Nigella sativa L. (Black Cumin): A Promising Natural Remedy for Wide Range of Illnesses
Identifieur interne : 000946 ( Pmc/Corpus ); précédent : 000945; suivant : 000947Nigella sativa L. (Black Cumin): A Promising Natural Remedy for Wide Range of Illnesses
Auteurs : Ebrahim M. Yimer ; Kald Beshir Tuem ; Aman Karim ; Najeeb Ur-Rehman ; Farooq AnwarSource :
- Evidence-based Complementary and Alternative Medicine : eCAM [ 1741-427X ] ; 2019.
Abstract
The seed of
Url:
DOI: 10.1155/2019/1528635
PubMed: 31214267
PubMed Central: 6535880
Links to Exploration step
PMC:6535880Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>Nigella sativa</italic> L. (Black Cumin): A Promising Natural Remedy for Wide Range of Illnesses</title><author><name sortKey="Yimer, Ebrahim M" sort="Yimer, Ebrahim M" uniqKey="Yimer E" first="Ebrahim M." last="Yimer">Ebrahim M. Yimer</name><affiliation><nlm:aff id="I1">Department of Pharmacology and Toxicology, College of Health Sciences, Mekelle University, Ethiopia</nlm:aff></affiliation></author><author><name sortKey="Tuem, Kald Beshir" sort="Tuem, Kald Beshir" uniqKey="Tuem K" first="Kald Beshir" last="Tuem">Kald Beshir Tuem</name><affiliation><nlm:aff id="I1">Department of Pharmacology and Toxicology, College of Health Sciences, Mekelle University, Ethiopia</nlm:aff></affiliation></author><author><name sortKey="Karim, Aman" sort="Karim, Aman" uniqKey="Karim A" first="Aman" last="Karim">Aman Karim</name><affiliation><nlm:aff id="I2">Department of Pharmacognosy, College of Health Sciences, Mekelle University, Ethiopia</nlm:aff></affiliation></author><author><name sortKey="Ur Rehman, Najeeb" sort="Ur Rehman, Najeeb" uniqKey="Ur Rehman N" first="Najeeb" last="Ur-Rehman">Najeeb Ur-Rehman</name><affiliation><nlm:aff id="I3">Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Anwar, Farooq" sort="Anwar, Farooq" uniqKey="Anwar F" first="Farooq" last="Anwar">Farooq Anwar</name><affiliation><nlm:aff id="I4">Department of Chemistry, University of Sargodha, Sargodha, Pakistan</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31214267</idno><idno type="pmc">6535880</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535880</idno><idno type="RBID">PMC:6535880</idno><idno type="doi">10.1155/2019/1528635</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000946</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000946</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>Nigella sativa</italic> L. (Black Cumin): A Promising Natural Remedy for Wide Range of Illnesses</title><author><name sortKey="Yimer, Ebrahim M" sort="Yimer, Ebrahim M" uniqKey="Yimer E" first="Ebrahim M." last="Yimer">Ebrahim M. Yimer</name><affiliation><nlm:aff id="I1">Department of Pharmacology and Toxicology, College of Health Sciences, Mekelle University, Ethiopia</nlm:aff></affiliation></author><author><name sortKey="Tuem, Kald Beshir" sort="Tuem, Kald Beshir" uniqKey="Tuem K" first="Kald Beshir" last="Tuem">Kald Beshir Tuem</name><affiliation><nlm:aff id="I1">Department of Pharmacology and Toxicology, College of Health Sciences, Mekelle University, Ethiopia</nlm:aff></affiliation></author><author><name sortKey="Karim, Aman" sort="Karim, Aman" uniqKey="Karim A" first="Aman" last="Karim">Aman Karim</name><affiliation><nlm:aff id="I2">Department of Pharmacognosy, College of Health Sciences, Mekelle University, Ethiopia</nlm:aff></affiliation></author><author><name sortKey="Ur Rehman, Najeeb" sort="Ur Rehman, Najeeb" uniqKey="Ur Rehman N" first="Najeeb" last="Ur-Rehman">Najeeb Ur-Rehman</name><affiliation><nlm:aff id="I3">Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Anwar, Farooq" sort="Anwar, Farooq" uniqKey="Anwar F" first="Farooq" last="Anwar">Farooq Anwar</name><affiliation><nlm:aff id="I4">Department of Chemistry, University of Sargodha, Sargodha, Pakistan</nlm:aff></affiliation></author></analytic><series><title level="j">Evidence-based Complementary and Alternative Medicine : eCAM</title><idno type="ISSN">1741-427X</idno><idno type="eISSN">1741-4288</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>The seed of<italic> Nigella sativa</italic> (<italic>N. sativa</italic>) has been used in different civilization around the world for centuries to treat various animal and human ailments. So far, numerous studies demonstrated the seed of<italic> Nigella sativa </italic>and its main active constituent, thymoquinone, to be medicinally very effective against various illnesses including different chronic illness: neurological and mental illness, cardiovascular disorders, cancer, diabetes, inflammatory conditions, and infertility as well as various infectious diseases due to bacterial, fungal, parasitic, and viral infections. In spite of limited studies conducted so far, the promising efficacy of<italic> N. sativa</italic> against HIV/AIDS can be explored as an alternative option for the treatment of this pandemic disease after substantiating its full therapeutic efficacy. Moreover, the strong antioxidant property of this valued seed has recently gained increasing attention with regard to its potential role as dietary supplement with minimal side effects. Besides, when combined with different conventional chemotherapeutic agents, it synergizes their effects resulting in reducing the dosage of concomitantly used drugs with optimized efficacy and least and/or no toxicity. A number of pharmaceutical and biological properties have been ascribed to seeds of<italic> N. sativa</italic>. The present review focuses on the profile of high-value components along with traditional medicinal and biological principles of<italic> N. sativa </italic>seed and its oil so as to explore functional food and nutraceutical potential of this valued herb.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Jamshidi Kia, F" uniqKey="Jamshidi Kia F">F. Jamshidi-Kia</name></author><author><name sortKey="Lorigooini, Z" uniqKey="Lorigooini Z">Z. Lorigooini</name></author><author><name sortKey="Amini Khoei, H" uniqKey="Amini Khoei H">H. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Evid Based Complement Alternat Med</journal-id><journal-id journal-id-type="iso-abbrev">Evid Based Complement Alternat Med</journal-id><journal-id journal-id-type="publisher-id">ECAM</journal-id><journal-title-group><journal-title>Evidence-based Complementary and Alternative Medicine : eCAM</journal-title></journal-title-group><issn pub-type="ppub">1741-427X</issn><issn pub-type="epub">1741-4288</issn><publisher><publisher-name>Hindawi</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31214267</article-id><article-id pub-id-type="pmc">6535880</article-id><article-id pub-id-type="doi">10.1155/2019/1528635</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review Article</subject></subj-group></article-categories><title-group><article-title><italic>Nigella sativa</italic> L. (Black Cumin): A Promising Natural Remedy for Wide Range of Illnesses</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0003-3140-4967</contrib-id><name><surname>Yimer</surname><given-names>Ebrahim M.</given-names></name><email>ebrahim99muhammed@gmail.com</email><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0003-2847-1392</contrib-id><name><surname>Tuem</surname><given-names>Kald Beshir</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0001-6198-1664</contrib-id><name><surname>Karim</surname><given-names>Aman</given-names></name><xref ref-type="aff" rid="I2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ur-Rehman</surname><given-names>Najeeb</given-names></name><xref ref-type="aff" rid="I3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Anwar</surname><given-names>Farooq</given-names></name><xref ref-type="aff" rid="I4"><sup>4</sup></xref></contrib></contrib-group><aff id="I1"><sup>1</sup>Department of Pharmacology and Toxicology, College of Health Sciences, Mekelle University, Ethiopia</aff><aff id="I2"><sup>2</sup>Department of Pharmacognosy, College of Health Sciences, Mekelle University, Ethiopia</aff><aff id="I3"><sup>3</sup>Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia</aff><aff id="I4"><sup>4</sup>Department of Chemistry, University of Sargodha, Sargodha, Pakistan</aff><author-notes><fn fn-type="other"><p>Academic Editor: Nativ Dudai</p></fn></author-notes><pub-date pub-type="collection"><year>2019</year></pub-date><pub-date pub-type="epub"><day>12</day><month>5</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>12</day><month>5</month><year>2019</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>2019</volume><elocation-id>1528635</elocation-id><history><date date-type="received"><day>20</day><month>10</month><year>2018</year></date><date date-type="rev-recd"><day>26</day><month>2</month><year>2019</year></date><date date-type="accepted"><day>30</day><month>4</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 Ebrahim M. Yimer et al.</copyright-statement><copyright-year>2019</copyright-year><license xlink:href="https://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>The seed of<italic> Nigella sativa</italic> (<italic>N. sativa</italic>) has been used in different civilization around the world for centuries to treat various animal and human ailments. So far, numerous studies demonstrated the seed of<italic> Nigella sativa </italic>and its main active constituent, thymoquinone, to be medicinally very effective against various illnesses including different chronic illness: neurological and mental illness, cardiovascular disorders, cancer, diabetes, inflammatory conditions, and infertility as well as various infectious diseases due to bacterial, fungal, parasitic, and viral infections. In spite of limited studies conducted so far, the promising efficacy of<italic> N. sativa</italic> against HIV/AIDS can be explored as an alternative option for the treatment of this pandemic disease after substantiating its full therapeutic efficacy. Moreover, the strong antioxidant property of this valued seed has recently gained increasing attention with regard to its potential role as dietary supplement with minimal side effects. Besides, when combined with different conventional chemotherapeutic agents, it synergizes their effects resulting in reducing the dosage of concomitantly used drugs with optimized efficacy and least and/or no toxicity. A number of pharmaceutical and biological properties have been ascribed to seeds of<italic> N. sativa</italic>. The present review focuses on the profile of high-value components along with traditional medicinal and biological principles of<italic> N. sativa </italic>seed and its oil so as to explore functional food and nutraceutical potential of this valued herb.