{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T16:56:23Z","timestamp":1791564983980,"version":"4.3.4"},"reference-count":184,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The bioactive compounds that are produced by leeches combine traditional and modern treatment since the saliva of the animal contains proteins and peptides with anticoagulant, anti-inflammatory, antimicrobial, antioxidant, and regenerative properties. In this review, their biochemical profile, mechanisms and clinical uses are considered with a special focus on the fact that they are utilized to combine traditional practices with the modern developments in biomedical approaches. Proteomic and transcriptomic research has recently found more than 100 bioactive molecules, such as hirudin, calin, eglins, bdellins and destabilase, which are related to the blood-feeding process and therapeutic processes. These compounds control blood clotting, control inflammatory mediators, block microbes and enhance wound healing and the development of new blood vessels. In clinical practice, leech therapy is common in the reconstruction and microsurgical practice to reduce venous congestion and enhance graft success. They are also shown to be useful in wound healing, cardiovascular health, musculoskeletal conditions and regenerative medicine, as well as emerging drug delivery systems of recombinant proteins and nanocarriers. Some of the challenges involve biological variation, infection or bleeding risks and stringent regulations on purity and standardization. Biotechnology has improved through other developments such as recombinant protein production, high-throughput omics, and nanotechnology, which will help resolve these problems, making them safe and scalable for clinical use. Altogether, leech bioactives are the prime examples of the sophisticated pharmacology of nature, which have the potential of being used as therapeutic agents in the future. The recent approach and incorporation in personalized medicine and bioengineering models reflect the leech\u2019s capacity to address complicated illness and unmet healthcare requirements to reassert its significance in preventive medicine and recent biomedicine.<\/jats:p>","DOI":"10.3390\/ijms27052112","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T16:58:18Z","timestamp":1771952298000},"page":"2112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Molecular Insights into Leech-Derived Bioactive Compounds: Biochemical Mechanisms and Therapeutic Potential"],"prefix":"10.3390","volume":"27","author":[{"given":"Suresh","family":"Raghavi","sequence":"first","affiliation":[{"name":"Department of Bioinformatics, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Thandalam, Chennai 602105, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balakrishnan","family":"Deva darshini","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Thandalam, Chennai 602105, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5541-234X","authenticated-orcid":false,"given":"Konda Mani","family":"Saravanan","sequence":"additional","affiliation":[{"name":"Centre for Research and Innovation, AMET University (Deemed to Be University), East Coast Road, Kanathur, Chennai 603112, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishnan","family":"Anbarasu","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Thandalam, Chennai 602105, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.33545\/26174693.2023.v7.i1b.175","article-title":"Bioactive compounds from plants and animals: A review","volume":"7","author":"Chaudhary","year":"2023","journal-title":"Int. J. Adv. Biochem. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"110769","DOI":"10.1016\/j.foodhyd.2024.110769","article-title":"Emerging biopolymer nanocarriers for controlled and protective delivery of food bioactive compounds\u2014Current status and future perspective","volume":"160","author":"Venkidasamy","year":"2025","journal-title":"Food Hydrocoll."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Martins, R., Sales, H., Pontes, R., Nunes, J., and Gouveia, I. (2023). Food wastes and microalgae as sources of bioactive compounds and pigments in a modern biorefinery: A review. Antioxidants, 12.","DOI":"10.3390\/antiox12020328"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"112780","DOI":"10.1016\/j.mtcomm.2025.112780","article-title":"Advancing one-pot green synthesis of plant-derived nanomaterials for extraction techniques, characterization, multifunctional biomedical applications, challenges and future perspectives","volume":"46","author":"Palani","year":"2025","journal-title":"Mater. Today Commun."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cuchillo-Hilario, M., Fournier-Ram\u00edrez, M.I., D\u00edaz Mart\u00ednez, M., Monta\u00f1o Benavides, S., Calvo-Carrillo, M.C., Carrillo Dom\u00ednguez, S., Carranco-J\u00e1uregui, M.E., Hern\u00e1ndez-Rodr\u00edguez, E., Mora-P\u00e9rez, P., and Cruz-Mart\u00ednez, Y.R. (2024). Animal food products to support human nutrition and to boost human health: The potential of feedstuffs resources and their metabolites as health-promoters. Metabolites, 14.","DOI":"10.3390\/metabo14090496"},{"key":"ref_6","first-page":"32","article-title":"Hirudotherapy in veterinary practice: A modern twist to ancient science","volume":"1","author":"Haq","year":"2021","journal-title":"Sci. World"},{"key":"ref_7","first-page":"405","article-title":"An overview of leech and its therapeutic applications","volume":"3","author":"Sivachandran","year":"2015","journal-title":"J. Coastal Life Med."},{"key":"ref_8","first-page":"59","article-title":"A systematic overview of the medicinal importance of sanguivorous leeches","volume":"16","author":"Zaidi","year":"2011","journal-title":"Altern. Med. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1645\/17-64","article-title":"Marine leech anticoagulant diversity and evolution","volume":"104","author":"Tessler","year":"2018","journal-title":"J. Parasitol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1515\/jcim-2024-0472","article-title":"Catechins in cancer therapy: Integrating traditional and complementary approaches","volume":"22","author":"Dwivedi","year":"2025","journal-title":"J. Complement. Integr. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s11095-025-03989-y","article-title":"Multi-Target anticoagulant regulation by peptides from medicinal leeches: A unique natural strategy against thrombosis","volume":"43","author":"Shi","year":"2025","journal-title":"Pharm. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1142\/S0192415X24500423","article-title":"Therapeutic potentials of medicinal leech in Chinese medicine","volume":"52","author":"Wu","year":"2024","journal-title":"Am. J. Chin. