Melittin Exerts Beneficial Effects on Paraquat-Induced Lung Injuries in Mice by Modifying Oxidative Stress and Apoptosis
Identifieur interne : 000546 ( Ncbi/Merge ); précédent : 000545; suivant : 000547Melittin Exerts Beneficial Effects on Paraquat-Induced Lung Injuries in Mice by Modifying Oxidative Stress and Apoptosis
Auteurs : Bishoy El-Aarag [Égypte, Japon] ; Mohamed Magdy ; Mohamed F. Alajmi ; Shaden A. M. Khalifa ; Hesham R. El-Seedi [Suède, Pakistan]Source :
- Molecules [ 1420-3049 ] ; 2019.
Abstract
Melittin (MEL) is a 26-amino acid peptide with numerous biological activities. Paraquat (PQ) is one of the most widely used herbicides, although it is extremely toxic to humans. To date, PQ poisoning has no effective treatment, and therefore the current study aimed to assess for the first time the possible effects of MEL on PQ-induced lung injuries in mice. Mice received a single intraperitoneal (IP) injection of PQ (30 mg/kg), followed by IP treatment with MEL (0.1 and 0.5 mg/kg) twice per week for four consecutive weeks. Histological alterations, oxidative stress, and apoptosis in the lungs were studied. Hematoxylin and eosin (H&E) staining indicated that MEL markedly reduced lung injuries induced by PQ. Furthermore, treatment with MEL increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity, and decreased malonaldehyde (MDA) and nitric oxide (NO) levels in lung tissue homogenates. Moreover, immunohistochemical staining showed that B-cell lymphoma-2 (Bcl-2) and survivin expressions were upregulated after MEL treatment, while Ki-67 expression was downregulated. The high dose of MEL was more effective than the low dose in all experiments. In summary, MEL efficiently reduced PQ-induced lung injuries in mice. Specific pharmacological examinations are required to determine the effectiveness of MEL in cases of human PQ poisoning.
Url:
DOI: 10.3390/molecules24081498
PubMed: 30995821
PubMed Central: 6514788
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Melittin Exerts Beneficial Effects on Paraquat-Induced Lung Injuries in Mice by Modifying Oxidative Stress and Apoptosis</title><author><name sortKey="El Aarag, Bishoy" sort="El Aarag, Bishoy" uniqKey="El Aarag B" first="Bishoy" last="El-Aarag">Bishoy El-Aarag</name><affiliation wicri:level="1"><nlm:aff id="af1-molecules-24-01498">Biochemistry Division, Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Koom 32512, Egypt</nlm:aff><country xml:lang="fr">Égypte</country><wicri:regionArea>Biochemistry Division, Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Koom 32512</wicri:regionArea><wicri:noRegion>Shebin El-Koom 32512</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-01498">Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530</wicri:regionArea><wicri:noRegion>Okayama 7008530</wicri:noRegion></affiliation></author><author><name sortKey="Magdy, Mohamed" sort="Magdy, Mohamed" uniqKey="Magdy M" first="Mohamed" last="Magdy">Mohamed Magdy</name><affiliation><nlm:aff id="af3-molecules-24-01498">Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koom 32512, Egypt;<email>mohamed_magdy201237@yahoo.com</email> (M.M.);<email>hesham.el-seedi@ilk.uu.se</email> (H.R.E.-S.)</nlm:aff></affiliation></author><author><name sortKey="Alajmi, Mohamed F" sort="Alajmi, Mohamed F" uniqKey="Alajmi M" first="Mohamed F." last="Alajmi">Mohamed F. Alajmi</name><affiliation><nlm:aff id="af4-molecules-24-01498">Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;<email>malajmii@ksu.edu.sa</email></nlm:aff></affiliation></author><author><name sortKey="Khalifa, Shaden A M" sort="Khalifa, Shaden A M" uniqKey="Khalifa S" first="Shaden A. M." last="Khalifa">Shaden A. M. Khalifa</name><affiliation><nlm:aff id="af5-molecules-24-01498">Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-106 91 Stockholm, Sweden;<email>shaden.khalifa@su.se</email></nlm:aff></affiliation></author><author><name sortKey="El Seedi, Hesham R" sort="El Seedi, Hesham R" uniqKey="El Seedi H" first="Hesham R." last="El-Seedi">Hesham R. 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Alajmi</name><affiliation><nlm:aff id="af4-molecules-24-01498">Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;<email>malajmii@ksu.edu.sa</email></nlm:aff></affiliation></author><author><name sortKey="Khalifa, Shaden A M" sort="Khalifa, Shaden A M" uniqKey="Khalifa S" first="Shaden A. M." last="Khalifa">Shaden A. M. Khalifa</name><affiliation><nlm:aff id="af5-molecules-24-01498">Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-106 91 Stockholm, Sweden;<email>shaden.khalifa@su.se</email></nlm:aff></affiliation></author><author><name sortKey="El Seedi, Hesham R" sort="El Seedi, Hesham R" uniqKey="El Seedi H" first="Hesham R." last="El-Seedi">Hesham R. El-Seedi</name><affiliation><nlm:aff id="af3-molecules-24-01498">Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koom 32512, Egypt;<email>mohamed_magdy201237@yahoo.com</email> (M.M.);<email>hesham.el-seedi@ilk.uu.se</email> (H.R.E.