jasmonate." And withal, continued attempts to identify the establish structure responsible for "counting and integrating mechano-electric signals" and adaptively respond to the external stimulus have failed.

It seems that the plant regulates the amount of digesting enzymes it releases in the "dark-green breadbasket" according to the number of APs activating the hormonal jasmonate (JA) pathway (Böhm et al. (2016); Volkov et al., 2007). What substantially occurs in this and other similar cases is that the information on the insect touching trap mechanosensors is taken equally input and processed by the plant to generate an output in the course of specific electric information which is further converted into a hormonal signal of touch hormone JA, activating the JA pathway and related consequences in expression of genes for enzymatic digestion also as the transport and assimilation of the victim's nutrients. The simplified causal concatenation comprises:

1.: The mechanical stimulus generates an action potential,
2.: The electrical input is processed to generate an output that activates the motor cells to close the trap lobes, and.
iii.: Activation of the hormonal JA pathway, leading to expression of genes for producing digestive enzymes and absorption and the transport of nutrients in other parts of the plants.

In experiments with touch-induced movements in plants as the carnivorous Venus flytrap (D. muscipula), creeping shy herb (Mimosa pudica), so on, information technology is observed that anesthetic treatment leads to complete loss of the touch-induced movements and the break of the electrical activity, two phenomena that also occur during the anesthetics treatment of mammals (De Luccia, 2012). Indispensable as it is for generating such adaptive behaviors, the inferred plant processing and integrating structure still remains elusive (Cabej, 2013).

Plants lack a recognized centralized stimulus-processing and integration structure, in distinction from eumetazoans in full general, and especially vertebrates, where a centralized processing and integrating heart, via electrical signals determines activation of specific betoken cascades ending with the hormonal regulation of gene expression. Even so, the relatively high degree of complexity of structure, physiology, and behavior of plants makes it theoretically indispensable the presence in them of a control organisation that may exist based on principles different from nervous organization in eumetazoans. A theoretical model of a control system in plants is presented in Fig. fifteen.17, in which extracellular/extraorganismal stimuli or changes in the environment are sensed by the plant and the quantity of the external input is compared with a reference bespeak (a prepare point in the brain in animals) that sends a correcting signal through effectors simply has nevertheless not been identified in plants.

In view of the primal part of hormones not just in regulation of the plant metabolism, development, reproduction, and adaptation to the changing conditions in environment, but besides of their office in the establishment of epigenetic marks and miRNA expression patterns, in the following will exist presented a general overview of the function of several of the near important plant hormones and their role in epigenetic processes.

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Genetic Susceptibility in Biochemical and Physiological Traits

R.One thousand. Dumitru , in Cardiovascular Diseases, 2016

Pharmacogenetics of Warfarin

Interindividual differences in response to warfarin are caused by both pharmacodynamic and pharmacokinetic factors. This vitamin K antagonist is arguably the near normally prescribed oral anticoagulant, used for prevention and treatment of thrombosis and thromboembolic disease, although information technology is believed to still be underused due to one major downside, which is its narrow therapeutic alphabetize. If dosed too low, it will be ineffective, whereas a dose that is also loftier may atomic number 82 to an overshooting reaction and increase the run a risk of both major and modest hemorrhage. It is therefore crucial to make up one's mind a safe only constructive initiation and stabilization dose as well as to arrange the dose regularly to adapt to changes in patients' nutrition, disease land, or comedication.

Several clotting factors, including the factors II (prothrombin), VII, Nine, and X, besides the anticoagulant proteins C and South [164], depend on vitamin K as a cofactor [165] in club to exert their anticoagulant effect. Warfarin inhibits vitamin G epoxide reductase VKORC1, the enzyme responsible for transforming vitamin K epoxide into the cofactor vitamin K hydroquinone [166] (run across Fig. 9.iv).

Different studies accept shown that polymorphisms in the cistron encoding VKORC1 account for upwardly to xxx% of the observed variability in stabilized warfarin dose [167]. A number of different polymorphisms and haplotypes take been defined, and dissimilar classifications are used in literature, well-nigh commonly the H haplotype terminology of Rieder et al. [180] and the star terminology introduced by Geisen et al. [181]. Generally, they may exist divided into low-dose, intermediate-dose, and high-dose haplotype groups.