</p></abstract></article-meta></front><body><sec id="sec1"><title>1. Introduction</title><p>Plants have long been used as a basis of traditional remedies in the history of mankind and also act as sources of modern medicines. According to the World Health Organization (WHO), more than three-fourths of the communities in resource-limited countries rely upon medicinal plants for their primary health care needs because more than 60% of the societies are unable to have access and/or afford allopathic medicines [<xref rid="B1" ref-type="bibr">1</xref>, <xref rid="B2" ref-type="bibr">2</xref>]. In line with the new progress in the area of optimum nutrition, nowadays there is a resurgence of interest in the use of plants as a source of food and medicine [<xref rid="B3" ref-type="bibr">3</xref>, <xref rid="B4" ref-type="bibr">4</xref>]. Recently, the usage of phytomedicine has been amplified dramatically for numerous ailments because of not only their easy accessibility and low cost but also the belief that natural remedies have fewer harmful effects as compared to synthetic medicines [<xref rid="B5" ref-type="bibr">5</xref>].</p><p>The development of new products from natural sources is also encouraged because it is estimated that, of the 300,000 herbal species that exist globally, only 15% have been explored for their pharmacological potential [<xref rid="B6" ref-type="bibr">6</xref>]. Among several medicinal plants,<italic> Nigella sativa </italic>L. (Ranunculaceae) has been considered one of the most treasured nutrient-rich herb in history around the world and numerous scientific studies are in progress to validate the traditionally claimed uses of small seed of this species [<xref rid="B7" ref-type="bibr">7</xref>, <xref rid="B8" ref-type="bibr">8</xref>].</p><p>The maximal nutritional value of black cumin can be linked to the presence of substantial amount of vegetable protein, fiber and minerals, and vitamins. The nutritional composition reported from different sources revealed 20-85% of protein, 38.20% of fat, 7-94% of fiber, and 31.94% of total carbohydrates. Among various amino acids identified, glutamate, arginine, and aspartate while cysteine and methionine were the major and minor amino acids, respectively. Black cumin seeds also contain significant levels of iron, copper, zinc, phosphorus, calcium, thiamin, niacin, pyridoxine, and folic acid [<xref rid="B7" ref-type="bibr">7</xref>, <xref rid="B8" ref-type="bibr">8</xref>]. In addition, phytochemical analyses of<italic> N. sativa</italic> displayed the presence of over hundreds of phytoconstituents which include mainly alkaloids, saponins, sterols, and essential oil but the composition of many of these have not been chemically recognized nor have been biologically verified. The<italic> N. sativa</italic> seed contain 26-34% fixed oil of which the major fatty acids are linoleic acid (64.6%) and palmitic acid (20.4%). The seed oil is comprised of 0.4%–2.5% essential oil [<xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B10" ref-type="bibr">10</xref>]. Amongst different active constituents reported so far, thymoquinone found as major component of the essential oil is the most bioactive compound and exhibits wide ranging therapeutic benefits [<xref rid="B11" ref-type="bibr">11</xref>].</p></sec><sec id="sec2"><title>2. High-Value Bioactive Compounds (Phytochemicals) in the Seed of<italic> Nigella sativa</italic></title><p>Several bioactive compounds from the seed of<italic> N. sativa</italic> have been reported in the literature; among those the most important bioactive ones are thymoquinones. Other main phytochemicals reported from different varieties of<italic> N. sativa</italic> include sterols and saponins, phenolic compounds, alkaloids, novel lipid constituents and fatty acids, and volatile oils of varying composition [<xref rid="B12" ref-type="bibr">12</xref>]. The essential oil composition (0.4-0.45%) reported in various studies represented about forty different compounds, amongst the abundantly constituents identified are<italic> tran</italic>s-anethole,<italic> p</italic>-cymene limonene, carvone, <italic>α</italic>-thujene, thymoquinone (TQ), thymohydroquinone (THQ), dithymoquinone, carvacrol, and <italic>β</italic>-Pinene with various concentration [<xref rid="B13" ref-type="bibr">13</xref>–<xref rid="B15" ref-type="bibr">15</xref>].</p><p>The quantity of most important bioactive constituent, thymoquinone, present in the volatile oil isolated by different extraction methods from the seeds of<italic> N. sativa</italic> varied over a wide range: using SC-CO<sub>2</sub> (1.06, 4.07 mg/g) [<xref rid="B16" ref-type="bibr">16</xref>] and by Soxhlet extraction (2940.43 mg/kg) [<xref rid="B17" ref-type="bibr">17</xref>] and (8.8 mg/g) oil [<xref rid="B18" ref-type="bibr">18</xref>].</p><p>The seed oil fatty acid composition (32-40%) has been reported by various authors to contain mainly, linoleic, linolenic, oleic, palmitoleic, palmitic acids together with arachidonic, eicosadienoic, stearic, and myristic acid [<xref rid="B15" ref-type="bibr">15</xref>, <xref rid="B16" ref-type="bibr">16</xref>, <xref rid="B19" ref-type="bibr">19</xref>]. A new dienoate and two known monoesters along with novel lipids have been isolated from the unsaponified extract of the seed, namely methylnonadeca-15,17-dienoate, pentyl hexadec-12-enoate, and pentyl pentadec-11-enoate [<xref rid="B20" ref-type="bibr">20</xref>].</p><p>Phytosterols are important part of human diet and are gaining greater interest due to their nutraceutical and medicinal benefits in lowering low density lipoprotein and total cholesterol level [<xref rid="B21" ref-type="bibr">21</xref>]. Phytosterols are also important as characteristic compounds for assessing the quality of vegetable oils and food labeling. The total sterols content of black cumin seed oil as estimated by different researchers was found to be between 18 and 42% of the unsaponified matter. The major sterols identified were <italic>β</italic>-sitosterol, campesterol, stigmasterol, and 5-avenasterol [<xref rid="B19" ref-type="bibr">19</xref>, <xref rid="B22" ref-type="bibr">22</xref>]. Tocopherols exhibited attractive scavenging potentials of free radicals which are believed to terminate lipids peroxidation [<xref rid="B23" ref-type="bibr">23</xref>]. The total tocopherol contents of black seed oil reported in varied quantities from diverse sources ranged from 9.15 to 27.92 mg/100 g. Among the foremost tocopherols recognized in black cumin seeds, <italic>α</italic>- and <italic>γ</italic>-tocopherol and <italic>β</italic>-tocotrienol are well recognized [<xref rid="B19" ref-type="bibr">19</xref>].</p><p>Steroidal glycosides of new and known structures have been isolated from<italic> N. sativa</italic> seeds which include 3-<italic>O</italic>-[<italic>β</italic>-D-xylopyranosyl-(1→2)-<italic>α</italic>-L-rhamnopyranosyl-(1→2)-<italic>β</italic>-D-glucopyranosyl]-11-methoxy-16, 23-dihydroxy-28-methylolean-12-enoate, stigma-5,22-dien-3-<italic>β</italic>-D-glucopyranoside [<xref rid="B24" ref-type="bibr">24</xref>], and 3-<italic>O</italic>-[<italic>β</italic>-D-xylopyranosyl-(1→3)-<italic>α</italic>-L-rhamnopyranosyl-(1→4)-<italic>β</italic>-D-glucopy-ranosyl]-11-methoxy-16-hydroxy-17-acetoxy hederagenin [<xref rid="B25" ref-type="bibr">25</xref>]. Moreover, alkaloids of diverse types have been isolated from the seeds of black cumin, which include novel Dolabellane-type diterpene alkaloids: nigellamines A<sub>1</sub>, A<sub>2</sub>, B<sub>1</sub>, and B<sub>2</sub> and nigellamines A3, A4, A5, and C [<xref rid="B26" ref-type="bibr">26</xref>, <xref rid="B27" ref-type="bibr">27</xref>] possessing lipid metabolizing property, and indazole class of alkaloids: nigellidine, nigellicine [<xref rid="B28" ref-type="bibr">28</xref>, <xref rid="B29" ref-type="bibr">29</xref>], and nigellidine-4-O-sulfite [<xref rid="B30" ref-type="bibr">30</xref>].</p></sec><sec id="sec3"><title>3. Traditional Uses of<italic> Nigella sativa</italic> in Folk Remedies</title><p><italic>Nigella sativa</italic> has been widely used as a spice and flavoring agent in variety of food preparations such as in bread, yogurt, pickles, sauces, and salads. Black seed or black cumin (English),<italic> Habbatul Barakah</italic> (Arabic),<italic> Tikur azmud</italic> (Amharic), has long been used in traditional remedy in the Arabian countries, Far East Asia, Europe, and Africa [<xref rid="B31" ref-type="bibr">31</xref>].<italic> Nigella sativa </italic>has also been described as the miraculous plant and considered by earliest herbal specialists as “The herb from heaven” [<xref rid="B32" ref-type="bibr">32</xref>]. The Prophet Mohammed (PBUH) had described the curative powers of the black seed as “Hold on to use this black seed, as it has a remedy for every illness except death” [<xref rid="B33" ref-type="bibr">33</xref>]. Avicenna, a well-known physician of 10th century famous for his book “The Canon of Medicine,” has recommended use of<italic> Nigella</italic> seeds for enhancement of body's energy and also support during recovery from fatigue and dispiritedness.<italic> Nigella sativa</italic> is also mentioned for its curative property in the Holy Bible and is also labelled as<italic> Melanthion</italic> by Hippocrates and Dioscorides [<xref rid="B34" ref-type="bibr">34</xref>, <xref rid="B35" ref-type="bibr">35</xref>].