Eye Diseases: When the Solution Comes from Plant Alkaloids

Riccardo Lorrai; Dario Cavaterra; Sara Giammaria; Diego Sbardella; Grazia Raffaella Tundo; Alessandra Boccaccini

doi:10.1055/a-2283-2350

Planta Medica, Table of Contents

Planta Med 2024; 90(06): 426-439
DOI: 10.1055/a-2283-2350

Biological and Pharmacological Activity

Reviews

Eye Diseases: When the Solution Comes from Plant Alkaloids

Riccardo Lorrai

¹Dipartimento di Biologia e Biotecnologie “Charles Darwin”, Sapienza Università di Roma, Rome, Italy.

,

Dario Cavaterra

²Dipartimento di Scienze e Tecnologie Chimiche, Università di Tor Vergata, Rome, Italy

,

Sara Giammaria

³IRCCS – Fondazione Bietti, Rome, Italy

,

Diego Sbardella

³IRCCS – Fondazione Bietti, Rome, Italy

,

Grazia Raffaella Tundo

⁴Dipartimento di Scienze Cliniche e Medicina Traslazionale, Università di Roma Tor Vergata, Rome, Italy

,

Alessandra Boccaccini

³IRCCS – Fondazione Bietti, Rome, Italy

› Author Affiliations

Abstract

Plants are an incredible source of metabolites showing a wide range of biological activities. Among these, there are the alkaloids, which have been exploited for medical purposes since ancient times. Nowadays, many plant-derived alkaloids are the main components of drugs used as therapy for different human diseases. This review deals with providing an overview of the alkaloids used to treat eye diseases, describing the historical outline, the plants from which they are extracted, and the clinical and molecular data supporting their therapeutic activity. Among the different alkaloids that have found application in medicine so far, atropine and pilocarpine are the most characterized ones. Conversely, caffeine and berberine have been proposed for the treatment of different eye disorders, but further studies are still necessary to fully understand their clinical value. Lastly, the alkaloid used for managing hypertension, reserpine, has been recently identified as a potential drug for ameliorating retinal disorders. Other important aspects discussed in this review are different solutions for alkaloid production. Given that the industrial production of many of the plant-derived alkaloids still relies on extraction from plants, and the chemical synthesis can be highly expensive and poorly efficient, alternative methods need to be found. Biotechnologies offer a multitude of possibilities to overcome these issues, spanning from genetic engineering to synthetic biology for microorganisms and bioreactors for plant cell cultures. However, further efforts are needed to completely satisfy the pharmaceutical demand.

Keywords

plant alkaloids - retinal disease - plant metabolites - myopia - diabetic retinopathy