One polymorphism in the promoter region of VKORC1, chosen G3673A, or 1639G > A, modifies the transcription cistron–binding site, whereby the activity of the G allele is over 40% greater compared to the A allele [182] (see Table 9.ii). Furthermore, Rieder et al. also plant reduced amounts of VKORC1 mRNA in carriers of the A allele [180], resulting in reduced numbers of functional VKORC1 enzyme, the rate-limiting cistron in the vitamin Thousand pathway. Some other well-known polymorphism is located on the first intron of VKORC1. It is chosen C6484T, or 1173C > T, and is found in virtually perfect linkage disequilibrium with G3673A, meaning the A allele in G3673A and the T allele in C6484T are mostly inherited together [165]. In fact, these two alleles define the VKORC1∗two haplotype as described by Geisen et al. [181,183], or the ii haplotypes VKORC1 H1 and H2 every bit defined past Rieder et al. [180], classified as the warfarin low-dose haplotype group A. Carriers of this haplotype have been shown in unlike studies to require a lower mean warfarin dose than carriers of the reference wild-type VKORC1∗1, and, even more than strikingly, carriers of haplotypes from the high-dose group B, such equally VKORC1∗3 and VKORC1∗4 co-ordinate to Geisen et al.'s classification [181], or haplotypes H7, H8, and H9 according to Rieder et al. [180]. The single nucleotide polymorphism G9041A, or 3730G > A, is located in the three prime number untranslated region (three′UTR) of VKORC1 and is associated with the warfarin loftier-dose haplotype VKORC1∗3.

Table 9.2. Polymorphisms of VKORC1 [seven,8,thirteen,14]

Haplotype [8]	SNP	Haplotype Group [7]	VKORC1 Activity	Hateful Warfarin Dose	Population
VKORC1∗ane	Wild-type		Normal	Intermediate	General population
VKORC1∗ii	G3673A (−1639G > A)	A	Reduced	Depression	85–90% Asian 38–43% Caucasian 8–13% African
VKORC1∗2	C6484T (1173C > T)	A	Reduced	Depression	85–90% Asian 38–43% Caucasian eight–13% African
VKORC1∗iii	G9041A (3730G > A)	B	Increased	High	10–15% Asian 20–39% Caucasian 42–53% African
VKORC1∗four	C6009T	B	Increased	High	<two% Asian 20–38% Caucasian 7–11% African

The described effect of genetic influences on the required warfarin dose seems to exist condiment, in that carriers of 2 VKORC1∗2 depression-dose haplotypes A, labeled A/A, reply to the lowest mean warfarin dose; carriers of 2 high-dose haplotypes from grouping B, labeled B/B, require the highest doses; and carriers of ii mixed haplotypes A/B require an intermediate hateful warfarin dose [180].

Moreover, there seems to non only exist an interindividual only too an interethnic variability. The VKORC1∗two haplotype is the predominant haplotype in the Asian population [180,182], who have been known to crave a lower warfarin maintenance dose than other ethnicities, fifty-fifty after weight adjustment [184,185]. Haplotype VKORC1∗3, in dissimilarity, is nearly common in people of African ethnicity, shown in studies to require college warfarin maintenance doses [186].