</p><p>The medicinal use of black cumin seeds in various traditional herbal systems is known for a wide range of ailments which include different airway disorders, for pain such as chronic headache and back pain, diabetes, paralysis, infection, inflammation, hypertension, and digestive tract related problems administered in different kind of preparations. It has also been used topically where it is applied directly to the blisters, nasal abscesses, orchitis, eczema, and swollen joints [<xref rid="B33" ref-type="bibr">33</xref>].</p><p>Keeping in view of the numerous traditional medicinal uses of<italic> N. sativa</italic> seeds and its active component, thymoquinone, this valuable herb can be explored as an effective folk medicine with multiple pharmacological actions.</p></sec><sec id="sec4"><title>4. Pharmacological Activities of<italic> Nigella sativa</italic></title><p><italic>Nigella sativa</italic> has been broadly studied in the last few decades and studies have reported that it possesses a number of medicinal properties and pharmacological actions. In order to retrieve the relevant literatures with respective subtopics, we have used PubMed, Science Direct, Scopus Google Scholar, and grey literatures using different searching terms such as “<italic>Nigella sativa</italic>” or “Black cumin” or “Black seed” and respective disease conditions. In the case of PubMed searching, we have used the respective “Mesh” terms and text words “tw” in order to retrieve all the relevant articles regardless of time boundaries.</p><sec id="sec4.1"><title>4.1. Antioxidant Activity</title><p>Oxidative stress and an intensification in the levels of free radicals are amongst the foremost central markers associated with several progressive pathological conditions, including neurological disorder, cancer, aging, and endocrine illness [<xref rid="B36" ref-type="bibr">36</xref>]. To date, there has been a growing importance in the therapeutic option of medicinal plants as natural antioxidants. Among the various naturally occurring medicinal plants,<italic> N. sativa</italic> has been reported for its effective antioxidant activities of<italic> in- vivo</italic> and<italic> in- vitro</italic> studies [<xref rid="B37" ref-type="bibr">37</xref>].</p><p>The concomitant usage of<italic> Allium sativum</italic> and<italic> N. sativa</italic> seed in thirty postmenopausal women after two months of consumption revealed a significant reduction in plasma malondialdehyde (MDA) levels with increased activity in erythrocyte glutathione peroxidase (GSH-Px) and superoxide dismutase [<xref rid="B38" ref-type="bibr">38</xref>]. Likewise, the fixed and essential oil of black cumin seed revealed a significant increment of Glutathione-S-transferase (GST), glutathione reductase and GSH-Px against oxidative stress brought by potassium bromate in rats' model [<xref rid="B39" ref-type="bibr">39</xref>].</p><p>The separate administration of<italic> N. sativa</italic> and nanosized clinoptilolite to Wistar rats also showed significant improvement on antioxidant parameters than concomitant uses of both extracts and diabetic groups [<xref rid="B40" ref-type="bibr">40</xref>]. A randomized controlled clinical trial in fifty volunteer obese subjects also demonstrated that<italic> N. sativa</italic> seed oil along with a less caloric diet significantly diminished the superoxide dismutase (SOD) level and body weight as compared to the placebo group in eight weeks' trial [<xref rid="B41" ref-type="bibr">41</xref>]. Moreover, the methanolic extract and essential oil fractioned from<italic> N. sativa</italic> seed in atherogenic suspension nourished rats has been reported effectively replenished the plasma total antioxidant power by eighty-eight percent against free radicals [<xref rid="B42" ref-type="bibr">42</xref>]. Similarly, the oil of<italic> N. sativa </italic>and thymoquinone administration markedly ameliorated cisplatin-induced alteration on carbohydrate biotransformation and enzymatic and nonenzymatic antioxidant defense system in the gastric mucosa [<xref rid="B43" ref-type="bibr">43</xref>]. Hence, the marked antioxidant activity of<italic> N. sativa</italic> and thymoquinone might be a potential newer antioxidant agent and used as essential nutrients for life for health promotion and diseases prevention.</p></sec><sec id="sec4.2"><title>4.2. Antidiabetic Activity</title><p>Even with the advancement in the management of diabetes mellitus, exploration for innovative agents continues since the existing synthetic agents have numerous limitations [<xref rid="B44" ref-type="bibr">44</xref>]. The administration of black cumin seed for one month to streptozotocin-induced diabetic rats displayed a significant reduction of fasting plasma glucose, serum MDA, interleukin-6, and immunoglobulin A, G, and M while substantial increment of endogenous antioxidant enzymes; SOD, Glutathione-S-transferase, and catalase expression were noticed. The histology of pancreas in<italic> N. sativa</italic> treated group also revealed an improvement in the pancreatic <italic>β</italic>-cells degeneration, inflammation, and congestion as compared to diabetic control [<xref rid="B45" ref-type="bibr">45</xref>]. The combination of administration of<italic> N. sativa</italic> and<italic> Cinnamomum cassia</italic> extracts (NSCCe) to experimentally STZ-induced diabetic rats also showed significantly stabilized serum glucose concentrations, lipid profile, and renal function parameters as compared to the diabetic control. Significant effects were observed in animals that received combined extract and metformin on these parameters. A substantial reversal of the histopathological pancreatic cell injury was also observed in animals receiving the concomitant extracts of NSCCe [<xref rid="B46" ref-type="bibr">46</xref>]. The marked antidiabetic activity upon three-month supplementation of<italic> N. sativa </italic>(2 g/day) along with oral antidiabetic agent in type 2 DM patients has also been reported. In this study,<italic> N. sativa </italic>received group showed significant reduction of fasting plasma glucose, hemoglobin A1c, and TBARBs, while marked elevation of the total antioxidant capacity, SOD, and glutathione levels were noted [<xref rid="B47" ref-type="bibr">47</xref>].</p><p>Furthermore, an experimental randomized controlled trial of 99 diabetes patients received the placebo and two treatment groups received oral black seed oil. Administration of 1.5 and 3 mL/day of black seed oil for 20 days showed meaningful reduction of glycated hemoglobin A1c and random blood sugar levels [<xref rid="B48" ref-type="bibr">48</xref>]. The effect of<italic> N. sativa</italic> seed on the glycemic control of patients with type-2 diabetes (DM-2) was also used as an adjunctive treatment added to their oral hypoglycemic agents.<italic> N. sativa</italic> at a dose of two g/day also influenced substantial reductions in fasting plasma glucose and glycated hemoglobin (HbA1c) without major alteration in body weight [<xref rid="B49" ref-type="bibr">49</xref>]. The oil of<italic> N. sativa </italic>(NSO) at 2 mL/kg also was showed to reduce fasting plasma glucose and intensification of insulin levels in diabetic rats compared to control. Diabetic rats that received NSO exhibited substantial improvements in lipid profile and expressive increment of pancreatic and hepatic antioxidant enzymes also augmented the histological image and glycogen contents other than improvements of average pancreatic islet extent than the diabetic groups [<xref rid="B50" ref-type="bibr">50</xref>].</p><p>The different doses of<italic> N. sativa</italic> seed (1, 2, and 3 g/day) in patients with DM-2 were also evaluated. A one g/day administration increased high-density lipoprotein cholesterol (HDL-c) levels after 3 months while two and three g/day of<italic> N. sativa</italic> seed significantly decreased serum levels of total cholesterol (TC) and triglyceride (TG) as well as low-density lipoprotein cholesterol (LDL-c) and increased plasma HDL-c [<xref rid="B51" ref-type="bibr">51</xref>]. In reference to modern scholars' devotion to the likely effects of medicinal herbs in diabetic management, a recent meta-analysis of antidiabetic effects of<italic> N. sativa</italic> [<xref rid="B44" ref-type="bibr">44</xref>] also exhibited the maintenance of glucose homeostasis and serum lipid profiles in diabetic human subjects [<xref rid="B44" ref-type="bibr">44</xref>, <xref rid="B51" ref-type="bibr">51</xref>].</p><p>Generally, the possible antidiabetic mechanisms of<italic> N. sativa </italic>might be mediated via modulation of oxidative status (either through upregulation of endogenous antioxidants or reduction of oxidative species) [<xref rid="B45" ref-type="bibr">45</xref>, <xref rid="B47" ref-type="bibr">47</xref>], attenuation of inflammation [<xref rid="B45" ref-type="bibr">45</xref>], improvement of lipid profiles, increased good cholesterol (HDL-c), while reducing bad cholesterols (LDL-c, TC, and TG) and body weight [<xref rid="B44" ref-type="bibr">44</xref>, <xref rid="B46" ref-type="bibr">46</xref>, <xref rid="B51" ref-type="bibr">51</xref>].</p></sec><sec id="sec4.3"><title>4.3. Antihypertensive Activity</title><p>Numerous antihypertensive agents have been clinically used to control hypertension and to relieve associated comorbid conditions. However, the effectiveness of these agents is only in 40-60% of hypertensive patients and commonly combination of two or more blood lowering agents from diverse antihypertensive classes is required to attain the desired outcomes [<xref rid="B52" ref-type="bibr">52</xref>]. This eventually increases the likelihoods of untoward effects and also raises the cost of therapy. A number of herbal products such as the seed of<italic> N. sativa</italic> have been used and claimed to have positive effects against elevated blood pressure (BP).