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lemke, S., and Vilcinskas, A. (2020). European medicinal leeches\u2014New roles in modern medicine. Biomedicines, 8.","DOI":"10.3390\/biomedicines8050099"},{"key":"ref_14","first-page":"261","article-title":"Time to change theory; medical leech from a molecular medicine perspective: Leech salivary proteins playing a potential role in medicine","volume":"11","author":"Shakouri","year":"2021","journal-title":"Adv. Pharm. Bull."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15","DOI":"10.53388\/TMR20200207159","article-title":"Research progress in the use of leeches for medical purposes","volume":"6","author":"Ma","year":"2021","journal-title":"Tradit. Med. Res."},{"key":"ref_16","unstructured":"Ammar, A.E. (2021). The Anticancer Activity of Leech Saliva Extract and the Role of Protease Activated Receptor 1 (PAR-1) in Prostate Cancer. [PhD Thesis, University of British Columbia]."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Younis, M.N. (2023). Role of natural sciences in new drug discovery and integrative medicine. Multidisciplinary Applications of Natural Science for Drug Discovery and Integrative Medicine, IGI Global.","DOI":"10.4018\/978-1-6684-9463-9.ch004"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.wem.2017.08.002","article-title":"A comprehensive review of hirudiniasis: From historic uses of leeches to modern treatments of their bites","volume":"28","author":"Joslin","year":"2017","journal-title":"Wilderness Environ. Med."},{"key":"ref_19","first-page":"227","article-title":"Therapeutic bloodletting in Ireland from the medieval period to modern times","volume":"121","author":"Grace","year":"2021","journal-title":"Proc. R. Ir. Acad."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1111\/j.1445-5994.2009.01965.x","article-title":"Medicinal use of leeches in ancient Greek, Roman and Byzantine texts","volume":"39","author":"Papavramidou","year":"2009","journal-title":"Intern. Med. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.jtcme.2019.08.003","article-title":"Medicinal leech therapy in venous congestion and ulcer forms: Perspectives of Western, Persian, and Indian medicine","volume":"10","author":"Koeppen","year":"2020","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_22","first-page":"724","article-title":"An evidence-based approach of Unani regimen: Irsal e Alaq (medicinal leech therapy)","volume":"139","author":"Asnah","year":"2003","journal-title":"Ann. Intern. Med."},{"key":"ref_23","first-page":"62","article-title":"A review on leech application (Jalaukacharana) in Ayurveda and Sri Lankan traditional medicine","volume":"2","author":"Ediriweera","year":"2014","journal-title":"J. Ayurveda Holist. Med."},{"key":"ref_24","first-page":"222","article-title":"Complications of leech therapy","volume":"10","author":"Pourrahimi","year":"2020","journal-title":"Avicenna J. Phytomed."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"37","DOI":"10.3897\/zookeys.545.6053","article-title":"Annotated checklist of the leech species diversity in the Maloe More Strait of Lake Baikal, Russia","volume":"545","author":"Kaygorodova","year":"2015","journal-title":"ZooKeys"},{"key":"ref_26","first-page":"1375","article-title":"Distribution of aquatic and terrestrial leeches in Assam","volume":"8","author":"Pathak","year":"2020","journal-title":"J. Entomol. Zool. Stud."},{"key":"ref_27","first-page":"493","article-title":"Indigenous curative and prophylactic traditional practices used against haematophagous leeches in Arunachal Pradesh and Sikkim","volume":"14","author":"Bam","year":"2015","journal-title":"Indian J. Tradit. Knowl."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/aqc.1071","article-title":"Distribution and status of medicinal leeches (genus Hirudo) in the Western Palaearctic: Anthropogenic, ecological, or historical effects?","volume":"20","author":"Utevsky","year":"2010","journal-title":"Aquat. Conserv. Mar. Freshw. Ecosyst."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1017\/mdh.2024.5","article-title":"Spanish\u2013French leech trade and its consequences: From the increase in medical demand to resource depletion and technical innovation","volume":"68","author":"Copena","year":"2024","journal-title":"Med. Hist."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3415\/VCOT-13-10-0122","article-title":"The use of medical leeches for venous congestion","volume":"27","author":"Buote","year":"2014","journal-title":"Vet. Comp. Orthop. Traumatol."},{"key":"ref_31","first-page":"49","article-title":"Hirudo-therapy in the past and its future potential","volume":"40","author":"Wilson","year":"2010","journal-title":"J. Indian Med. Herit."},{"key":"ref_32","unstructured":"Duan, Y., Gong, S., and Wang, Y. (2025). The Fusion of Traditional and Modern Medicine Under the Framework of Active Medicine: An Exploration Based on the DIKWP Theory, ResearchGate. manuscript in preparation."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1608\/FRJ-4.1.417","article-title":"Medicinal leeches: Historical use, ecology, genetics and conservation","volume":"4","author":"Elliott","year":"2011","journal-title":"Freshw. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.jaim.2018.11.006","article-title":"Scientometric analysis of medicinal leech therapy","volume":"11","author":"Mumcuoglu","year":"2020","journal-title":"J. Ayurveda Integr. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"100355","DOI":"10.1016\/j.prmcm.2023.100355","article-title":"Development of leech extract as a therapeutic agent: A chronological review","volume":"10","author":"Alaama","year":"2024","journal-title":"Pharmacol. Res. Mod. Chin. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Arias, V., Surugiu, R., Carballeira, R., Popa, O.P., Popa, L.O., and Utevsky, S. (2021). Unravelling the extent of diversity within the Iberian medicinal leeches (Hirudinea: Hirudo) using molecules and morphology. Biology, 10.","DOI":"10.3390\/biology10040315"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3897\/zookeys.1095.74071","article-title":"A new species of medicinal leech in the genus Hirudo Linnaeus, 1758 (Hirudiniformes, Hirudinidae) from Tianjin City, China","volume":"1095","author":"Wang","year":"2022","journal-title":"ZooKeys"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"20630","DOI":"10.1038\/s41598-022-24989-7","article-title":"Cryptic taxonomic diversity and high-latitude melanism in the glossiphoniid leech assemblage from the Eurasian Arctic","volume":"12","author":"Bolotov","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s11230-024-10169-w","article-title":"A high-altitude population of Hyperboreomyzon polaris (Hirudinea: Glossiphoniidae) in Altai Mountains, South Siberia, Russia","volume":"101","author":"Eliseeva","year":"2024","journal-title":"Syst. Parasitol."