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 <!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Publishing DTD v1.0 20120330//EN" "http://jats.nlm.nih.gov/publishing/1.0/JATS-journalpublishing1.dtd"> <article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" article-type="mini-review" dtd-version="1.0" xml:lang="en">
  <front>
    <journal-meta>
      <journal-id journal-id-type="publisher-id">IJNE</journal-id>
      <journal-title-group>
        <journal-title>International Journal of Neonatology</journal-title>
      </journal-title-group>
      <issn pub-type="epub">2998-4785</issn>
      <publisher>
        <publisher-name>Open Access Pub</publisher-name>
        <publisher-loc>United States</publisher-loc>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id">IJNE-24-5138</article-id>
      <article-id pub-id-type="doi">10.14302/issn.2998-4785.ijne-24-5138</article-id>
      <article-categories>
        <subj-group>
          <subject>mini-review</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Newborns' MicroRNA Expression as Potential Biomarkers for Disease Diagnosis</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Raúl</surname>
            <given-names>Isea</given-names>
          </name>
          <xref ref-type="aff" rid="idm1849167516">1</xref>
          <xref ref-type="aff" rid="idm1849166436">*</xref>
        </contrib>
      </contrib-group>
      <aff id="idm1849167516">
        <label>1</label>
        <addr-line>Fundación IDEA. Hoyo de la Puerta, Baruta, Venezuela</addr-line>
      </aff>
      <aff id="idm1849166436">
        <label>*</label>
        <addr-line>Corresponding Author </addr-line>
      </aff>
      <contrib-group>
        <contrib contrib-type="editor">
          <name>
            <surname>Oliver</surname>
            <given-names>Chukwujekwu Ezechi</given-names>
          </name>
          <xref ref-type="aff" rid="idm1849029604">1</xref>
        </contrib>
      </contrib-group>
      <aff id="idm1849029604">
        <label>1</label>
        <addr-line>Nigerian Institute of Medical Research, Division of Clinical Science Lagos</addr-line>
      </aff>
      <author-notes>
        <corresp>
  Raúl Isea, <addr-line>Fundación IDEA. Hoyo de la Puerta, </addr-line><addr-line>Baruta</addr-line><addr-line>, Venezuela</addr-line>, <email>raul.isea@gmail.com</email></corresp>
        <fn fn-type="conflict" id="idm1849863028">
          <p>The authors have declared that no competing interests exist.</p>
        </fn>
      </author-notes>
      <pub-date pub-type="epub" iso-8601-date="2024-06-25">
        <day>25</day>
        <month>06</month>
        <year>2024</year>
      </pub-date>
      <volume>1</volume>
      <issue>1</issue>
      <fpage>22</fpage>
      <lpage>27</lpage>
      <history>
        <date date-type="received">
          <day>27</day>
          <month>05</month>
          <year>2024</year>
        </date>
        <date date-type="accepted">
          <day>21</day>
          <month>06</month>
          <year>2024</year>
        </date>
        <date date-type="online">
          <day>25</day>
          <month>06</month>
          <year>2024</year>
        </date>
      </history>
      <permissions>
        <copyright-statement>© </copyright-statement>
        <copyright-year>2024</copyright-year>
        <copyright-holder>Raúl Isea</copyright-holder>
        <license xlink:href="http://creativecommons.org/licenses/by/4.0/" xlink:type="simple">
          <license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
        </license>
      </permissions>
      <self-uri xlink:href="http://openaccesspub.org/ijne/article/2136">This article is available from http://openaccesspub.org/ijne/article/2136</self-uri>
      <abstract>
        <p>The work emphasizes the need for additional research to create novel biomarkers based on the use of microRNAs as a less invasive and precise diagnostic                         technique for identifying diseases in newborns. </p>
      </abstract>
      <kwd-group>
        <kwd>Newborn</kwd>
        <kwd>microRNA</kwd>
        <kwd>biomarker</kwd>
        <kwd>Diagnosis</kwd>
      </kwd-group>
      <counts>
        <fig-count count="0"/>
        <table-count count="0"/>
        <page-count count="6"/>