</p><p>According to a nonrandomized controlled trials, 57 patients who were allocated to receive 2 g daily supplementations of black cumin for one year displayed a noticeable reduction in systolic, diastolic, and mean arterial BP, heart rate, TC, LDL-c, the fractions of TC/HDL-c, and LDL-c/HDL-c while serum HDL-c was suggestively raised compared with the corresponding baseline values and the control group [<xref rid="B53" ref-type="bibr">53</xref>]. Although a trend towards reduction in BP was observed after<italic> N. sativa </italic>administration, one randomized controlled clinical trial failed to show a significant reduction of BP in elderly patients with hypertension [<xref rid="B54" ref-type="bibr">54</xref>]. This might be because of the sample size, dosage (300 mg BID for 4 weeks) of the<italic> N. sativa</italic> used in this study, the severity of hypertension, and study population used. For instance, previous clinical studies conducted by Dehkordi et al. [<xref rid="B55" ref-type="bibr">55</xref>] and Qidwai et al. [<xref rid="B56" ref-type="bibr">56</xref>] conducted on mild hypertensive patients with the dosage of 200 mg BID for 4 weeks and 500 mg BID for 6 weeks, respectively, showed a significant reduction of SPB.</p><p>In addition, it has been employed to determine the blood pressure lowering potential and possible mechanisms of<italic> N. sativa</italic> in rats' model, and it was found that the seed oil and nicardipine received groups' revealed substantial reduction in BP. The BP diminishing effect was related with a reduction in cardiac lipid peroxidation product and inhibitory activity of angiotensin converting enzyme in both groups but plasma nitric oxide level significantly increased in<italic> N. sativa</italic> oil received group than the placebo and nicardipine received groups [<xref rid="B57" ref-type="bibr">57</xref>]. Black cumin and its active component, thymoquinone, exhibited a reduction in oxidative stress via calcium channel blockade and increasing urine output activity which might have been linked to reduction in blood pressure [<xref rid="B58" ref-type="bibr">58</xref>]. Based on majority of these reports, various preparation of<italic> N. sativa </italic>showed a sustainable reduction of the BP in animal models and clinical studies hence can be explored as a promising basis of natural antihypertensive drugs.</p></sec><sec id="sec4.4"><title>4.4. Neuroprotective Effects</title><p>Neurological disorder such as depression is amongst the most prevailing illnesses globally. It is principally affected by the hypoactivity of neurotransmitters, particularly owing to inadequate activity of serotonin [<xref rid="B59" ref-type="bibr">59</xref>]. Stress is the chief triggering aspect in the initiation of depression and this premise is steadily supported by various clinical observations. Studies in experimental animals displayed that overwhelming stress conditions produce neurochemical modifications and behavioral deficits [<xref rid="B60" ref-type="bibr">60</xref>]. A large number of medicinal herbs and their isolated compounds have been revealed to have medicinal benefits and therapeutic potential. Among the promising medicinal plants, black cumin is a worthwhile herb with a rich historical and religious basis to manage depression and many other neurological disorders.</p><p>The intragastric supplementation of TQ (20 mg/mL) in aluminum trichloride and D-galactose induced neurotoxicity in rats showed a meaningful improvement of cognition, SOD, and total antioxidant capacity while reducing acetylcholinesterase activities. It also exhibited a reduction in MDA, nitric oxide levels, and tumor necrosis factor-<italic>α</italic> immunoreactivity and amplified brain derived neurotrophic factor and Bcl-2 levels [<xref rid="B61" ref-type="bibr">61</xref>]. While the effects of repeated administration of<italic> N. sativa</italic> in rats indicated that, there was an improvement in learning and recall status [<xref rid="B62" ref-type="bibr">62</xref>]. In addition, flavonoids isolated from black cumin have been shown to modulate critical neuronal signaling paths involved in the processes of memory and are likely to affect synaptic plasticity and long-standing potentiating mechanisms [<xref rid="B63" ref-type="bibr">63</xref>]. The neuropharmacological effects of the seed and oils of<italic> N. sativa</italic> and its active component, TQ, are described in <xref rid="tab1" ref-type="table">Table 1</xref>. Based on the wide ranging neuropharmacological effects, black cumin seed, its oil, and the active principle thymoquinone (TQ) can be explored as a promising natural remedy for improvement of numerous neurological disorders.</p></sec><sec id="sec4.5"><title>4.5. Anti-Inflammatory and Analgesic Effects</title><p>Inflammation has a key role in various medical conditions such as cystic fibrosis, rheumatoid arthritis, osteoarthritis, asthma, allergies, and cancer which all are associated with acute and/or chronic pain. The existing anti-inflammatory agents commonly comprise classes of drugs that produce severe adverse effects such as gastric ulcer, bone marrow depression, water, and salt retention, resulting from the extended use [<xref rid="B80" ref-type="bibr">80</xref>]. Medicinal herbs including black cumin might be a potential source of novel biological compounds that are safer and with fewer side effects. The volatile oil of black cumin and thymoquinone at various doses revealed a dose-reliant anti-inflammatory activity against carrageenan-induced hind paw edema in rats' parallel to indomethacin [<xref rid="B81" ref-type="bibr">81</xref>]. The volatile oil of<italic> N. sativa </italic>seed also displayed a substantial pain-relieving effect in acetic acid-induced writhing, formalin, and tail flick tests [<xref rid="B82" ref-type="bibr">82</xref>]. As stated by Al-Ghamdi, the water extract of black cumin also retained anti-inflammatory effects in carrageenan-induced paw edema comparable to acetyl salicylic acid at corresponding doses but failed to display antipyretic activity against yeast-induced pyrexia [<xref rid="B83" ref-type="bibr">83</xref>]. Furthermore, the alcoholic extract of black cumin exhibited a noteworthy pain-relieving effect in mice as compared to diclofenac sodium [<xref rid="B84" ref-type="bibr">84</xref>]. Additional study also showed that essential oil of black cumin has notable activity as a painkiller in acetic acid-induced writing, formalin, and tail flick tests. It was also revealed that this extract might elevate a significant swimming and anoxia tolerance time [<xref rid="B85" ref-type="bibr">85</xref>]. The anti-inflammatory action of TQ might be related to inhibition of the oxidative product of arachidonic acid formation, such as thromboxane B2 and leukotriene by blocking both cyclooxygenase and lipoxygenase enzymes [<xref rid="B86" ref-type="bibr">86</xref>, <xref rid="B87" ref-type="bibr">87</xref>].</p><p>In addition, the action of black cumin seed on tracheal sensitivity and pulmonary inflammation of guinea pigs, which were exposed to breathe Sulphur mustard together with black cumin, displayed expressively lower magnitude compared to that of only Sulphur mustard exposed group [<xref rid="B88" ref-type="bibr">88</xref>]. The bronchial relaxation effects of the boiled extract of<italic> N. sativa</italic> in contrast with theophylline were assessed in asthmatic patients and it was found that black cumin extract caused substantial rises in entirely measured respiratory function tests and the starting time of bronchodilator action of the extract was comparable to that of theophylline [<xref rid="B89" ref-type="bibr">89</xref>]. The various extracts, oil, and active constituent (<italic>α</italic>-hederin) of<italic> N. sativa </italic>also showed an improvement of tracheal responsiveness and significant anti-inflammatory activity via decreasing the release of histamine and leukotrienes while increasing the PGE2 from the mast cells and perfused lungs in anima model of allergic asthma [<xref rid="B90" ref-type="bibr">90</xref>–<xref rid="B93" ref-type="bibr">93</xref>]. This antiasthmatic effect is further substantiated by different clinical studies, and majority of them reported that different<italic> N. sativa </italic>preparations showed an improvements of clinical symptoms and pulmonary function as well as various asthma biomarkers [<xref rid="B89" ref-type="bibr">89</xref>, <xref rid="B94" ref-type="bibr">94</xref>–<xref rid="B98" ref-type="bibr">97</xref>]. These preclinical and clinical studies evidenced the potential antiasthmatic effects of<italic> N. sativa </italic>but further investigations are required to assure its efficacy.</p><p>The efficacy of black cumin oil in patients with rheumatoid arthritis (RA) was also evaluated and data from 40 female patients diagnosed with RA who took<italic> N. sativa</italic> oil capsules (500 mg) twice daily exhibited improvement in disease activity score compared to placebo (P < 0.05). Correspondingly, a noticeable improvement was displayed in number of inflamed joints, incidence of morning stiffness, and disease activity after the consumption of black cumin [<xref rid="B99" ref-type="bibr">98</xref>].</p><p>Chronic inflammation has been implicated in various chronic illnesses [(cancer, cardiovascular disorders, diabetes, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, rheumatoid arthritis, and asthma) that involve progressive and irreversible damage to the cell and/or neurons] as well as in many infectious conditions [<xref rid="B100" ref-type="bibr">99</xref>, <xref rid="B101" ref-type="bibr">100</xref>]. Therefore, the crucial role of anti-inflammatory actions of different<italic> N. sativa</italic> preparations and TQ might be the possible sources for the development of a new generation of anti-inflammatory agent to treat these wide ranging conditions.</p></sec><sec id="sec4.6"><title>4.6. Antimicrobial Activity</title><p>Antimicrobials have been the bases of clinical medicine since the second half of the 20th century and have saved prominent number of people from serious microbial infections. Nevertheless, in the late 20th century and the earliest 21st century it has perceived the advent and widespread of antimicrobial resistance in pathogenic microorganisms throughout the globe [<xref rid="B102" ref-type="bibr">101</xref>, <xref rid="B103" ref-type="bibr">102</xref>]. The ever-increasing terrorization of microbial infections and antimicrobial resistant bacteria demands for a global struggle to discover for novel solutions that might be grounded on the natural products such as plants, which are selected on the basis of renowned ethnomedicinal use [<xref rid="B104" ref-type="bibr">103</xref>, <xref rid="B105" ref-type="bibr">104</xref>]. Among the inspiring medicinal plants, black cumin is the one that displayed strong antibacterial, antifungal, antiviral, and antiparasitic actions.