Alkaloids – Bridging Natural Products in Antidiabetic Therapy
Abstract
This review thoroughly assesses the antidiabetic properties of natural alkaloids, addressing their modes of action and treatment prospects for diabetes mellitus. Following PRISMA 2020 guidelines, literature from databases like PubMed/MEDLINE, Scopus, and Science Direct, published from 2000 to May 2025, was analyzed. The review highlights several promising alkaloids, including berberine, vindoline, harmine, trigonelline, oxymatrine, and solanine. These compounds have various anti-diabetic actions via improving insulin sensitivity, increasing insulin secretion, blocking digestive enzymes, modifying gut microbiota, and reducing oxidative stress and inflammation. For instance, berberine demonstrates efficacy comparable to standard hypoglycemics, partly through gut microbiota modulation. Harmine uniquely promotes pancreatic β-cell regeneration. Despite their therapeutic promise, significant challenges persist, including issues of bioavailability, varying toxicity profiles, and a notable scarcity of robust clinical trials. Standardization of plant sources and extraction methods also remains a critical challenge. Future research must prioritize rigorous clinical validation, advanced formulation development to enhance efficacy and safety, and strengthened regulatory frameworks. Alkaloids represent a promising frontier for developing novel, effective, and safe antidiabetic therapies.
Keywords:
Diabetes Mellitus, Medicinal Plants, Alkaloids, Antidiabetic, Insulin Sensitivity, Oxidative StressDOI
https://doi.org/10.25004/IJPSDR.2025.170507References
Low CY, Gan WL, Lai SJ, Tam RS, Tan JF, Dietl S, Chuah LH, Voelcker N, Bakhtiar A. Critical updates on oral insulin drug delivery systems for type 2 diabetes mellitus. Journal of Nanobiotechnology. 2025 Jan 15;23(1):16. https://doi.org/10.1186/s12951-024-03062-7
Idris IB, Dahlan SA, Rahman RA, Nawi AM. Beyond individual-level factors that influence family planning uptake among women with diabetes mellitus: a systematic literature review. BMC Public Health. 2025 Jan 24;25(1):317. https://doi.org/10.1186/s12889-024-20784-3
Ong KL, Stafford LK, McLaughlin SA, Boyko EJ, Vollset SE, Smith AE, Dalton BE, Duprey J, Cruz JA, Hagins H, Lindstedt PA. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet. 2023 Jul 15;402(10397):203-34. https://doi.org/10.1016/S0140-6736(23)01301-6
Malongane F, Phoswa WN, Berejena T. The effect of indigenous African diet on inflammatory markers linked to type 2 diabetic mellitus. Human Nutrition & Metabolism. 2024 Mar 1;35:200236. https://doi.org/10.1016/j.hnm.2023.200236
ElSayed NA, Aleppo G, Bannuru RR, Bruemmer D, Collins BS, Ekhlaspour L, Gaglia JL, Hilliard ME, Johnson EL, Khunti K, Lingvay I. 2. Diagnosis and classification of diabetes: Standards of care in diabetes—2024. Diabetes Care. 2024 Jan 2;47. https://doi.org/10.2337/dc25-S002
Behl T, Gupta A, Albratty M, Najmi A, Meraya AM, Alhazmi HA, Anwer MK, Bhatia S, Bungau SG. Alkaloidal phytoconstituents for diabetes management: exploring the unrevealed potential. Molecules. 2022 Sep 9;27(18):5851. https://doi.org/10.3390/molecules27185851
Umashankar DD. Plant secondary metabolites as potential usage in regenerative medicine. J. Phytopharmacol. 2020;9(4):270-3P. https://doi.org/10.31254/phyto.2020.9410
Yedjou CG, Grigsby J, Mbemi A, Nelson D, Mildort B, Latinwo L, Tchounwou PB. The management of diabetes mellitus using medicinal plants and vitamins. International journal of molecular sciences. 2023 May 22;24(10):9085. https://doi.org/10.3390/ijms24109085
Zhu J, Song L, Shen S, Fu W, Zhu Y, Liu L. Bioactive alkaloids as secondary metabolites from plant endophytic Aspergillus genus. Molecules. 2023 Nov 27;28(23):7789. https://doi.org/10.3390/molecules28237789
Bhambhani S, Kondhare KR, Giri AP. Diversity in chemical structures and biological properties of plant alkaloids. Molecules. 2021 Jun 3;26(11):3374. https://doi.org/10.3390/molecules26113374
Dey P, Kundu A, Kumar A, Gupta M, Lee BM, Bhakta T, Dash S, Kim HS. Analysis of alkaloids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids). InRecent advances in natural products analysis 2020 Jan 1 (pp. 505-567). Elsevier. https://doi.org/10.1016/B978-0-12-816455-6.00015-9
Shehadeh MB, Suaifan GA, Abu-Odeh AM. Plants secondary metabolites as blood glucose-lowering molecules. Molecules. 2021 Jul 17;26(14):4333. https://doi.org/10.3390/molecules26144333
Xu X, Yi H, Wu J, Kuang T, Zhang J, Li Q, Du H, Xu T, Jiang G, Fan G. Therapeutic effect of berberine on metabolic diseases: Both pharmacological data and clinical evidence. Biomedicine & Pharmacotherapy. 2021 Jan 1;133:110984. https://doi.org/10.1016/j.biopha.2020.110984
Ng CY, Zhong L, Ng HS, Goh KS, Zhao Y. Managing type 2 diabetes mellitus via the regulation of gut microbiota: a chinese medicine perspective. Nutrients. 2024 Nov 18;16(22):3935. https://doi.org/10.3390/nu16223935
Wang Z, Wu J, Zhou Q, Wang Y, Chen T. Berberine nanosuspension enhances hypoglycemic efficacy on streptozotocin induced diabetic C57BL/6 mice. Evidence‐Based Complementary and Alternative Medicine. 2015;2015(1):239749. https://doi.org/10.1155/2015/239749
Zou K, Li Z, Zhang Y, Zhang HY, Li B, Zhu WL, Shi JY, Jia Q, Li YM. Advances in the study of berberine and its derivatives: a focus on anti-inflammatory and anti-tumor effects in the digestive system. Acta Pharmacologica Sinica. 2017 Feb;38(2):157-67. https://doi.org/10.1038/aps.2016.125
Behl T, Singh S, Sharma N, Zahoor I, Albarrati A, Albratty M, Meraya AM, Najmi A, Bungau S. Expatiating the pharmacological and nanotechnological aspects of the alkaloidal drug berberine: current and future trends. Molecules. 2022 Jun 9;27(12):3705. https://doi.org/10.3390/molecules27123705
World Health Organization. WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems. InWHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems 2004.
