Assessment of the Effect of Berberine on Metalloprotease Enzymes Inhibition and Antioxidant Activity: Possible Application in Skin Aging

Abstract

Skin aging has been defined to enclose both intrinsic and extrinsic aging. Phytochemicals are frequently used for developing skin care formulations and could protect the skin’s epidermal and dermal layers, consisting mainly of elastin and collagen, from UV radiation. Berberine is an isoquinoline alkaloid and a biologically active component from plant sources. Our objective was to assess Berberine’s anti-aging capabilities by conducting elastase and collagenase enzyme inhibition and kinetic studies and to also evaluating its antioxidant capacity with three different methods. Furthermore, heat stability, pH and sun protection factor (SPF) of the formulated cream containing 1.5% berberine was evaluated. The elastase and collagenase IC50 values of berberine were estimated to be 47.54 and, 22.16 µg/mL respectively. Berberine was determined as an un-competitive inhibitor of elastase and collagenase. It scavenged DPPH and ABTS free radicals with IC50 values of 66.81 and 180.5 µg/mL respectively. 210.387 mg/L of berberine was equivalent in reducing power of 176 mg/L of ascorbic acid. SPF and pH value of cream containing berberine was found to be 12.3 and 5.62 respectively. In conclusion, these findings suggest that Berberine is a promising candidate for use as an active ingredient in cosmeceuticals, offering a natural approach to enhance skin health and reduce the visible signs of aging.

Keywords

• Skin aging
• Berberine
• Collagenase
• Elastase

References

1. 1. Svobodová A, Vostálová J. Solar radiation induced skin damage: Review of protective and preventive options. Int J Radiat Biol [Internet]. 2010 Dec;86(12):999–1030. Available from: .
2. 2. Polefka TG, Meyer TA, Agin PP, Bianchini RJ. Effects of solar radiation on the skin. J Cosmet Dermatol [Internet]. 2012 Jun 4;11(2):134–43. Available from: .
3. 3. Shin DW. Various biological effects of solar radiation on skin and their mechanisms: implications for phototherapy. Animal Cells Syst (Seoul) [Internet]. 2020 Jul 3;24(4):181–8. Available from: .
4. 4. Masaki H. Role of antioxidants in the skin: Anti-aging effects. J Dermatol Sci [Internet]. 2010 May 1;58(2):85–90. Available from: .
5. 5. Garg C, Sharma H, Garg M. Skin photo-protection with phytochemicals against photo-oxidative stress, photo-carcinogenesis, signal transduction pathways and extracellular matrix remodeling—An overview. Ageing Res Rev [Internet]. 2020 Sep 1;62:101127. Available from: .
6. 6. Malik A, Hoenig LJ. Can aging be slowed down? Clin Dermatol [Internet]. 2019 Jul 1;37(4):306–11. Available from: .
7. 7. Lee C. Fifty years of research and development of cosmeceuticals: A contemporary review. J Cosmet Dermatol [Internet]. 2016 Dec 6;15(4):527–39. Available from: .
8. 8. Kerscher M, Buntrock H. Update on cosmeceuticals. JDDG J der Dtsch Dermatologischen Gesellschaft [Internet]. 2011 Apr 3;9(4):314–28. Available from: .