</p><sec id="sec4.6.1"><title>4.6.1. Antibacterial Activity</title><p>Thymoquinone obtained from seeds of<italic> N. sativa</italic> revealed broader spectrum activities against multiple strains of gram-positive and gram-negative bacteria, including<italic> Bacillus</italic>,<italic> Listeria</italic>,<italic> Enterococcus</italic>,<italic> Micrococcus</italic>,<italic> Staphylococcus</italic>,<italic> Pseudomonas</italic>,<italic> Escherichia, Salmonella</italic>,<italic> Serovar</italic>, and<italic> Vibrio parahaemolyticus </italic>in addition to inhibiting bacterial biofilm formation [<xref rid="B106" ref-type="bibr">105</xref>]. The methyl alcoholic extract of the seed also displayed a larger inhibition zone on gram-positive (<italic>S. pyogenes</italic>) as compared to gram-negative bacteria (<italic>P. aeruginosa, K. pneumoniae, </italic>and<italic> P. vulgaris</italic>) [<xref rid="B107" ref-type="bibr">106</xref>]. For different isolates of methicillin-resistant<italic> S. aureus</italic>, various concentrations of (100%, 80%, 50%, 40%, 30%, and 20%)<italic> N. sativa</italic> oils displayed an expressively higher zone of inhibitions against all the tested bacterial strains [<xref rid="B108" ref-type="bibr">107</xref>]. Thymoquinone also revealed a significant bactericidal activity against gram-positive cocci with MICs ranging from 8 to 32 <italic>μ</italic>g/mL and proved the minimum biofilm inhibition concentration at 22 and 60 <italic>μ</italic>g/mL for<italic> S. aureus</italic> and<italic> S. epidermidis,</italic> respectively [<xref rid="B109" ref-type="bibr">108</xref>]. Moreover, black seed (2 g/day) owed clinically valuable anti<italic>-H. pylori</italic> effect comparable to triple therapy [<xref rid="B110" ref-type="bibr">109</xref>] and this can provide a scientific basis for the exploration of potential uses of this valued seed for the treatment of<italic> H. pylori</italic>-induced gastric ulcers.</p></sec><sec id="sec4.6.2"><title>4.6.2. Antifungal Activity</title><p>The essential oil of<italic> N. sativa</italic> of different origins has been reported to possess moderate inhibitory action against pathogenic strains of yeasts, dermatophytes and nondermatophytic filamentous fungi along with aflatoxin-producing fungi. The<italic> N. sativa</italic> treatment targeted the cell wall, plasma membrane, and membranous organelles, mainly in the nuclei and mitochondria as were evident in the morphology of these toxigenic fungi [<xref rid="B111" ref-type="bibr">110</xref>]. Moreover, different extracts of black cumin and TQ exhibited powerful fungicidal activity against dermatophyte strains including<italic> Trichophyton mentagrophytes</italic> and<italic> Microsporum gypseum</italic> superior to fluconazole, but lesser than that of ketoconazole [<xref rid="B112" ref-type="bibr">111</xref>]. Thymoquinone also arrested the growth of<italic> Aspergillus niger</italic> and<italic> Fusarium solani</italic> comparable to Amphotericin-B [<xref rid="B113" ref-type="bibr">112</xref>] and was effective against<italic> C. albicans</italic>,<italic> C. tropicalis</italic>, and<italic> C. krusei</italic> [<xref rid="B114" ref-type="bibr">113</xref>]. Similarly, as stated by Taha et al., the active constituent of black cumin such as TQ, thymohydroquinone, and thymol revealed potent antifungal effect against several clinically isolated fungal strains including dermatophytes, molds, and yeasts [<xref rid="B115" ref-type="bibr">114</xref>]. As a potential candidate with multiple antimicrobial activities,<italic> N. sativa</italic> can also be explored as a natural preservative and food additive to protect foods from spoilage.</p></sec><sec id="sec4.6.3"><title>4.6.3. Antiviral Activity</title><p><italic>N. sativa </italic>seed oil was found to suppress viral load in murine model: cytomegalovirus infected mice to undetectable level in the liver and spleen in 10 days' intraperitoneal administration. This was possibly due to the increase in number and function of CD4<sup>+ve</sup> T cells and increased production of interferon- (INF-) gamma [<xref rid="B116" ref-type="bibr">115</xref>]. Interestingly, patients (30) with hepatitis C virus (HCV) infection, who were not eligible for IFN-<italic>α</italic>/ribavirin therapy showed significant improvement in HCV viral load (16.67% became seronegative and 50% showing significant decrement) and proved laboratory parameter like total protein, red blood cell, and platelet count, decreased fasting blood glucose, and postprandial glucose in both diabetic and nondiabetic HCV patients and reduced lower-limb edema after they are managed with black cumin seed oil [<xref rid="B117" ref-type="bibr">116</xref>].</p><p>According to a case report conducted by Onifade et al., after treatment with 10 mL of black seed twice daily for 6 months, a complete regaining and seroreversion of a 46-year-old HIV positive patient was evidenced [<xref rid="B118" ref-type="bibr">117</xref>]. In addition, a 27-year-old HIV infected woman was diagnosed during ante-natal care; she was not eligible for antiretroviral therapy; hence herbal therapist initiated her on black cumin and honey mixture (10 mL) thrice daily for a year. The repeat serology assessments for HIV infection became negative with undetectable viral load. The woman also got 3 children (2007, 2010, and 2012) that all were breastfed and none of the children infected with HIV and her repeat CD4 count was not less than 750 cells/<italic>μ</italic>L [<xref rid="B119" ref-type="bibr">118</xref>]. Nowadays HIV/AIDS is a serious global threat and in this regard,<italic> N. sativa</italic> can be a promising natural therapy to cure such a chronic infectious disease, after validating its full therapeutic efficacy by further investigations.</p></sec><sec id="sec4.6.4"><title>4.6.4. Antiparasitic Activity</title><p><italic>Nigella sativa </italic>seeds have shown schistosomicidal properties against<italic> Schistosoma mansoni</italic> (<italic>in vitro</italic>), through a strong biocidal effect against all stages of the parasite and an inhibitory effect on egg-laying of adult female worms [<xref rid="B120" ref-type="bibr">119</xref>, <xref rid="B121" ref-type="bibr">120</xref>]. An ointment of<italic> N. sativa </italic>seed significantly contracted and inhibited the inflammatory reactions to cutaneous leishmaniasis produced experimentally in mice by a subcutaneous inoculation of<italic> Leishmania major</italic> at the abaxial base of the tail [<xref rid="B122" ref-type="bibr">121</xref>].<italic> N. sativa</italic> extract at a dose of 1.25 g/kg prominently lowered<italic> Plasmodium yoelii</italic> infection in mice by 94%; however, the effect of chloroquine was only 86% as compared to the untreated group. In addition, methanolic extract of<italic> N. sativa </italic>revealed higher parasite clearance and restoration of altered biochemical indicators by<italic> P. yoelii</italic> infection than chloroquine [<xref rid="B123" ref-type="bibr">122</xref>]. Thus, considering<italic> N. sativa </italic>for future antiparasitic agents will have a very important input after conduction of further investigation of its curative, prophylactic and chemopreventive activity particularly in the era of emerging antimalarial drug resistance.</p></sec></sec><sec id="sec4.7"><title>4.7. Anticancer Activity</title><p>Cancer is a bigger challenge in medical science as the incidence of this health disorder is rapidly growing across the world. This prompts the efforts to search some effective natural anticancer therapies alternative to currently employed chemotherapies with limited applications. The effect of black seed in different types of cancer cells is summarized in <xref rid="tab2" ref-type="table">Table 2</xref>. As there are ten cancer hallmarks which are common to most tumors, TQ, a major active component of<italic> N. sativa</italic>, plays great role in affecting all markers of cancer [<xref rid="B124" ref-type="bibr">123</xref>].</p></sec><sec id="sec4.8"><title>4.8. Effects on Male Infertility</title><p>Infertility is the incapability of a copulate to attain offspring after 12 months of intercourse without contraception. It is more prevalent among men than women [<xref rid="B143" ref-type="bibr">142</xref>]. Sperm dysfunction is the main problem related with men infertility which accounts 60% of all reasons. The structure, function, motility, and survival of sperm are deleteriously affected by oxidative stress that prominently leads to infertility. Hence, increasing spermatozoa counts, functionality, and sperm quality using antioxidants can improve fertility status [<xref rid="B144" ref-type="bibr">143</xref>, <xref rid="B145" ref-type="bibr">144</xref>]. Evidence proves that some herbal medicines can reduce negative effects of oxidative stress by salvaging free radicals [<xref rid="B146" ref-type="bibr">145</xref>]. Among the various traditional plants,<italic> N. sativa</italic> was found to exhibit remarkable antioxidant effect [<xref rid="B147" ref-type="bibr">146</xref>].