A COMPREHENSIVE REVIEW ON POTENTIAL THERAPEUTIC EFFECTS OF PEGANUM HARMALA IN MANAGING TYPE 2 DIABETES AND ITS RELATED COMPLICATIONS
Main Article Content
Keywords
Peganum harmala, Harmine, antidiabetic activity
Abstract
Peganum harmala, also known as Syrian rue or Wild rue, is a medicinal plant that has been used for centuries in traditional medicine for various diseases. It contains several alkaloids, flavonoids, and other phytochemicals that have shown pharmacological activities such as anti-amicrobial, neuroprotective, antidiabetic, and antitumor effects.
This review summarizes the current evidence on the antidiabetic effects of P. harmala and its main alkaloid, harmine, in animal models and human studies. P. harmala extracts and harmine have been reported to lower blood glucose levels, increase insulin sensitivity, and protect against diabetic nephropathy and retinopathy. The mechanisms of action involve the activation of peroxisome proliferator-activated receptor gamma (PPAR-γ), the stimulation of beta-cell proliferation and regeneration, and the suppression of oxidative stress and inflammation. P. harmala and harmine may have potential therapeutic effects in managing type 2 diabetes and its related complications.
References
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11. Ghaffar S, et al. Attenuation of palmitate induced insulin resistance in muscle cells by harmala, clove and river red gum. Pak J Pharm Sci. 2016;29:1795–1800.
12. Akinlade OM, Owoyele BV, Soladoye AO. Streptozotocin-induced type 1 and 2 diabetes in rodents: a model for studying diabetic cardiac autonomic neuropathy. Afr Health Sci. 2021;21(2):719–727.
13. Miller MJ, Albarracin-Jordan J, Moore C, Capriles JM. Chemical evidence for the use of multiple psychotropic plants in a 1,000-year-old ritual bundle from South America. Proc Natl Acad Sci USA. 2019;116:11207–11212.
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15. Shabani SH, Tehrani SS, Rabiei Z, Enferadi ST, Vannozzi GP. Peganum harmala L.'s anti-growth effect on a breast cancer cell line. Biotechnol Rep. 2015;8:138-143.
16. Hara ES, Ono M, Kubota S, Sonoyama W, Oida Y, Hattori T, Nishida T, Furumatsu T, Ozaki T, Takigawa M, Kuboki T. Novel chondrogenic and chondroprotective effects of the natural compound harmine. Biochimie. 2013;95:374-381.
17. Choi WT, Youn YC, Han ES, Lee CS. Protective effect of 1-methylated beta-carbolines against 3-morpholinosydnonimine-induced mitochondrial damage and cell viability loss in PC12 cells. Neurochem Res. 2004;29:1807-1816.
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19. Herraiz T. Evaluation of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to toxic pyridinium cations by monoamine oxidase (MAO) enzymes and its use to search for new MAO inhibitors and protective agents. J Enzyme Inhib Med Chem. 2012;27:810-817.
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22. Li S, Teng L, Liu W, Cheng X, Jiang B, Wang Z, Wang C. Interspecies metabolic diversity of harmaline and harmine in in vitro mammalian liver microsomes. Drug Test Anal. 2017;9:754-768.
23. Ogawa Y, et al. Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1a. Nat Commun. 2010;1:86. doi: 10.1038/ncomms1090.
24. Adayev T, Wegiel J, Hwang YW. Harmine is an ATP-competitive inhibitor for dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A). Arch Biochem Biophys. 2011;507:212-218.
25. Gockler N, Jofre G, Papadopoulos C, Soppa U, Tejedor FJ, Becker W. Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation. FEBS J. 2009;276:6324-6337.
26. Frost D, Meechoovet B, Wang T, Gately S, Giorgetti M, Shcherbakova I, Dunckley T. Beta-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer’s disease-related sites. PLoS ONE. 2011;6:e19264-e19272.
27. Yanuk JG, Denofrio MP, Fao R-S, Villarruel FD, Fassetta F, Garcia Einschlag FS, Erra-Balsells R, Epe B, Cabrerizo FM. DNA damage photo-induced by chloroharmine isomers: hydrolysis versus oxidation of nucleobases. Org Biomol Chem. 2018;16:2170-2184.
28. Begum S, Imran Hassan S, Siddiqui BS, Ifzal R, Perwaiz S, Kiran T, Shaheen F, Ghayur MN, Gilani AH. Preparation, structure and spasmolytic activities of some derivatives of harmine series of alkaloids. Nat Prod Res. 2006;20:213-227.