Di S, Han L, An X, Kong R, Gao Z, Yang Y, Wang X, Zhang P, Ding Q, Wu H, Wang H. In silico network pharmacology and in vivo analysis of berberine-related mechanisms against type 2 diabetes mellitus and its complications. Journal of Ethnopharmacology. 2021 Aug 10;276:114180. https://doi.org/10.1016/j.jep.2021.114180
Ye Y, Liu X, Wu N, Han Y, Wang J, Yu Y, Chen Q. Efficacy and safety of berberine alone for several metabolic disorders: a systematic review and meta-analysis of randomized clinical trials. Frontiers in pharmacology. 2021 Apr 26;12:653887. https://doi.org/10.3389/fphar.2021.653887
Londzin P, Kocik S, Kisiel-Nawrot E, Janas A, Skoczyńska A, Krivošíková Z, Štefíková K, Gajdoš M, Cegieła U, Folwarczna J. Lack of berberine effect on bone mechanical properties in rats with experimentally induced diabetes. Biomedicine & Pharmacotherapy. 2022 Feb 1;146:112562. https://doi.org/10.1016/j.biopha.2021.112562
Zhang H, Wang X, Wang T, Chen K, Wang H, Jia Q, Li Y. Enhancement of berberine hypoglycemic activity by oligomeric proanthocyanidins. Molecules. 2018 Dec 14;23(12):3318. https://doi.org/10.3390/molecules23123318
Khater SI, Almanaa TN, Fattah DM, Khamis T, Seif MM, Dahran N, Alqahtani LS, Metwally MM, Mostafa M, Albedair RA, Helal AI. Liposome-Encapsulated berberine alleviates liver injury in type 2 diabetes via promoting AMPK/mTOR-Mediated autophagy and reducing ER stress: morphometric and immunohistochemical scoring. Antioxidants. 2023 Jun;12(6):1220. https://doi.org/10.3390/antiox12061220
Ren G, Ding YW, Wang LL, Jiang JD. Berberine stimulates lysosomal AMPK independent of PEN2 and maintains cellular AMPK activity through inhibiting the dephosphorylation regulator UHRF1. Frontiers in pharmacology. 2023 Apr 18;14:1148611. https://doi.org/10.3389/fphar.2023.1148611
Chen Y, Li Q, Zhao S, Sun L, Yin Z, Wang X, Li X, Iwakiri Y, Han J, Duan Y. Berberine protects mice against type 2 diabetes by promoting PPARγ-FGF21-GLUT2-regulated insulin sensitivity and glucose/lipid homeostasis. Biochemical Pharmacology. 2023 Dec 1;218:115928. https://doi.org/10.1016/j.bcp.2023.115928
Shrivastava S, Sharma A, Saxena N, Bhamra R, Kumar S. Addressing the preventive and therapeutic perspective of berberine against diabetes. Heliyon. 2023 Nov 1;9(11). https://doi.org/10.1016/j.heliyon.2023.e21233
Nam SW, Hwang JW, Han YH. A novel berberine derivative targeting adipocyte differentiation to alleviate TNF-α-induced inflammatory effects and insulin resistance in OP9 cells. Biomedicine & Pharmacotherapy. 2023 Nov 1;167:115433. https://doi.org/10.1016/j.biopha.2023.115433
Almowallad S, Al-Massabi R. Berberine modulates cardiovascular diseases as a multitarget-mediated alkaloid with insights into its downstream signals using in silico prospective screening approaches. Saudi Journal of Biological Sciences. 2024 May 1;31(5):103977. https://doi.org/10.1016/j.sjbs.2024.103977
Chen X, Mei XY, Ren ZM, Chen SS, Tong YL, Zhang CP, Chen J, Dai GH. Comprehensive insights into berberine's hypoglycemic mechanisms: A focus on ileocecal microbiome in db/db mice. Heliyon. 2024 Jul 15;10(13). https://doi.org/10.1016/j.heliyon.2024.e33704
Yang HC, Wang GJ, Xia Y, Tian JJ, Xie J, Zhang K, Li ZF, Yu EM, Li HY, Gong WB, Xie WP. Dietary berberine ameliorates glucose metabolism by regulating the FXR pathway in largemouth bass (Micropterus salmoides). Aquaculture Reports. 2024 Apr 1;35:101988. https://doi.org/10.1016/j.aqrep.2024.101988
Liu H, Wei M, Tan B, Dong X, Xie S. The supplementation of berberine in high-carbohydrate diets improves glucose metabolism of tilapia (Oreochromis niloticus) via transcriptome, bile acid synthesis gene expression and intestinal flora. Animals. 2024 Apr 20;14(8):1239. https://doi.org/10.3390/ani14081239
Xie W, Su F, Wang G, Peng Z, Xu Y, Zhang Y, Xu N, Hou K, Hu Z, Chen Y, Chen R. Glucose-lowering effect of berberine on type 2 diabetes: A systematic review and meta-analysis. Frontiers in pharmacology. 2022 Nov 16;13:1015045. https://doi.org/10.3389/fphar.2022.1015045
Wang F, Neumann D, Kapsokalyvas D, Hoes MF, Schianchi F, Glatz JF, Nabben M, Luiken JJ. Specific compounds derived from Traditional Chinese Medicine ameliorate lipid-induced contractile dysfunction in cardiomyocytes. International Journal of Molecular Sciences. 2024 Jul 25;25(15):8131. https://doi.org/10.3390/ijms25158131
