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Mediterranean Journal of Chemistry 2021, 11(2), 126-132

Phytomolecules investigated for the prevention and treatment of urinary stones

Fatima Ezzahra El oumari 1,*, Dalila Bousta 2, Andriy Grafov 3 and Tarik Sqalli Houssaini 1

1 University Sidi Mohammed Ben Abdellah, Faculty of Medicine and Pharmacy, Fez, Morocco 2 University Sidi Mohammed Ben Abdellah, Faculty of Sciences Dhar El Mahraz, Fez, Morocco 3 University of Helsinki, Department of chemistry, Helsinki, Finland

Abstract: Urolithiasis is a recurrent pathology manifested by the stone formation in the urinary system; it has long been treated in traditional medicine by remedies. Several studies have provided the efficacy of medicinal as well as their chemical compounds against stone formation. The present work aims to summarize the antiurolithiatic effect of phytochemicals, including quercetin, rutin, catechin, , and thymoquinone. In this context, various databases, including PubMed, Science Direct, Scopus, and google scholar, were searched using keywords like antiurolithiatic bioactive molecules and chemistry of phytomolecules. The results confirmed that phytochemicals, including particularly flavonoid molecules, could be effective against lithogenesis via different strategies such as decreasing the binding between crystals and cells, decreasing the growth of crystals, and increasing magnesium level. Nevertheless, more studies are required, such as determination of toxicity and clinical studies. This review may help researchers achieve more results about the mechanism and the side effects of phytochemicals administration.

Keywords: Urolithiasis; phytomolecules; lithogenesis; toxicity.

1. Introduction The treatment is medical or surgical; the medical one is mainly based on applying hygienic and dietary Urolithiasis, a recurrent disease known as urinary rules, surveillance, and stones' spontaneous calculi or urinary stones, are hard deposits of minerals expulsion. Among the prescribed drugs for treating and salt formed anywhere in the urinary tract. We can stones, there are synthetic drugs like thiazide distinguish 3 terms; nephrolithiasis term used to diuretics(hydrochlorothiazide), alkali (potassium indicate stones formed in the kidneys. Ureterolithiasis citrate), allopurinol, sodium cellulose phosphate refers to ureteral stones, and Cystolithiasis term (SCP), penicillamine (Cuprimine), analgesic means the bladder calculi ¹. This disorder is the (diclofenac sodium), bisphosphonates, potassium, outcome of physicochemical steps; the initial step is phosphate, and probiotics (Oxalobacter formigenes) 9. the nucleation, characterized by the association of free For the surgical treatment, among the techniques ions into micro-particles after urine supersaturation. used, there are: percutaneous lithotripsy (PCNL), The following event is crystal growth, making crystals extracorporeal shock wave lithotripsy (ESWL), and grow by removing promoters of a stone formation transurethral lithotripsy (TL) 10,11. These treatments such as uric acid and urate from the urine ². The can lead to a decrease in renal function, hemorrhage, aggregation is the last event, during which the crystals and hypertension. Besides, they are expensive and do bind to those already established to form larger not prevent the recurrence of stone formation 12,13. particles ³. The etiology of this disease consists of Moreover, till now, there is no satisfactory drug to increased excretion of stone-forming components treat and prevent urolithiasis. such as calcium, oxalate, urate, cystine, xanthine, and phosphate and decreased urine volume 4. An excess of Medicinal plants possess a wide range of biological vitamin D can cause it, vitamin A deficiency, activities, such as antidiabetic, anticancer, hyperthyroidism, gout, intestinal dysfunction 5, and antiurolithiatic, and analgesic effects 14. Besides, it infection by bacteria such as Klebsiella pneumoniae, exhibits an antimicrobial property, including Pseudomonas and Oxalobacter formigenes 6. There antibacterial and antifungal activities 15. In addition, it are other etiological factors such as dietary risk, hot can also act as an anti-infertile agent 16. climate, and genetic factors 7,8. In folk medicine, urolithiasis has been treated by different herbal formulations. The decoction was the *Corresponding author: Fatima Ezzahra El oumari Received December 29, 2020 Email address: [email protected] Accepted January 29, 2021 DOI: http://dx.doi.org/10.13171/mjc02102271568fee Published February 27, 2021