In addition to the described furnishings of multiple VKORC1 haplotypes, genetic influences on the metabolism of warfarin straight contribute approximately 12% to interindividual differences in response to warfarin therapy [168]. Warfarin, equally information technology is administered in clinical practice, is a racemic mixture of two isomers [169], with South-warfarin being a much more potent vitamin K antagonist than its R-enantiomer [170] and, under steady state weather, accounting for roughly two-thirds of warfarin's anticoagulant effect [167]. In add-on to this, Southward- and R-warfarin slightly differ in their metabolism past cytochrome P450. S-warfarin is principally metabolized past CYP2C9, the main CYP2C in human being liver, which is likewise responsible for the metabolic clearance of numerous other drugs, including phenytoin and other convulsants, the antidiabetic drugs glipizide and tolbutamide, and nonsteroidal anti-inflammatory drugs [171–173]. R-warfarin, on the other hand, is metabolized mainly by CYP3A4, CYP1A1, and CYP1A2 [167]. Currently, most of the data is bachelor for CYP2C9, peculiarly its two most mutual allelic variants CYP2C9∗2, or 430C > T, and CYP2C9∗3, also labeled 1075A > C, although dozens of different CYP2C9 variants have been identified to this date [187]. Both CYP2C9∗two and CYP2C9∗3 feature a reduced metabolic activeness compared to CYP2C9∗1, which is considered the wild blazon and is the most prevalent CYP2C9 allele [188]. The maximum metabolism rate of CYP2C9∗2, for instance, is but virtually half of the CYP2C9∗1 rate [167]. Carriers of a reduction-of-function variant, either CYP2C9∗2 or CYP2C9∗3, therefore crave lower warfarin doses than carriers of the wild blazon, and have a college risk of bleeding complications, which were most obvious during the initiation and dose titration of warfarin therapy [189,190].

Afterwards studies suggested that, in add-on to the influences of VKORC1 and CYP2C9, about 1–2% of warfarin dose variance might be attributed to polymorphisms in cytochrome P450 4F2 (CYP4F2), affecting a unlike pathway in the vitamin K cycle [168]. CYP4F2 was shown to be involved in vitamin Thou catabolism by oxidizing vitamin K₁ to hydroxyvitamin K_ane. The V433M polymorphism (rs2108622) of the CYP4F2 gene is thought to be associated with express translation or degradation of CYP4F2, while seemingly leaving the enzyme'south intrinsic catalytic action unaffected [174]. Carriers of this variant have a reduced ability to catabolize vitamin Chiliad₁, resulting in raised hepatic levels of vitamin Thou and a warfarin dose requirement nigh ane mg/twenty-four hours college than that of individuals carrying the CYP4F2 wild type [175].

In recent years, a number of studies take examined the effects of polymorphisms in the GGCX factor, encoding the vitamin-K-dependent gamma-glutamyl carboxylase on warfarin dose requirements and dose variance. The enzyme, found in the membrane of rough endoplasmic reticulum, carboxylates glutamic acid residues of vitamin K-dependent proteins, such equally the clotting factors II, VII, Ix, and X, to calcium-bounden gamma-carboxyglutamate residues, an important footstep required for their activation [176]. Different studies focused on different factor variants and different ethnic groups. Cavallari et al. [177], for example, suggested that the GGCX genotype rs10654848, characterized past a (CAA)sixteen/17 repeat polymorphism, is 10-fold more common in African Americans than it is in Caucasians, and was more frequent in individuals requiring warfarin doses of 7.5 mg/day or greater. Some other study by Huang et al. [178] focused on the GGCX 3261G > A polymorphism and concluded that, among a group of Chinese patients on stable warfarin handling, carriers of the 3261AA genotype had a significantly higher daily warfarin dose requirement than individuals with the 3261GG genotype. A systematic review and meta-analysis from 2015 by Sun et al. [179] summarized that, while certain GGCX polymorphisms accept indeed been shown to influence warfarin dose requirements, this event seems to differ between ethnicities.

Ever since the discovery of the commencement genetic influences, apart from age, sex, and weight, on interindividual warfarin dose variability, numerous algorithms have been created, aiming to better predict required warfarin starting and maintenance doses for patients, in lodge to maximize its therapeutic outcome while keeping the risk of bleeding, the well-nigh feared adverse effect of warfarin therapy, as low as possible. Some of the virtually recently developed algorithms combine genetic polymorphisms of VKORC1, CYP2C9, CYP4F2, and GGCX [191]. The bulk of studies comparing different algorithms accept shown that those incorporating both clinical information and genetic data have a better predictive power compared with those using clinical parameters alone [192]. In spite of this, clinical applicability of these more circuitous dosing algorithms has not yet been established. Ane reason is that some studies relating to pharmacogenetics-guided dosing regimens have, in fact, not shown any improved outcomes [193]. Another factor making pharmacogenomics-based warfarin dose algorithms somewhat less feasible is its arguable cost effectiveness, and future studies will certainly give further information regarding the practicability of pharmacogenetics-guided algorithms in an everyday clinical setting.