},{"key":"ref_40","first-page":"235","article-title":"Therapeutic importance of leech and impact of leech in domestic animals","volume":"2","author":"Abdisa","year":"2018","journal-title":"MOJ Drug Des. Dev. Ther."},{"key":"ref_41","first-page":"127","article-title":"Leech therapeutic applications","volume":"75","author":"Abdualkader","year":"2013","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_42","unstructured":"Ali, S.K., and Wunu, A.G. (2025). The most commonly known and the identified potential bioactive molecules of leech saliva, their putative medical use, current status and future potential implications in medicine: A review. Preprints, 2025041943."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1460053","DOI":"10.3389\/fphar.2024.1460053","article-title":"Identification, screening, and comprehensive evaluation of novel thrombin inhibitory peptides from the Hirudo produced using pepsin","volume":"15","author":"Chai","year":"2024","journal-title":"Front. Pharmacol."},{"key":"ref_44","first-page":"703","article-title":"Proteinase inhibitors from the medicinal leech Hirudo medicinalis","volume":"66","author":"Baskova","year":"2001","journal-title":"Biochemistry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1046\/j.1432-1327.1998.2530212.x","article-title":"Bdellastasin, a serine protease inhibitor of the antistasin family from the medical leech (Hirudo medicinalis): Primary structure, expression in yeast, and characterisation of native and recombinant inhibitor","volume":"253","author":"Moser","year":"1998","journal-title":"Eur. J. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s004380050291","article-title":"Genes from the medicinal leech (Hirudo medicinalis) coding for unusual enzymes that specifically cleave endo-\u03b5(\u03b3-Glu)-Lys isopeptide bonds and help to dissolve bloof clots","volume":"253","author":"Zavalova","year":"1996","journal-title":"Mol. Gen. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.imr.2017.08.001","article-title":"Medicinal leech therapy\u2014An overall perspective","volume":"6","author":"Sig","year":"2017","journal-title":"Integr. Med. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s43556-025-00299-y","article-title":"Hyaluronidase: Structure, mechanism of action, diseases and therapeutic targets","volume":"6","author":"Lu","year":"2025","journal-title":"Mol. Biomed."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Ye, T., Zhao, F., Xiao, M., Yin, J., Ai, R., Tang, L., Liu, Z., Huang, Z., and Lin, G. (2025). Comparative study of Lefaxin family in two Asian leeches: Hirudinaria manillensis and Whitmania pigra. Biology, 14.","DOI":"10.3390\/biology14080918"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Shen, H., Cai, M., Li, J., and Luo, Y. (2022). High-throughput sequencing reveals the effect of feeding on overwintering Hirudo nipponia. Diversity, 14.","DOI":"10.3390\/d14090768"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s12864-022-08290-5","article-title":"The genome of medicinal leech (Whitmania pigra) and comparative genomic study for exploration of bioactive ingredients","volume":"23","author":"Tong","year":"2022","journal-title":"BMC Genomics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.jprot.2019.03.009","article-title":"In-depth profiles of bioactive large molecules in saliva secretions of leeches determined by combining salivary gland proteome and transcriptome data","volume":"200","author":"Liu","year":"2019","journal-title":"J. Proteom."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Bilden, A., Sabanc\u0131lar, \u0130., Yal\u00e7\u0131n Azarkan, S., Karada\u011fl\u0131, K., Kaya, S., Kahraman, M., and \u00c7i\u00e7ek, M. (2025). Investigating the therapeutic potential of crude leech saliva based on its anticancer, antioxidant, and anti-inflammatory effects. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47050328"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"160","DOI":"10.22271\/tpi.2021.v10.i2Sc.5720","article-title":"Effect of environmental and physiological variables on saliva production in Hirudinaria granulosa (Indian cattle leech)","volume":"10","author":"Haq","year":"2021","journal-title":"J. Pharm. Innov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"115","DOI":"10.34172\/bi.2021.39","article-title":"Nanoencapsulation of Hirudo medicinalis proteins in liposomes as a nanocarrier for inhibiting angiogenesis through targeting VEGFA in the breast cancer cell line (MCF-7)","volume":"12","author":"Shakouri","year":"2022","journal-title":"Bioimpacts"},{"key":"ref_56","first-page":"7","article-title":"Biochemical analysis of the saliva extracted from two different leech species","volume":"66","author":"Habeeb","year":"2025","journal-title":"Iraqi J. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"615915","DOI":"10.3389\/fvets.2020.615915","article-title":"Prostaglandin E1 is an efficient molecular tool for forest leech blood sucking","volume":"7","author":"Zheng","year":"2021","journal-title":"Front. Vet. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"105125","DOI":"10.1016\/j.dci.2023.105125","article-title":"Transcriptomic profiling and the first spatial expression analysis of candidate genes in the salivary gland of the East Asian medicinal leech, Hirudo nipponia","volume":"154","author":"Kim","year":"2024","journal-title":"Dev. Comp. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"409","DOI":"10.26842\/binhm.7.2023.17.3.0409","article-title":"Comparative ultrastructural study of the salivary glands of two hematophagous leeches (Annelida, Clitellata, Arhynchobdellida) in Iraq","volume":"17","author":"Bilal","year":"2023","journal-title":"Bull. Iraq Nat. Hist. Mus."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"122153","DOI":"10.1016\/j.jchromb.2020.122153","article-title":"A novel thrombin inhibitory peptide discovered from leech using affinity chromatography combined with ultra-high performance liquid chromatography\u2013high resolution mass spectroscopy","volume":"1151","author":"Huang","year":"2020","journal-title":"J. Chromatogr. B"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"79","DOI":"10.31436\/iiumej.v12i4.156","article-title":"Some biological activities of Malaysian leech saliva extract","volume":"12","author":"Abdualkader","year":"2011","journal-title":"IIUM Eng. J."