Li C, Cao H, Huan Y, Ji W, Liu S, Sun S, Liu Q, Lei L, Liu M, Gao X, Fu Y. Berberine combined with stachyose improves glycometabolism and gut microbiota through regulating colonic microRNA and gene expression in diabetic rats. Life Sciences. 2021 Nov 1;284:119928. https://doi.org/10.1016/j.lfs.2021.119928
Wang Z, Shao Y, Wu F, Luo D, He G, Liang J, Quan X, Chen X, Xia W, Chen Y, Liu Y. Berberine ameliorates vascular dysfunction by downregulating TMAO-endoplasmic reticulum stress pathway via gut microbiota in hypertension. Microbiological Research. 2024 Oct 1;287:127824. https://doi.org/10.1016/j.micres.2024.127824
Das K, Iyer KR, Orfali R, Asdaq SM, Alotaibi NS, Alotaibi FS, Alshehri S, Quadri MS, Almarek A, Makhashin NB, Alrashed AA. In silico studies and evaluation of in vitro antidiabetic activity of berberine from ethanol seed extract of Coscinium fenestratum (Gaertn.) Colebr. Journal of King Saud University-Science. 2023 Jul 1;35(5):102666. https://doi.org/10.1016/j.jksus.2023.102666
Yang F, Gao R, Luo X, Liu R, Xiong D. Berberine influences multiple diseases by modifying gut microbiota. Frontiers in Nutrition. 2023 Aug 3;10:1187718. https://doi.org/10.3389/fnut.2023.1187718
Zhang JJ, Zhou R, Deng LJ, Cao GZ, Zhang Y, Xu H, Hou JY, Ju S, Yang HJ. Huangbai liniment and berberine promoted wound healing in high-fat diet/Streptozotocin-induced diabetic rats. Biomedicine & Pharmacotherapy. 2022 Jun 1;150:112948. https://doi.org/10.1016/j.biopha.2022.112948
Hareeri RH, Hofni A. Berberine alleviates uterine inflammation in rats via modulating the TLR-2/p-PI3K/p-AKT axis. International Immunopharmacology. 2024 Nov 15;141:112931. https://doi.org/10.1016/j.intimp.2024.112931
Sun J, Zeng Q, Wu Z, Huang L, Sun T, Ling C, Zhang B, Chen C, Wang H. Berberine inhibits NLRP3 inflammasome activation and proinflammatory macrophage M1 polarization to accelerate peripheral nerve regeneration. Neurotherapeutics. 2024 Jul 1;21(4):e00347. https://doi.org/10.1016/j.neurot.2024.e00347
Alnuqaydan AM, Almutary AG, Azam M, Manandhar B, De Rubis G, Madheswaran T, Paudel KR, Hansbro PM, Chellappan DK, Dua K. Phytantriol-based berberine-loaded liquid crystalline nanoparticles attenuate inflammation and oxidative stress in lipopolysaccharide-induced RAW264. 7 macrophages. Nanomaterials. 2022 Dec 5;12(23):4312. https://doi.org/10.3390/nano12234312
Tang Y, Gao Y, Nie K, Wang H, Chen S, Su H, Huang W, Dong H. Jiao-tai-wan and its effective component-berberine improve diabetes and depressive disorder through the cAMP/PKA/CREB signaling pathway. Journal of Ethnopharmacology. 2024 Apr 24;324:117829. https://doi.org/10.1016/j.jep.2024.117829
Skonieczna M, Adamiec-Organisciok M, Hudy D, Dziedzic A, Los L, Skladany L, Grgurevic I, Filipec-Kanizaj T, Jagodzinski M, Kukla M, Nackiewicz J. Hepatocellular cancer cell lines, Hep-3B and Hep-G2 display the pleiotropic response to resveratrol and berberine. Advances in Medical Sciences. 2022 Sep 1;67(2):379-85. https://doi.org/10.1016/j.advms.2022.09.003
Zhang M, Li J, Guo X, Wang X, Shi D, Cui L, Zhou Y. Co-administration of berberine/gypenosides/bifendate ameliorates metabolic disturbance but not memory impairment in type 2 diabetic mice. Heliyon. 2021 Jan 1;7(1). https://doi.org/10.1016/j.heliyon.2021.e06004
Panda DS, Eid HM, Elkomy MH, Khames A, Hassan RM, Abo El-Ela FI, Yassin HA. Berberine encapsulated lecithin–chitosan nanoparticles as innovative wound healing agent in type II diabetes. Pharmaceutics. 2021 Aug 4;13(8):1197. https://doi.org/10.3390/pharmaceutics13081197
Khvostov MV, Gladkova ED, Borisov SA, Zhukova NA, Marenina MK, Meshkova YV, Luzina OA, Tolstikova TG, Salakhutdinov NF. Discovery of the first in class 9-N-berberine derivative as hypoglycemic agent with extra-strong action. Pharmaceutics. 2021 Dec 12;13(12):2138. https://doi.org/10.3390/pharmaceutics13122138
Nguyen DV, Hengphasatporn K, Danova A, Suroengrit A, Boonyasuppayakorn S, Fujiki R, Shigeta Y, Rungrotmongkol T, Chavasiri W. Structure—yeast α-glucosidase inhibitory activity relationship of 9-O-berberrubine carboxylates. Scientific Reports. 2023 Nov 1;13(1):18865. https://doi.org/10.1038/s41598-023-45116-0
Ren G, Wang YX, Li YH, Song DQ, Kong WJ, Jiang JD. Structure-activity relationship of berberine derivatives for their glucose-lowering activities. Int. J. Clin. Exp. Med. 2017 Jan 1;10(3):5054-60.