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Cardiomyocyte biology: new pathways of differentiation and regeneration

Marijn G.C. Peters , ... Paula A. da Costa Martins , in Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2020

1.1.1 miRNAs

miRNAs (miRs) are unmarried stranded, minor ncRNA molecules (~22 nucleotides) encoded in intergenic regions of the genome that inhibit gene expression past binding to the iii prime number untranslated region (3′UTR) of complementary target mRNAs [ 4]. Binding can block the translation of the target mRNA or cause mRNA degradation depending on the degree of complementarity between the miRNA and the target mRNA. miRNAs have been found to command many cellular processes including cell survival, differentiation and proliferation [35]. Furthermore, alterations in cardiac miRNA pathways can induce cardiomyopathies and HF [36,37]. The discovery that miRNAs are likewise important in angiogenesis came from a genetic knockout of the endoRNAse Dicer, an essential protein processing pre-miRNAs into mature miRNAs, equally these animals displayed severely impaired angiogenesis [38,39]. Multiple miRNAs have been found to play a pivotal function in regulating angiogenesis by impairing or inducing EC proliferation [2,35,40]. miRNAs that influence angiogenesis can influence the expression of coding genes in angiogenic signalling pathways (e.g. multiple miRNAs expressed during hypoxia were found to regulate vascular endothelial growth gene (Vegf) expression [41]) (Tabular array i). Inversely, the expression of miRNAs can be influenced past coding genes involved in angiogenesis. VEGF has been shown to induce the expression of miR-20a and miR-31, ii miRNAs that can bind the 3'UTR of a negative regulator of angiogenesis, tumour necrosis factor superfamily-15 (TNFSF15) [42]. Furthermore, hypoxia was also shown to affect miRNA-mediated signalling between ECs and CMs [40,43]. miRNAs that are involved in the hypoxia signalling were recently named hypoxamiRs and were identified equally crucial components to regulate cellular and molecular responses to decreased oxygen tension [40,44]. HIF1α is modulated by several miRNAs in ischaemic middle affliction [44,45] and prevents hypoxia-induced mitochondrial damage [32]. Indeed, downregulation of hypoxamiR-199 in ischaemic CMs led to the stabilization and upregulation of hif1α expression. This occurs through de-repression of SIRTUIN-1, a grade III histone deacetylase targeted by hypoxamiR-199 which, in turn, prevents PHD2-mediated destabilization of HIF1α [32]. PHD2 downregulation by SIRTUIN-1 is mediated by NAD-dependent deacetylase activity of SIRTUIN-1. Sirtuin-1 is also targeted by the endothelial expressed miR-24, a miRNA involved in endothelial jail cell apoptosis through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4 [33]. Silencing of endothelial miR-24 in mouse hearts after MI limited the infarct size and increased cardiac office.

Tabular array i. NcRNAs in endothelial jail cell signalling during cardiac injury and regeneration.