-S.)</nlm:aff></affiliation><affiliation wicri:level="4"><nlm:aff id="af6-molecules-24-01498">Division of Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, SE-75123 Uppsala, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, SE-75123 Uppsala</wicri:regionArea><orgName type="university">Université d'Uppsala</orgName><placeName><settlement type="city">Uppsala</settlement><region nuts="1">Svealand</region><region nuts="1">East Middle Sweden</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="af7-molecules-24-01498">International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan</nlm:aff><country xml:lang="fr">Pakistan</country><wicri:regionArea>International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270</wicri:regionArea><wicri:noRegion>Karachi-75270</wicri:noRegion></affiliation></author></analytic><series><title level="j">Molecules</title><idno type="eISSN">1420-3049</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Melittin (MEL) is a 26-amino acid peptide with numerous biological activities. Paraquat (PQ) is one of the most widely used herbicides, although it is extremely toxic to humans. To date, PQ poisoning has no effective treatment, and therefore the current study aimed to assess for the first time the possible effects of MEL on PQ-induced lung injuries in mice. Mice received a single intraperitoneal (IP) injection of PQ (30 mg/kg), followed by IP treatment with MEL (0.1 and 0.5 mg/kg) twice per week for four consecutive weeks. Histological alterations, oxidative stress, and apoptosis in the lungs were studied. Hematoxylin and eosin (H&E) staining indicated that MEL markedly reduced lung injuries induced by PQ. Furthermore, treatment with MEL increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity, and decreased malonaldehyde (MDA) and nitric oxide (NO) levels in lung tissue homogenates. Moreover, immunohistochemical staining showed that B-cell lymphoma-2 (Bcl-2) and survivin expressions were upregulated after MEL treatment, while Ki-67 expression was downregulated. The high dose of MEL was more effective than the low dose in all experiments. In summary, MEL efficiently reduced PQ-induced lung injuries in mice. Specific pharmacological examinations are required to determine the effectiveness of MEL in cases of human PQ poisoning.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Tortorelli, M C" uniqKey="Tortorelli M">M.C. Tortorelli</name></author><author><name sortKey="Hernandez, D A" uniqKey="Hernandez D">D.A. Hernandez</name></author><author><name sortKey="Rey Vazquez, G" uniqKey="Rey Vazquez G">G. Rey Vazquez</name></author><author><name sortKey="Salibian, A" uniqKey="Salibian A">A. Salibian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baltazar, T" uniqKey="Baltazar T">T. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Molecules</journal-id><journal-id journal-id-type="iso-abbrev">Molecules</journal-id><journal-id journal-id-type="publisher-id">molecules</journal-id><journal-title-group><journal-title>Molecules</journal-title></journal-title-group><issn pub-type="epub">1420-3049</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30995821</article-id><article-id pub-id-type="pmc">6514788</article-id><article-id pub-id-type="doi">10.3390/molecules24081498</article-id><article-id pub-id-type="publisher-id">molecules-24-01498</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Melittin Exerts Beneficial Effects on Paraquat-Induced Lung Injuries in Mice by Modifying Oxidative Stress and Apoptosis</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-8520-347X</contrib-id><name><surname>El-Aarag</surname><given-names>Bishoy</given-names></name><xref ref-type="aff" rid="af1-molecules-24-01498">1</xref><xref ref-type="aff" rid="af2-molecules-24-01498">2</xref><xref rid="c1-molecules-24-01498" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Magdy</surname><given-names>Mohamed</given-names></name><xref ref-type="aff" rid="af3-molecules-24-01498">3</xref></contrib><contrib contrib-type="author"><name><surname>AlAjmi</surname><given-names>Mohamed F.