29. Quintana VM, Piccini LE, Panozzo Zenere JD, Damonte EB, Ponce MA, Castilla V. Antiviral activity of natural and synthetic beta-carbolines against dengue virus. Antiviral Res. 2016;134:26-33.
30. Cuny GD, Ulyanova NP, Patnaik D, Liu JF, Lin X, Auerbach K, Ray SS, Xian J, Glicksman MA, Stein RL, Higgins JM. Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors. Bioorg Med Chem Lett. 2012;22:2015-2019.
31. Pierson E, Haufroid M, Gosain TP, Chopra P, Singh R, Wouters J. Identification and repurposing of trisubstituted harmine derivatives as novel inhibitors of Mycobacterium tuberculosis phosphoserine phosphatase. Molecules. 2020;25:415-431.
32. Shi CC, Liao JF, Chen CF. Comparative study on the vasorelaxant effects of three harmala alkaloids in vitro. Jpn J Pharmacol. 2001;85:299-305.
33. Singh AB, Khaliq T, Chaturvedi JP, Narender T, Srivastav AK. Anti-diabetic and anti-oxidative effects of 4-hydroxypipecolic acid in C57BL/KsJ-db/db mice. Hum Exp Toxicol. 2012;31(1):57-65.
34. Saleh RA, Eissa TF, Abdallah DM, Saad MA, El-Abhar HS. Peganum harmala enhanced GLP-1 and restored insulin signaling to alleviate AlCl3-induced Alzheimer-like pathology model. Sci Rep. 2021;11(1):12040.
35. Araujo e Amariz I, da Silva JP, Valença Pereira EC, de Souza NAC, de Alencar Filho JMT, Pereira RN, de Oliveira AP, Rolim LA. Chemical study of Peganum harmala seed. Afr. J. Biotechnol. 2019;18(21):462-471.
36. Li S, Cheng X, Wang C. A review on traditional uses, phytochemistry, pharmacology, pharmacokinetics, and toxicology of the genus Peganum. 2017.03.049.
37. Poorbarkhordari E, Fooladsaz K, Hosseini H, Danafar H, Kheiri Manjili H, Ramazani A. The Hypoglycemic Effects of an Ethanol Extract of Peganum harmala in Streptozotocin-Induced Diabetic Rats. Iranian Journal of Pharmaceutical Sciences. 2014;10(3):47-54.
38. Abd El Baky HH, Abd EL Rahman AA, Mekawia EM, Ibrahema EA, Shalapya NM. The Anti-Diabetic and Anti-Lipidemic Effects of Peganum harmala Seeds in Diabetic Rats. Der Pharmacia Lettre. 2016;8(10):1-10.
39. Chen C, Cohrs CM, Stertmann J, Bozsak R, Speier S. Human beta cell mass and function in diabetes: recent advances in knowledge and technologies to understand disease pathogenesis. Mol Metab. 2017;6:943-957.
40. Aguayo-Mazzucato C, Bonner-Weir S. Pancreatic beta cell regeneration as a possible therapy for diabetes. Cell Metab. 2018;27:57-67.
41. Waki H, Park KW, Mitro N, Pei L, Damoiseaux R, Wilpitz DC, Reue K, Saez E, Tontonoz P. The small molecule harmine is an antidiabetic cell-type-specific regulator of PPAR gamma expression. Cell Metab. 2007;5:357-370.
42. Olmedo GM, Cerioni L, Gonzalez MM, Cabrerizo FM, Rapisarda VA, Volentini SI. Antifungal activity of beta-carbolines on Penicillium digitatum and Botrytis cinerea. Food Microbiol. 2017;62:9-14.
43. Akhtar MS, Iqbal Z, Khan MN, Lateef M. Anthelmintic activity of medicinal plants with particular reference to their use in animals in the Indo-Pakistan subcontinent. Small Rumin Res. 2000;38:99-107.
44. Bnouham M, Mekhfi H, Legssyer A, Ziyyat A. Medicinal plants used in the treatment of diabetes in Morocco. Int J Diabetes Metab. 2002;10:33-50.
45. Karaki H, Kishimoto T, Ozaki H, Sakata K, Umeno H, Urakawa N. Inhibition of calcium channels by harmaline and other harmala alkaloids in vascular and intestinal smooth muscles. Br J Pharmacol. 1986;89:367-375.
46. Herraiz T, González D, Ancin‑Azpilicueta C, Arán VJ, Guillé H. Beta‑Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO). Food Chem Toxicol. 2010;48:839-845.