miRNA	Target	Role	Cell Type	Model	References
miR-20a	TNFSF15	Inhibition of angiogenesis	EC	HUVEC	Deng (ex. 42)
miR-31	TNFSF15	Inhibition of angiogenesis	EC	HUVEC	Deng (ex. 42)
miR-199	Sirtuin1	Primary regulator of a hypoxia-triggered pathway	CM	Neonatal CM	Rane (ex. 32)
miR-24	Gata2, PAK4	EC apoptosis	EC	Zebrafish, Mouse	Fiedler (ex. 33)
miR-210	Ptp1b, Efna3, Hif3a	CM proliferation, survival and EC proliferation	EC, SMC, CM	Mouse, Rat	Arif (ex. 43), Zaccagnini (ex. 45), Ghosh (ex. 46), Hu (ex. 47)
miR-210	Hif1a, Runx3	CM apoptosis	EC, CM	Mouse, Human	Wang Y. (ex. 48)
miR-15a,b	Vegf, Arl2, Bcl2	Inhibition of angiogenesis, mitochondrial degeneration, CM apoptosis	CM	Mouse	Nishi (ex. 49), Minor (ex. 50)
miR-16	Vegf, Fgfr1	Negative feedback on EC proliferation and migration	EC	Mouse	Chamorro-Jorganes (ex. 51)
miR-424	Vegf, Fgfr1	Negative feedback on EC proliferation and migration	EC	Mouse	Chamorro-Jorganes (ex. 51)
miR-424	Cullin2	Promoting angiogenesis	EC	Mouse, Rat	Ghosh (ex. 46)
miR-195	Chek1	Inhibition CM proliferation/post-natal CM cell bicycle arrest	CM	Mouse	Porrello (ex.52)
miR-26a	Smad1	Inhibition of angiogenesis	EC	Mouse	Icli (ex. 55)
miR-223-3	Rps6kb1	Inhibition of angiogenesis	EC	Ischemic MCEC	Dai (ex. 56)
miR-200c	Zeb1	EC apoptosis and senescence	EC	HUVEC	Magenta (ex. 57)
miR-101	mTor	Inhibition of angiogenesis	EC	HUVEC	Chen K. (ex. 61)
miR-101	Cullin3	EC proliferation	EC	HUVEC	Kim (ex. 57)
miR-100	mTor	Inhibition of angiogenesis	EC, SMC	Murine hindlimb	Grundmann (ex. 60)
miR-126	Spred1, PIK3R2/p85-b	EC proliferation	EC	HUVEC, Murine hindlimb	Wang (ex. 62)
miR-106b~25	PTEN	EC proliferation	EC	Murine hindlimb	Semo (ex. 64)
miR17-5p	ERK	Inhibition of CM proliferation and angiogenesis	EC, CM	Rat	Yang (ex. 68)

lncRNA	Target	Function	Prison cell Type	Model	References
CARL	miR-539	CM survival	CM	Mouse	Wang (ex. 73)
miR503hg	miR-503	EC proliferation	EC	HUVEC	Fiedler (ex. 33)
MANTIS	BRG1	EC proliferation	EC	HUVEC, Rat, Monkey, Human	Leisegang (ex. 73)
NONHSAT073641	PAFAH1B1	EC proliferation	EC	HUVEC	Josipovic (ex. 75)
MIAT	miR-150‐5p	EC proliferation	EC	HUVEC, Rat, Human	Ishii (ex. 76), Yan (ex. 77)
PUNISHER	Unknown	EC maturity	EC	HUVEC, hESC, hiPSC	Kurian (ex. 78)
Linc00323	IF4A3	EC proliferation	EC	HUVEC	Fiedler (ex. 33), Hou (ex. 79)
MALAT1	CBX4	migratory EC phenotype	EC	HUVEC, Murine hindlimb	Michalik (ex. 80)
TUG1	miR-145-5p	CM apoptosis	CM	Cardiomyocyte cell line H9c2	Wu (ex. 85)
GATA6-AS	LOXL2	Inhibition of angiogenesis	EC	HUVEC	Neumann (ex. 88)
STEEL	PARP1, eNOS	EC proliferation, microvascular identity, shear stress responsiveness	EC	HUVEC	Human being (ex. 66)
LEENE	eNOS	EC function, NO production	EC	HUVEC	Miao (ex. 82)
HOTTIP	β-catenin	EC proliferation	EC	Human CAD samples	Liao (ex. 83)
ECRAR	ERK1/two	EC and CM proliferation	EC, CM	Mouse, Homo	Chen (ex. 87)

miR-210, some other hypoxamiR, is ubiquitously upregulated in multiple cardiac cell types during ischaemic injury including ECs, SMCs and CMs [46]. During hif1α stabilization, miR-210 expression is increased in CMs repressing its targets poly peptide tyrosine phosphatase 1b (Ptp1b), ephrin A3 (Efna3) and Hif3a. Intramyocardial injections of miR-210 increased CM proliferation and survival and endothelial jail cell proliferation [43,45,47]. Nonetheless, another written report establish detrimental effects of miR-210 in mouse hearts through repression of its target hif1α in ECs and CMs [48]. The authors too suggest that miR-210 might play a different role in the mouse and human ischaemic myocardium. The verbal molecular mechanisms of miR-210 signalling in the postal service-ischaemic human being heart remain to be investigated.