</given-names></name><xref ref-type="aff" rid="af4-molecules-24-01498">4</xref></contrib><contrib contrib-type="author"><name><surname>Khalifa</surname><given-names>Shaden A.M.</given-names></name><xref ref-type="aff" rid="af5-molecules-24-01498">5</xref></contrib><contrib contrib-type="author"><name><surname>El-Seedi</surname><given-names>Hesham R.</given-names></name><xref ref-type="aff" rid="af3-molecules-24-01498">3</xref><xref ref-type="aff" rid="af6-molecules-24-01498">6</xref><xref ref-type="aff" rid="af7-molecules-24-01498">7</xref></contrib></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Gomes</surname><given-names>Paula A.C.</given-names></name><role>Academic Editor</role></contrib></contrib-group><aff id="af1-molecules-24-01498"><label>1</label>Biochemistry Division, Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Koom 32512, Egypt</aff><aff id="af2-molecules-24-01498"><label>2</label>Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan</aff><aff id="af3-molecules-24-01498"><label>3</label>Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koom 32512, Egypt;<email>mohamed_magdy201237@yahoo.com</email> (M.M.);<email>hesham.el-seedi@ilk.uu.se</email> (H.R.E.-S.)</aff><aff id="af4-molecules-24-01498"><label>4</label>Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;<email>malajmii@ksu.edu.sa</email></aff><aff id="af5-molecules-24-01498"><label>5</label>Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-106 91 Stockholm, Sweden;<email>shaden.khalifa@su.se</email></aff><aff id="af6-molecules-24-01498"><label>6</label>Division of Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, SE-75123 Uppsala, Sweden</aff><aff id="af7-molecules-24-01498"><label>7</label>International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan</aff><author-notes><corresp id="c1-molecules-24-01498"><label>*</label>Correspondence: <email>bishoy.yousef@gmail.com</email>; Tel.: +20-127-367-2673</corresp></author-notes><pub-date pub-type="epub"><day>16</day><month>4</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>4</month><year>2019</year></pub-date><volume>24</volume><issue>8</issue><elocation-id>1498</elocation-id><history><date date-type="received"><day>04</day><month>3</month><year>2019</year></date><date date-type="accepted"><day>08</day><month>4</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Melittin (MEL) is a 26-amino acid peptide with numerous biological activities. Paraquat (PQ) is one of the most widely used herbicides, although it is extremely toxic to humans. To date, PQ poisoning has no effective treatment, and therefore the current study aimed to assess for the first time the possible effects of MEL on PQ-induced lung injuries in mice. Mice received a single intraperitoneal (IP) injection of PQ (30 mg/kg), followed by IP treatment with MEL (0.1 and 0.5 mg/kg) twice per week for four consecutive weeks. Histological alterations, oxidative stress, and apoptosis in the lungs were studied. Hematoxylin and eosin (H&E) staining indicated that MEL markedly reduced lung injuries induced by PQ. Furthermore, treatment with MEL increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity, and decreased malonaldehyde (MDA) and nitric oxide (NO) levels in lung tissue homogenates. Moreover, immunohistochemical staining showed that B-cell lymphoma-2 (Bcl-2) and survivin expressions were upregulated after MEL treatment, while Ki-67 expression was downregulated. The high dose of MEL was more effective than the low dose in all experiments. In summary, MEL efficiently reduced PQ-induced lung injuries in mice. Specific pharmacological examinations are required to determine the effectiveness of MEL in cases of human PQ poisoning.</p></abstract><kwd-group><kwd>paraquat</kwd><kwd>lung injury</kwd><kwd>melittin</kwd><kwd>oxidative stress</kwd><kwd>apoptosis</kwd></kwd-group></article-meta></front><floats-group><fig id="molecules-24-01498-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Histopathological graphs of lung sections from all groups. The lung sections were analyzed by hematoxylin and eosin (H&E) staining. Control group (<bold>a</bold>,<bold>b</bold>): (<bold>a</bold>) indicated normal terminal bronchiole ended with respiratory portion (arrow) (X200, scale bar = 100 µm), (<bold>b</bold>) showed alveoli lined with alveolar epithelial cells pnemocyte type I (arrow) and type II (arrowhead) (X400, scale bar = 50 µm). Paraquat (PQ) group (<bold>c</bold>,<bold>d</bold>): (<bold>c</bold>) presented necrosis in the alveolar tissue (arrow) (X200, scale bar = 100 µm), (<bold>d</bold>) showed