47. Chen Q, Chao R, Chen H, Hou X, Yan H, Zhou S, et al. Antitumor and neurotoxic effects of novel harmine derivatives and structure‑activity relationship analysis. Int J Cancer. 2005;114:675-682.
48. Li Y, Liang F, Jiang W, Yu F, Cao R, Ma Q, et al. DH334, a beta‑carboline anti‑cancer drug, inhibits the CDK activity of budding yeast. Cancer Biol Ther. 2007;6:1193-1199.
49. Shahrajabian MH, Sun W, Cheng Q. Improving health benefits with considering traditional and modern health benefits of Peganum harmala. Clinical Phytoscience. 2021;7:18.
50. Shabani SHS, Tehrani SSH, Rabiei Z, Enferadi ST, Vannozzi GP. Peganum harmala L.'s anti-growth effect on a breast cancer cell line. Biotechnol Rep. 2018;8:138–143
2. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. A position statement of the American Diabetes Association. Diabetes Care. 2009;32:62-67.
3. Rossini AA. Autoimmune diabetes and the circle of tolerance. Diabetes. 2004;53:267-275.
4. Bearse MJ, Han T, Schneck ME, Barez S, Jacobsen C, Adams AJ. Invest Ophthalmol Vis Sci. 2004;45:3259-3265.
5. Madadkar Sobhani A, Ebrahimi SA, Mahmoudian M. An in vitro evaluation of human DNA topoisomerase I inhibition by Peganum harmala L. seeds extract and its beta-carboline alkaloids. J Pharm Pharmaceut Sci. 2002;5(1):19-23.
6. Asghari and Lockwood, 2002; Ehsanpour and Saadat, 2002; Yousefi et al., 2009.
7. Eissa TA, Palomino OM, Carretero ME, Gómez-serranillos MP. Ethnopharmacological study of medicinal plants used in the treatment of CNS disorders in Sinai Peninsula, Egypt. J Ethnopharmacol. 2014;151:317-332.
8. Sassoui D, Seridi R, Azin K, Usai M. Evaluation of phytochemical constituents by GC–MS and antidepressant activity of Peganum harmala L. seeds extract. Asian Pacific Journal of Tropical Disease. 2005;5(12):971-974.
9. Moloudizargari M, Mikaili P, Aghajanshakeri S, Asghari MH, Shayegh J. Pharmacogn Rev. 2013;7(14):199–212.
10. Komeili G, Hashemi M, Bameri-niafar M. Evaluation of antidiabetic and antihyperlipidemic effects of Peganum harmala seeds in diabetic rats. Cholesterol. 2016;1–6.
11. Ghaffar S, et al. Attenuation of palmitate induced insulin resistance in muscle cells by harmala, clove and river red gum. Pak J Pharm Sci. 2016;29:1795–1800.
12. Akinlade OM, Owoyele BV, Soladoye AO. Streptozotocin-induced type 1 and 2 diabetes in rodents: a model for studying diabetic cardiac autonomic neuropathy. Afr Health Sci. 2021;21(2):719–727.
13. Miller MJ, Albarracin-Jordan J, Moore C, Capriles JM. Chemical evidence for the use of multiple psychotropic plants in a 1,000-year-old ritual bundle from South America. Proc Natl Acad Sci USA. 2019;116:11207–11212.
14. Filali I, Bouajila J, Znati M, Bousejra-El Garah F, Ben Jannet H. Synthesis of new isoxazoline derivatives from harmine and evaluation of their anti-Alzheimer, anti-cancer, and anti-inflammatory activities. J Enzyme Inhib Med Chem. 2015;30:371-376.
15. Shabani SH, Tehrani SS, Rabiei Z, Enferadi ST, Vannozzi GP. Peganum harmala L.'s anti-growth effect on a breast cancer cell line. Biotechnol Rep. 2015;8:138-143.
16. Hara ES, Ono M, Kubota S, Sonoyama W, Oida Y, Hattori T, Nishida T, Furumatsu T, Ozaki T, Takigawa M, Kuboki T. Novel chondrogenic and chondroprotective effects of the natural compound harmine. Biochimie. 2013;95:374-381.
17. Choi WT, Youn YC, Han ES, Lee CS. Protective effect of 1-methylated beta-carbolines against 3-morpholinosydnonimine-induced mitochondrial damage and cell viability loss in PC12 cells. Neurochem Res. 2004;29:1807-1816.
18. Salman S, Idrees F, Pervaiz S, Shah FH, Badshah S, Abdullah, Usman M, Halimi SA, Idrees J. Short communication: Evaluation of antimicrobial activities of harmine, harmaline, nicotine and their complexes. Pakistan J Pharm Sci. 2016;29:1317-1320.