      </counts>
    </article-meta>
  </front>
  <body>
    <sec id="idm1849026364" sec-type="intro">
      <title>Introduction</title>
      <p>Traditional indicators, such as a newborn's weight and height, are still utilized since they can approximate a child's future risk of getting any disease. However, the implications of these indicators on the child's future adult development remain uncertain; for example, infants who are overweight or short in stature may suffer insulin insufficiency at birth, increasing their chances of developing diabetes as adults<xref ref-type="bibr" rid="ridm1849785660">1</xref>.</p>
      <p>In fact, a mother's nutritional and hormonal state during pregnancy (including the postpartum period) can affect various aspects of his or her child's adult life,               including the development of metabolic diseases like obesity, high blood                     pressure, hypercholesterolemia, hyperlipidemia, and so on<xref ref-type="bibr" rid="ridm1849849740">2</xref>.</p>
      <p>One method for diagnosing potential abnormalities in neonates is the detection of acidosis, which is a pH shift in the umbilical cord that suggests hypoxic stress in the developing baby<xref ref-type="bibr" rid="ridm1849796180">3</xref>. The cord's low pH was shown to be independent of the existence of hypoxic ischemic lesions<xref ref-type="bibr" rid="ridm1849889052">4</xref>. </p>
      <p>The majority of the diagnostic procedures done on babies in the first few days after delivery are called neonatal screening (NS)<xref ref-type="bibr" rid="ridm1849651228">5</xref>. On this test, a heel pinch is used to draw blood, which is then stored as a drop of dried blood (DBS) on                     neonatal detection cards (NSCs). This makes it possible to diagnose diseases including cystic fibers, phenylcetonuria, biotinidase deficiency, galactosemia, central congenital hypothyroidism, primary congenital hypothyroidism, and                     congenital adrenal hyperplasia<xref ref-type="bibr" rid="ridm1849649644">6</xref>.</p>
      <p>On the other hand, despite improvements in neonatal care and scientific knowledge, neonates may also die from sepsis, suffer significant impairment, or undergo neurological deterioration a condition that affects 4 out of 10 newborns on average in affluent nations<xref ref-type="bibr" rid="ridm1849647268">7</xref><xref ref-type="bibr" rid="ridm1849639140">8</xref>.</p>
      <p>It's important to remember that neonatal sepsis, along with other clinical                       symptoms and hemodynamic alterations that raise newborn morbidity and                   mortality, is a systemic inflammation brought on by bacteria, viruses, or fungi<xref ref-type="bibr" rid="ridm1849647268">7</xref>. Neonatal sepsis still has few pharmacological therapy options, most of which center on supportive care and early antibiotic administration. Various clinical and blood markers have been examined in this  context in order to identify sepsis and characterize its severity and cause<xref ref-type="bibr" rid="ridm1849636116">9</xref>.</p>
      <p>On the other hand, neonates with neonatal pneumonia (NE) are among the most common causes of death in neonatal intensive care unit (NICU) because of the high chance that they will experience               neurological difficulties and disabilities throughout their lifetimes<xref ref-type="bibr" rid="ridm1849625972">10</xref>.</p>
      <p>In parallel, microRNA was discovered during research on the nematode <italic>Caenorhabditis elegans</italic><xref ref-type="bibr" rid="ridm1849624388">11</xref>, and their use as a diagnostic tool has only recently begun because they are useful for determining the onset and progression of disease due to their high specificity for different tissue or cell types. MicroRNAs have been shown to be sensitive, with levels fluctuating in response to treatment or the rate at which the disease advances<xref ref-type="bibr" rid="ridm1849627916">12</xref>.</p>
      <p>There is a growing focus on the application of microRNA-based biomarkers for real-time therapeutic decision-making in the context of neonatal sepsis and other disorders affecting neonates<xref ref-type="bibr" rid="ridm1849625972">10</xref>. The primary benefit is that the patient can receive highly accurate disease diagnosis and surveillance with the least invasive techniques.</p>