Martini D, Pucci C, Gabellini C, Pellegrino M, Andreazzoli M. Exposure to the natural alkaloid Berberine affects cardiovascular system morphogenesis and functionality during zebrafish development. Scientific reports. 2020 Oct 15;10(1):17358. https://doi.org/10.1038/s41598-020-73661-5
Rigillo G, Cappellucci G, Baini G, Vaccaro F, Miraldi E, Pani L, Tascedda F, Bruni R, Biagi M. Comprehensive Analysis of Berberis aristata DC. Bark Extracts: In Vitro and In Silico Evaluation of Bioavailability and Safety. https://doi.org/10.3390/nu16172953
Liu T, Huang Y, Jiang L, Dong C, Gou Y, Lian J. Efficient production of vindoline from tabersonine by metabolically engineered Saccharomyces cerevisiae. Communications Biology. 2021 Sep 16;4(1):1089. https://doi.org/10.1038/s42003-021-02617-w
Jain MN, Kumar MA, Singh MN, Kumar MD, Singh MS. CATHARANTHUS ROSEUS: TRADITIONAL USES, PHYTOCHEMISTRY, AND MODERN PHARMACOLOGY: ARTICL HISTORY-Date of Submission: Mar 09, 2025, Revision: April 05, 2025, Acceptance: April 24, 2025. International Journal of Medical Science. 2025 May 5:41-70. https://doi.org/10.56815/ijmsci.v5i1.2025.41-70
Singh P, Singh DP, Patel MK, Binwal M, Kaushik A, Mall M, Sahu M, Khare P, Shanker K, Bawankule DU, Sundaresan V. Vindoline is a key component of Catharanthus roseus leaf juice extract prepared through an Ayurveda-based method for ameliorating insulin-resistant type 2 diabetes. Protoplasma. 2025 May;262(3):667-81. https://doi.org/10.1007/s00709-024-02026-w
Khan A, Kanwal F, Ullah S, Fahad M, Tariq L, Altaf MT, Riaz A, Zhang G. Plant secondary metabolites—Central regulators against abiotic and biotic stresses. Metabolites. 2025 Apr 16;15(4):276. https://doi.org/10.3390/metabo15040276
Zhou P, Chen M. Exploration of the mechanisms of differential indole alkaloid biosynthesis in dedifferentiated and cambial meristematic cells of catharanthus roseus using transcriptome sequencing. Frontiers in Genetics. 2022 Jun 30;13:867064. https://doi.org/10.3389/fgene.2022.867064
Rahman N, Muhammad I, Khan H, Aschner M, Filosa R, Daglia M. Molecular docking of isolated alkaloids for possible α-glucosidase inhibition. Biomolecules. 2019 Sep 27;9(10):544. https://doi.org/10.3390/biom9100544
Goboza M, Meyer M, Aboua YG, Oguntibeju OO. In vitro antidiabetic and antioxidant effects of different extracts of Catharanthus roseus and its indole alkaloid, vindoline. Molecules. 2020 Nov 26;25(23):5546. https://doi.org/10.3390/molecules25235546
Goyal R, Kumar M, Mallick MA. Analysis of multi-disease targeting effect of phytochemicals by AMPK stimulation–diabetes: A computational approach. Gene & Protein in Disease. 2023 Sep 12;2(3):0927. https://doi.org/10.36922/gpd.0927
Shijina BN, Radhika A, Sherin S, Biju PG. Vindoline Exhibits Anti-Diabetic Potential in Insulin-Resistant 3T3-L1 Adipocytes and L6 Skeletal Myoblasts. Nutrients. 2023 Jun 24;15(13):2865. https://doi.org/10.3390/nu15132865
Goboza M, Aboua YG, Chegou N, Oguntibeju OO. Vindoline effectively ameliorated diabetes-induced hepatotoxicity by docking oxidative stress, inflammation and hypertriglyceridemia in type 2 diabetes-induced male Wistar rats. Biomedicine & pharmacotherapy. 2019 Apr 1;112:108638. https://doi.org/10.1016/j.biopha.2019.108638
Oguntibeju OO, Aboua Y, Goboza M. Vindoline—a natural product from Catharanthus roseus reduces hyperlipidemia and renal pathophysiology in experimental type 2 diabetes. Biomedicines. 2019 Aug 13;7(3):59. https://doi.org/10.3390/biomedicines7030059
Oguntibeju OO, Aboua Y, Kachepe P. Possible therapeutic effects of vindoline on testicular and epididymal function in diabetes-induced oxidative stress male Wistar rats. Heliyon. 2020 Apr 1;6(4). https://doi.org/10.1016/j.heliyon.2020.e03817
Tiong SH, Looi CY, Hazni H, Arya A, Paydar M, Wong WF, Cheah SC, Mustafa MR, Awang K. Antidiabetic and antioxidant properties of alkaloids from Catharanthus roseus (L.) G. Don. Molecules. 2013 Aug 15;18(8):9770-84. https://doi.org/10.3390/molecules18089770
Adhikari B. Roles of alkaloids from medicinal plants in the management of diabetes mellitus. Journal of Chemistry. 2021;2021(1):2691525. https://doi.org/10.1155/2021/2691525
Nisat UT, Jahan N, Afrin SR, Akter B, Nahar A, Islam MR, Hossain MK. Phytochemical, Ethnopharmacological, and Medicinal Importance of Catharanthus roseus (Apocyanaceae): A Mini-review. South Asian Research Journal of Natural Products. 2024 May 4;7(2):87-101.
