{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T14:09:42Z","timestamp":1764079782592,"version":"build-2065373602"},"reference-count":66,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T00:00:00Z","timestamp":1653264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Apart from the nutritional value, Cucumis sativus L. has also been used in the traditional medicine of Iran, Pakistan, and India. Its seeds are used by herbalists to treat gastrointestinal, respiratory, and urinary problems. However, more investigations are required to explain its mechanisms for treating GI, respiratory, and urinary diseases. Accordingly, the aim of the present work was to investigate the antispasmodic, bronchodilator, and antidiarrheal activities of C. sativus seeds extracts and the underlying mechanisms of action. For this purpose, sequential extracts of C. sativus seeds were prepared in n-hexane, dichloromethane, ethanol, and water. Bioactive compounds in C. sativus seed extracts were identified and quantified by utilizing LC ESI\u2013MS\/MS and HPLC. Moreover, network pharmacology and molecular docking were employed to examine the antispasmodic and bronchodilator effects of the bioactive substances in the extracts. In vitro and in vivo experiments were also conducted to validate the mechanistic insights gained from the in silico analysis. Results indicated the presence of kaempferol with a concentration of 813.74 \u00b5g\/g (highest concentration) in the seed extract of C. sativus, followed by quercetin (713.83 \u00b5g\/g), narcissin (681.87 \u00b5g\/g), and orientin (676.19 \u00b5g\/g). In silico investigations demonstrated that the bioactive chemicals in C. sativus seeds inhibited the expression of the target genes involved in smooth muscle contraction and calcium-mediated signaling. Sequential seed extracts of C. sativus caused a dose-dependent relaxant response for spasmolytic reaction and resulted in a relaxation of K+ (80 mM) spastic contraction. In animal models, C. sativus seed extracts exhibited partial or complete antiperistalsis, antidiarrheal, and antisecretory actions. By modulating the contractile response through calcium-mediated signaling target proteins, C. sativus seeds generated bronchodilator, antispasmodic, and antidiarrheal therapeutic effects.<\/jats:p>","DOI":"10.3390\/ph15050641","type":"journal-article","created":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T03:16:55Z","timestamp":1653362215000},"page":"641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Possible Mechanisms Underlying the Antispasmodic, Bronchodilator, and Antidiarrheal Activities of Polarity\u2013Based Extracts of Cucumis sativus L. Seeds in In Silico, In Vitro, and In Vivo Studies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9935-3321","authenticated-orcid":false,"given":"Muqeet","family":"Wahid","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6242-7147","authenticated-orcid":false,"given":"Fatima","family":"Saqib","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saeed","family":"Akhtar","sequence":"additional","affiliation":[{"name":"Institute of Food Science and Nutrition, Bahauddin Zakariya University, Multan 60000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anam","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2730-7788","authenticated-orcid":false,"given":"Polrat","family":"Wilairatana","sequence":"additional","affiliation":[{"name":"Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9782-0835","authenticated-orcid":false,"given":"Mohammad S.","family":"Mubarak","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The University of Jordan, Amman 11942, Jordan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mariod, A.A., Saeed Mirghani, M.E., and Hussein, I. (2017). Cucumis Sativus Cucumber. Unconventional Oilseeds and Oil Sources, Elsevier.","DOI":"10.1016\/B978-0-12-809435-8.00016-0"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3897\/phytokeys.20.3948","article-title":"The Cucurbitaceae of India: Accepted Names, Synonyms, Geographic Distribution, and Information on Images and DNA Sequences","volume":"20","author":"Renner","year":"2013","journal-title":"PhytoKeys"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.jtcme.2021.07.009","article-title":"Mechanistic