</p><p>Alcoholic extract of<italic> N. sativa</italic> indicated remarkable increment in the production of viable and motile sperm cells, enhanced epididymal sperm reservation, weight gaining of reproductive organs, blood testosterone density, gonadotropins content, amount of mature Leydig cells, and fertility indexes compared to the control group in male rats [<xref rid="B148" ref-type="bibr">147</xref>]. According to Mohammad et al., black cumin thought to trigger a rise in spermatogenesis hormones on pituitary gland, and an increase in the weight of reproductive organs. The study also reveals that<italic> N. sativa</italic> can affect oxidative phosphorylation enzymes and increase sperm motility [<xref rid="B148" ref-type="bibr">147</xref>]. In addition, a randomized, double-blind, placebo-controlled clinical trial was conducted on 68 Iranian infertile men and half of them receive 2.5 mL of black seed oil and the remaining received placebo twice daily for two months. The amount and the motility of sperm and the content of semen volume were raised significantly in black seed oil treated group compared with placebo group after two months of therapy [<xref rid="B149" ref-type="bibr">148</xref>]. This indicates that<italic> N. sativa</italic> can be a potential source for development of natural<italic> aphrodisiac </italic>agents.</p></sec></sec><sec id="sec5"><title>5. Toxicological Properties</title><p>The acute oral toxicity of active constituents of black cumin seed, TQ, lethal dose 50 (LD<sub>50</sub>) value has been reported to be 2.4 g per kg of body weight of Swiss albino mice, whereas the instant behavioral alteration at two and three g per kg of body weight of the composite was hypoactivity and trouble in breathing, while late toxicities comprising a substantial lessening in the virtual organ weight and glutathione distribution of the hepatic, renal, and cardiovascular system have been reported [<xref rid="B150" ref-type="bibr">149</xref>]. Daily administration of aqueous extract (AqE) of<italic> N. sativa</italic> to mice for six weeks led to death of one mouse after 2 weeks of treatment with 6.4 g/kg of AqE. On the other hand, 2 and 3 mice experienced death at 3rd and 5th weeks while they received 21 g/kg and 60 g/kg of the extract, respectively. Otherwise, no other deaths were recorded for the application of other doses used [<xref rid="B151" ref-type="bibr">150</xref>]. In addition, the subchronic toxicity study in mice treated with 30, 60, and 90 mg/kg/day of TQ for 90 days resulted in no mortality or signs of toxicity but substantial decrement of fasting plasma glucose and also showed no change in toxicological significance in body organs and histological investigation [<xref rid="B150" ref-type="bibr">149</xref>]. The toxicity of the fixed oil of black cumin in mice and rats was also examined and the LD<sub>50</sub> values were found to be 28.8 ml/kg and 2.06 ml/kg when given by oral and intraperitoneal routes, respectively. Chronic toxicity was also studied in rats treated daily with an oral dose of 2 ml/kg for 12 weeks' black cumin oil, while alterations in vital liver enzyme levels and histopathological modifications (heart, liver, kidneys, and pancreas) were not detected [<xref rid="B152" ref-type="bibr">151</xref>]. The minor and/or negligible toxicological effects and wider therapeutic margin of<italic> N. sativa</italic> and its active constituents, thymoquinone, as evident by various scientific studies support its safe use for the long-term traditional food and medicinal purposes.</p></sec><sec id="sec6"><title>6. Conclusion and Future Prospects</title><p>Traditional medicinal plants have received much attention due to several factors such as low cost, ease of access, and lower adverse effect profiles as compared to synthetic medicines. Besides, various medicinal floras and their products are used on the basis of religious and cultural traditions. Among various plants, black cumin has been used by diverse human cultures around the world especially in Muslim population for centuries to treat numerous ailments. To date, a number of studies showed that black seed and its component including TQ have revealed a remarkable natural therapy for treatment of a wide range of illnesses including chronic noninfectious (neurologic disorders, DM, hypertension, dyslipidemia, inflammatory disorders, cancer, etc.) and infectious disease (bacterial, fungal, viral, and parasitic infections). Both animal and human studies also showed that black seed and TQ have potential to treat male infertility and their antioxidant activities have recently gained greater attention due to their role as dietary supplements with minimal side effects. Furthermore, when combined with different conventional chemotherapeutic agents, they synergize the effects which may reduce the dosage of the concomitantly used medicines and optimizing efficacy versus toxicity and it might also overcome drug resistance problem. Therefore, having wider safety margins and praiseworthy efficacy against wide range of maladies, it would be a potential herbal remedy to be assessed under clinical trial for numerous conditions. Isolation of novel bioactive components from black cumin and its oil and studies of their therapeutic effects using specific clinical models are further recommended.</p></sec></body><back><glossary><title>Abbreviations</title><def-list><def-item><term>AqE:</term><def><p>Aqueous extract</p></def></def-item><def-item><term><italic>N. sativa</italic>:</term><def><p><italic> Nigella sativa</italic></p></def></def-item><def-item><term>TQ:</term><def><p>Thymoquinone</p></def></def-item><def-item><term>LD:</term><def><p>Lethal dose</p></def></def-item><def-item><term>PTEN:</term><def><p>Phosphatase and tensin homolog</p></def></def-item><def-item><term>MCF-7:</term><def><p>Michigan Cancer Foundation-7</p></def></def-item><def-item><term>TBARs:</term><def><p>Thiobarbituric acid</p></def></def-item><def-item><term>GABA:</term><def><p>Gamma amino butyric acid</p></def></def-item><def-item><term>5-HT:</term><def><p>5-Hydroxytryptamine</p></def></def-item><def-item><term>MDA:</term><def><p>Malondialdehyde</p></def></def-item><def-item><term>DA:</term><def><p>Dopamine</p></def></def-item><def-item><term>5HIAA:</term><def><p>5 Hydroxyindoleacetic acid</p></def></def-item><def-item><term>GSH-Px:</term><def><p>Glutathione peroxidase</p></def></def-item><def-item><term>SOD:</term><def><p>Superoxide dismutase</p></def></def-item><def-item><term>A<italic>β</italic>:</term><def><p>Beta amyloid peptides</p></def></def-item><def-item><term>HCV:</term><def><p>Hepatitis C virus</p></def></def-item><def-item><term>INF:</term><def><p>Interferon</p></def></def-item><def-item><term>MIC:</term><def><p>Minimum inhibitory concentration</p></def></def-item><def-item><term>RA:</term><def><p>Rheumatoid arthritis</p></def></def-item><def-item><term>BP:</term><def><p>Blood pressure</p></def></def-item><def-item><term>DM:</term><def><p>Diabetic mellitus</p></def></def-item><def-item><term>CQ:</term><def><p>Chloroquine.</p></def></def-item></def-list></glossary><sec><title>Conflicts of Interest</title><p>The authors declare no conflict of interest.</p></sec><sec><title>Authors' Contributions</title><p>Ebrahim M. Yimer developed the research conception and took the initiatives of this work and drafted the manuscript. Kald Beshir Tuem, Aman Karim, Najeeb Ur-Rehman, and Farooq Anwar provide greater contribution towards collecting, extracting, and organizing relevant data and also revising the review paper and agreed to be accountable for all aspects of the work.</p></sec><ref-list><ref id="B1"><label>1</label><element-citation publication-type="book"><collab>World Health Organization</collab><source><italic toggle="yes">Traditional Medicine Fact sheet No 134</italic></source><year>2017</year><comment><ext-link ext-link-type="uri" xlink:href="http://www.siav-itvas.org/images/stories/doc/.../WHO_Traditional_medicine_2008.pdf/">http://www.siav-itvas.org/images/stories/doc/.../WHO_Traditional_medicine_2008.pdf/</ext-link></comment></element-citation></ref><ref id="B2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jamshidi-Kia</surname><given-names>F.</given-names></name><name><surname>Lorigooini</surname><given-names>Z.</given-names></name><name><surname>Amini-Khoei</surname><given-names>H.</given-names></name></person-group><article-title>Medicinal plants: Past history and future perspective</article-title><source><italic toggle="yes">Journal of HerbMed Pharmacology</italic></source><year>2018</year><volume>7</volume><issue>1</issue><fpage>1</fpage><lpage>7</lpage><pub-id pub-id-type="other">2-s2.0-85039853998</pub-id><pub-id pub-id-type="doi">10.15171/jhp.2018.01</pub-id></element-citation></ref><ref id="B3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Anwar</surname><given-names>F.</given-names></name><name><surname>Anwar</surname><given-names>F.</given-names></name><name><surname>Muhammad</surname><given-names>G.</given-names></name><etal></etal></person-group><article-title>Capparis spinosa L.: A plant with high potential for development of functional foods and nutraceuticals/pharmaceuticals</article-title><source><italic toggle="yes">International Journal of Pharmacology</italic></source><year>2016</year><volume>12</volume><issue>3</issue><fpage>201</fpage><lpage>219</lpage><pub-id pub-id-type="other">2-s2.0-84961187045</pub-id><pub-id pub-id-type="doi">10.3923/ijp.2016.201.219</pub-id></element-citation></ref><ref id="B4"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hassanien</surname><given-names>M. 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I.</given-names></name><name><surname>Haffaf</surname><given-names>E.-M.</given-names></name><name><surname>Berdja</surname><given-names>S.</given-names></name><name><surname>Aouichat-Bouguerra</surname><given-names>S.</given-names></name></person-group><article-title>In vivo subacute toxicity and antidiabetic effect of aqueous extract of<italic> Nigella sativa</italic></article-title><source><italic toggle="yes">Evidence-Based Complementary and Alternative Medicine</italic></source><year>2017</year><volume>2017</volume><fpage>13</fpage><pub-id pub-id-type="publisher-id">8427034</pub-id><pub-id pub-id-type="doi">10.1155/2017/8427034</pub-id></element-citation></ref><ref id="B152"><label>151</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zaoui</surname><given-names>A.</given-names></name><name><surname>Cherrah</surname><given-names>Y.</given-names></name><name><surname>Mahassini</surname><given-names>N.</given-names></name><name><surname>Alaoui</surname><given-names>K.