Goyal R, Kumar M, Mallick MA. Drug innovation studies targeting Diabetes: A computational docking approach on multi-drug targets including COVID Inhibitors. https://doi.org/10.21203/rs.3.rs-2457415/v1
Keglevich P, Hazai L, Kalaus G, Szántay C. Modifications on the basic skeletons of vinblastine and vincristine. Molecules. 2012 May 18;17(5):5893-914. https://doi.org/10.3390/molecules17055893
Yao XG, Chen F, Li P, Quan L, Chen J, Yu L, Ding H, Li C, Chen L, Gao Z, Wan P. Natural product vindoline stimulates insulin secretion and efficiently ameliorates glucose homeostasis in diabetic murine models. Journal of ethnopharmacology. 2013 Oct 28;150(1):285-97. https://doi.org/10.1016/j.jep.2013.08.043
Silvestri R. New prospects for vinblastine analogues as anticancer agents. Journal of medicinal chemistry. 2013 Feb 14;56(3):625-7. https://doi.org/10.1021/jm400002j
Zsoldos B, Nagy N, Donkó-Tóth V, Keglevich P, Weber M, Dékány M, Nehr-Majoros A, Szőke É, Helyes Z, Hazai L. Novel Piperazine Derivatives of Vindoline as Anticancer Agents. International Journal of Molecular Sciences. 2024 Jul 19;25(14):7929. https://doi.org/10.3390/ijms25147929
Dhanwad RM, Usha R, Ganesh S. In Silico Evaluation of Pharmacokinetics and Toxicity Profile of Alkaloids Present in Leaves of Catharanthus roseus L. RGUHS Journal of Pharmaceutical Sciences. 2024;14(4). https://doi.org/10.26463/rjps.14_4_2
Guo Y, Li L, Yao Y, Li H. Regeneration of pancreatic β-cells for diabetes therapeutics by natural DYRK1A inhibitors. Metabolites. 2022 Dec 29;13(1):51. https://doi.org/10.3390/metabo13010051
Pucelik B, Barzowska A, Dąbrowski JM, Czarna A. Diabetic kinome inhibitors—A new opportunity for β-cells restoration. International Journal of Molecular Sciences. 2021 Aug 23;22(16):9083. https://doi.org/10.3390/ijms22169083
Wang P, Alvarez-Perez JC, Felsenfeld DP, Liu H, Sivendran S, Bender A, Kumar A, Sanchez R, Scott DK, Garcia-Ocaña A, Stewart AF. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nature medicine. 2015 Apr;21(4):383-8. https://doi.org/10.1038/nm.3820
Liu Q, Yang C, Qi J, Shen Q, Ye M, Li H, Zhang L. Bioactivities and Structure–Activity Relationships of Harmine and Its Derivatives: A Review. Chemistry & Biodiversity. 2025 Mar 15:e202402953. https://doi.org/10.1002/cbdv.202402953
Akl MM, Ahmed A. Exploring Peganum harmala as a natural alternative to semaglutide: A novel approach to glucagon-like peptide-1 stimulation and insulin sensitization. Innovative Medicines & Omics. 2025 Mar 19:025060009. https://doi.org/10.36922/IMO025060009
Title AC, Karsai M, Mir-Coll J, Grining ÖY, Rufer C, Sonntag S, Forschler F, Jawurek S, Klein T, Yesildag B. Evaluation of the effects of harmine on β-cell function and proliferation in standardized human islets using 3D high-content confocal imaging and automated analysis. Frontiers in Endocrinology. 2022 Jul 4;13:854094. https://doi.org/10.3389/fendo.2022.854094
Barzowska A, Pucelik B, Pustelny K, Matsuda A, Martyniak A, Stępniewski J, Maksymiuk A, Dawidowski M, Rothweiler U, Dulak J, Dubin G. DYRK1A Kinase inhibitors promote β-cell survival and insulin homeostasis. Cells. 2021 Aug 31;10(9):2263. https://doi.org/10.3390/cells10092263
Wang X, Zhang L, Qin L, Wang Y, Chen F, Qu C, Miao J. Physicochemical properties of the soluble dietary fiber from laminaria japonica and its role in the regulation of type 2 diabetes mice. Nutrients. 2022 Jan 13;14(2):329. https://doi.org/10.3390/nu14020329
Mohammadi F, Karimi E, Homayouni-Tabrizi M, Oskoueian E. Nanoparticle-based delivery of harmine: A comprehensive study on synthesis, characterization, anticancer activity, angiogenesis and toxicity Evaluation. Heliyon. 2024 Jun 15;10(11). https://doi.org/10.1016/j.heliyon.2024.e31678
Morsy MH, Nabil ZI, Darwish ST, Al-Eisa RA, Mehana AE. Anti-diabetic and anti-adipogenic effect of harmine in high-fat-diet-induced diabetes in mice. Life. 2023 Aug 5;13(8):1693. https://doi.org/10.3390/life13081693
Kumar K, Wang P, A. Swartz E, Khamrui S, Secor C, B. Lazarus M, Sanchez R, F. Stewart A, DeVita RJ. Structure–activity relationships and biological evaluation of 7-substituted harmine analogs for human β-cell proliferation. Molecules. 2020 Apr 23;25(8):1983. https://doi.org/10.3390/molecules25081983
Wang P, Alvarez-Perez JC, Felsenfeld DP, Liu H, Sivendran S, Bender A, Kumar A, Sanchez R, Scott DK, Garcia-Ocaña A, Stewart AF. Induction of human pancreatic beta cell replication by inhibitors of dual specificity tyrosine regulated kinase. Nature medicine. 2015 Apr;21(4):383. https://doi.org/10.1038/nm.3820
Wurzlbauer A, Rüben K, Gürdal E, Chaikuad A, Knapp S, Sippl W, Becker W, Bracher F. How to separate kinase inhibition from undesired monoamine oxidase a inhibition—The development of the DYRK1A inhibitor AnnH75 from the Alkaloid Harmine. Molecules. 2020 Dec 16;25(24):5962. https://doi.org/10.3390/molecules25245962
Pustelny K, Grygier P, Barzowska A, Pucelik B, Matsuda A, Mrowiec K, Slugocka E, Popowicz GM, Dubin G, Czarna A. Binding mechanism and biological effects of flavone DYRK1A inhibitors for the design of new antidiabetics. Scientific reports. 2023 Oct 23;13(1):18114. https://doi.org/10.1038/s41598-023-44810-3
Chen Q, Chao R, Chen H, Hou X, Yan H, Zhou S, Peng W, Xu A. Antitumor and neurotoxic effects of novel harmine derivatives and structure‐activity relationship analysis. International Journal of Cancer. 2005 May 1;114(5):675-82. https://doi.org/10.1002/ijc.20703