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commonly used mode of herbal remedies 17. Dried phytomolecule substituted with two sugars: glucose powder, fresh leaves 14, and juice were also used 18. and rhamnose 34 (Figure 2), it has been studied for several biological activities among them, The side effects of medicinal plants and natural antihypercholesterolemic 35, anticancer 36, molecules are lesser than conventional treatment; antidiabetic 37, and antimicrobial activity 38. In therefore, several studies have examined medicinal addition, rutin exhibits a nephroprotective effect plants' anti-urolithiatic activity. Its effectiveness is against nephrotoxicity by diminishing the levels of due to its rich phytomolecules. The goal of this work MDA, urea, and creatinine and increasing glutathione is to summarize some chemical properties of peroxidase and superoxide dismutase 39,40. Rutin has phytomolecules and their antiurolithiatic effects. been found to be capable of inhibiting calcium oxalate

formation. Additionally, administration of rutin and 2. Search Methodology curcumin has been found to be capable of restoring PubMed, Science Direct, Scopus, and Google scholar the normal urinary levels of calcium and oxalate and databases were searched for bioactive phytomolecules inhibiting aggregation and growth of calcium oxalate investigated to prevent and treat urolithiasis. For monohydrate crystals 41. Catechin is another searching, we have used keywords like urolithiasis, nutraceutical bioactive chemical, chemically named anti-urolithiasis, antiurolithiatic bioactive molecules, (2S,3R)-2-(3,4 dihydroxyphenyl) chroman-3,5,7- the chemistry of phytomolecules. We considered that triol, has 4 enantiomers which are epicatechin, the studies are valuables if they include in vitro, in epicatechin gallate, epigallocatechin, and vivo studies for anti-urolithiatic effects, review, and epigallocatechin gallate (EGCG) (Figure 3), those research articles for bioactive molecules' chemistry. molecules have been found in many dietary plants Concerning the selection, collection, and synthesis of such as green tea, blackberries, and apricot. Various data, we have based on the articles' title and abstracts; studies have demonstrated the antiviral, anti-oxidant, then, we extracted a standard data form based on the and anti-inflammatory activities of catechin 42,43. first author's last name and year of publication. Additionally, epigallocatechin gallate (EGCG) has been reported to protect kidneys against acute kidney 3. Phytochemicals with anti-urolithiatic activity injury caused by cardiopulmonary bypass and its Chemical properties operation 44. Similarly, and regardless of the cause, EGCG exerts a protective effect against AKI 45. Anti- Many diseases can be prevented and/or treated by urolihiatic effect of catechin against stone formation phytomolecules, among them urolithiasis; within this suggested inhibiting renal papillary calcification 46. In context, multiple studies were carried out for the another study, catechin has shown a significant antiurolithiatic effect of phytoconstituents (Table 1). decrease in the number of crystals induced by Quercetin (pentahydroxyflavone) is one of the melamine-cyanuric acid mixture; this effect could be phytomolecules investigated for anti-urolithiatic attributed to its inhibitory effect of reactive oxygen 48 effect. It is a lipophilic molecule with five hydroxyl species, phospho-P38, and apoptosis . In addition, groups (Figure 1), categorized in flavonol class, EGCG has been found to be effective in the synthesized in leaves, flowers, or fruit plant parts, and prevention of stone formation via inhibiting the found in many dietary plants such as Onions 19, expression of alpha-enolase protein and thus Blueberry 20, and Mango 21. Due to the presence of decreasing the binding between crystals and MDCK 49 free hydroxyl groups, quercetin has exhibited a strong cells . 22 anti-oxidant activity . Additionally, it is effective Diosmin or 3’,5,7-trihydroxy-49-methoxyflavone 7- 23 against inflammation and diabetes . In an in vitro rutinoside (Figure 4), is a flavone glycoside study, the result showed that the decrease in MDCK compound, belongs to the family of citrus flavonoid, (Madin–Darby canine kidney) cell viability and lipid exhibits several remarkable biological activities such peroxidation were inhibited in the presence of as anti-inflammatory, antihypertensive, anti-oxidant, 24 quercetin . Quercetin and hyperoside were studied vascular-protecting activity and chemopreventive using Ethylene Glycol Induced calcium oxalate effect against colon carcinogenesis 51. This kidney stones in a rat model. The result showed a nutraceutical agent exerts a nephroprotective effect by significant increase in superoxide dismutase and attenuating lipid peroxidation and modulating Bax catalase levels; the histopathological examination and p53 protein expression 52. In addition, diosmin has showed a significant decrease of crystals in the been reported to modulate capillaries and vessels 25 kidneys of quercetin-hyperoside treated group . diameter of the cortex; it could prevent urolithiasis by Additionally, the co-administration of quercetin and keeping the acidic value of urinary pH; its preventive betulin (isolated from aerva lanata L.) reduced the property against stone formation could also be risk of stone formation by decreasing oxalate attributed to the decrease of urinary protein level and excretion, nucleation, and growth of crystals as well the increase of potassium and magnesium urinary 26 as increasing magnesium level . levels 53,54. Thymoquinone (2-Isopropyl-5-methyl-1, Rutin or 3, 3ʹ, 4ʹ, 5, 7-pentahydroxyflavone-3- 4-benzoquinone) (Figure 5) is a nonpolar bioactive Rhamnoglucoside is a derivative of quercetin also phytochemical and a major compound of Nigella named quercetin 3-O-rutinoside, it is a bioactive Sativa seeds that categorized in monoterpenes class; it Mediterr.J.Chem., 2021, 11(2) F. E. El oumari et al. 128

can be found in other plants like Juniperus Cedrus activity 55. This phytochemical has been investigated Webb & Berthel and Tetraclinis articulate (Vahl) on Ethylene Glycol-Induced urolithiasis in the Rats Mast. 32, it covers a wide range of pharmacological model. The result of this study indicated that a low properties which include antioxidant, anti- dose of thymoquinone (5mg/Kg) could be more inflammatory, anti-Alzheimer, hepatoprotective, effective with a significant prophylactic effect against neuroprotective, anticancer, and nephroprotective CaOx stone formation 56.