</given-names></name><name><surname>Amarouch</surname><given-names>H.</given-names></name><name><surname>Hassar</surname><given-names>M.</given-names></name></person-group><article-title>Acute and chronic toxicity of <italic>Nigella sativa</italic> fixed oil</article-title><source><italic toggle="yes">Phytomedicine</italic></source><year>2002</year><volume>9</volume><issue>1</issue><fpage>69</fpage><lpage>74</lpage><pub-id pub-id-type="doi">10.1078/0944-7113-00084</pub-id><pub-id pub-id-type="other">2-s2.0-0036184031</pub-id><pub-id pub-id-type="pmid">11924767</pub-id></element-citation></ref></ref-list></back><floats-group><table-wrap id="tab1" orientation="portrait" position="float"><label>Table 1</label><caption><p>The effects of <italic>N. sativa</italic> and its active component, thymoquinone (TQ) on neurological and mental disorders.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Neurological or mental Disorders</th><th align="left" rowspan="1" colspan="1">Model used and intervention (s)</th><th align="left" rowspan="1" colspan="1">Finding (mechanism)</th><th align="center" rowspan="1" colspan="1">References</th></tr></thead><tbody><tr><td rowspan="2" align="left" colspan="1">Alzheimer's disease (AD)</td><td align="left" rowspan="1" colspan="1">Lipopolysaccharide-induced AD in mice, received TQ (2.5 & 5mg/kg) for 7 days.</td><td align="left" rowspan="1" colspan="1">(i) ↓ TBARS & 5-LOX levels <break></break>(ii) ↑ GSH extent and SOD action<break></break>(iii) Causes disaggregation of A<italic>β</italic> peptide<break></break>(iv) prevents declining of neurons<break></break>(v) Slows degeneration of cognitive ability</td><td align="center" rowspan="1" colspan="1">[<xref rid="B64" ref-type="bibr">64</xref>, <xref rid="B65" ref-type="bibr">65</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">A<italic>β</italic>-induced neurotoxicity (analyzed by culturing hippocampus and cortical neurons).<break></break>TQ is administered along with A<italic>β</italic><sub>1−42</sub> for 72 hours</td><td align="left" rowspan="1" colspan="1">(i) Reducing A<italic>β</italic>-induced neurotoxicity. (Improved cell viability) by:<break></break>(ii) Inhibiting mitochondrial membrane potential depolarization <break></break>(iii) Hindering reactive oxygen species generation</td><td align="center" rowspan="1" colspan="1">[<xref rid="B66" ref-type="bibr">66</xref>]<break></break></td></tr><tr><td colspan="4" rowspan="1"><hr></hr></td></tr><tr><td rowspan="2" align="left" colspan="1">Parkinson's disease (PD)</td><td align="left" rowspan="1" colspan="1">1-methyl-4-phenylpyridinium (MPP<sup>+</sup>) and rotenone-induced neurotoxicity in PD model, cultures were treated with TQ (0.01, 0.1, 1 and, 10 <italic>μ</italic>M) on day 8th for 4 days.</td><td align="left" rowspan="1" colspan="1">(i) Rescued dopaminergic neurons through:<break></break>(ii) Its antioxidant and anti-inflammatory effects</td><td align="center" rowspan="1" colspan="1">[<xref rid="B67" ref-type="bibr">67</xref>]<break></break></td></tr><tr><td align="left" rowspan="1" colspan="1">Experimental model of early PD induced by 6-hydroxydopamine neurotoxicity, pretreatment of daily TQ (5 & 10 mg/kg) and one additional dose after surgery were used.</td><td align="left" rowspan="1" colspan="1">(i) ↓ MDA level <break></break>(ii) Prevents loss of neurons in substantia nigra<break></break>(iii) Protects hippocampal & human induced pluripotent stem cell against <italic>α</italic>-synuclein induced synaptic toxicity</td><td align="center" rowspan="1" colspan="1"> [<xref rid="B68" ref-type="bibr">68</xref>, <xref rid="B69" ref-type="bibr">69</xref>]<break></break></td></tr><tr><td colspan="4" rowspan="1"><hr></hr></td></tr><tr><td rowspan="3" align="left" colspan="1">Depression and anxiety</td><td align="left" rowspan="1" colspan="1">(i) Open field and elevated plus maze models; forced swim test <break></break>(ii) Locomotor behavior in familiar and new environment in rats, <italic>N. sativa </italic> oil (0.1 mL/day) aqueous seed extract (2 mL/day) orally for 4-6 weeks</td><td align="left" rowspan="1" colspan="1">(i) ↑ in open field activity & struggling time<break></break>(ii) ↑ 5-HT <break></break>(iii) ↓ 5HIAA level in the brain <break></break>(iv) ↑ tryptophan level in plasma & brain<break></break>(v) ↑ locomotors activity in novel environment <break></break>(vi) ↑ brain DA level</td><td align="center" rowspan="1" colspan="1">[<xref rid="B59" ref-type="bibr">59</xref>, <xref rid="B70" ref-type="bibr">70</xref>, <xref rid="B71" ref-type="bibr">71</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Stressed and unstressed mice, 10 and 20 mg/kg of TQ for 4 weeks</td><td align="left" rowspan="1" colspan="1">Unstressed mice: at 10 & 20 mg/Kg showed anti-anxiety <break></break>(i) without altering nitrite levels<break></break>(ii) ↑ GABA content (only 20mg/Kg).<break></break>Stressed mice: 20 mg/kg showed anxiolytic effects with <break></break>(i) ↓ plasma nitrite level<break></break>(ii) Reversal of reduced GABA</td><td align="center" rowspan="1" colspan="1">[<xref rid="B72" ref-type="bibr">72</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Randomized control trial on healthy human subjects, <italic>N. sativa</italic> capsule (500 mg) daily for 4 weeks.</td><td align="left" rowspan="1" colspan="1">(i) Stabilize disturbed mood<break></break>(ii) ↓ anxiety<break></break>(iii) Modulate memory positively</td><td align="center" rowspan="1" colspan="1">[<xref rid="B73" ref-type="bibr">73</xref>]</td></tr><tr><td colspan="4" rowspan="1"><hr></hr></td></tr><tr><td rowspan="2" align="left" colspan="1">Epilepsy</td><td align="left" rowspan="1" colspan="1">Pentylenetetrazole-induced seizure, <italic>N. sativa</italic> oil; TQ</td><td align="left" rowspan="1" colspan="1">(i) Prevented seizure occurrence<break></break>(ii) ↓ Reactive oxygen species generation<break></break>(iii) Reduced seizure score <break></break>(iv) Showed additive effects with phenobarbitone</td><td align="center" rowspan="1" colspan="1">[<xref rid="B74" ref-type="bibr">74</xref>–<xref rid="B76" ref-type="bibr">76</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Double-blinded placebo randomized control trial (refractory epilepsy), TQ as adjunctive therapy for 4 weeks</td><td align="left" rowspan="1" colspan="1">(i) Significant reduction of seizure frequency (those who received combination therapy)</td><td align="center" rowspan="1" colspan="1">[<xref rid="B77" ref-type="bibr">77</xref>]</td></tr><tr><td colspan="4" rowspan="1"><hr></hr></td></tr><tr><td rowspan="2" align="left" colspan="1">Opioid dependence and Tolerance</td><td align="left" rowspan="1" colspan="1">Morphine brought tolerance and dependency in mice, 4mL/kg of <italic>N. sativa</italic> oil along with morphine (5mg/kg)</td><td align="left" rowspan="1" colspan="1">(i) Attenuated the development of tolerance<break></break>(ii) Inhibited nitric oxide overproduction <break></break>(iii) ↓ in brain MDA level</td><td align="center" rowspan="1" colspan="1">[<xref rid="B78" ref-type="bibr">78</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Randomized trial (on 35 known addicts of opiates), 500 mg <italic>N. Sativa </italic>three times daily<break></break></td><td align="left" rowspan="1" colspan="1">(i) ↓ the withdrawal effects significantly<break></break>(ii) ↑ appetite (no significant weight gain)<break></break>(iii) No changes in physiological parameters (blood pressure, pulse and respiratory rate)</td><td align="center" rowspan="1" colspan="1">[<xref rid="B79" ref-type="bibr">79</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p>TBARs= Thiobarbituric acid reactive substances, GABA= gamma amino butyric acid, 5-HT= 5 hydroxytryptamine, MDA= malondialdehyde, DA= dopamine, 5HIAA= 5 hydroxyindoleacetic acid, GSH= glutathione peroxidase, SOD= superoxide dismutase, TQ= thymoquinone, A<italic>β</italic>= beta amyloid peptides, ↑=increase, ↓=decrease.</p></fn></table-wrap-foot></table-wrap><table-wrap id="tab2" content-type="sidewaystable" orientation="portrait" position="float"><label>Table 2</label><caption><p>Effects of <italic>N. sativa</italic> and thymoquinone against various types of cancer models and their effects on anticancer agents.</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="2" align="center" rowspan="1">Cancer models or effects of anticancer agents</th><th align="left" rowspan="1" colspan="1">Intervention (s)</th><th align="left" rowspan="1" colspan="1">Findings (Mechanisms)</th><th align="center" rowspan="1" colspan="1">References</th></tr></thead><tbody><tr><td rowspan="8" align="left" colspan="1"><italic>In vitro </italic>studies</td><td align="left" rowspan="1" colspan="1">Doxorubicin-resistant <break></break>human breast cancer cells line (MCF-7/DOX cells)</td><td align="left" rowspan="1" colspan="1">TQ (25, 50 or 100 <italic>µ</italic>M) for 48 hours & NSO Nano emulsion</td><td align="left" rowspan="1" colspan="1">(i) Concentration dependent growth inhibition<break></break>(ii) Induce apoptosis, p53 protein <break></break>(iii) Upregulation of PTEN (inhibit PI3K/Akt pathway)</td><td align="center" rowspan="1" colspan="1">[<xref rid="B125" ref-type="bibr">124</xref>, <xref rid="B126" ref-type="bibr">125</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Human cervical squamous <break></break>cancer cells</td><td align="left" rowspan="1" colspan="1">TQ (1.0 to 30 <italic>μ</italic>g/mL) for 24, 48 and 72 hours</td><td align="left" rowspan="1" colspan="1">(i) More cytotoxic than cisplatin towards this cancerous cell (but less cytotoxicity towards normal cells)<break></break>(ii) Downregulates Bcl-2 protein</td><td align="center" rowspan="1" colspan="1">[<xref rid="B127" ref-type="bibr">126</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Myeloblastic leukemia <break></break>(HL-60 cells)</td><td align="left" rowspan="1" colspan="1">TQ</td><td align="left" rowspan="1" colspan="1">(i) Induces apoptosis, disrupts mitochondrial membrane potential, triggers the activation of caspases 3, 8 & 9 in HL-60 cells</td><td align="center" rowspan="1" colspan="1"> [<xref rid="B128" ref-type="bibr">127</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Human bladder cancer cells (T24 and 253J)</td><td align="left" rowspan="1" colspan="1">TQ (20-160 <italic>µ</italic>mol/L) for different periods (24h, 48h, and 72h)</td><td align="left" rowspan="1" colspan="1">(i) TQ showed marked cytotoxicity on bladder cancer cells<break></break>(ii) It inhibited cancerous cells rapid multiplication and evoked apoptosis via activation of caspase.