Full Text

References

References
1 Thompson RC. The Assyrian Herbal. Luzac and Company; 1924
2 “The Papyrus Ebers”/translated from the German version by Cyril P. Bryan; with an introduction by G. Elliot Smith. London; 1930
3 Serturner F. Darstellung der reinen Mohnsäure (Opiumsäure) nebst einer Untersuchung des Opiums mit vorzüglicher Hinsicht auf einen darin neu entdeckten Stoff und die dahin gehörigen Bemerkungen. Vom Herrn Serturner in Paderborn. Journal der Pharmacie 1806; 14: 47-93
4 Li J, Liu A, Najeeb U, Zhou W, Liu H, Yan G, Gill RA, Yun X, Bai Q, Xu L. Genome-wide investigation and expression analysis of membrane-bound fatty acid desaturase genes under different biotic and abiotic stresses in sunflower (Helianthus annuus L.). Int J Biol Macromol 2021; 175: 188-198
5 Xu L, Cao M, Wang Q, Xu J, Liu C, Ullah N, Li J, Hou Z, Liang Z, Zhou W, Liu A. Insights into the plateau adaptation of Salvia castanea by comparative genomic and WGCNA analyses. J Advanc Res 2022; 42: 221-235
6 Makhumbila P, Rauwane ME, Muedi HH, Madala NE, Figlan S. Metabolome profile variations in common bean (Phaseolus vulgaris L.) resistant and susceptible genotypes incited by rust (Uromyces appendiculatus). Frontiers in Genetics 2023; 14
7 Yang L, Stöckigt J. Trends for diverse production strategies of plant medicinal alkaloids. Nat Prod Rep 2010; 27: 1469-1479
8 Dey P, Kundu A, Kumar A, Gupta M, Lee BM, Bhakta T, Dash S, Kim HS. Chapter 15 – Analysis of alkaloids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids). In: Sanches Silva A, Nabavi SF, Saeedi M, et al., Hrsg. Recent Advances in Natural Products Analysis. Elsevier; 2020: 505-567
9 do Nascimento NC, Menguer PK, Sperotto RA, de Almeida MR, Fett-Neto AG. The alkaloid brachycerine contributes to protection against acute UV-B damage in Psychotria. Ind Crops Prod 2020; 147: 112216
10 Steppuhn A, Gase K, Krock B, Halitschke R, Baldwin IT. Nicotineʼs defensive function in nature. PLoS Biol 2004; 2: E217
11 Santos AP, Moreno PRH. Alkaloids Derived from Histidine: Imidazole (Pilocarpine, Pilosine). In: Ramawat KG, Mérillon J - M. Hrsg. Natural Products: Phytochemistry, Botany and Metabolism of Alkaloids, Phenolics and Terpenes. Berlin, Heidelberg: Springer; 2013: 861-882
12 Marciniak P, Kolińska A, Spochacz M. et al. Differentiated Effects of Secondary Metabolites from Solanaceae and Brassicaceae Plant Families on the Heartbeat of Tenebrio molitor Pupae. Toxins (Basel) 2019; 11: 287
13 González-Lamothe R, Mitchell G, Gattuso M, Diarra MS, Malouin F, Bouarab K. Plant Antimicrobial Agents and Their Effects on Plant and Human Pathogens. Int J Mol Sci 2009; 10: 3400-3419
14 Ettefagh KA, Burns JT, Junio HA, Kaatz GW, Cech NB. Goldenseal (Hydrastis canadensis L.) extracts synergistically enhance the antibacterial activity of berberine via efflux pump inhibition. Planta Med 2011; 77: 835-840
15 An T, Huang RQ, Yang Z, Zhang DK, Li GR, Yao YC, Gao J. Alkaloids from Cynanchum komarovii with inhibitory activity against the tobacco mosaic virus. Phytochemistry 2001; 58: 1267-1269
16 Chen J, Yan XH, Dong JH, Sang P, Fang X, Di YT, Zhang ZK, Hao XJ. Tobacco mosaic virus (TMV) inhibitors from Picrasma quassioides Benn. J Agric Food Chem 2009; 57: 6590-6595
17 Kohnen-Johannsen KL, Kayser O. Tropane Alkaloids: Chemistry, Pharmacology, Biosynthesis and Production. Molecules 2019; 24: 796
18 Grynkiewicz G, Gadzikowska M. Tropane alkaloids as medicinally useful natural products and their synthetic derivatives as new drugs. Pharmacological Reports 2008;.