Insights into the Antimycobacterial Action of Unani Formulation, Qurs Sartan Kafoori","volume":"12","author":"Hameed","year":"2021","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"624006","DOI":"10.3389\/fphar.2021.624006","article-title":"Potentials of Antitussive Traditional Persian Functional Foods for COVID-19 Therapy","volume":"12","author":"Mosleh","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jep.2003.12.029","article-title":"Diuretic and Nephroprotective Effect of Jawarish Zarooni Sada\u2014A Polyherbal Unani Formulation","volume":"91","author":"Afzal","year":"2004","journal-title":"J. Ethnopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Khare, C.P. (2007). Indian Medicinal Plants, Springer.","DOI":"10.1007\/978-0-387-70638-2"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1080\/13880209.2021.1949357","article-title":"Cucumis sativus Extract Elicits Chloride Secretion by Stimulation of the Intestinal TMEM16A Ion Channel","volume":"59","author":"Saha","year":"2021","journal-title":"Pharm. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.jep.2010.01.052","article-title":"Ethnopharmacological Application of Medicinal Plants to Cure Skin Diseases and in Folk Cosmetics among the Tribal Communities of North-West Frontier Province, Pakistan","volume":"128","author":"Abbasi","year":"2010","journal-title":"J. Ethnopharmacol."},{"key":"ref_9","first-page":"234","article-title":"Evaluation of Antacid and Carminative Properties of Cucumis sativus under Simulated Conditions","volume":"4","author":"Sharma","year":"2012","journal-title":"Sch. Res. Libr. Der Pharm. Lett."},{"key":"ref_10","first-page":"129","article-title":"First Report on Laxative Activity of Cucumis sativus","volume":"12","author":"Sharma","year":"2012","journal-title":"Int. J. Pharm. Sci. Rev. Res."},{"key":"ref_11","first-page":"113","article-title":"Phytochemicals of Cucurbitaceae Family\u2014A Review","volume":"8","author":"Rajasree","year":"2016","journal-title":"Int. J. Pharmacogn. Phytochem. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.sjbs.2018.07.012","article-title":"Phytochemical Screening and in Vitro Antibacterial and Anticancer Activities of the Aqueous Extract of Cucumis sativus","volume":"26","author":"Tuama","year":"2019","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"112704","DOI":"10.1016\/j.biopha.2022.112704","article-title":"Metabolomics Analysis Delineates the Therapeutic Effects of Hydroethanolic Extract of Cucumis Sativus L. Seeds on Hypertension and Isoproterenol-Induced Myocardial Infarction","volume":"148","author":"Wahid","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.9734\/BJPR\/2015\/19700","article-title":"Anti-Inflammatory Activity of Cucumis sativus L.","volume":"8","author":"Agatemor","year":"2015","journal-title":"Br. J. Pharm. Res."},{"key":"ref_15","first-page":"436","article-title":"Effect of Hydroalcoholic and Buthanolic Extract of Cucumis sativus Seeds on Blood Glucose Level of Normal and Streptozotocin-Induced Diabetic Rats","volume":"14","author":"Minaiyan","year":"2011","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/1750-3841.13569","article-title":"Evaluation of the Effects of Cucumis sativus Seed Extract on Serum Lipids in Adult Hyperlipidemic Patients: A Randomized Double-Blind Placebo-Controlled Clinical Trial","volume":"82","author":"Soltani","year":"2017","journal-title":"J. Food Sci."},{"key":"ref_17","first-page":"34","article-title":"Anti-Inflammatory Activity of Cucumis sativus Seed in Carrageenan and Xylene Induced Edema Model Using Albino Wistar Rats","volume":"4","author":"Vetriselvan","year":"2013","journal-title":"Int. J. Biopharm."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wahid, M., Saqib, F., Ahmedah, H.T., Gavris, C.M., De Feo, V., Hogea, M., Moga, M., and Chicea, R. (2021). Cucumis sativus L. Seeds Ameliorate Muscular Spasm-Induced Gastrointestinal and Respiratory Disorders by Simultaneously Inhibiting Calcium Mediated Signaling Pathway. Pharmaceuticals, 14.","DOI":"10.3390\/ph14111197"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3923\/ajcn.2009.131.138","article-title":"Evaluation of Antioxidant and Antiulcer Potential of Cucumis sativum L. Seed Extract in Rats","volume":"1","author":"Gill","year":"2009","journal-title":"Asian J. Clin. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"183","DOI":"10.30574\/wjarr.2021.11.1.0339","article-title":"Medicinal Treatment of Multiple Renal Calculi (Hisat-E-Kulyah) and Bilateral Ureteric Calculi (Hisat-E-Halib) by Unani Pharmacopoeial Formulations\u2014A Case Study","volume":"11","author":"Khan","year":"2021","journal-title":"World J. Adv. Res. Rev."},{"key":"ref_21","first-page":"31","article-title":"Effects of Banadiq-Al Buzoor in Some Renal Disorders","volume":"42","author":"Anwar","year":"1999","journal-title":"Hamdard Med."},{"key":"ref_22","first-page":"1","article-title":"The Effect of Qurs-e-Zarishk Sagheer (A Compound Unani Formulation) on Liver Enzymes in CCl4 Induced Hepatotoxicity in Rats","volume":"9","author":"Alam","year":"2014","journal-title":"Hippocrat. J. Unani Med."},{"key":"ref_23","first-page":"1","article-title":"Thrombolytic (in Vitro) and Analgesic (in Vivo) Effect of Methanolic Extract of Cucumis sativus","volume":"3","author":"Siddika","year":"2016","journal-title":"Pharma Innov."},{"key":"ref_24","first-page":"31","article-title":"An Ethno-Botanical Review of Seeds of Cucumis Sativa (Maghz-e-Tukhme Khiyarain) from Unani Medicine and Its Pharmacological Updates","volume":"9","author":"Rehman","year":"2021","journal-title":"Int. J. Adv. Pharm. Med. Bioallied Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.fitote.2012.10.003","article-title":"Phytochemical and Therapeutic Potential of Cucumber","volume":"84","author":"Mukherjee","year":"2013","journal-title":"Fitoterapia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1016\/S0031-9422(00)84516-1","article-title":"Occurrence of \u03945-Sterols in Plants Producing Predominantly \u03947-Sterols: Studies on the Sterol Compositions of Six Cucurbitaceae Seeds","volume":"25","author":"Garg","year":"1986","journal-title":"Phytochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.foodres.2011.11.026","article-title":"HPLC-ESI-Q-TOF-MS for a Comprehensive Characterization of Bioactive Phenolic Compounds in Cucumber Whole Fruit Extract","volume":"46","year":"2012","journal-title":"Food Res. Int."},{"key":"ref_28","first-page":"e12733","article-title":"A Potential New Source: Nutritional and Antioxidant Properties of Edible Oils from Cucurbit Seeds and Their Impact on Human Health","volume":"43","author":"Karrar","year":"2019","journal-title":"J. Food Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1055\/s-0028-1088338","article-title":"Inhibitory Effect of Cucumis sativus on Melanin Production in Melanoma B16 Cells by Downregulation of Tyrosinase Expression","volume":"74","author":"Kai","year":"2008","journal-title":"Planta Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.foodres.2009.04.012","article-title":"Vegetables Antioxidant Losses during Industrial Processing and Refrigerated Storage","volume":"42","year":"2009","journal-title":"Food Res. Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1021\/np030150y","article-title":"Complex C-Glycosyl Flavonoid Phytoalexins from Cucumis sativus","volume":"66","author":"McNally","year":"2003","journal-title":"J. Nat. Prod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"113634","DOI":"10.1016\/j.jep.2020.113634","article-title":"Ethnopharmacological Basis for Folkloric Claims of Anagallis arvensis Linn. (Scarlet pimpernel) as Prokinetic, Spasmolytic and Hypotensive in Province of Punjab, Pakistan","volume":"267","author":"Saqib","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"107105","DOI":"10.1016\/j.compbiolchem.2019.107105","article-title":"An Integrated in Silico Screening Strategy for Identifying Promising Disruptors of P53-MDM2 Interaction","volume":"83","author":"Sirous","year":"2019","journal-title":"Comput. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3786","DOI":"10.1021\/jm000241h","article-title":"Binding of a Diverse Set of Ligands to Avidin and Streptavidin: An Accurate Quantitative Prediction of Their Relative Affinities by a Combination of Molecular Mechanics and Continuum Solvent Models","volume":"43","author":"Kuhn","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1076\/phbi.37.3.173.6304","article-title":"Spasmogenic and Spasimolytic Constituents in Sida Pakistanica","volume":"37","author":"Aziz","year":"1999","journal-title":"Pharm. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1002\/ptr.2098","article-title":"Presence of Cholinergic and Calcium Antagonist Constituents in Saussurea Lappa Explains Its Use in Constipation and Spasm","volume":"21","author":"Gilani","year":"2007","journal-title":"Phyther. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Salehi, B., Capanoglu, E., Adrar, N., Catalkaya, G., Shaheen, S., Jaffer, M., Giri, L., Suyal, R., Jugran, A.K., and Calina, D. (2019). Cucurbits Plants: A Key Emphasis to Its Pharmacological Potential. Molecules, 24.","DOI":"10.3390\/molecules24101854"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.biopha.2017.04.090","article-title":"Edible Seeds from Cucurbitaceae Family as Potential Functional Foods: Immense Promises, Few Concerns","volume":"91","author":"Patel","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1007\/s11130-010-0175-3","article-title":"Protective Role of Three Vegetable Peels in Alloxan Induced Diabetes Mellitus in Male Mice","volume":"65","author":"Dixit","year":"2010","journal-title":"Plant Foods Hum. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3089","DOI":"10.1002\/ptr.6742","article-title":"Pharmacological Exploration of Traditional Plants for the Treatment of Neurodegenerative Disorders","volume":"34","author":"Wahid","year":"2020","journal-title":"Phyther. Res."},{"key":"ref_41","first-page":"1","article-title":"Pharmacological Activity of Cucumis sativus L.\u2014A Complete Review","volume":"1","author":"Mallik","year":"2013","journal-title":"Asian J. Pharm. Res. Dev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3923\/rjphyto.2012.25.30","article-title":"Cytotoxicity and Antifungal Activities of Ethanolic and Chloroform Extracts of Cucumis sativus Linn (Cucurbitaceae) Leaves and Stems","volume":"6","author":"Das","year":"2012","journal-title":"Res. J. Phytochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1472-8206.2007.00561.x","article-title":"Gastrointestinal, Selective Airways and Urinary Bladder Relaxant Effects of Hyoscyamus Niger Are Mediated through Dual Blockade of Muscarinic Receptors and Ca2+ Channels","volume":"22","author":"Gilani","year":"2008","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/j.1742-7843.2006.pto_507.x","article-title":"Antispasmodic Effects of Rooibos Tea (Aspalathus Linearis) Is Mediated Predominantly through K+-Channel Activation","volume":"99","author":"Gilani","year":"2006","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_45","unstructured":"Brunton, L.L., Hilal-Dandan, R., and Knollmann, B.C. (2018). Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease. Goodman & Gilman\u2019s the Pharmacological Basis of Therapeutics, McGraw-Hill."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.nutres.2006.06.009","article-title":"Ca2+ Antagonist and Cholinergic Activities Explain the Medicinal Use of Olive in Gut Disorders","volume":"26","author":"Gilani","year":"2006","journal-title":"Nutr. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.pupt.2008.09.006","article-title":"Ion Channel Regulation of Intracellular Calcium and Airway Smooth Muscle Function","volume":"22","author":"Karner","year":"2009","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1016\/j.lfs.2004.03.035","article-title":"Presence of Cholinomimetic and Acetylcholinesterase Inhibitory Constituents in Betel Nut","volume":"75","author":"Gilani","year":"2004","journal-title":"Life Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"153978","DOI":"10.1016\/j.phymed.2022.153978","article-title":"Scientific Basis for Medicinal Use of Citrullus Lanatus (Thunb.) in Diarrhea and Asthma: In Vitro, in Vivo and in Silico Studies","volume":"98","author":"Wahid","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jep.2016.02.017","article-title":"Rationalizing Ethnopharmacological Uses of Alternanthera Sessilis: A Folk Medicinal Plant of Pakistan to Manage Diarrhea, Asthma and Hypertension","volume":"182","author":"Saqib","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_51","unstructured":"Hall, J.E., and Hall, M.E. (2020). Excitation and Contraction of Smooth Muscle. Guyton and Hall Textbook of Medical Physiology, Elsevier Health Sciences."