excessive interstitial tissue thickening associated with septal cell proliferation (arrow) and alveolar hyaline membrane formation (arrowhead) (X400, scale bar = 50 µm). PQ + MEL (melittin) (0.1 mg/kg) group (<bold>e</bold>,<bold>f</bold>): (<bold>e</bold>) illustrated mild focal serous exudate within the alveoli (arrow) accompanied with a moderate degree of inter-alveolar interstitial tissue thickening (arrowhead) (X200, scale bar = 100 µm) (<bold>f</bold>) presented a moderate degree of thickening in the inter-alveolar septa and marked hyperplasia of pneumocyte type II in the lining epithelium (arrow) (X400, scale bar = 50 µm). PQ + MEL (0.5 mg/kg) group (<bold>g</bold>,<bold>h</bold>): (<bold>g</bold>) displayed decrease in the inter-alveolar thickening (arrowhead) with marked hyperplasia of pneumocyte type II (arrow) (X200, scale bar = 100 µm) (<bold>h</bold>) presented a decrease in the inter-alveolar septa (arrowhead) with an increase in the alveolar spaces associated with hyperplasia of pneumocyte type II (arrow) (X400, scale bar = 50 µm).</p></caption><graphic xlink:href="molecules-24-01498-g001"></graphic></fig><fig id="molecules-24-01498-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Effect of treatment with melittin (MEL) on the levels of malonaldehyde (MDA) in lung tissue homogenate. MDA (lipid peroxidation index) levels were determined in the lung tissue homogenate using MDA colorimetric assay. The absorbance of the formed product was measured at 534 nm. The results were expressed as nmol MDA per g tissue. Data are presented as mean ±SD. Significantly (* <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01) different from PQ group.</p></caption><graphic xlink:href="molecules-24-01498-g002"></graphic></fig><fig id="molecules-24-01498-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Effect of treatment with melittin (MEL) on the levels of nitric oxide (NO) level in lung tissue homogenate. The level of NO in the lung homogenate was measured according to the Griess method, using NO colorimetric assay. The formed azo dye was measured at 540 nm. NO levels were measured and expressed as µM. Data are presented as mean ±SD. Significantly (* <italic>p</italic> < 0.05, *** <italic>p</italic> < 0.001) different from PQ group.</p></caption><graphic xlink:href="molecules-24-01498-g003"></graphic></fig><fig id="molecules-24-01498-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Effect of treatment with melittin (MEL) on superoxide dismutase (SOD) activity in lung tissue homogenate. SOD activity was measured according to Beyer method, using SOD colorimetric assay. SOD activity was measured and expressed as U/g tissue. Data are presented as mean ±SD. Significantly (* <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01) different from PQ group.</p></caption><graphic xlink:href="molecules-24-01498-g004"></graphic></fig><fig id="molecules-24-01498-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Effect of treatment with melittin (MEL) on catalase (CAT) activity in lung tissue homogenate. CAT was determined in the lung tissue homogenate through the Aebi method, using CAT colorimetric assay. The color intensity was measured, and CAT activity was determined and expressed as U/g tissue. Data are presented as mean ±SD. Results are significantly (** <italic>p</italic> < 0.01) different from the PQ group.</p></caption><graphic xlink:href="molecules-24-01498-g005"></graphic></fig><fig id="molecules-24-01498-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Effect of treatment with melittin (MEL) on glutathione Peroxidase (GPx) activity in lung tissue homogenate. GPx was measured in the lung tissue homogenate by UV spectroscopic method. The decrease in the absorbance was measured at 340 nm. The level of GPx was measured and expressed as U/g tissue. Data are presented as mean ±SD. Results are significantly (* <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01) different from PQ group.</p></caption><graphic xlink:href="molecules-24-01498-g006"></graphic></fig><fig id="molecules-24-01498-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Effect of treatment with melittin (MEL) on the B-cell lymphoma-2 (Bcl-2) protein level in lung tissues. <bold>A</bold>: Representative lung immunohistochemical graphs (a: control group, b: paraquat (PQ) group, c: PQ + MEL (0.1 mg/kg) group, d: PQ + MEL (0.5 mg/kg) group); (<bold>a</bold>) showed a noticeable expression of bcl-2 immunostaining in the alveolar lining epithelium (arrow). (<bold>b</bold>) presented marked decrease in bcl-2 expression within the alveolar lining epithelium (arrow). (<bold>c</bold>) displayed mild to moderate increase of bcl-2 expression in the alveolar epithelium (arrow). (<bold>d</bold>) illustrated an obvious increase in bcl-2 expression within the alveolar epithelium (arrow). Magnification = X200 and scale bar = 100 µm. <bold>B</bold>: Statistical analysis of Bcl-2 H-score. Data are expressed as mean ±SD. Significantly (** <italic>p</italic> < 0.01) different to the PQ group.