<break></break>(iii) TQ also resulted in activation of ER stress, mitochondrial disturbance and enhanced mitochondrial mediated apoptotic path.</td><td align="center" rowspan="1" colspan="1">[<xref rid="B129" ref-type="bibr">128</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Renal cell cancer (RCC) cell lines (786-O and ACHN)</td><td align="left" rowspan="1" colspan="1">TQ (40 <italic>μ</italic>mol/L) for 24 hours</td><td align="left" rowspan="1" colspan="1">(i) TQ suppressed migration, invasion and epithelial-mesenchymal transition in RCC cells.<break></break>(ii) TQ exhibited significant inhibition of the metastasis of RCC cells through induction of autophagy via AMPK/mTOR signalling.</td><td align="center" rowspan="1" colspan="1">[<xref rid="B130" ref-type="bibr">129</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Human renal tubular epithelial cell (HK2) and the human RCC cell lines (769-P & 786-O)</td><td align="left" rowspan="1" colspan="1">TQ (0.5, 1, 2.5, 5, 10, 15 & 20 <italic>µ</italic>M) at various durations (0, 24, 48 & 72 h).</td><td align="left" rowspan="1" colspan="1">(i) TQ markedly inhibited the migration and invasion of the human RCC 769-P and 786-O cell lines.<break></break>(ii) TQ also increased the expression of E-cadherin and reduced the expression of Snail, ZEB1 and vimentin at the mRNA as well as protein levels in dose-dependent fashion.<break></break>(iii) As a result, the extents of phosphorylation of hepatic kinase B1 and AMPK were upregulated.</td><td align="center" rowspan="1" colspan="1">[<xref rid="B131" ref-type="bibr">130</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Human prostate cancer cell lines (DU145 and C3)</td><td align="left" rowspan="1" colspan="1">TQ (2.5, 5.0 & 10 <italic>µ</italic>M) for 24 hours.</td><td align="left" rowspan="1" colspan="1">(i) TQ substantially arrested the proliferation of prostate cancer.<break></break>(ii) It inhibited the migrating and invading capability of prostate cancer DU145 and PC3 cells.<break></break>(iii) TQ also downregulated the expression of TGF-<italic>β</italic>, Smad2 and Smad3 in prostate cancer cells.</td><td align="center" rowspan="1" colspan="1">[<xref rid="B132" ref-type="bibr">131</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Hepatocellular cancer cell line (HepG2)</td><td align="left" rowspan="1" colspan="1">TQ (3–24 <italic>µ</italic>M) for 24 hours.</td><td align="left" rowspan="1" colspan="1">(i) Decreased both the no. of viable HepG2 cells and the levels<break></break>(ii) TQ induced cell cycle arrest and apoptosis<break></break>(iii) Increased total antioxidant status (dose dependently) <break></break>(iv) TQ reduced the release of VEGF of HepG2 cells</td><td align="center" rowspan="1" colspan="1">[<xref rid="B133" ref-type="bibr">132</xref>]</td></tr><tr><td colspan="5" rowspan="1"><hr></hr></td></tr><tr><td rowspan="5" align="left" colspan="1"><italic>In vivo </italic>studies</td><td align="left" rowspan="1" colspan="1">Diethyl nitrosamine inducedhepatocarcinogenesis in Wistar rats</td><td align="left" rowspan="1" colspan="1">Ethanolic extract of NS (250 mg/kg) for 5 consecutive days.</td><td align="left" rowspan="1" colspan="1">(i) The chemical induced increment of liver weight, hepato-somatic indices, serum AFP and VEGF levels, and hepatic HGF<italic>β</italic> protein expression were significantly reversed by the extract.<break></break>(ii) The histopathological alteration of the livers due to the chemical was decreased in NS extract received rats without harmful effects.</td><td align="center" rowspan="1" colspan="1">[<xref rid="B134" ref-type="bibr">133</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Orthotopic model inmice [triple-negative breast cancer (TNBC) cell lines]</td><td align="left" rowspan="1" colspan="1">TQ (20 or 100 mg/k) once every 3 days</td><td align="left" rowspan="1" colspan="1">(i) TQ markedly reduced the growth of MDA-MB-231 tumor.<break></break>(ii) TQ decreased TNBC cell viability and proliferation as well as the migration and invasion of TNBC cells.<break></break>(iii) TQ also downregulated the expression of eEF-2K (via modulation of the NF-<italic>κ</italic>B/miR-603), Src/FAK, and Akt in TNBC cells.</td><td align="center" rowspan="1" colspan="1">[<xref rid="B135" ref-type="bibr">134</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Colon carcinogenesis of rats model</td><td align="left" rowspan="1" colspan="1">NSO for 14 weeks</td><td align="left" rowspan="1" colspan="1">(i) NSO revealed a significant antiproliferative activity in both initiation and post-initiation phases<break></break>(ii) Inhibited colon carcinogenesis of rats mainly in the post-initiation stage with no evident of adverse effects</td><td align="center" rowspan="1" colspan="1">[<xref rid="B136" ref-type="bibr">135</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Mouse model of colorectal carcinogenesis & C26 cell</td><td align="left" rowspan="1" colspan="1">TQ (5 mg/kg) for 3 weeks & TQ (0, 20, 40, 60 <italic>μ</italic>M) <italic>in vitro</italic></td><td align="left" rowspan="1" colspan="1">(i) TQ reduced tumor multiplicity<break></break>(ii) TQ impeded tumor growth and induce apoptosis in HCT116 xenografts<break></break>(iii) Sub-cytotoxic conc. of TQ (40<italic>μ</italic>M) also reduced C26 cell invasion<break></break>(iv) Anti-neoplastic and pro-apoptotic p53-dependent mechanism</td><td align="center" rowspan="1" colspan="1">[<xref rid="B137" ref-type="bibr">136</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Rat multi-organ <break></break>carcinogenesis</td><td align="left" rowspan="1" colspan="1">NSO for 30 weeks</td><td align="left" rowspan="1" colspan="1">(i) Reduction in malignant and benign colon tumor sizes, tumors in the lungs and in diverse parts of the alimentary canal principally the oesophagus and fore stomach</td><td align="center" rowspan="1" colspan="1">[<xref rid="B138" ref-type="bibr">137</xref>]</td></tr><tr><td colspan="5" rowspan="1"><hr></hr></td></tr><tr><td rowspan="4" align="left" colspan="1">Effect on anti-cancer drugs</td><td align="left" rowspan="1" colspan="1">Cyclophosphamide <break></break>Induced toxicity (abnormal RF & LFT and reduced Hgb) in rat</td><td align="left" rowspan="1" colspan="1">NSO (1ml/kg) and TQ (10 mg/kg) EOD for 12 days</td><td align="left" rowspan="1" colspan="1">(i) Substantial reduction in overall cyclophosphamide induced toxicity in both NSO and TQ treated groups.</td><td align="center" rowspan="1" colspan="1">[<xref rid="B139" ref-type="bibr">138</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Antitumor Effect of TQ and gemcitabine on xenograft mouse and PANC-1, AsPC-1 and BxPC-3 cell lines of pancreatic cancer models,</td><td align="left" rowspan="1" colspan="1">TQ (0–50 <italic>µ</italic>mol/L) & 1.0 mg/ mouse daily<break></break></td><td align="left" rowspan="1" colspan="1">(i) TQ pre-treatment synergistically increased the gemcitabine actions of apoptotic and tumor growth inhibition of pancreatic cancer cells.<break></break>(ii) Concomitant uses resulted in the change of several molecular signaling, including the downregulation of Notch1, NICD associated with up-regulation of PTEN, via the inactivation of Akt/mTOR/S6 signaling.<break></break>(iii) TQ and gemcitabine also induced suppression of anti-apoptotic Bcl-2, Bcl-xL, XIAP and overexpression and activation Caspase-3, Caspase-9, & Bax.</td><td align="center" rowspan="1" colspan="1">[<xref rid="B140" ref-type="bibr">139</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Cytotoxicity assay of TQ and paclitaxel on mouse breast cancer cell line (4T1) and animal models</td><td align="left" rowspan="1" colspan="1">TQ (6.25, 12.5, 25, 50, & 100 <italic>μ</italic>M) for 24 & 48 hours; (0.64, 2.4 & 3.2 mg/kg of mouse body weight).</td><td align="left" rowspan="1" colspan="1">(i) TQ induced marked cytotoxicity and apoptosis, while inhibiting wound healing and migration of 4T1 cells.<break></break>(ii) Co-administration of TQ and paclitaxel significantly induced cytotoxicity and apoptosis compared to separate administration.<break></break>(iii) The combination of paclitaxel and the lower dose TQ markedly inhibited the tumor growth.<break></break>(iv) Both agents also modulated the apoptosis genes, p53 and JAK-STAT signaling, while overexpressing the levels of Caspase-3, Caspase-7, and Caspase-12.</td><td align="center" rowspan="1" colspan="1">[<xref rid="B141" ref-type="bibr">140</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Anti-tumor activity of TQ and topotecan in colorectal cancer cell line (HT-29)</td><td align="left" rowspan="1" colspan="1">TQ (40, 55 & 60 <italic>µ</italic>M)<break></break></td><td align="left" rowspan="1" colspan="1">(i) TQ significantly enhanced the anti-tumor effect of non-cytotoxic dose of topotecan.<break></break>(ii) Both drugs induced apoptosis via a p53-independent mechanism, while the expression of p21 was only noted in TQ therapy.<break></break>(iii) TQ improved the effectiveness of topotecan by inhibiting proliferationand lowering toxicity via p53- and Bax/Bcl2-independent mechanisms.</td><td align="center" rowspan="1" colspan="1">[<xref rid="B142" ref-type="bibr">141</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p>AMPK: Adenosine monophosphate-activated protein kinase, NS: <italic>Nigella sativa</italic>, NSO: <italic>Nigella sativa</italic> oil, TQ: Thymoquinone, PTEN: phosphatase and tensin homolog, MCF-7: Michigan Cancer Foundation-7, EOD: every other day, mTOR: Mammalian Target of Rapamycin.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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