      <p>For example, Dakroub et al.<xref ref-type="bibr" rid="ridm1849618180">13</xref> discovered ten microRNAs in the group of newborns with NE when compared to healthy controls, where microARNs in these neonates experience significant alterations within a few hours of birth. Additionally, research has been done on microRNAs as early indicators of newborn sepsis<xref ref-type="bibr" rid="ridm1849625972">10</xref>.</p>
      <p>Another example of how microRNAs benefit newborns is the range of macronutrients available in breast milk, which includes lactose, oligosaccharides, lipids, proteins, and nonprotein nitrogen. Breast milk is one of the most microRNA-rich biological fluids, with over 1400 distinct microRNAs                       accounting for approximately 25% of the total nitrogen in milk<xref ref-type="bibr" rid="ridm1849614004">14</xref>. </p>
      <p>Two more examples. Ibrahim et al.'s study<xref ref-type="bibr" rid="ridm1849610476">15</xref>, for instance, children with asthma exhibit reduced                     expression of miRNA-196a-2 and elevated serum levels of Annexin A1 (ANXA1, an essential                         anti-inflammatory mediator that may be crucial in bronchial asthma), indicating their potential as                  diagnostic biomarkers and therapeutic targets as well as their involvement in the etiology of asthma. Finally, MicroRNAs' function in controlling the expression of sirtuin 1 (a potential target for slowing down aging) <xref ref-type="bibr" rid="ridm1849606516">16</xref><xref ref-type="bibr" rid="ridm1849603708">17</xref><xref ref-type="bibr" rid="ridm1849593884">18</xref><xref ref-type="bibr" rid="ridm1849590068">19</xref>.</p>
      <sec id="idm1848997316">
        <title>But, what are microRNAs?</title>
        <p>MicroARN are short ARN molecules ranging in size from 18 to 22 nucleotides that bind to ARNm, resulting in translational and genetic suppression, and are found in all eukaryotic cells<xref ref-type="bibr" rid="ridm1849587332">20</xref>. MicroRNAs (sometimes abbreviated as miRNAs) have crucial regulatory roles in several biological and cellular processes<xref ref-type="bibr" rid="ridm1849583588">21</xref>. Its presence in biological fluids such as blood, saliva, tears, and even mother's milk has sparked concern about its potential influence on human health and early disease detection<xref ref-type="bibr" rid="ridm1849580924">22</xref>. Although several studies have been published on the presence of microARN in breast milk, further research is needed to fully understand their role<xref ref-type="bibr" rid="ridm1849573636">23</xref>.</p>
        <p>Rapid advances in sequencing techniques have improved the sensitivity of detection, resulting in the discovery of several microRNAs in serum and blood<xref ref-type="bibr" rid="ridm1849573060">24</xref>. MicroRNAs are highly stable in peripheral blood, which contains ribozimas and other microRNAs, and their levels vary significantly across                  patients with various diseases<xref ref-type="bibr" rid="ridm1849569028">25</xref>. MicroRNAs expression levels in peripheral blood correlate with                   clinical-pathological factors, potentially serving as a diagnostic biomarker for disease detection and monitoring<xref ref-type="bibr" rid="ridm1849568164">26</xref>.</p>
        <p>The microRNA nomenclature involves the suffix "mir" and a unique identification number. The                   identification numbers are assigned progressively, independent of the organism.  Identical or                        comparable miRNA sequences within a species might be assigned the same number. For example, the transcripts of <italic>Drosophila</italic> mir-13a and mir-13b differ slightly in sequence, although mir-6-1 and                       mir-6-2 are identical<xref ref-type="bibr" rid="ridm1849563196">27</xref>.</p>
      </sec>
      <sec id="idm1848991436">
        <title>MicroRNA Biogenesis</title>