Yonezawa T, Hasegawa SI, Asai M, Ninomiya T, Sasaki T, Cha BY, Teruya T, Ozawa H, Yagasaki K, Nagai K, Woo JT. Harmine, a β-carboline alkaloid, inhibits osteoclast differentiation and bone resorption in vitro and in vivo. European journal of pharmacology. 2011 Jan 15;650(2-3):511-8. https://doi.org/10.1016/j.ejphar.2010.10.048
SRS Mota N, R. Kviecinski M, B. Felipe K, MAS Grinevicius V, Siminski T, M. Almeida G, C. Zeferino R, T. Pich C, W. Filho D, C. Pedrosa R. β-carboline alkaloid harmine induces DNA damage and triggers apoptosis by a mitochondrial pathway: study in silico, in vitro and in vivo. International Journal of Functional Nutrition. 2020 Sep;1(1):1. https://doi.org/10.3892/ijfn.2020.1
Jiang N, Chen L, Li J, Li W, Jiang S. Lethal and sublethal toxicity of beta-carboline alkaloids from Peganum harmala (L.) against aedes albopictus larvae (Diptera: Culicidae). Toxics. 2023 Apr 3;11(4):341. https://doi.org/10.3390/toxics11040341
Rezzagui A, Merghem M, Derafa I, Dahamna S. Acute and Sub-acute Toxic Effects of Algerian Peganum harmala L. Crud Extract. Journal of Drug Delivery & Therapeutics. 2020 Mar 1;10(2). https://doi.org/10.22270/jddt.v10i2.3920
Walvekar MV, Jadhav NA, Daunde JA, Potphode ND, Desai SS. Trigonelline: An Emerging Paradigm for Effective Therapy in Diabetes Mellitus. Journal of Endocrinology and Reproduction. 2023 May 12:15-28. https://doi.org/10.18311/jer/2023/29609
Hamden K, Bengara A, Amri Z, Elfeki A. Experimental diabetes treated with trigonelline: effect on key enzymes related to diabetes and hypertension, β-cell and liver function. Molecular and cellular biochemistry. 2013 Sep;381(1):85-94. https://doi.org/10.1007/s11010-013-1690-y
Membrez M, Migliavacca E, Christen S, Yaku K, Trieu J, Lee AK, Morandini F, Giner MP, Stiner J, Makarov MV, Garratt ES. Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nature metabolism. 2024 Mar;6(3):433-47. https://doi.org/10.1038/s42255-024-00997-x
Liu XY, Li YL, Zhang HT, Zuo J, Gregersen H, Ou H. Combination of ultrasound and supercritical carbon dioxide extraction for trigonelline production from Quisqualis indica. Ultrasonics Sonochemistry. 2025 May 1;116:107317. https://doi.org/10.1016/j.ultsonch.2025.107317
Chen C, Shi Y, Ma J, Chen Z, Zhang M, Zhao Y. Trigonelline reverses high glucose-induced proliferation, fibrosis of mesangial cells via modulation of Wnt signaling pathway. Diabetology & Metabolic Syndrome. 2022 Feb 9;14(1):28. https://doi.org/10.1186/s13098-022-00798-w
Nguyen V, Taine EG, Meng D, Cui T, Tan W. Pharmacological Activities, Therapeutic Effects, and Mechanistic Actions of Trigonelline. International Journal of Molecular Sciences. 2024 Mar 16;25(6):3385. https://doi.org/10.3390/ijms25063385
Li M, Li S, Jiang S, Li W. The Hepatoprotective Effect of Trigonelline in Diabetic Rat through Insulin-related IRS1-GLUT2 Pathway: A Biochemical, Molecular, Histopathological, and Immunohistochemical Study. Pharmacognosy Magazine. 2024 Dec;20(4):1215-25. https://doi.org/10.1177/09731296241247365
Chen C, Ma J, Miao CS, Zhang H, Zhang M, Cao X, Shi Y. Trigonelline induces autophagy to protect mesangial cells in response to high glucose via activating the miR-5189-5p-AMPK pathway. Phytomedicine. 2021 Nov 1;92:153614. https://doi.org/10.1016/j.phymed.2021.153614
Tanveer MA, Rashid H, Nazir LA, Archoo S, Shahid NH, Ragni G, Umar SA, Tasduq SA. Trigonelline, a plant derived alkaloid prevents ultraviolet-B-induced oxidative DNA damage in primary human dermal fibroblasts and BALB/c mice via modulation of phosphoinositide 3-kinase-Akt-Nrf2 signaling axis. Experimental Gerontology. 2023 Jan 1;171:112028. https://doi.org/10.1016/j.exger.2022.112028
Sekhar MG, Shanmugam KR, Chakrapani IS. Trigonelline, a Fenugreek Bioactive protects Heart tissue against alcohol intoxication: An in-vivo study focusing on antioxidant perspective. Journal of Ayurveda and Integrative Medicine. 2024 Jul 1;15(4):100963. https://doi.org/10.1016/j.jaim.2024.100963
Folwarczna J, Janas A, Pytlik M, Cegieła U, Śliwiński L, Krivošíková Z, Štefíková K, Gajdoš M. Effects of trigonelline, an alkaloid present in coffee, on diabetes-induced disorders in the rat skeletal system. Nutrients. 2016 Mar 2;8(3):133. https://doi.org/10.3390/nu8030133
Peerapen P, Boonmark W, Chantarasaka S, Thongboonkerd V. Trigonelline prevents high-glucose-induced endothelial-to-mesenchymal transition, oxidative stress, mitochondrial dysfunction, and impaired angiogenic activity in human endothelial EA. hy926 cells. Biomedicine & Pharmacotherapy. 2024 Oct 1;179:117320. https://doi.org/10.1016/j.biopha.2024.117320
Kabiri-Samani N, Amini-Khoei H, Rahimi-Madiseh M, Sureda A, Lorigooini Z. Trigonelline as an anticonvulsant agent: mechanistic insights into NMDA receptor expression and oxidative stress balance. Scientific Reports. 2024 Jun 20;14(1):14239. https://doi.org/10.1038/s41598-024-65301-z
Singh S, Chaurasia PK, Bharati SL. Hypoglycemic and hypocholesterolemic properties of Fenugreek: A comprehensive assessment. Applied Food Research. 2023 Dec 1;3(2):100311. https://doi.org/10.1016/j.afres.2023.100311