},{"key":"ref_62","first-page":"57","article-title":"Evaluating the impact of leech saliva on Streptococcus mutans and Streptococcus sobrinus","volume":"14","author":"Ghafoorzadeh","year":"2025","journal-title":"Biol. J. Microbiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"9","DOI":"10.54319\/jjbs\/180102","article-title":"Effects of lyophilized leech saliva extract on cell migration and apoptosis in MDA-MB-231 breast cancer and HUVEC cell lines","volume":"18","author":"Tirik","year":"2025","journal-title":"Jordan J. Biol. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1111\/j.1600-0722.2011.00886.x","article-title":"Effect of rinsing with ethanol-containing mouthrinses on the production of salivary acetaldehyde","volume":"119","author":"Moazzez","year":"2011","journal-title":"Eur. J. Oral Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.fsi.2012.08.020","article-title":"Humoral response of captive zebra sharks Stegostoma fasciatum to salivary gland proteins of the leech Branchellion torpedinis","volume":"33","author":"Marancik","year":"2012","journal-title":"Fish Shellfish Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"012061","DOI":"10.1088\/1755-1315\/251\/1\/012061","article-title":"A study on antioxidative and antimicrobial activities of saliva extract of Indonesian local leeches","volume":"251","author":"Malik","year":"2019","journal-title":"IOP Conf. Ser. Earth Environ. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Wang, W., Liu, Y., Lou, W., Chen, L., Xie, T., Wang, Z., Ma, Y., and Gao, H. (2025). A comprehensive quality evaluation system for medicinal leeches by integrating macromolecular protein analysis and small-molecule marker detection as well as quantitative bioassays. Pharmaceuticals, 18.","DOI":"10.3390\/ph18060887"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1177\/2472555218822098","article-title":"Drug discovery on natural products: From ion channels to nAChRs, from nature to libraries, from analytics to assays","volume":"24","author":"Otvos","year":"2019","journal-title":"SLAS Discov."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"giad023","DOI":"10.1093\/gigascience\/giad023","article-title":"Molecular mechanisms underlying hematophagia revealed by comparative analyses of leech genomes","volume":"12","author":"Zheng","year":"2023","journal-title":"GigaScience"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"178","DOI":"10.46239\/ejbcs.1569164","article-title":"An overview of leech saliva and cosmetic potential","volume":"7","author":"Kaymak","year":"2024","journal-title":"Eurasian J. Biol. Chem. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.3389\/fphar.2020.01132","article-title":"From animal poisons and venoms to medicines: Achievements, challenges and perspectives in drug discovery","volume":"11","author":"Bordon","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Liu, Z., Zhao, F., Huang, Z., He, B., Liu, K., Shi, F., Zhao, Z., and Lin, G. (2024). A chromosome-level genome assembly of the non-hematophagous leech Whitmania pigra (Whitman 1884): Identification and expression analysis of antithrombotic genes. Genes, 15.","DOI":"10.3390\/genes15020164"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/gtc.12774","article-title":"Histamine and histidine decarboxylase: Immunomodulatory functions and regulatory mechanisms","volume":"25","author":"Moriguchi","year":"2020","journal-title":"Genes Cells"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"660757","DOI":"10.3389\/fphar.2021.660757","article-title":"Pharmacological activities and mechanisms of hirudin and its derivatives\u2014A review","volume":"12","author":"Junren","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"evaa242","DOI":"10.1093\/gbe\/evaa242","article-title":"The origin and evolution of antistasin-like proteins in leeches (Hirudinida, Clitellata)","volume":"13","author":"Iwama","year":"2021","journal-title":"Genome Biol. Evol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"6641","DOI":"10.1038\/s41598-023-32459-x","article-title":"Structural insights into thrombolytic activity of destabilase from the medicinal leech","volume":"13","author":"Marin","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1160\/TH07-11-0693","article-title":"The direct thrombin inhibitor hirudin","volume":"99","author":"Greinacher","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"94","DOI":"10.30704\/http-www-jivs-net.1663195","article-title":"Relationship of leeches and blood parasites","volume":"9","author":"Jilta","year":"2025","journal-title":"J. Istanbul Vet. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1182\/blood.V85.3.712.bloodjournal853712","article-title":"Calin from Hirudo medicinalis, an inhibitor of platelet adhesion","volume":"85","author":"Deckmyn","year":"1995","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1111\/j.1742-4658.2007.05689.x","article-title":"The leech product saratin is a potent inhibitor of platelet integrin \u03b12\u03b21 and von Willebrand factor binding to collagen","volume":"274","author":"White","year":"2007","journal-title":"FEBS J."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"75","DOI":"10.47748\/tjvr.1570036","article-title":"Integrative treatment method in veterinary medicine: Hirudotherapy","volume":"9","author":"Ayhan","year":"2025","journal-title":"Turk. J. Vet. Res."},{"key":"ref_82","first-page":"0001","article-title":"The medicinal leech possesses all mechanisms of influence for preventing pathogenesis of SARS-CoV-2","volume":"5","author":"Bowen","year":"2021","journal-title":"J. Pulm. Med."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Elango, K., Javaid, A., Khetarpal, B.K., Ramalingam, S., Kolandaivel, K.P., Gunasekaran, K., and Ahsan, C. (2021). The effects of warfarin and direct oral anticoagulants on systemic vascular calcification: A review. Cells, 10.","DOI":"10.3390\/cells10040773"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"30973","DOI":"10.1074\/jbc.M312156200","article-title":"Molecular characterization of two novel antibacterial peptides inducible upon bacterial challenge in an annelid, the leech Theromyzon tessulatum","volume":"279","author":"Tasiemski","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"114474","DOI":"10.1016\/j.ejpb.2024.114474","article-title":"Hyaluronidase overcomes the extracellular matrix barrier to enhance local drug delivery","volume":"203","author":"Zhao","year":"2024","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"17","DOI":"10.51847\/GRccY6BTJ6","article-title":"Anticoagulants: An overview of natural and synthetic therapeutic anticoagulants","volume":"12","author":"Chanda","year":"2021","journal-title":"J. Biochem. Technol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"55","DOI":"10.22270\/ajprd.v10i4.1157","article-title":"Phytochemical of some plants with anticoagulant","volume":"10","author":"Sitiawani","year":"2022","journal-title":"Asian J. Pharm. Res. Dev."