Members of the miR-15 family (miR-195, miR-15b, miR-16-1, miR-16-2, miR-424, and miR-497) are also increased during hypoxia [40,49]. miR-15b inhibits the translation of Vegf, therefore limiting neovascularisation of the ischaemic tissue. In addition, ADP ribosylation factor-like two (Arl2) targeting by miR-15 has been reported to be involved in mitochondrial degeneration and resulting cardiac dysfunction [49]. Moreover, miR-15 targets B-jail cell lymphoma 2 (Bcl-two) mRNA promoting CM apoptosis during hypoxia [50]. miR-16 and miR-424 target Vegf and fibroblast growth factor receptor 1 (Fgfr1) reducing proliferation and migration of ECs [51]. In contrast, hypoxia increased expression of miRNA-424 in cardiac ECs was reported to promote angiogenesis by repressing Cullin2 [46]. Cullin2 is a scaffolding protein required to assemble the ubiquitin ligase organization involved in the degradation of HIF1A and inhibition of Cullin2 led to HIF1A stabilization [46]. Differential reported effects of the miR-424 might exist caused past different transfection methods and efficiencies or prison cell autonomous/non-democratic documented effects [41,51]. Furthermore, cardiac specific mechanisms might explicate the reported diverging effects equally cardiac ECs can have a different phenotype and response to miRNA signalling.

Recent studies have demonstrated the role of the miR-fifteen family unit in regulating the postnatal CM jail cell cycle arrest [52]. Transfecting mouse hearts with antimiR-195 inhibited the target-binding function of miR-195 and improved cardiac function by stimulating CM proliferation [53]. From this perspective, the miR-15 family, in preventing both CM proliferation and angiogenesis, serves as a promising target for regenerative therapy.

Endogenous endothelial miRNAs (e.g. miR-26a, miR-24, miR-34c, miR-375, miR-223) are upregulated in the infarct area after MI and inhibit angiogenesis [33,54–56]. Furthermore, miRNA-200c is upregulated in ischaemic ECs and induces endothelial cell apoptosis past targeting Zeb1 [57]. In dissimilarity, some miRNAs promote coronary circulation and cardiac microcirculation [58]. Other pro-angiogenic hypoxamiRs similar miRNA-101 and miRNA-100 express their functional properties by targeting Heme oxygenase-i and Cullin-3 signalling and Rapamycin, respectively [59–61]. miR-126 has been found to exist highly expressed in healthy ECs and decreased levels could predict impaired coronary vascularisation and coronary collaterals [62]. miR-126 is peculiarly enriched in mouse embryos and regulates the response of ECs to VEGF through targeting of Sprouty-related protein SPRED1 and phosphoinositol-3kinase regulatory sub-unit ii (PIK3R2/p85-b) [63]. As well, the miR-106b~25 cluster has been found to be essential for EC proliferation in hindlimb ischemia in mice [64]. Similar mechanisms are likely to play a role in cardiac revascularisation.

miRNAs expressed by CMs can also contribute to the secretion of specific factors that influence endothelial prison cell behaviour and angiogenesis [65] or be transported themselves via exosomes to ECs and regulate angiogenesis [66,67]. This allows for tight regulation of neovascularisation in the adult heart and provides multiple entry-points for possible therapeutic targets to stimulate cardiac regeneration. A recent study performed a genome-broad profiling of ncRNAs in the developing and maturing centre and identified differentially expressed miRNAs that could underlie the change in regenerative capacity including miR-17-5p, miR-122-5p and miR-20a-5p [130]. Additionally, miR-17-5p was found to suppress the germination of blood vessels [68]. Furthermore, RNA sequencing data of murine hearts during early on stages of postnatal life, at which the regenerative capacity of the middle is gradually lost, showed a marked change in expression of miRNAs both in ECs and CMs between P3 and P5 [69].