19 Nietgen GW, Schmidt J, Hesse L, Hönemann CW, Durieux ME. Muscarinic receptor functioning and distribution in the eye: Molecular basis and implications for clinical diagnosis and therapy. Eye (Lond) 1999; 13: 285-300
20 Ruan Y, Patzak A, Pfeiffer N, Gericke A. Muscarinic Acetylcholine Receptors in the Retina-Therapeutic Implications. Int J Mol Sci 2021; 22: 4989
21 Smulyan H. The Beat Goes On: The Story of Five Ageless Cardiac Drugs. Am J Med Sci 2018; 356: 441-450
22 Morgan IG, Ohno-Matsui K, Saw SM. Myopia. Lancet 2012; 379: 1739-1748
23 Chierigo A, Ferro Desideri L, Traverso CE, Vagge A. The Role of Atropine in Preventing Myopia Progression: An Update. Pharmaceutics 2022; 14: 900
24 Gong Q, Janowski M, Luo M, Wei H, Chen B, Yang G, Liu L. Efficacy and Adverse Effects of Atropine in Childhood Myopia. JAMA Ophthalmol 2017; 135: 624-630
25 McBrien NA, Moghaddam HO, Reeder AP. Atropine reduces experimental myopia and eye enlargement via a nonaccommodative mechanism. Invest Ophthalmol Vis Sci 1993; 34: 205-215
26 McBrien NA, Stell WK, Carr B. How does atropine exert its anti-myopia effects?. Ophthalmic Physiol Opt 2013; 33: 373-378
27 Upadhyay A, Beuerman RW. Biological Mechanisms of Atropine Control of Myopia. Eye Contact Lens 2020; 46: 129-135
28 Barathi VA, Beuerman RW. Molecular mechanisms of muscarinic receptors in mouse scleral fibroblasts: Prior to and after induction of experimental myopia with atropine treatment. Mol Vis 2011; 17: 680-692
29 Gallego P, Martínez-García C, Pérez-Merino P, Ibares-Frías L, Mayo-Iscar A, Merayo-Lloves J. Scleral changes induced by atropine in chicks as an experimental model of myopia. Ophthalmic Physiol Opt 2012; 32: 478-484
30 Zou L, Liu R, Zhang X, Chu R, Dai J, Zhou H, Liu H. Upregulation of regulator of G-protein signaling 2 in the sclera of a form deprivation myopic animal model. Mol Vis 2014; 20: 977-987
31 Hsiao YT, Chang WA, Kuo MT, Lo J, Lin HC, Yen MC, Jian SF, Chen YJ, Kuo PL. Systematic Analysis of Transcriptomic Profile of the Effects of Low Dose Atropine Treatment on Scleral Fibroblasts using Next-Generation Sequencing and Bioinformatics. Int J Med Sci 2019; 16: 1652-1667
32 Cristaldi M, Olivieri M, Pezzino S, Spampinato G, Lupo G, Anfuso CD, Rusciano D. Atropine Differentially Modulates ECM Production by Ocular Fibroblasts, and Its Ocular Surface Toxicity Is Blunted by Colostrum. Biomedicines 2020; 8: 78
33 Boote C, Sigal IA, Grytz R, Hua Y, Nguyen TD, Girard MJA. Scleral structure and biomechanics. Prog Retin Eye Res 2020; 74: 100773
34 Schwahn HN, Kaymak H, Schaeffel F. Effects of atropine on refractive development, dopamine release, and slow retinal potentials in the chick. Vis Neurosci 2000; 17: 165-176
35 Thomson K, Kelly T, Karouta C, Morgan I, Ashby R. Insights into the mechanism by which atropine inhibits myopia: evidence against cholinergic hyperactivity and modulation of dopamine release. Br J Pharmacol 2021; 178: 4501-4517
36 Zhu Y, Bian JF, Lu DQ, To CH, Lam CS, Li KK, Yu FJ, Gong BT, Wang Q, Ji XW, Zhang HM, Nian H, Lam TC, Wei RH. Alteration of EIF2 Signaling, Glycolysis, and Dopamine Secretion in Form-Deprived Myopia in Response to 1 % Atropine Treatment: Evidence From Interactive iTRAQ-MS and SWATH-MS Proteomics Using a Guinea Pig Model. Front Pharmacol 2022; 13: 814814
37 Liu Y, Wang L, Xu Y, Pang Z, Mu G. The influence of the choroid on the onset and development of myopia: from perspectives of choroidal thickness and blood flow. Acta Ophthalmol 2021; 99: 730-738
38 Wang Y, Zhu X, Xuan Y, Wang M, Zhou X, Qu X. Short-Term Effects of Atropine 0.01 % on the Structure and Vasculature of the Choroid and Retina in Myopic Chinese Children. Ophthalmol Ther 2022; 11: 833-856