19. Herraiz T. Evaluation of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to toxic pyridinium cations by monoamine oxidase (MAO) enzymes and its use to search for new MAO inhibitors and protective agents. J Enzyme Inhib Med Chem. 2012;27:810-817.
20. Hamid HA, Ramli AN, Yusoff MM. Indole alkaloids from plants as potential leads for antidepressant drugs: A mini review. Front Pharmacol. 2017;8:96.
21. Wang P, Alvarez-Perez JC, Felsenfeld DP, Liu H, Sivendran S, Bender A, Kumar A, Sanchez R, Scott DK, Garcia-Ocana A, Stewart AF. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med. 2015;21:383-388.
22. Li S, Teng L, Liu W, Cheng X, Jiang B, Wang Z, Wang C. Interspecies metabolic diversity of harmaline and harmine in in vitro mammalian liver microsomes. Drug Test Anal. 2017;9:754-768.
23. Ogawa Y, et al. Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1a. Nat Commun. 2010;1:86. doi: 10.1038/ncomms1090.
24. Adayev T, Wegiel J, Hwang YW. Harmine is an ATP-competitive inhibitor for dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A). Arch Biochem Biophys. 2011;507:212-218.
25. Gockler N, Jofre G, Papadopoulos C, Soppa U, Tejedor FJ, Becker W. Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation. FEBS J. 2009;276:6324-6337.
26. Frost D, Meechoovet B, Wang T, Gately S, Giorgetti M, Shcherbakova I, Dunckley T. Beta-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer’s disease-related sites. PLoS ONE. 2011;6:e19264-e19272.
27. Yanuk JG, Denofrio MP, Fao R-S, Villarruel FD, Fassetta F, Garcia Einschlag FS, Erra-Balsells R, Epe B, Cabrerizo FM. DNA damage photo-induced by chloroharmine isomers: hydrolysis versus oxidation of nucleobases. Org Biomol Chem. 2018;16:2170-2184.
28. Begum S, Imran Hassan S, Siddiqui BS, Ifzal R, Perwaiz S, Kiran T, Shaheen F, Ghayur MN, Gilani AH. Preparation, structure and spasmolytic activities of some derivatives of harmine series of alkaloids. Nat Prod Res. 2006;20:213-227.
29. Quintana VM, Piccini LE, Panozzo Zenere JD, Damonte EB, Ponce MA, Castilla V. Antiviral activity of natural and synthetic beta-carbolines against dengue virus. Antiviral Res. 2016;134:26-33.
30. Cuny GD, Ulyanova NP, Patnaik D, Liu JF, Lin X, Auerbach K, Ray SS, Xian J, Glicksman MA, Stein RL, Higgins JM. Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors. Bioorg Med Chem Lett. 2012;22:2015-2019.
31. Pierson E, Haufroid M, Gosain TP, Chopra P, Singh R, Wouters J. Identification and repurposing of trisubstituted harmine derivatives as novel inhibitors of Mycobacterium tuberculosis phosphoserine phosphatase. Molecules. 2020;25:415-431.
32. Shi CC, Liao JF, Chen CF. Comparative study on the vasorelaxant effects of three harmala alkaloids in vitro. Jpn J Pharmacol. 2001;85:299-305.
33. Singh AB, Khaliq T, Chaturvedi JP, Narender T, Srivastav AK. Anti-diabetic and anti-oxidative effects of 4-hydroxypipecolic acid in C57BL/KsJ-db/db mice. Hum Exp Toxicol. 2012;31(1):57-65.
34. Saleh RA, Eissa TF, Abdallah DM, Saad MA, El-Abhar HS. Peganum harmala enhanced GLP-1 and restored insulin signaling to alleviate AlCl3-induced Alzheimer-like pathology model. Sci Rep. 2021;11(1):12040.
35. Araujo e Amariz I, da Silva JP, Valença Pereira EC, de Souza NAC, de Alencar Filho JMT, Pereira RN, de Oliveira AP, Rolim LA. Chemical study of Peganum harmala seed. Afr. J. Biotechnol. 2019;18(21):462-471.
36. Li S, Cheng X, Wang C. A review on traditional uses, phytochemistry, pharmacology, pharmacokinetics, and toxicology of the genus Peganum. 2017.03.049.
37. Poorbarkhordari E, Fooladsaz K, Hosseini H, Danafar H, Kheiri Manjili H, Ramazani A. The Hypoglycemic Effects of an Ethanol Extract of Peganum harmala in Streptozotocin-Induced Diabetic Rats. Iranian Journal of Pharmaceutical Sciences. 2014;10(3):47-54.