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SOX9: An emerging driving factor from cancer progression to drug resistance

Munmun Panda , ... Bijesh Chiliad. Biswal , in Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2021

2.2.1 Role of miRNA in the regulation of SOX9

Many reports suggested that SOX9 is upregulated in many cancers, and diverse miRNAs regulated its expression. In NSCLC, enforced expression of miR-216b inhibited cell proliferation, invasion, and metastasis by targeting iii prime untranslated region (3′ UTR) of SOX9 directly. As well, miR-216b expression is lowered in NSCLC tissue than in healthy lung tissue, so SOX9 is upregulated in NSCLC tissue [ 68]. Also this, several miRNAs such equally miR-206, miR-185, miR-32, and miR-592 regulated SOX9 expression by targeting its 3′ UTR region in NSCLC [69–72]. Additionally, bioinformatics data suggests that putative binding sites of miR-124 are located in the 3′ UTR region of SOX9, and luciferase reporter assay shows that miR-124 targeted SOX9 straight in lung adenocarcinoma [73]. Furthermore, SOX9 is also directly regulated by other miRNAs in various cancers such every bit miR-140, miR-511, miR-133b, and miR-190 in chest cancer [74–77], miR-145, miR-105, miR-613, and miR-605 in glioma [78–81], miR-101, miR-one-3p, and miR-138 in hepatocellular carcinoma [82,83], and miR-494 in chondrosarcoma [84]. Interestingly, SOX9 also inversely regulated miR-130a through straight bounden of SOX9 to the promoter region of miR-130a in cervical cancer [85]. Several miRNAs, which downregulated SOX9 expression, are depicted in Table ane. Henceforth, to unreveal the regulation network of SOX9 and miRNAs, further written report is needed to develop SOX9 based therapeutic strategies for better chemotherapeutics.

Table ane. Correlation of SOX9 expression with miRNA

Cancer	miRNA expression	SOX9 expression	Mechanism of action	Reference
NSCLC	Downregulation of miR-216b, miR-206, miR-185, miR-32, miR-592, and miR-30e	Overexpression of SOX9	promotes cell proliferation, invasion, and migration by activating Wnt signaling	[68–71,86,87]
Lung adenocarcinoma	Lower expression of miR-124	Upregulation of SOX9	promotes cell proliferation, invasion, and migration	[73]
Chest cancer	Downregulation of miR-140 due to methylation at CpG islands of miR-140	College expression of SOX9	maintains breast CSC properties	[74]
	Lower expression of miR-511		promotes malignant progression by activating PI3K/Akt signaling	[75]
	Lower expression of miR-133b		promotes prison cell proliferation, invasion, and cell migration	[76]
	Downregulation of miR-190 due to bounden of ERα and ZEB1 competitively to the promoter region of miR-190		activates Wnt/β-catenin signaling	[77]
Glioma	Hypermethylation of miR-145 at promoter region of it	Upregulates SOX9 expression	results in cell proliferation, cell adhesion, and invasion	[78]
	Reduced level of miR-105		promotes glioma jail cell progression	[79]
	Downregulation of miR-613		helps in jail cell proliferation and invasion	[80]
	Lower expression of miR-605		activation of the PI3K/Akt pathway	[81]
	Reduction in miR-101 levels		correlated with tumor aggressiveness and cocky-renewal backdrop of stem cells, and poor prognosis	[88]
Hepatocellular carcinoma	Lower levels of miR-101	Upregulation of SOX9	correlated with tumor aggressiveness and poor prognosis	[82]
	Downregulation of miR-1-3p		promotes cell proliferation in vitro and increases tumor book in vivo	[83]
	Lower expression of miR-138		promotes HCC proliferation and cell invasion	[89]
Chondrosarcoma	Downregulation of miR-494	Overexpression of SOX9	promotes cell growth and invasion and correlated with poor survival and prognosis marker	[84]
Head and neck cancer	Lower expression of miR-145	Higher expression of SOX9	maintains TICs backdrop	[90]
Gastric cancer	Reduced levels of miRNA-524-5p	Upregulation of SOX9	correlated with gastric cancer cell proliferation and metastasis	[91]
Gastric cancer	Lower expression of miR-613	Upregulation of SOX9	leads to cell proliferation and migration	[92]
Osteosarcoma	Downregulation of miR-590-3p	Overexpression of SOX9	leads to cell proliferation and metastasis	[93]
Renal jail cell carcinoma	Lower levels of miR-138	Higher expression of SOX9	correlated with tumor phase, histological grade, and lymph node metastasis	[94]