39 Yam JC, Jiang Y, Lee J, Li S, Zhang Y, Sun W, Yuan N, Wang YM, Yip BHK, Kam KW, Chan HN, Zhang XJ, Young AL, Tham CC, Cheung CY, Chu WK, Pang CP, Chen LJ. The Association of Choroidal Thickening by Atropine With Treatment Effects for Myopia: Two-Year Clinical Trial of the Low-concentration Atropine for Myopia Progression (LAMP) Study. Am J Ophthalmol 2022; 237: 130-138
40 Sander BP, Collins MJ, Read SA. The effect of topical adrenergic and anticholinergic agents on the choroidal thickness of young healthy adults. Exp Eye Res 2014; 128: 181-189
41 Ringer S, Gould A. ON JABORANDI. The Lancet 1875; 105: 157-159
42 Maehle AH. “Receptive Substances”: John Newport Langley (1852–1925) and his Path to a Receptor Theory of Drug Action. Med Hist 2004; 48: 153-174
43 Fang F, Huang F, Xie R, Li C, Liu Y, Zhu Y, Qu J, Zhou X. Effects of muscarinic receptor modulators on ocular biometry of guinea pigs. Ophthalmic Physiol Opt 2015; 35: 60-69
44 Tong L, Cui D, Zeng J. Effects of topical pilocarpine on ocular growth and refractive development in rabbits. Eur J Ophthalmol 2021; 31: 2107-2115
45 Maltsev DS, Kulikov AN, Vasiliev AS. Effect of Topical Pilocarpine on Choroidal Thickness in Healthy Subjects. Optom Vis Sci 2020; 97: 457
46 Packer M, Brandt JD. Ophthalmologyʼs botanical heritage. Surv Ophthalmol 1992; 36: 357-365
47 Jonas JB, Aung T, Bourne RR, Bron AM, Ritch R, Panda-Jonas S. Glaucoma. The Lancet 2017; 390: 2183-2193
48 Coleman AL, Miglior S. Risk factors for glaucoma onset and progression. Surv Ophthalmol 2008; 53 Suppl 1: S3-10
49 Lütjen-Drecoll E, Wiendl H, Kaufman PL. Acute and chronic structural effects of pilocarpine on monkey outflow tissues. Trans Am Ophthalmol Soc 1998; 96: 171-191 discussion 192–195
50 Li G, Farsiu S, Chiu SJ, Gonzalez P, Lütjen-Drecoll E, Overby DR, Stamer WD. Pilocarpine-Induced Dilation of Schlemmʼs Canal and Prevention of Lumen Collapse at Elevated Intraocular Pressures in Living Mice Visualized by OCT. Invest Ophthalmol Vis Sci 2014; 55: 3737-3746
51 Skaat A, Rosman MS, Chien JL, Mogil RS, Ren R, Liebmann JM, Ritch R, Park SC. Effect of Pilocarpine Hydrochloride on the Schlemm Canal in Healthy Eyes and Eyes With Open-Angle Glaucoma. JAMA Ophthalmol 2016; 134: 976-981
52 Zimmerman TJ, Wheeler TM. Miotics: side effects and ways to avoid them. Ophthalmology 1982; 89: 76-80
53 Ritch R. The pilocarpine paradox. J Glaucoma 1996; 5: 225-227
54 Price Jr FW, Hom M, Moshirfar M, Evans D, Liu H, Penzner J, Robinson MR, Lee S, Wirta DL. Combinations of Pilocarpine and Oxymetazoline for the Pharmacological Treatment of Presbyopia: Two Randomized Phase 2 Studies. Ophthalmology Science 2021; 1
55 Waring 4th GO, Price Jr FW, Wirta D, McCabe C, Moshirfar M, Guo Q, Gore A, Liu H, Safyan E, Robinson MR. Safety and Efficacy of AGN-190584 in Individuals With Presbyopia: The GEMINI 1 Phase 3 Randomized Clinical Trial. JAMA Ophthalmol 2022; 140: 363-371
56 Westheimer G. Topical Review: Pilocarpine-induced Miosis as Help for Early Presbyopes?. Optom Vis Sci 2022; 99: 632
57 Tucker T, Early J. Pilocarpine 1.25 % Ophthalmic Solution (Vuity) for the Treatment of Presbyopia. Am Fam Physician 2023; 107: 659-660
58 Neag MA, Mocan A, Echeverría J, Pop RM, Bocsan CI, Crişan G, Buzoianu AD. Berberine: Botanical Occurrence, Traditional Uses, Extraction Methods, and Relevance in Cardiovascular, Metabolic, Hepatic, and Renal Disorders. Frontiers in Pharmacology 2018; 9
59 Sobhani Z, Akaberi M, Amiri MS, Ramezani M, Emami SA, Sahebkar A. Medicinal Species of the Genus Berberis: A Review of Their Traditional and Ethnomedicinal Uses, Phytochemistry and Pharmacology. In: Barreto GE, Sahebkar A. Hrsg. Pharmacological Properties of Plant-Derived Natural Products and Implications for Human Health. Cham: Springer International Publishing; 2021: 547-577