Li Y, Li Q, Wang C, Lou Z, Li Q. Trigonelline reduced diabetic nephropathy and insulin resistance in type 2 diabetic rats through peroxisome proliferator activated receptor γ. Experimental and Therapeutic Medicine. 2019 Aug 1;18(2):1331-7. https://doi.org/10.3892/etm.2019.7698
Yoshinari O, Igarashi K. Anti-diabetic effect of trigonelline and nicotinic acid, on KK-Ay mice. Current Medicinal Chemistry. 2010 Jul 1;17(20):2196-202. https://doi.org/10.2174/092986710791299902
Perchat N, Saaidi PL, Darii E, Pellé C, Petit JL, Besnard-Gonnet M, de Berardinis V, Dupont M, Gimbernat A, Salanoubat M, Fischer C. Elucidation of the trigonelline degradation pathway reveals previously undescribed enzymes and metabolites. Proceedings of the National Academy of Sciences. 2018 May 8;115(19):E4358-67. https://doi.org/10.1073/pnas.1722368115
Konstantinidis N, Franke H, Schwarz S, Lachenmeier DW. Risk assessment of trigonelline in coffee and coffee by-products. Molecules. 2023 Apr 14;28(8):3460. https://doi.org/10.3390/molecules28083460
Zhang W, Zhang Y, Chen S, Zhang H, Yuan M, Xiao L, Lu Y, Xu H. Trigonelline, an alkaloid from Leonurus japonicus Houtt., suppresses mast cell activation and OVA-induced allergic asthma. Frontiers in Pharmacology. 2021 Aug 4;12:687970. https://doi.org/10.3389/fphar.2021.687970
Membrez M, Migliavacca E, Christen S, Yaku K, Trieu J, Lee AK, Morandini F, Giner MP, Stiner J, Makarov MV, Garratt ES. Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nature metabolism. 2024 Mar;6(3):433-47. https://doi.org/10.1038/s42255-024-00997-x
Huang Y, Li X, Zhang X, Tang J. Oxymatrine ameliorates memory impairment in diabetic rats by regulating oxidative stress and apoptosis: involvement of NOX2/NOX4. Oxidative medicine and cellular longevity. 2020;2020(1):3912173. https://doi.org/10.1155/2020/3912173
Huang Y, He B, Song C, Long X, He J, Huang Y, Liu L. Oxymatrine ameliorates myocardial injury by inhibiting oxidative stress and apoptosis via the Nrf2/HO-1 and JAK/STAT pathways in type 2 diabetic rats. BMC Complementary Medicine and Therapies. 2023 Jan 3;23(1):2. https://doi.org/10.1186/s12906-022-03818-4
Lou D, Fang Q, He Y, Ma R, Wang X, Li H, Qi M. Oxymatrine alleviates high-fat diet/streptozotocin-induced non-alcoholic fatty liver disease in C57BL/6 J mice by modulating oxidative stress, inflammation and fibrosis. Biomedicine & Pharmacotherapy. 2024 May 1;174:116491. https://doi.org/10.1016/j.biopha.2024.116491
Kang S, Chen T, Hao Z, Yang X, Wang M, Zhang Z, Hao S, Lang F, Hao H. Oxymatrine alleviates gentamicin-induced renal injury in rats. Molecules. 2022 Sep 21;27(19):6209. https://doi.org/10.3390/molecules27196209
Xiong Z, Xu J, Liu X. Oxymatrine exerts a protective effect in myocardial ischemia/reperfusion-induced acute lung injury by inhibiting autophagy in diabetic rats. Molecular Medicine Reports. 2021 Mar;23(3):183. https://doi.org/10.3892/mmr.2021.11822
Han X, Ma T, Wang Q, Jin C, Han Y, Liu G, Li H. The mechanism of oxymatrine on atopic dermatitis in mice based on SOCS1/JAK-STAT3 pathway. Frontiers in Pharmacology. 2023 Jan 10;13:1091090. https://doi.org/10.3389/fphar.2022.1091090
Shalaby AM, Aboregela AM, Alabiad MA, Tayssir Sadek M. The effect of induced diabetes mellitus on the cerebellar cortex of adult male rat and the possible protective role of oxymatrine: a histological, immunohistochemical and biochemical study. Ultrastructural Pathology. 2021 May 4;45(3):182-96. https://doi.org/10.1080/01913123.2021.1926610
Zhang X, Jiang W, Zhou AL, Zhao M, Jiang DR. Inhibitory effect of oxymatrine on hepatocyte apoptosis via TLR4/PI3K/Akt/GSK-3β signaling pathway. World Journal of Gastroenterology. 2017 Jun 7;23(21):3839. https://doi.org/10.3748/wjg.v23.i21.3839
Wang SB, Jia JP. Oxymatrine attenuates diabetes-associated cognitive deficits in rats. Acta pharmacologica sinica. 2014 Mar;35(3):331-8. https://doi.org/10.1038/aps.2013.158
Seksaria S, Mehan S, Dutta BJ, Gupta GD, Ganti SS, Singh A. Oxymatrine and insulin resistance: Focusing on mechanistic intricacies involve in diabetes associated cardiomyopathy via SIRT1/AMPK and TGF‐β signaling pathway. Journal of Biochemical and Molecular Toxicology. 2023 May;37(5):e23330. https://doi.org/10.1002/jbt.23330
Zhu YX, Hu HQ, Zuo ML, Mao L, Song GL, Li TM, Dong LC, Yang ZB, Ali Sheikh MS. Effect of oxymatrine on liver gluconeogenesis is associated with the regulation of PEPCK and G6Pase expression and AKT phosphorylation. Biomedical reports. 2021 Jul;15(1):56. https://doi.org/10.3892/br.2021.1432
Zhang X, Ge J, Zhu X, Zhang H, Wang Y, Xu T, Jiang W, Zhang B. Effects and mechanism of oxymatrine combined with compound Yinchen granules on the apoptosis of hepatocytes through the Akt/FoxO3a/Bim pathway. BioMed research international. 2022;2022(1):8644356. https://doi.org/10.1155/2022/8644356
Nong Y, Qin H, Wei L, Wei X, Lv J, Huang X, Wu B. Oxymatrine Inhibits PD-L1 by Downregulating IFN-γ to Promote Ferroptosis and Enhance Anti-PD-L1 Efficacy in Liver Cancer. Journal of Hepatocellular Carcinoma. 2024 Dec 31:2427-40. https://doi.org/10.2147/JHC.S492582
Liu W, Shi J, Zhu L, Dong L, Luo F, Zhao M, Wang Y, Hu M, Lu L, Liu Z. Reductive metabolism of oxymatrine is catalyzed by microsomal CYP3A4. Drug design, development and therapy. 2015 Oct 30:5771-83. https://doi.org/10.2147/DDDT.S92276