38. Abd El Baky HH, Abd EL Rahman AA, Mekawia EM, Ibrahema EA, Shalapya NM. The Anti-Diabetic and Anti-Lipidemic Effects of Peganum harmala Seeds in Diabetic Rats. Der Pharmacia Lettre. 2016;8(10):1-10.
39. Chen C, Cohrs CM, Stertmann J, Bozsak R, Speier S. Human beta cell mass and function in diabetes: recent advances in knowledge and technologies to understand disease pathogenesis. Mol Metab. 2017;6:943-957.
40. Aguayo-Mazzucato C, Bonner-Weir S. Pancreatic beta cell regeneration as a possible therapy for diabetes. Cell Metab. 2018;27:57-67.
41. Waki H, Park KW, Mitro N, Pei L, Damoiseaux R, Wilpitz DC, Reue K, Saez E, Tontonoz P. The small molecule harmine is an antidiabetic cell-type-specific regulator of PPAR gamma expression. Cell Metab. 2007;5:357-370.
42. Olmedo GM, Cerioni L, Gonzalez MM, Cabrerizo FM, Rapisarda VA, Volentini SI. Antifungal activity of beta-carbolines on Penicillium digitatum and Botrytis cinerea. Food Microbiol. 2017;62:9-14.
43. Akhtar MS, Iqbal Z, Khan MN, Lateef M. Anthelmintic activity of medicinal plants with particular reference to their use in animals in the Indo-Pakistan subcontinent. Small Rumin Res. 2000;38:99-107.
44. Bnouham M, Mekhfi H, Legssyer A, Ziyyat A. Medicinal plants used in the treatment of diabetes in Morocco. Int J Diabetes Metab. 2002;10:33-50.
45. Karaki H, Kishimoto T, Ozaki H, Sakata K, Umeno H, Urakawa N. Inhibition of calcium channels by harmaline and other harmala alkaloids in vascular and intestinal smooth muscles. Br J Pharmacol. 1986;89:367-375.
46. Herraiz T, González D, Ancin‑Azpilicueta C, Arán VJ, Guillé H. Beta‑Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO). Food Chem Toxicol. 2010;48:839-845.
47. Chen Q, Chao R, Chen H, Hou X, Yan H, Zhou S, et al. Antitumor and neurotoxic effects of novel harmine derivatives and structure‑activity relationship analysis. Int J Cancer. 2005;114:675-682.
48. Li Y, Liang F, Jiang W, Yu F, Cao R, Ma Q, et al. DH334, a beta‑carboline anti‑cancer drug, inhibits the CDK activity of budding yeast. Cancer Biol Ther. 2007;6:1193-1199.
49. Shahrajabian MH, Sun W, Cheng Q. Improving health benefits with considering traditional and modern health benefits of Peganum harmala. Clinical Phytoscience. 2021;7:18.
50. Shabani SHS, Tehrani SSH, Rabiei Z, Enferadi ST, Vannozzi GP. Peganum harmala L.'s anti-growth effect on a breast cancer cell line. Biotechnol Rep. 2018;8:138–143
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Dec 16, 2023
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Mr. Rohan Purohit, Mr. Vijendra Rajan, & Dr. Pragnesh Patani. (2023). A COMPREHENSIVE REVIEW ON POTENTIAL THERAPEUTIC EFFECTS OF PEGANUM HARMALA IN MANAGING TYPE 2 DIABETES AND ITS RELATED COMPLICATIONS. Journal of Population Therapeutics and Clinical Pharmacology, 30(19), 1968-1975. https://doi.org/10.53555/jptcp.v30i19.4122
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Author Biographies
Mr. Rohan Purohit
Khyati College of Pharmacy, Palodia, Ahmedabad
Mr. Vijendra Rajan
Khyati College of Pharmacy, Palodia, Ahmedabad
Dr. Pragnesh Patani
Khyati College of Pharmacy, Palodia, Ahmedabad
How to Cite
Mr. Rohan Purohit, Mr. Vijendra Rajan, & Dr. Pragnesh Patani. (2023). A COMPREHENSIVE REVIEW ON POTENTIAL THERAPEUTIC EFFECTS OF PEGANUM HARMALA IN MANAGING TYPE 2 DIABETES AND ITS RELATED COMPLICATIONS. Journal of Population Therapeutics and Clinical Pharmacology, 30(19), 1968-1975. https://doi.org/10.53555/jptcp.v30i19.4122