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"852","DOI":"10.3389\/fphar.2020.00852","article-title":"A review on the potential use of medicinal plants from Asteraceae and Lamiaceae plant family in cardiovascular diseases","volume":"11","author":"Michel","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Zhang, F., and Linhardt, R.J. (2019). Heparin contamination and issues related to raw materials and controls. The Science and Regulations of Naturally Derived Complex Drugs, Springer International Publishing.","DOI":"10.1007\/978-3-030-11751-1_11"},{"key":"ref_90","first-page":"59","article-title":"Isolation, synthesis and medicinal applications of heparin","volume":"8","author":"Jena","year":"2021","journal-title":"Chem. Biol. Lett."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"677","DOI":"10.2174\/0929866524666180614100101","article-title":"Potential applications of venom peptides as anti-thrombotic agents for management of arterial and deep-vein thrombosis","volume":"25","author":"Khan","year":"2018","journal-title":"Protein Pept. Lett."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/zoolinnean\/zlab126","article-title":"Leech anticoagulants are ancestral and likely to be multifunctional","volume":"196","author":"Iwama","year":"2022","journal-title":"Zool. J. Linn. Soc."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"114990","DOI":"10.1016\/j.jep.2022.114990","article-title":"Purification and characterization of a novel thermostable anticoagulant protein from medicinal leech Whitmania pigra Whitman","volume":"288","author":"Zhang","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1017\/S0031182019000593","article-title":"The salivary transcriptome of Limnobdella mexicana (Annelida: Clitellata: Praobdellidae) and orthology determination of major leech anticoagulants","volume":"146","author":"Iwama","year":"2019","journal-title":"Parasitology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0167-4838(88)90156-2","article-title":"Design, synthesis and antithrombin activity for conformationally restricted analogs of peptide anticoagulants based on the C-terminal region of the leech peptide, hirudin","volume":"957","author":"Krstenansky","year":"1988","journal-title":"Biochim. Biophys. Acta Protein Struct. Mol. Enzymol."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Placha, D., and Jampilek, J. (2021). Chronic inflammatory diseases, anti-inflammatory agents and their delivery nanosystems. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13010064"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3622","DOI":"10.2174\/0929867327999200917150939","article-title":"Natural COX-2 inhibitors as promising anti-inflammatory agents: An update","volume":"28","author":"Cui","year":"2021","journal-title":"Curr. Med. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Tawalbeh, D., Al-U\u2019datt, M.H., Wan Ahmad, W.A.N., Ahmad, F., and Sarbon, N.M. (2023). Recent advances in in vitro and in vivo studies of antioxidant, ACE-inhibitory and anti-inflammatory peptides from legume protein hydrolysates. Molecules, 28.","DOI":"10.3390\/molecules28062423"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"9","DOI":"10.5530\/gjpb.2023.3.8","article-title":"Potentials of plant derived products for the treatment of skin disorders","volume":"2","author":"Maurya","year":"2023","journal-title":"Ger. J. Pharm. Biomater."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1080\/23308249.2024.2388563","article-title":"Omega-3 futures in aquaculture: Exploring the supply and demands for long-chain omega-3 essential fatty acids by aquaculture species","volume":"33","author":"Glencross","year":"2025","journal-title":"Rev. Fish. Sci. Aquac."},{"key":"ref_101","first-page":"146","article-title":"Leech therapy and its efficacy in management of non-healing ulcer\u2014A review","volume":"13","author":"Zakariyya","year":"2024","journal-title":"Int. J. Sci. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"314","DOI":"10.20473\/j.djmkg.v58.i3.p314-324","article-title":"Understanding the role of salivary proteomic markers in detecting chronic periodontitis in adults with obesity\u2014A systematic review","volume":"58","author":"Ramya","year":"2025","journal-title":"Majalah Kedokt. Gigi"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s12026-024-09575-5","article-title":"Immunomodulatory effects of medicinal leech saliva extract on in vitro activated macrophages","volume":"73","author":"Ayhan","year":"2025","journal-title":"Immunol. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"6043698","DOI":"10.1155\/2022\/6043698","article-title":"Hirudin regulates vascular function in chronic renal failure through modulating macrophage polarization","volume":"2022","author":"Chen","year":"2022","journal-title":"Biomed. Res. Int."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1002\/jsde.12293","article-title":"Surfactants as antimicrobials: A brief overview of microbial interfacial chemistry and surfactant antimicrobial activity","volume":"22","author":"Falk","year":"2019","journal-title":"J. Surfactants Deterg."},{"key":"ref_106","first-page":"179","article-title":"Antioxidants for the prevention and treatment of non-communicable diseases","volume":"7","author":"Ayoka","year":"2022","journal-title":"J. Explor. Res. Pharmacol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Elshafie, H.S., Camele, I., and Mohamed, A.A. (2023). A comprehensive review on the biological, agricultural and pharmaceutical properties of secondary metabolites based-plant origin. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043266"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3778","DOI":"10.1111\/1750-3841.15854","article-title":"Banana plant as a source of valuable antimicrobial compounds and its current applications in the food sector","volume":"86","author":"Mostafa","year":"2021","journal-title":"J. Food Sci."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Shahidi, F., and Saeid, A. (2025). Bioactivity of marine-derived peptides and proteins: A review. Mar. Drugs, 23.","DOI":"10.3390\/md23040157"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"12947","DOI":"10.1021\/acs.jafc.1c05883","article-title":"Omics as a window to unravel the dynamic changes of egg components during chicken embryonic development","volume":"69","author":"Meng","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1134\/S0012496623700436","article-title":"Role of antimicrobial peptides in immunity of parasitic leeches","volume":"511","author":"Kaygorodova","year":"2023","journal-title":"Dokl. Biol. Sci."