60 Song D, Hao J, Fan D. Biological properties and clinical applications of berberine. Front Med 2020; 14: 564-582
61 Lan J, Zhao Y, Dong F, Yan Z, Zheng W, Fan J, Sun G. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol 2015; 161: 69-81
62 Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. The Lancet 2010; 376: 124-136
63 Madsen-Bouterse SA, Kowluru RA. Oxidative stress and diabetic retinopathy: Pathophysiological mechanisms and treatment perspectives. Rev Endocr Metab Disord 2008; 9: 315-327
64 Zhai J, Li Z, Zhang H, Ma L, Ma Z, Zhang Y, Zou J, Li M, Ma L, Wang X, Li X. Berberine protects against diabetic retinopathy by inhibiting cell apoptosis via deactivation of the NF-κB signaling pathway. Mol Med Rep 2020;
65 Fang W, Huang X, Wu K, Zong Y, Yu J, Xu H, Shi J, Wei J, Zhou X, Jiang C. Activation of the GABA-alpha receptor by berberine rescues retinal ganglion cells to attenuate experimental diabetic retinopathy. Front Mol Neurosci 2022; 15: 930599
66 Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Sig Transduct Target Ther 2017; 2: 17023
67 Chen H, Ji Y, Yan X, Su G, Chen L, Xiao J. Berberine attenuates apoptosis in rat retinal Müller cells stimulated with high glucose via enhancing autophagy and the AMPK/mTOR signaling. Biomed Pharmacother 2018; 108: 1201-1207
68 Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 2018; 19: 349-364
69 Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 2007; 8: 741-752
70 Mecchia A, Palumbo C, De Luca A, Sbardella D, Boccaccini A, Rossi L, Parravano M, Varano M, Caccuri AM. High glucose induces an early and transient cytoprotective autophagy in retinal Müller cells. Endocrine 2022; 77: 221-230
71 Sbardella D, Tundo GR, Mecchia A, Palumbo C, Atzori MG, Levati L, Boccaccini A, Caccuri AM, Cascio P, Lacal PM, Graziani G, Varano M, Coletta M, Parravano M. A novel and atypical NF-KB pro-inflammatory program regulated by a CamKII-proteasome axis is involved in the early activation of Muller glia by high glucose. Cell Biosci 2022; 12: 108
72 Wang N, Zhang C, Xu Y, Tan HY, Chen H, Feng Y. Berberine improves insulin-induced diabetic retinopathy through exclusively suppressing Akt/mTOR-mediated HIF-1α/VEGF activation in retina endothelial cells. Int J Biol Sci 2021; 17: 4316-4326
73 Jingi AM, Tankeu AT, Ateba NA, Noubiap JJ. Mechanism of worsening diabetic retinopathy with rapid lowering of blood glucose: the synergistic hypothesis. BMC Endocr Disord 2017; 17: 63
74 Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E. Insulin Stimulates Hypoxia-inducible Factor 1 through a Phosphatidylinositol 3-Kinase/Target of Rapamycin-dependent Signaling Pathway. J Biol Chem 2002; 277: 27975-27981
75 Meng D, Mei A, Liu J, Kang X, Shi X, Qian R, Chen S. NADPH Oxidase 4 Mediates Insulin-Stimulated HIF-1α and VEGF Expression, and Angiogenesis In Vitro. PLoS One 2012; 7: e48393
76 Arrigo A, Aragona E, Bandello F. VEGF-targeting drugs for the treatment of retinal neovascularization in diabetic retinopathy. Ann Med 2022; 54: 1089-1111
77 Fu D, Yu JY, Connell AR, Yang S, Hookham MB, McLeese R, Lyons TJ. Beneficial Effects of Berberine on Oxidized LDL-Induced Cytotoxicity to Human Retinal Müller Cells. Invest Ophthalmol Vis Sci 2016; 57: 3369
78 Imenshahidi M, Hosseinzadeh H. Berberine and barberry (Berberis vulgaris): A clinical review. Phytother Res 2019; 33: 504-523