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Frontiers of Mitochondrial Research

Aaron P. Russell , ... Glenn D. Wadley , in Biochimica et Biophysica Acta (BBA) - General Subjects, 2014

5 microRNAs and mitochondrial biogenesis and function

microRNAs (miRNAs) are small (~ 20–30 nucleotides) noncoding ribonucleic acids (RNAs) that inhibit protein translation or enhance messenger RNA (mRNA) deposition [122,123]. They have been observed to play a part in regulating numerous diseases including cancers, hepatitis C, eye disease, neurodegenerative disease and myopathies [124]. Recently, miRNAs have been observed to be present in the mitochondria and regulate mitochondrial biogenesis in the musculus tissue and cells.

A decrease in miR-494 occurs in C2C12 myoblasts during differentiation and is paralleled past an increment in mtDNA [125]. Reporter assay experiments revealed that the knockdown of miR-494 increased the activeness and poly peptide content of Tfam and Forkhead box j3 (Foxj3), a transcriptional regulator of Myocyte enhancer gene 2c (Mef2c) [126]. These observations were reversed following the overexpression of miR-494.

miRNAs are also able to translocate into the mitochondrial to regulate mitochondrial encoded genes. The nuclear encoded miR-181c is translocated to the mitochondria in cardiac myocytes [127] . miR-181c binds to the three prime untranslated region (three′UTR) of mt-COX1 and the overexpression of a miR-181c precursor results in a subtract in COX1 protein only not mRNA, suggesting that it acts as a translational regulator. The overexpression of miR-181c also increases mRNA and protein levels of COX1 and COX2 and alters mitochondrial function as shown past an elevation in oxygen consumption that is related to increased ROS product [127].

miR-484 represses Fis1 translation resulting in an inhibition of mitochondrial fission and apoptosis in cardiomyocytes and cancer cells [128]. It was also established that miR-484 is transactivated past Foxo3a. These results show that FoXo3a tin have a cardioprotective role that is mediated via its increase in miR-484, which functions to attenuate mitochondrial fission and apoptosis. The role of miR-484 is yet to be established in skeletal muscle.

Equally mentioned before, PGC-1α positively regulates mitochondrial biogenesis and function via the induction and activation of several nuclear transcription factors, such as NRF-1 [129] and ERRα [130–132]. Using reporter assays nosotros have recently demonstrated that miR-23a binds to the PGC-1α 3'-UTR to reduce PGC-1α reporter activity [fifty]. Additionally, transgenic overexpression of miR-23a in mice results in reduction in PGC-1α, cytochrome c and COX4 protein levels. Similarly, it was shown in C2C12 cells that overexpression and inhibition of miR-696 reduced and increased, respectively, PGC-1α poly peptide levels [133]. This was also paralleled by the respective attenuation and increases in fatty acid oxidation and pyruvate dehydrogenase kinase, isoenzyme four (PDK4) and COX2 mRNA levels. However, whether miR-696 directly regulates PGC-1α, via bounden to the PGC-1α 3′UTR, has non yet been confirmed. The role of miRNAs in the control of mitochondrial biogenesis and role in health and disease is still emerging. As the field evolves information technology will significantly contribute to our understanding of mitochondrial function and potentially identify new potential therapeutic targets.

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Source: https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/three-prime-untranslated-region

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