9. 9. Nam EJ, Yoo G, Lee JY, Kim M, Jhin C, Son YJ, et al. Glycosyl flavones from Humulus japonicus suppress MMP-1 production via decreasing oxidative stress in UVB irradiated human dermal fibroblasts. BMB Rep [Internet]. 2020 Jul 31;53(7):379–84. Available from: .
10. 10. Varma S, Mishra A, Vijayakumar M, Paramesh R. Anti-skin ageing phytochemicals in cosmetics: An appraisal. Agro Food Ind Hi-Tech [Internet]. 2017;28(2):15–8. Available from: .
11. 11. Shoko T, Maharaj VJ, Naidoo D, Tselanyane M, Nthambeleni R, Khorombi E, et al. Anti-aging potential of extracts from Sclerocarya birrea (A. Rich.) Hochst and its chemical profiling by UPLC-Q-TOF-MS. BMC Complement Altern Med [Internet]. 2018 Dec 7;18(1):54. Available from: .
12. 12. Satyavani K, Gurudeeban S, Ramanathan T. Inhibitory effect of Excoecaria Agallocha L. extracts on elastase and collagenase and identification of metabolites using HPLC-UV-MS techniques. Pharm Chem J [Internet]. 2018 Feb 14;51(11):960–4. Available from: .
13. 13. Panzarini E, Dwikat M, Mariano S, Vergallo C, Dini L. Administration dependent antioxidant effect of Carica papaya seeds water extract. Eddouks M, editor. Evidence-Based Complement Altern Med [Internet]. 2014 Jan 25;2014(1):281508. Available from: .
14. 14. Seo SA, Ngo HTT, Hwang E, Park B, Yi TH. Protective effects of Carica papaya leaf against skin photodamage by blocking production of matrix metalloproteinases and collagen degradation in UVB-irradiated normal human dermal fibroblasts. South African J Bot [Internet]. 2020 Jul 1;131:398–405. Available from: .
15. 15. Maity N, Nema NK, Abedy MK, Sarkar BK, Mukherjee PK. Exploring Tagetes erecta Linn flower for the elastase, hyaluronidase and MMP-1 inhibitory activity. J Ethnopharmacol [Internet]. 2011 Oct 11;137(3):1300–5. Available from: .
16. 16. Pacheco-Palencia LA, Noratto G, Hingorani L, Talcott ST, Mertens-Talcott SU. Protective effects of standardized pomegranate (Punica granatum L.) polyphenolic extract in ultraviolet-irradiated human skin fibroblasts. J Agric Food Chem [Internet]. 2008 Sep 24;56(18):8434–41. Available from: .
17. 17. Chaikul P, Sripisut T, Chanpirom S, Ditthawutthikul N. Anti-skin aging activities of green tea (Camelliasinensis (L) Kuntze) in B16F10 melanoma cells and human skin fibroblasts. Eur J Integr Med [Internet]. 2020 Dec 1;40:101212. Available from: .
18. 18. Mao F, Wu Z, Shen Y, Ren Y, Yang M, Li X, et al. Regulatory mechanism of rosemary extract (Rosmarinus officinalis) on human skin fibroblasts during ultraviolet a photoaging. Iran J Sci Technol Trans A Sci [Internet]. 2021 Apr 23;45(2):427–36. Available from: .
19. 19. Lohakul J, Chaiprasongsuk A, Jeayeng S, Saelim M, Muanjumpon P, Thanachaiphiwat S, et al. The protective effect of polyherbal formulation, harak formula, on UVA-induced photoaging of human dermal fibroblasts and mouse skin via promoting Nrf2-regulated antioxidant defense. Front Pharmacol [Internet]. 2021 Apr 12;12:649820. Available from: .
20. 20. Md Jaffri J. Reactive oxygen species and antioxidant system in selected skin disorders. Malaysian J Med Sci [Internet]. 2023 Feb 28;30(1):7–20. Available from: .
21. 21. Ascenso A, Margarida Ribeiro H, Cabral Marques H, Simoes S. Topical delivery of antioxidants. Curr Drug Deliv [Internet]. 2011 Nov 1;8(6):640–60. Available from: .
22. 22. Yang F, Gao R, Luo X, Liu R, Xiong D. Berberine influences multiple diseases by modifying gut microbiota. Front Nutr [Internet]. 2023 Aug 3;10:1187718. Available from: .
23. 23. Rojsanga P, Gritsanapan W, Suntornsuk L. Determination of berberine content in the stem extracts of Coscinium fenestratum by TLC densitometry. Med Princ Pract [Internet]. 2006 Aug 1;15(5):373–8. Available from: .
24. 24. Sakai T. Solvent extraction–spectrophotometric determination of berberine and benzethonium in drugs with tetrabromophenolphthalein ethyl ester by batchwise and flow injection methods. Analyst [Internet]. 1991 Jan 1;116(2):187–90. Available from: .