79 Bindu S, Rameshkumar KB, Kumar B, Awantika S, Anilkumar C. Distribution of reserpine in Rauvolfia species from India – HPTLC and LC–MS studies. Ind Crops Prod 2014; 62: 430-436
80 Curzon G. How reserpine and chlorpromazine act: the impact of key discoveries on the history of psychopharmacology. Trends Pharmacol Sci 1990; 11: 61-63
81 Shamon SD, Perez MI. Blood pressure‐lowering efficacy of reserpine for primary hypertension. Cochrane Database Syst Rev 2016; (2016) CD007655
82 Tsioufis C, Thomopoulos C. Combination drug treatment in hypertension. Pharmacol Res 2017; 125: 266-271
83 Weir MR. Reserpine: A New Consideration of an Old Drug for Refractory Hypertension. Am J Hypertens 2020; 33: 708-710
84 Beers MH, Passman LJ. Antihypertensive Medications and Depression. Drugs 1990; 40: 792-799
85 Strawbridge R, Javed RR, Cave J, Jauhar S, Young AH. The effects of reserpine on depression: A systematic review. J Psychopharmacol 2023; 37: 248-260
86 Yaffe D, Forrest LR, Schuldiner S. The ins and outs of vesicular monoamine transporters. J Gen Physiol 2018; 150: 671-682
87 Wimalasena K. Vesicular monoamine transporters: Structure-function, pharmacology, and medicinal chemistry: VESICULAR MONOAMINE TRANSPORTERS. Med Res Rev 2011; 31: 483-519
88 Adams NA, Awadein A, Toma HS. The retinal ciliopathies. Ophthalmic Genet 2007; 28: 113-125
89 Chen HY, Swaroop M, Papal S, Mondal AK, Song HB, Campello L, Tawa GJ, Regent F, Shimada H, Nagashima K, de Val N, Jacobson SG, Zheng W, Swaroop A. Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects. Elife 2023; 12: e83205
90 Rachel RA, Yamamoto EA, Dewanjee MK, May-Simera HL, Sergeev YV, Hackett AN, Pohida K, Munasinghe J, Gotoh N, Wickstead B, Fariss RN, Dong L, Li T, Swaroop A. CEP290 alleles in mice disrupt tissue-specific cilia biogenesis and recapitulate features of syndromic ciliopathies. Hum Mol Genet 2015; 24: 3775-3791
91 Ashihara H, Sano H, Crozier A. Caffeine and related purine alkaloids: Biosynthesis, catabolism, function and genetic engineering. Phytochemistry 2008; 69: 841-856
92 Fredholm BB. Notes on the History of Caffeine Use. In: Fredholm BB. Hrsg. Methylxanthines. Berlin, Heidelberg: Springer; 2011: 1-9
93 Fischer E, Ach L. Synthese des Caffeïns. In: Fischer E. Hrsg. Untersuchungen in der Puringruppe. Berlin, Heidelberg: Springer; 1907: 219-227
94 Faudone G, Arifi S, Merk D. The Medicinal Chemistry of Caffeine. J Med Chem 2021; 64: 7156-7178
95 Dunwiddie TV, Masino SA. The Role and Regulation of Adenosine in the Central Nervous System. Annu Rev Neurosci 2001; 24: 31-55
96 Baratloo A, Rouhipour A, Forouzanfar MM, Safari S, Amiri M, Negida A. The Role of Caffeine in Pain Management: A Brief Literature Review. Anesth Pain Med 2016; 6: e33193
97 World Health Organization. World Health Organization Model List of Essential Medicines, 21st List, 2019. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. 2019;
98 Kolahdouzan M, Hamadeh MJ. The neuroprotective effects of caffeine in neurodegenerative diseases. CNS Neurosci Ther 2017; 23: 272-290
99 Madeira MH, Ortin-Martinez A, Nadal-Nícolas F, Ambrósio AF, Vidal-Sanz M, Agudo-Barriuso M, Santiago AR. Caffeine administration prevents retinal neuroinflammation and loss of retinal ganglion cells in an animal model of glaucoma. Sci Rep 2016; 6: 27532
100 Conti F, Lazzara F, Romano GL, Platania CBM, Drago F, Bucolo C. Caffeine Protects Against Retinal Inflammation. Frontiers in Pharmacology 2022; 12
101 Madeira MH, Elvas F, Boia R, Gonçalves FQ, Cunha RA, Ambrósio AF, Santiago AR. Adenosine A2AR blockade prevents neuroinflammation-induced death of retinal ganglion cells caused by elevated pressure. J Neuroinflammation 2015; 12: 115