},{"key":"ref_112","first-page":"413","article-title":"Leech therapy (hirudotherapy)","volume":"7","author":"Kumar","year":"2018","journal-title":"World J. Pharm. Res."},{"key":"ref_113","unstructured":"Babayi, H., Owolabi, B.I., Adelere, I.A., Mustapha, A., and Amadi, E.D. (2022). Antibacterial Activities of Leech Salivary Extract-Mediated Silver Nanoparticles Against Some Pathogenic Bacteria, Unpublished work."},{"key":"ref_114","first-page":"688","article-title":"Evaluation of biochemical and antioxidant properties of crude extracts from the Indian cattle leech Poecilobdella granulosa","volume":"51","author":"Padmanaban","year":"2022","journal-title":"Indian J. Geo-Mar. Sci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"111","DOI":"10.2174\/1574888X14666191104151928","article-title":"Recent approaches for angiogenesis in search of successful tissue engineering and regeneration","volume":"15","author":"Reddy","year":"2020","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"370","DOI":"10.34172\/apb.2020.045","article-title":"Medicinal plants extracts with antiangiogenic activity: Where is the link?","volume":"10","author":"Hoseinkhani","year":"2020","journal-title":"Adv. Pharm. Bull."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"639299","DOI":"10.3389\/fcell.2021.639299","article-title":"Rebuilding the vascular network: In vivo and in vitro approaches","volume":"9","author":"Meng","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1111\/bph.16232","article-title":"Natural products targeting tumour angiogenesis","volume":"182","author":"Lu","year":"2025","journal-title":"Br. J. Pharmacol."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"M\u00e9resse, S., Fodil, M., Fleury, F., and Ch\u00e9nais, B. (2020). Fucoxanthin, a marine-derived carotenoid from brown seaweeds and microalgae: A promising bioactive compound for cancer therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239273"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Cao, Y., Sun, J., Guo, L., Wang, M., Su, L., Zhang, T., Wang, S., Chai, L., Yuan, Q., and Hu, L. (2025). Leech extract enhances the pro-angiogenic effects of endothelial cell-derived exosomes in a mouse model of ischemic stroke. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47070499"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.1039\/D4BM00394B","article-title":"A comprehensive exploration of hydrogel applications in multi-stage skin wound healing","volume":"12","author":"Lu","year":"2024","journal-title":"Biomater. Sci."},{"key":"ref_122","first-page":"tkaf020","article-title":"Targeting oxidative damage in diabetic foot ulcers: Integrative strategies involving antioxidant drugs and nanotechnologies","volume":"13","author":"Wang","year":"2025","journal-title":"BurnsTrauma"},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Lu, T., Zhou, X., Jiang, S.Y., Zhao, Q.A., Liu, Z.Y., and Ding, D.F. (2025). Natural bioactive compound-integrated nanomaterials for diabetic wound healing: Synergistic effects, multifunctional designs, and challenges. Molecules, 30.","DOI":"10.3390\/molecules30122562"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Vitale, S., Colanero, S., Placidi, M., Di Emidio, G., Tatone, C., Amicarelli, F., and D\u2019Alessandro, A.M. (2022). Phytochemistry and biological activity of medicinal plants in wound healing: An overview of current research. Molecules, 27.","DOI":"10.3390\/molecules27113566"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Zulkefli, N., Che Zahari, C.N.M., Sayuti, N.H., Kamarudin, A.A., Saad, N., Hamezah, H.S., Bunawan, H., Baharum, S.N., Mediani, A., and Ahmed, Q.U. (2023). Flavonoids as potential wound-healing molecules: Emphasis on pathways perspective. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054607"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"21","DOI":"10.22271\/phyto.2023.v12.i1a.14543","article-title":"Medicinal leech therapy and related case study: Overview in current medical field","volume":"12","author":"Dudhrejiya","year":"2023","journal-title":"J. Pharmacogn. Phytochem."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"151","DOI":"10.5505\/amj.2023.20280","article-title":"Literature review on the effectiveness of medicinal leech therapy in wound healing","volume":"23","author":"Erol","year":"2023","journal-title":"Ankara Med. J."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"286","DOI":"10.4103\/jras.jras_34_24","article-title":"Effect of leech therapy on biomarkers of angiogenesis in chronic non-healing ulcers: A pilot randomized study","volume":"8","author":"Aadithyaraj","year":"2024","journal-title":"J. Res. Ayurvedic Sci."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"e113910","DOI":"10.5812\/jjnpp.113910","article-title":"Semi-solid product of medicinal leech enhances wound healing in rats","volume":"16","author":"Amani","year":"2021","journal-title":"Jundishapur J. Nat. Pharm. Prod."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.rvsc.2022.10.015","article-title":"Study on the effect of medicinal leech therapy (Hirudo medicinalis) on full-thickness excisional wound healing in the animal model","volume":"153","author":"Zakian","year":"2022","journal-title":"Res. Vet. Sci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"64","DOI":"10.14730\/aaps.2022.00710","article-title":"Tissue engineering in plastic and reconstructive surgery: Fostering advances in the 21st century via an understanding of the present state of the art and future possibilities","volume":"29","author":"Anand","year":"2023","journal-title":"Arch. Aesthetic Plast. Surg."},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Grosu-Bularda, F., Hodea, V., Cretu, A., Lita, F.F., Bordeanu-Diaconescu, E.M., Vancea, C.V., Lascar, I., and Popescu, S.A. (2024). Reconstructive paradigms: A problem-solving approach in complex tissue defects. J. Clin. Med., 13.","DOI":"10.3390\/jcm13061728"},{"key":"ref_133","first-page":"125","article-title":"The use of medicinal leeches in plastic surgery","volume":"33","author":"Mumcuoglu","year":"2025","journal-title":"Turk. J. Plast. Surg."