        <p>The biosynthesis of microRNA involves several phases, beginning in the nucleus and ending in the cytoplasm<xref ref-type="bibr" rid="ridm1849563196">27</xref>. The transcription phase is first carried out by RNA polymerase II (pol II), followed by the production of capped, spliced, and polyadenylated miRNAs. Drosha and DGCR8 then digest these to produce 70–100 nucleotide pre-miRNAs. Exportin-5 transports these to the cytoplasm. Another RNAse called Dicer cuts the pre-miRNA into double-stranded RNA, which is then added to the RISC complex, which includes the Argonaute protein (Ago-2)<xref ref-type="bibr" rid="ridm1849560028">28</xref>. This inclusion causes translation inhibition, or mRNA cleavage. MicroRNAs can also be processed using the miRtron, an intron of a protein-coding gene                    involved with host gene expression<xref ref-type="bibr" rid="ridm1849544812">29</xref>.</p>
        <p>MicroRNAs are small non-coding RNAs that regulate gene expression by silencing messenger RNAs (mRNA)<xref ref-type="bibr" rid="ridm1849560028">28</xref>. They are almost 22 nucleotides long and occur predominantly via the canonical pathway, which involves Drosha processing pri-miRNA to pre-microRNA and Dicer splicing the pre-miRNA into mature miRNA<xref ref-type="bibr" rid="ridm1849544524">30</xref>. The classic microRNA genesis route terminates with the 5p or 3p strand binding to argonaute (Ago) proteins in an ATP-dependent manner<xref ref-type="bibr" rid="ridm1849560028">28</xref>. The choice of strand for Ago integration is based on thermodynamic stability at the 5' end of the miRNA duplex or a 5' uracil at the first nucleotide position<xref ref-type="bibr" rid="ridm1849587332">20</xref>.</p>
      </sec>
      <sec id="idm1848990284">
        <title>Finally, demonstrating the advantages of using microRNA-based biomarkers </title>
        <p>An example of the application of microRNA-based biomarkers in the diagnosis of diseases is, for                   example, neonatal hypoxic-ischemic encephalopathy (HIE)<xref ref-type="bibr" rid="ridm1849538836">31</xref>, the clinical phenotype resulting from hypoxic-ischemic brain injury (HIBI), a severe neurological lesion that happens during the perinatal period<xref ref-type="bibr" rid="ridm1849551652">32</xref>.</p>
        <p> Neonatal hypoxic brain damage (HIBI) is characterized by rapid free radical generation and enhanced biomolecule oxidation, particularly during the secondary phase<xref ref-type="bibr" rid="ridm1849550284">33</xref>. The majority of previous research on microRNAs in newborn HIBI has focused on a subset of microRNAs known as hypoxamiRs, which are regulated by hypoxia and modulate the cell's response to low oxygen<xref ref-type="bibr" rid="ridm1849551652">32</xref>. These include not only the well-known miR-21 and -210 but also miR-335, mir-137, and mir-376c. It has been proven that these                      hypoxamiRs play a significant role in a variety of clinical disorders, including cancer and heart injury, and altering brain microRNA levels may provide neuroprotection following HIBI<xref ref-type="bibr" rid="ridm1849551652">32</xref>.</p>
      </sec>
    </sec>
    <sec id="idm1848987332" sec-type="conclusions">
      <title>Conclusions</title>
      <p>The purpose of the study is to emphasize the benefits of implementing microRNA-based biomarkers for diagnosing and monitoring diseases in newborns. However, there is a lack of study into detecting a wider range of illnesses.</p>
      <p>The main benefit of using microRNA-based biomarkers is that they are selective and minimally                    invasive, making them ideal for newborn diagnoses. It is possible to apply procedures developed in hospitals and clinics, such as newborn screening cards, but further research is required.</p>
      <p>As a consequence of all this, the generation of new biomarkers employing microRNA could help in the early identification and development of individualized therapy for a variety of pediatric disorders. This approach isn't limited to the newborn period and could offer a substantial improvement over other disease.</p>
    </sec>
    <sec id="idm1848985604">
      <title>Acknowledge</title>
      <p>I would like to thank the reviewers for their time spent evaluating the article and their comments, which helped me enhance the work.</p>
    </sec>
  </body>
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