102 Boia R, Elvas F, Madeira MH, Aires ID, Rodrigues-Neves AC, Tralhão P, Szabó EC, Baqi Y, Müller CE, Tomé ÂR, Cunha RA, Ambrósio AF, Santiago AR. Treatment with A2A receptor antagonist KW6002 and caffeine intake regulate microglia reactivity and protect retina against transient ischemic damage. Cell Death Dis 2017; 8: e3065
103 Kim J, Aschard H, Kang JH, Lentjes MAH, Do R, Wiggs JL, Khawaja AP, Pasquale LR. Intraocular Pressure, Glaucoma, and Dietary Caffeine Consumption: A Gene–Diet Interaction Study from the UK Biobank. Ophthalmology 2021; 128: 866-876
104 Kronschläger M, Löfgren S, Yu Z, Talebizadeh N, Varma SD, Söderberg P. Caffeine eye drops protect against UV-B cataract. Exp Eye Res 2013; 113: 26-31
105 Varma SD, Hegde KR. Prevention of Oxidative Damage to Lens by Caffeine. J Ocul Pharmacol Ther 2010; 26: 73-78
106 Varma SD, Hegde KR. Kynurenine-induced photo oxidative damage to lens in vitro: protective effect of caffeine. Mol Cell Biochem 2010; 340: 49-54
107 Varma SD, Kovtun S, Hegde K. Effectiveness of topical caffeine in cataract prevention: Studies with galactose cataract. Mol Vis 2010; 16: 2626-2633
108 Srinivasan P, Smolke CD. Biosynthesis of medicinal tropane alkaloids in yeast. Nature 2020; 585: 614-619
109 Srinivasan P, Smolke CD. Engineering cellular metabolite transport for biosynthesis of computationally predicted tropane alkaloid derivatives in yeast. Proc Natl Acad Sci U S A 2021; 118: e2104460118
110 Galanie S, Smolke CD. Optimization of yeast-based production of medicinal protoberberine alkaloids. Microb Cell Fact 2015; 14: 144
111 Han J, Li S. De novo biosynthesis of berberine and halogenated benzylisoquinoline alkaloids in Saccharomyces cerevisiae. Commun Chem 2023; 6: 27
112 McCoy E, OʼConnor SE. Natural products from plant cell cultures. In: Petersen F, Amstutz R. Hrsg. Natural Compounds as Drugs Volume I. Basel: Birkhäuser; 2008: 329-370
113 Furusaki S, Takeda T. 2.36 – Bioreactors for Plant Cell Culture☆. In: Moo-Young M. Hrsg. Comprehensive Biotechnology (Third Edition). Oxford: Pergamon; 2017: 519-530
114 Zhang F, Qiu F, Zeng J, Xu Z, Tang Y, Zhao T, Gou Y, Su F, Wang S, Sun X, Xue Z, Wang W, Yang C, Zeng L, Lan X, Chen M, Zhou J, Liao Z. Revealing evolution of tropane alkaloid biosynthesis by analyzing two genomes in the Solanaceae family. Nat Commun 2023; 14: 1446
115 Gong H, He P, Lan X, Zeng L, Liao Z. Biotechnological Approaches on Engineering Medicinal Tropane Alkaloid Production in Plants. Front Plant Sci 2022; 13: 924413
116 Humbal A, Pathak B. Influence of exogenous elicitors on the production of secondary metabolite in plants: A review (“VSI: secondary metabolites”). Plant Stress 2023; 8: 100166
117 Li W, Jiang R, Zhu Y, Zhou J, Cui C. Effect of 0.01 % atropine eye drops on choroidal thickness in myopic children. J Fr Ophtalmol 2020; 43: 862-868
118 Ye L, Shi Y, Yin Y, Li S, He J, Zhu J, Xu X. Effects of Atropine Treatment on Choroidal Thickness in Myopic Children. Invest Ophthalmol Vis Sci 2020; 61: 15
119 Jiang Y, Zhang Z, Wu Z, Sun S, Fu Y, Ke B. Change and Recovery of Choroid Thickness after Short-term Application of 1 % Atropine Gel and Its Influencing Factors in 6–7-year-old Children. Curr Eye Res 2021; 46: 1171-1177
120 Mathis U, Feldkaemper MP, Schaeffel F. Effects of Single and Repeated Intravitreal Applications of Atropine on Choroidal Thickness in Alert Chickens. Ophthalmic Res 2021; 64: 664-674
121 Zhou Y, Zhu Y, Huang XB, Xiong YJ, Guo YL, Cai Q, Wang M, Gong YX, Cao X, Li JJ, Cai JR, Song Y, Sun ZM. Changes of Choroidal Thickness in Children after Short-erm Application of 1 % Atropine Gel. Ophthalmic Res 2022;