25. 25. Wang Y, Yin S, Zhao C, Chen G, Yang F. Preparation of a zirconium terephthalate metal‐organic framework coated magnetic nanoparticle for the extraction of berberine prior to high‐performance liquid chromatography analysis. J Sep Sci [Internet]. 2021 Mar 18;44(6):1220–30. Available from: .
26. 26. Liu S, Chen Y, Gu L, Li Y, Wang B, Hao J, et al. Effects of ultrahigh pressure extraction conditions on yields of berberine and palmatine from cortex Phellodendri amurensis. Anal Methods [Internet]. 2013 Aug 8;5(17):4506–12. Available from: .
27. 27. Naz I, Masoud MS, Chauhdary Z, Shah MA, Panichayupakaranant P. Anti‐inflammatory potential of berberine‐rich extract via modulation of inflammation biomarkers. J Food Biochem [Internet]. 2022 Dec 19;46(12):e14389. Available from: .
28. 28. Aly S, El-Kamel AH, Sheta E, El-Habashy SE. Chondroitin/Lactoferrin-dual functionalized pterostilbene-solid lipid nanoparticles as targeted breast cancer therapy. Int J Pharm [Internet]. 2023 Jul 25;642:123163. Available from: .
29. 29. Hu H, Zhou S, Sun X, Xue Y, Yan L, Sun X, et al. A potent antiarrhythmic drug N-methyl berbamine extends the action potential through inhibiting both calcium and potassium currents. J Pharmacol Sci [Internet]. 2020 Apr 1;142(4):131–9. Available from: .
30. 30. Huang M, He Y, Tian L, Yu L, Cheng Q, Li Z, et al. Gut microbiota-SCFAs-brain axis associated with the antidepressant activity of berberine in CUMS rats. J Affect Disord [Internet]. 2023 Mar 15;325:141–50. Available from: .
31. 31. Yang L, Cheng CF, Li ZF, Huang XJ, Cai SQ, Ye SY, et al. Berberine blocks inflammasome activation and alleviates diabetic cardiomyopathy via the miR‑18a‑3p/Gsdmd pathway. Int J Mol Med [Internet]. 2023 Apr 24;51(6):49. Available from: .
32. 32. Tehrani SO, Rahbardar MG, Shoorgashti K, Nayeri MJD, Mohammadpour AH, Hosseinzadeh H. Evaluation of berberine pellet effect on clinical recovery time in COVID-19 outpatients: A pilot clinical trial. Avicenna J Phytomedicine [Internet]. 2023 May 1;13(3):265–79. Available from: .
33. 33. Dadgostar E, Moghanlou M, Parvaresh M, Mohammadi S, Khandan M, Aschner M, et al. Can berberine serve as a new therapy for parkinson’s disease? Neurotox Res [Internet]. 2022 Aug 6;40(4):1096–102. Available from: .
34. 34. Shekarabi SPH, Mehrgan MS, Ramezani F, Dawood MAO, Van Doan H, Moonmanee T, et al. Effect of dietary barberry fruit (Berberis vulgaris) extract on immune function, antioxidant capacity, antibacterial activity, and stress-related gene expression of Siberian sturgeon (Acipenser baerii). Aquac Reports [Internet]. 2022 Apr 1;23:101041. Available from: .
35. 35. El-Zahar KM, Al-Jamaan ME, Al-Mutairi FR, Al-Hudiab AM, Al-Einzi MS, Mohamed AAZ. Antioxidant, antibacterial, and antifungal activities of the ethanolic extract obtained from Berberis vulgaris roots and leaves. Molecules [Internet]. 2022 Sep 19;27(18):6114. Available from: .
36. 36. Gholampour F, Masoudi R, Khaledi M, Rooyeh MM, Farzad SH, Ataellahi F, et al. Berberis integerrima hydro-alcoholic root extract and its constituent berberine protect against cisplatin-induced nephro- and hepato-toxicity. Am J Med Sci [Internet]. 2022 Jul 1;364(1):76–87. Available from: .
37. 37. Ashraf H, Zare S. Preventive effects of aqueous extract of Berberis integerrima Bge. Root on liver injury induced by diabetes mellitus (Type 1) in rats. Iran J Pharm Res IJPR [Internet]. 2015 Dec 1;14(1):335–43. Available from: .
38. 38. Yadawa AK, Srivastava P, Singh A, Kesherwani R, Bhoumik S, Kumar R, et al. Berberine may provide redox homeostasis during aging in rats. Zeitschrift für Naturforsch C [Internet]. 2023 Jul 26;78(7–8):307–15. Available from: .
39. 39. Cometa S, Bonifacio MA, Licini C, Bellissimo A, Pinto L, Baruzzi F, et al. Innovative eco-friendly hydrogel film for berberine delivery in skin applications. Molecules [Internet]. 2021 Aug 13;26(16):4901. Available from: .
40. 40. Kim S, Chung JH. Berberine prevents UV-induced MMP-1 and reduction of type I procollagen expression in human dermal fibroblasts. Phytomedicine [Internet]. 2008 Sep 3;15(9):749–53. Available from: .
41. 41. Dzobo K, Dandara C. The extracellular matrix: Its composition, function, remodeling, and role in tumorigenesis. Biomimetics [Internet]. 2023 Apr 5;8(2):146. Available from: .