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Thamm, O.C., Eschborn, J., Sch\u00e4fer, R.C., and Schmidt, J. (2024). Advances in modern microsurgery. J. Clin. Med., 13.","DOI":"10.3390\/jcm13175284"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1089\/ten.teb.2023.0038","article-title":"Exploring the use of animal models in craniofacial regenerative medicine: A narrative review","volume":"30","author":"Mosaddad","year":"2024","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"4090","DOI":"10.1097\/MS9.0000000000003400","article-title":"Animal models for surgeries and implants: A vital tool in medical research and development","volume":"87","author":"Choudhary","year":"2025","journal-title":"Ann. Med. Surg."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"4839","DOI":"10.1039\/C9GC02391G","article-title":"Plants and plant-based polymers as scaffolds for tissue engineering","volume":"21","author":"Iravani","year":"2019","journal-title":"Green Chem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"2202827","DOI":"10.1002\/adhm.202202827","article-title":"Plant-derived biomaterials and their potential in cardiac tissue repair","volume":"12","author":"Dai","year":"2023","journal-title":"Adv. Healthc. Mater."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"55","DOI":"10.4103\/tjosr.tjosr_16_19","article-title":"Leech as a lifeboat: Reminiscent role in plastic and reconstructive surgery","volume":"57","author":"Newadkar","year":"2019","journal-title":"TNOA J. Ophthalmic Sci. Res."},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Rajaram, R., Cevik, J., Bhindi, N., Seth, I., and Rozen, W.M. (2024). The use of medicinal leeching in breast surgery: A systematic review. J. Clin. Med., 13.","DOI":"10.3390\/jcm13051243"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.joms.2011.02.083","article-title":"Leech therapy in reconstructive maxillofacial surgery","volume":"70","author":"Michalsen","year":"2012","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Sankar, V., and Villa, A. (2021). Hematologic diseases. Burket\u2019s Oral Medicine, Wiley.","DOI":"10.1002\/9781119597797.ch17"},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Georgatzakou, H.T., Fortis, S.P., Papageorgiou, E.G., Antonelou, M.H., and Kriebardis, A.G. (2022). Blood cell-derived microvesicles in hematological diseases and beyond. Biomolecules, 12.","DOI":"10.3390\/biom12060803"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Lockhart, P.B., and Sun, Y.P. (2021). Diseases of the cardiovascular system. Burket\u2019s Oral Medicine, Wiley.","DOI":"10.1002\/9781119597797.ch14"},{"key":"ref_145","first-page":"27","article-title":"Most common cardiovascular diseases of the elderly: A review article","volume":"4","author":"Szabo","year":"2022","journal-title":"Dev. Health Sci."},{"key":"ref_146","first-page":"S1","article-title":"Pan Arab Conference for Bleeding Disorders","volume":"10","author":"Elalfy","year":"2019","journal-title":"J. Appl. Hematol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"157","DOI":"10.2174\/011871529X262371231009132426","article-title":"Current perspective and mechanistic insights on bioactive plant secondary metabolites for the prevention and treatment of cardiovascular diseases","volume":"23","author":"Grewal","year":"2023","journal-title":"Cardiovasc. Haematol. Disord. Drug Targets"},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Leuci, R., Brunetti, L., Poliseno, V., Laghezza, A., Loiodice, F., Tortorella, P., and Piemontese, L. (2020). Natural compounds for the prevention and treatment of cardiovascular and neurodegenerative diseases. Foods, 10.","DOI":"10.3390\/foods10010029"},{"key":"ref_149","first-page":"146","article-title":"A review on Digitalis in congestive heart failure","volume":"4","author":"Tandale","year":"2025","journal-title":"Int. J. Res. Pharm. Allied Sci."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"422","DOI":"10.3389\/fphar.2020.00422","article-title":"Herbal medicine for cardiovascular diseases: Efficacy, mechanisms, and safety","volume":"11","author":"Shaito","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Jafarnezhad, F., Nazarzadeh, A., Bazavar, H., Keramat, S., Ryszkiel, I., and Stanek, A. (2025). Vegan and plant-based diets in the management of metabolic syndrome: A narrative review from anti-inflammatory and antithrombotic perspectives. Nutrients, 17.","DOI":"10.3390\/nu17162656"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1055\/s-0038-1661384","article-title":"Toxins are an excellent source of therapeutic agents against cardiovascular diseases","volume":"44","author":"Koh","year":"2018","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_153","first-page":"252","article-title":"Leech therapy protects free flaps against venous congestion, thrombus formation, and ischemia\/reperfusion injury: Benefits, complications, and contradictions","volume":"10","author":"Mousavian","year":"2022","journal-title":"Arch. Bone Jt. Surg."},{"key":"ref_154","first-page":"107","article-title":"An overview on medicinal leech therapy","volume":"11","author":"Chhayani","year":"2023","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"e27461","DOI":"10.1016\/j.heliyon.2024.e27461","article-title":"Efficacy and potential mechanism of atherosclerosis prevention by the active components of leech based on network pharmacology combined with animal experiments","volume":"10","author":"Lv","year":"2024","journal-title":"Heliyon"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"111813","DOI":"10.1016\/j.jep.2019.03.040","article-title":"Leeches attenuate blood hyperviscosity and related metabolic disorders in rats differently than aspirin","volume":"238","author":"Wang","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_157","doi-asserted-by":"crossref","unstructured":"Reis, I.L., Lopes, B., Sousa, P., Sousa, A.C., Caseiro, A.R., Mendon\u00e7a, C.M., Santos, J.M., Atayde, L.M., Alvites, R.D., and Maur\u00edcio, A.C. (2024). Equine musculoskeletal pathologies: Clinical approaches and therapeutical perspectives\u2014A review. Vet. Sci., 11.","DOI":"10.20944\/preprints202403.0582.v1"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"104","DOI":"10.26502\/ijpaes.4490170","article-title":"Therapeutic efficacy of medicinal plants with allopathic medicine in musculoskeletal diseases","volume":"14","author":"Rajalekshmi","year":"2024","journal-title":"Int. J. Plant Anim. Environ. Sci."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.pop.2018.02.006","article-title":"Common soft tissue musculoskeletal pain disorders","volume":"45","author":"Hubbard","year":"2018","journal-title":"Prim. Care Clin. Office Pract."