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.jep.2005.01.017","article-title":"Studies on the Antihypertensive, Antispasmodic, Bronchodilator and Hepatoprotective Activities of the Carum Copticum Seed Extract","volume":"98","author":"Gilani","year":"2005","journal-title":"J. Ethnopharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.jep.2014.02.024","article-title":"Pharmacological Basis for the Medicinal Use of Carissa Carandas in Constipation and Diarrhea","volume":"153","author":"Mehmood","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_54","first-page":"479","article-title":"Bronchodilator, Vasodilator and Spasmolytic Activities of Methanolic Extract of Myrtus communis L.","volume":"64","author":"Janbaz","year":"2013","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Janbaz, K.H., Zaeem Ahsan, M., Saqib, F., Imran, I., Zia-Ul-Haq, M., Abid Rashid, M., Jaafar, H.Z.E., and Moga, M. (2015). Scientific Basis for Use of Pyrus Pashia Buch.-Ham. Ex D. Don. Fruit in Gastrointestinal, Respiratory and Cardiovascular Ailments. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0118605"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1540\/jsmr1965.7.83","article-title":"Excitation and Contraction of the Smooth Muscle","volume":"7","author":"Miyazaki","year":"1971","journal-title":"Jpn. J. Smooth Muscle Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1254\/jjp.12.137","article-title":"On the Mechanism of Diarrhea Due to Castor Oil","volume":"12","author":"Iwao","year":"1962","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.jep.2004.03.017","article-title":"Antidiarrhoeal Activity of Some Egyptian Medicinal Plant Extracts","volume":"92","author":"Atta","year":"2004","journal-title":"J. Ethnopharmacol."},{"key":"ref_59","first-page":"628","article-title":"Loperamide: Blockade of Calcium Channels as a Mechanism for Antidiarrheal Effects","volume":"231","author":"Reynolds","year":"1984","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0041-008X(03)00372-7","article-title":"Potential Roles of P-Gp and Calcium Channels in Loperamide and Diphenoxylate Transport","volume":"193","author":"Crowe","year":"2003","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.foodres.2016.06.019","article-title":"Development and Validation of a LC-ESI-MS\/MS Method for the Determination of Phenolic Compounds in Honeydew Honeys with the Diluted-and-Shoot Approach","volume":"87","author":"Seraglio","year":"2016","journal-title":"Food Res. Int."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Rowan, A.N. (1979). Guide for the Care and Use of Laboratory Animals, National Academies Press.","DOI":"10.1159\/000460187"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"105279","DOI":"10.1016\/j.ejps.2020.105279","article-title":"Immuno-Informatics Approach to Design a Multi-Epitope Vaccine to Combat Cytomegalovirus Infection","volume":"147","author":"Chauhan","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"128728","DOI":"10.1016\/j.foodchem.2020.128728","article-title":"Identification of Novel Umami Peptides from Myosin via Homology Modeling and Molecular Docking","volume":"344","author":"Yu","year":"2021","journal-title":"Food Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.biopha.2015.02.009","article-title":"Homology Modelling and Molecular Docking of MDR1 with Chemotherapeutic Agents in Non-Small Cell Lung Cancer","volume":"71","author":"Subhani","year":"2015","journal-title":"Biomed. Pharmacother."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"174194","DOI":"10.1016\/j.ejphar.2021.174194","article-title":"Andrographolide Protects against Isoproterenol-Induced Myocardial Infarction in Rats through Inhibition of L-Type Ca2+ and Increase of Cardiac Transient Outward K+ Currents","volume":"906","author":"Elasoru","year":"2021","journal-title":"Eur. J. Pharmacol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/5\/641\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:17:02Z","timestamp":1760138222000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/5\/641"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,23]]},"references-count":66,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ph15050641"],"URL":"https:\/\/doi.org\/10.3390\/ph15050641","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2022,5,23]]}}}