42. 42. Kraunsoe JAE, Claridge TDW, Lowe G. Inhibition of human leukocyte and porcine pancreatic elastase by homologues of bovine pancreatic trypsin inhibitor. Biochemistry [Internet]. 1996 Jan 1;35(28):9090–6. Available from: .
43. 43. Senol Deniz FS, Orhan IE, Duman H. Profiling cosmeceutical effects of various herbal extracts through elastase, collagenase, tyrosinase inhibitory and antioxidant assays. Phytochem Lett [Internet]. 2021 Oct 1;45:171–83. Available from: .
44. 44. Kozachok S, Pecio Ł, Orhan IE, Deniz FSS, Marchyshyn S, Oleszek W. Reinvestigation of Herniaria glabra L. saponins and their biological activity. Phytochemistry [Internet]. 2020 Jan 1;169:112162. Available from: .
45. 45. Tarbiat S, Unver D, Tuncay S, Isik S, Yeman KB, Mohseni AR. Neuroprotective effects of Cubebin and Hinokinin lignan fractions of Piper cubeba fruit in Alzheimer’s disease in vitro model. Turkish J Biochem [Internet]. 2023 Jul 19;48(3):303–10. Available from: .
46. 46. Sharma T, Tyagi V, Bansal M. Determination of sun protection factor of vegetable and fruit extracts using UV–Visible spectroscopy: A green approach. Sustain Chem Pharm [Internet]. 2020 Dec 1;18:100347. Available from: .
47. 47. Pujimulyani D, Suryani L, Setyawati A, Amalia A, Qodaniah RL, Kusuma HSW, et al. Elastase, Hyaluronidase and Tyrosinase inhibitor activities antiaging of Curcuma mangga Val. extract and its fractions. IOP Conf Ser Earth Environ Sci [Internet]. 2019 Nov 1;379(1):012004. Available from: .
48. 48. Bourgeois C, Leclerc ÉA, Corbin C, Doussot J, Serrano V, Vanier JR, et al. Nettle (Urtica dioica L.) as a source of antioxidant and anti-aging phytochemicals for cosmetic applications. Comptes Rendus Chim [Internet]. 2016 May 19;19(9):1090–100. Available from: .
49. 49. Masson P, Mukhametgalieva AR. Partial reversible inhibition of enzymes and its metabolic and pharmaco-toxicological implications. Int J Mol Sci [Internet]. 2023 Aug 19;24(16):12973. Available from: .
50. 50. Copeland RA. Reversible modes of inhibitor interactions with enzymes. In: Evaluation of enzyme inhibitors in drug discovery: A guide for medicinal chemists and pharmacologists. John Wiley & Sons, Inc. Hoboken, New Jersey; 2005. p. 57–121.
51. 51. Bosch R, Philips N, Suárez-Pérez J, Juarranz A, Devmurari A, Chalensouk-Khaosaat J, et al. Mechanisms of photoaging and cutaneous photocarcinogenesis, and photoprotective strategies with phytochemicals. Antioxidants [Internet]. 2015 Mar 26;4(2):248–68. Available from: .
52. 52. Madhan B, Krishnamoorthy G, Rao JR, Nair BU. Role of green tea polyphenols in the inhibition of collagenolytic activity by collagenase. Int J Biol Macromol [Internet]. 2007 Jun 1;41(1):16–22. Available from: .
53. 53. Thomas N, Kim SK. Beneficial effects of marine algal compounds in cosmeceuticals. Mar Drugs [Internet]. 2013 Jan 14;11(1):146–64. Available from: .
54. 54. Chen X, Yang C, Jiang G. Research progress on skin photoaging and oxidative stress. Adv Dermatology Allergol [Internet]. 2021;38(6):931–6. Available from: .
55. 55. Luo A, Fan Y. Antioxidant activities of berberine hydrochloride. 2011;5(16):3702–7. Available from: .
56. 56. Lee CY, Sharma A, Semenya J, Anamoah C, Chapman KN, Barone V. Computational study of ortho-substituent effects on antioxidant activities of phenolic dendritic antioxidants. Antioxidants [Internet]. 2020 Feb 25;9(3):189. Available from: .
57. 57. Kockler J, Oelgemöller M, Robertson S, Glass BD. Photostability of sunscreens. J Photochem Photobiol C Photochem Rev [Internet]. 2012 Mar 1;13(1):91–110. Available from: .
58. 58. Brinda S, Gitika D, Varsha V. Formulation and in-vitro evaluation of sun protection factor in a polyherbal cream. Internatıonal J Pharm Scıences Res [Internet]. 2017;8(1):197–200. Available from: .
59. 59. Frasheri L, Schielein MC, Tizek L, Mikschl P, Biedermann T, Zink A. Great green tea ingredient? A narrative literature review on epigallocatechin gallate and its biophysical properties for topical use in dermatology. Phyther Res [Internet]. 2020 Sep 18;34(9):2170–9. Available from: .