</p></caption><graphic xlink:href="molecules-24-01498-g007"></graphic></fig><fig id="molecules-24-01498-f008" orientation="portrait" position="float"><label>Figure 8</label><caption><p>Effect of treatment with melittin (MEL) on the survivin protein level in lung tissues. <bold>A</bold>: Representative lung immunohistochemical graphs (a: control group, b: paraquat (PQ) group, c: PQ + MEL (0.1 mg/kg) group, d: PQ + MEL (0.5 mg/kg) group); (<bold>a</bold>) showed a strong survivin expression within the alveolar epithelium (arrow) (X400, scale bar = 50 µm). (<bold>b</bold>) presented a low to mild survivin expression within the alveolar epithelium (arrow) (X400, scale bar = 50 µm). (<bold>c</bold>) indicated a moderate survivin expression in the alveolar epithelium (arrow) as well as in the bronchial epithelium (arrowhead) (X400, scale bar = 50 µm). (<bold>d</bold>) illustrated an increase in the survivin expression in the alveolar epithelium (arrow) and in the bronchial epithelium (arrowhead) (X200, scale bar = 100 µm). <bold>B</bold>: Statistical analysis of survivin H-score. Data are expressed as mean ±SD. Significantly (* <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01, *** <italic>p</italic> < 0.001) different from PQ group.</p></caption><graphic xlink:href="molecules-24-01498-g008"></graphic></fig><fig id="molecules-24-01498-f009" orientation="portrait" position="float"><label>Figure 9</label><caption><p>Effect of treatment with melittin (MEL) on Ki-67 protein level in lung tissues. <bold>A</bold>: Representative lung immunohistochemical graphs (a: control group, b: paraquat (PQ) group, c: PQ + MEL (0.1 mg/kg) group, d: PQ + MEL (0.5 mg/kg) group); (<bold>a</bold>) showed mild expression of Ki-67 immunostaining within the alveolar and bronchial lining epithelium (arrow). (<bold>b</bold>) presented an obvious increase in the inter-alveolar septa (arrow) as well as in the necrotic epithelial bronchial lining (arrowhead). (<bold>c</bold>) illustrated a marked decrease in Ki-67 expression within the alveolar and bronchial epithelium (arrowhead). (<bold>d</bold>) indicated a noticeable decline in Ki-67 expression within the alveolar and bronchial epithelium (arrowhead). Magnification = X200 and scale bar = 100 µm. <bold>B</bold>: Statistical analysis of Ki-67 H-score. Data are expressed as mean ±SD. Significantly (* <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01, *** <italic>p</italic> < 0.001) different from the PQ group.</p></caption><graphic xlink:href="molecules-24-01498-g009"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Japon</li><li>Pakistan</li><li>Suède</li><li>Égypte</li></country><region><li>East Middle Sweden</li><li>Svealand</li></region><settlement><li>Uppsala</li></settlement><orgName><li>Université d'Uppsala</li></orgName></list><tree><noCountry><name sortKey="Alajmi, Mohamed F" sort="Alajmi, Mohamed F" uniqKey="Alajmi M" first="Mohamed F." last="Alajmi">Mohamed F. Alajmi</name><name sortKey="Khalifa, Shaden A M" sort="Khalifa, Shaden A M" uniqKey="Khalifa S" first="Shaden A. M." last="Khalifa">Shaden A. M. Khalifa</name><name sortKey="Magdy, Mohamed" sort="Magdy, Mohamed" uniqKey="Magdy M" first="Mohamed" last="Magdy">Mohamed Magdy</name></noCountry><country name="Égypte"><noRegion><name sortKey="El Aarag, Bishoy" sort="El Aarag, Bishoy" uniqKey="El Aarag B" first="Bishoy" last="El-Aarag">Bishoy El-Aarag</name></noRegion></country><country name="Japon"><noRegion><name sortKey="El Aarag, Bishoy" sort="El Aarag, Bishoy" uniqKey="El Aarag B" first="Bishoy" last="El-Aarag">Bishoy El-Aarag</name></noRegion></country><country name="Suède"><region name="Svealand"><name sortKey="El Seedi, Hesham R" sort="El Seedi, Hesham R" uniqKey="El Seedi H" first="Hesham R." last="El-Seedi">Hesham R. El-Seedi</name></region></country><country name="Pakistan"><noRegion><name sortKey="El Seedi, Hesham R" sort="El Seedi, Hesham R" uniqKey="El Seedi H" first="Hesham R." last="El-Seedi">Hesham R. 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