Dong PL, Li Z, Teng CL, Yin X, Cao XK, Han H. Synthesis and evolution of neuroprotective effects of oxymatrine derivatives as anti‐Alzheimer’s disease agents. Chemical Biology & Drug Design. 2021 Jul;98(1):175-81. https://doi.org/10.1111/cbdd.13862
Mao, J., Hu, Y., Zhou, A., Zheng, B., Liu, Y., Du, Y., Li, J., Lu, J., & Zhou, P. (2012). Oxymatrine reduces neuroinflammation in rat brain: A signaling pathway. Neural regeneration research, 7(30), 2333–2339. https://doi.org/10.3969/j.issn.1673-5374.2012.30.002
Daungsupawong H, Wiwanitkit V. Re: Modified Oxymatrine as Novel Therapeutic Inhibitors Against Monkeypox and Marburg Virus Through Computational Drug Design Approaches. Journal of Cellular and Molecular Medicine. 2024 Dec 4;28(23):e70266. https://doi.org/10.1111/jcmm.70266
Zhang X, Shi J, Lu Y, Ji R, Guan Z, Peng F, Zhao C, Gao W, Gao F. Mechanism of oxymatrine in the treatment of cryptosporidiosis through TNF/NF-κB signaling pathway based on network pharmacology and experimental validation. Scientific Reports. 2024 Jun 24;14(1):14469. https://doi.org/10.1038/s41598-024-65362-0
Fischer BC, Musengi Y, König J, Sachse B, Hessel-Pras S, Schäfer B, Kneuer C, Herrmann K. Matrine and Oxymatrine: evaluating the gene mutation potential using in silico tools and the bacterial reverse mutation assay (Ames test). Mutagenesis. 2024 Jan 1;39(1):32-42. https://doi.org/10.1093/mutage/gead032
Gu Y, Lu J, Sun W, Jin R, Ohira T, Zhang Z, Tian X. Oxymatrine and its metabolite matrine contribute to the hepatotoxicity induced by radix Sophorae tonkinensis in mice. Experimental and Therapeutic Medicine. 2019 Apr;17(4):2519-28. https://doi.org/10.3892/etm.2019.7237
Senizza B, Rocchetti G, Sinan KI, Zengin G, Mahomoodally MF, Glamocilja J, Sokovic M, Lobine D, Etienne OK, Lucini L. The phenolic and alkaloid profiles of Solanum erianthum and Solanum torvum modulated their biological properties. Food Bioscience. 2021 Jun 1;41:100974. https://doi.org/10.1016/j.fbio.2021.100974
Karaca M, Erbaş O. Solanine Poisoning: Effects, Risks, and Management Strategies. Journal of Experimental and Basic Medical Sciences. 2024;5(2):189-93. https://doi.org/10.5606/jebms.2024.1090
Satyanarayana N, Chinni SV, Gobinath R, Sunitha P, Uma Sankar A, Muthuvenkatachalam BS. Antidiabetic activity of Solanum torvum fruit extract in streptozotocin-induced diabetic rats. Frontiers in nutrition. 2022 Oct 28;9:987552. https://doi.org/10.3389/fnut.2022.987552
Shin JS, Lee KG, Lee HH, Lee HJ, An HJ, Nam JH, Jang DS, Lee KT. α‐Solanine isolated from Solanum tuberosum L. cv Jayoung abrogates LPS‐induced inflammatory responses via NF‐κB inactivation in RAW 264.7 macrophages and endotoxin‐induced shock model in mice. Journal of cellular biochemistry. 2016 Oct;117(10):2327-39. https://doi.org/10.1002/jcb.25530
Amssayef A, Eddouks M. Alkaloids as promising agents for the management of insulin resistance: a review. Current Pharmaceutical Design. 2023 Nov 1;29(39):3123-36. https://doi.org/10.2174/0113816128270340231121043038
Jan S, Iram S, Bashir O, Shah SN, Kamal MA, Rahman S, Kim J, Jan AT. Unleashed Treasures of Solanaceae: Mechanistic Insights into Phytochemicals with Therapeutic Potential for Combatting Human Diseases. Plants. 2024 Mar 4;13(5):724. https://doi.org/10.3390/plants13050724
Borsoi FT, Pastore GM, Arruda HS. Health Benefits of the Alkaloids from Lobeira (Solanum lycocarpum St. Hill): A Comprehensive Review. Plants. 2024 May 17;13(10):1396. https://doi.org/10.3390/plants13101396
Nandi S, Sikder R, Nag A, Khatua S, Sen S, Chakraborty N, Naskar A, Zhakipbekov K, Acharya K, Habtemariam S, Arslan Ateşşahin D. Updated aspects of alpha‐Solanine as a potential anticancer agent: Mechanistic insights and future directions. Food Science & Nutrition. 2024 Oct;12(10):7088-107. https://doi.org/10.1002/fsn3.4221
Hasanain M, Bhattacharjee A, Pandey P, Ashraf R, Singh N, Sharma S, Vishwakarma AL, Datta D, Mitra K, Sarkar J. α-Solanine induces ROS-mediated autophagy through activation of endoplasmic reticulum stress and inhibition of Akt/mTOR pathway. Cell Death & Disease. 2015 Aug;6(8):e1860-. https://doi.org/10.1038/cddis.2015.219
Saleh BH, Salman MD, Salman AD, Alardhi SM, Mohammed MM, Gyurika IG, Le PC, Ali OI. In silico analysis of the use of solanine derivatives as a treatment for Alzheimer's disease. Heliyon. 2024 Jun 15;10(11). https://doi.org/10.1016/j.heliyon.2024.e32209
Gao SY, Wang QJ, Ji YB. Effect of solanine on the membrane potential of mitochondria in HepG2 cells and [Ca2+] i in the cells. World Journal of Gastroenterology: WJG. 2006 Jun 7;12(21):3359. https://doi.org/10.3748/wjg.v12.i21.3359
Okada K, Matsuo K. Development of new antibodies and an ELISA system to detect the potato alkaloids α-Solanine and α-Chaconine. Foods. 2023 Apr 12;12(8):1621. https://doi.org/10.3390/foods12081621
Ordóñez-Vásquez A, Aguirre-Arzola V, De la Garza-Ramos MA, Urrutia-Baca VH, Suárez-Obando F. Toxicity, Teratogenicity and Anti-cancer Activity of α-solanine: A Perspective on Anti-cancer Potential. International Journal of Pharmacology.;15(3):301-10. https://doi.org/10.3923/ijp.2019.301.310
Al Masaoud FS, Alharbi A, Behir MM, Siddiqui AF, Al-Murayeh LM, Al Dail A, Siddiqui R. A challenging case of suspected solanine toxicity in an eleven-year-old Saudi boy. Journal of Family Medicine and Primary Care. 2022 Jul 1;11(7):4039-41. https://doi.org/10.4103/jfmpc.jfmpc_1159_21
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