Table 1. Chemical properties of phytomolecules and their effect on calculi formation. Molecular Molecular Phytochemical weight Plant source Effect on stone formation formula g/mol Inhibits the Decrease of lipid peroxidation Allium cepa L., and cell viability caused by oxalate 24. Camellia sinensis (L.) Kuntze, Moringa oleifera Decrease crystal deposition in kidneys Quercetin C15H10O7 302.23 25 Lam., Apium graveolens L., and urine . Prunus avium (L.) L. Reduce oxidative damage and increase Coriandrum sativum L... 27 serum paraoxonase 1(PON1) which can protect kidneys against oxidative stress 33. Ruta graveolens L., Sophora Decrease MDA, urea, and creatinine. japonica L., Canna indica Increase glutathione peroxidase and Rutin 39 C27H30O16 610.5 L., Canna edulis superoxide dismutase . KerGawl…28 Restores normal calcium and oxalate urinary levels 41.

Arrabidaea Decrease calcium oxalate crystals and brachypoda Bureau, reduce papillary calcification 40. Rhizophora mangle L.29 Increase osteopontin (OPN), decrease Camellia sinensis (L.) malondialdehyde (MDA) and calcium Catechin C15H14O6 290.27 Kuntze, crystallization 47. Actinidia deliciosa (A.Chev.) Decrease crystal deposition in kidneys C.F.Liang & A.R.Ferguson, induced by melamine-cyanuric acid Malus pumila Mill...30 mixture 48. Decrease the binding between crystals and Camellia sinensis (L.) MDCK cells by inhibiting the expression Epigallocatechin C22H18O11 458.4 Kuntze, of alpha-enolase protein 49. gallate Theobroma cacao L...31 Reduce free radical production and oxalate excretion in urine 50.

Citrus lemon (L.), Citrus Increase urinary magnesium and 52 reticulate Blanco, and Citrus potassium levels . Diosmin C28H32O15 608.5 sinensis (L. Osbeck) Prevent stone formation by attenuating gnaphalodes lipid peroxidation and modulating Bax 53 L'Hér... 54. and p53 proteins expression . Reduce CaOx crystal deposition in the Nigella Sativa L., Nigella kidneys 56. arvensis L., Juniperus Decrease serum creatinine and urea levels. Thymoquinone C10H12O2 164.2 Cedrus Webb & Berthel. and Reduce lipid peroxidation, Tetraclinis articulate (Vahl) malondialdehyde (MDA) and 8- Mast. 32 isoprostane 57.

Figure 1. Chemical structure of quercetin Figure 2. Chemical structure of rutin

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Figure 3. Chemical structure of the four enantiomers of catechin

Figure.4 Chemical structure of Diosmin Figure.5 Chemical structure of thymoquinone

Urinary stones are a recurrent disorder that can lead to suppression of the bound between crystals and tubular chronic kidney diseases (CKD) and acute kidney epithelial cells, Decreasing MDA, and regulation of injury (AKI) 58. The actual treatments (medical or serum PON1 33,47. The mechanism by which surgical) described to patients with urinary calculi are thymoquinone can manage kidney stones is still quite restricted. Some drugs like alkali-citrate are unknown. But as some studies have demonstrated it, described to patients to prevent calculi formation, but thymoquinone can probably inhibit urolithiasis by their efficacy is low. Thus, they are not entirely decreasing lipid peroxidation and MDA, as well as preventing urolithiasis 59. Medicinal plants represent reducing the serum levels of creatinine and urea 57. an essential source of prophylactic and therapeutic The result obtained from the available literature remedies to treat several disorders, including urinary showed that all of the phytochemicals are stones. nutraceutical. They can be effective against stone In vitro and in vivo studies on the preventive and formation through several mechanisms, among them therapeutic effect of phytomolecules revealed that the the antioxidant activity. This later is strongly mentioned chemicals could inhibit stone formation correlated to the anti urolithiatic effect. Unfortunately, using various mechanisms, including decreasing the current results cannot confirm the effectiveness of crystal deposition in the kidneys and increasing these molecules without testing their toxicity and their glutathione peroxidase superoxide dismutase, and cell effects on human health. Further research is needed to viability 24,58. Phytochemicals also use other strategies establish more results about the safety and efficacy of to prevent urinary stone formation, such as patients with urinary stones.

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