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1080\/10942912.2022.2157425","article-title":"Antioxidant, phytochemical, and therapeutic properties of medicinal plants: A review","volume":"26","author":"Nwozo","year":"2023","journal-title":"Int. J. Food Prop."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"3270","DOI":"10.22270\/jmpas.V10I4.1379","article-title":"Anti-inflammatory perspectives of diverse natural resources","volume":"10","author":"Gakhar","year":"2021","journal-title":"J. Med. Pharm. Allied Sci."},{"key":"ref_162","first-page":"1","article-title":"Immunomodulation by hydrolysates and peptides derived from milk proteins","volume":"71","year":"2018","journal-title":"Int. J. Dairy Technol."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Prates, J.A. (2025). Nutritional value and health implications of meat from monogastric animals exposed to heat stress. Nutrients, 17.","DOI":"10.3390\/nu17081390"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.joim.2020.07.003","article-title":"Hirudotherapy attenuates arthritic pain in patients with various chronic pain syndromes: A retrospective analysis","volume":"18","author":"Loeser","year":"2020","journal-title":"J. Integr. Med."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"151","DOI":"10.15406\/mojor.2023.15.00637","article-title":"Hirudotherapy in pain management","volume":"15","author":"Mordeniz","year":"2023","journal-title":"MOJ Orthop. Rheumatol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"118","DOI":"10.53388\/TMR20190225105","article-title":"Leech therapy indications: A scoping review","volume":"4","author":"Ghods","year":"2019","journal-title":"Tradit. Med. Res."},{"key":"ref_167","first-page":"318","article-title":"The observational study of reduction in inflammatory markers and simultaneous reduction in joint inflammation in patients of rheumatoid arthritis treated by leech therapy","volume":"15","author":"Asutkar","year":"2021","journal-title":"Indian J. Forensic Med. Toxicol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00441-019-03010-0","article-title":"The medicinal leech as a valuable model for better understanding the role of a TLR4-like receptor in the inflammatory process","volume":"377","author":"Girardello","year":"2019","journal-title":"Cell Tissue Res."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"54","DOI":"10.35882\/jeeemi.v6i1.351","article-title":"Advancements within molecular engineering for regenerative medicine and biomedical applications: An investigation analysis towards a computing retrospective","volume":"6","author":"Akhtar","year":"2024","journal-title":"J. Electron. Electromed. Eng. Med. Inform."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1089\/ten.teb.2018.0027","article-title":"cTissue engineering and regenerative medicine 2017: A year in review","volume":"24","author":"Park","year":"2018","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.addr.2018.05.001","article-title":"Electrospinning: An enabling nanotechnology platform for drug delivery and regenerative medicine","volume":"132","author":"Chen","year":"2018","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1177\/0885328220979273","article-title":"Plant based cross-linkers for tissue engineering applications","volume":"36","author":"Indurkar","year":"2021","journal-title":"J. Biomater. Appl."},{"key":"ref_173","doi-asserted-by":"crossref","unstructured":"Marrazzo, P., and O\u2019Leary, C. (2020). Repositioning natural antioxidants for therapeutic applications in tissue engineering. Bioengineering, 7.","DOI":"10.3390\/bioengineering7030104"},{"key":"ref_174","doi-asserted-by":"crossref","unstructured":"Klimek, K., and Ginalska, G. (2020). Proteins and peptides as important modifiers of the polymer scaffolds for tissue engineering applications\u2014A review. Polymers, 12.","DOI":"10.3390\/polym12040844"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"1417041","DOI":"10.3389\/fmed.2024.1417041","article-title":"Applications of leech therapy in medicine: A systematic review","volume":"11","author":"Hosseini","year":"2024","journal-title":"Front. Med."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"186","DOI":"10.3389\/fphar.2018.00186","article-title":"Novel sodium channel inhibitor from leeches","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Li, X., Zhang, X., Zhao, W., Tian, P., and Tulugan, K. (2024). Preparation of hirudin-loaded chitosan\/polycaprolactone bowl-shaped particles and an application for a drug delivery system. Appl. Sci., 14.","DOI":"10.3390\/app14051939"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1089\/ars.2013.5559","article-title":"Techniques for the analysis of cysteine sulfhydryls and oxidative protein folding","volume":"21","author":"Borges","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/S0140-6736(17)31366-1","article-title":"Lancet Commission: Stem cells and regenerative medicine","volume":"391","author":"Cossu","year":"2018","journal-title":"Lancet"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.2174\/0113892010275850240102105033","article-title":"Recent advances in pharmaceutical design: Unleashing the potential of novel therapeutics","volume":"25","author":"Prajapati","year":"2024","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Matthews, H., Hanison, J., and Nirmalan, N. (2016). \u201cOmics\u201d-informed drug and biomarker discovery: Opportunities, challenges and future perspectives. Proteomes, 4.","DOI":"10.3390\/proteomes4030028"},{"key":"ref_182","first-page":"2135","article-title":"A case of medical leech therapy for venous congestion following forearm flap reconstruction","volume":"45","author":"Karino","year":"2018","journal-title":"Gan To Kagaku Ryoho. Cancer Chemother."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"867655","DOI":"10.3389\/fonc.2022.867655","article-title":"Nano-drug delivery systems entrapping natural bioactive compounds for cancer: Recent progress and future challenges","volume":"12","author":"Chavda","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"01025","DOI":"10.1051\/e3sconf\/202345301025","article-title":"Harmonizing innovation: The path to sustainable design and production","volume":"453","author":"Singh","year":"2023","journal-title":"E3S Web Conf."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2112\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T05:27:05Z","timestamp":1772515625000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/5\/2112"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,24]]},"references-count":184,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27052112"],"URL":"https:\/\/doi.org\/10.3390\/ijms27052112","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,24]]}}}