Antiurolithiatic Potential of Tagetes erecta: A Review of Its Phytochemistry and Pharmacological Insights

Kidney stone disease, also known as urolithiasis, is a common urological condition marked by the development of calculi in the urinary tract. Urolithiasis has been becoming more common worldwide; research shows that its lifetime frequency in Western nations ranges from 3% to 5% for females and from 8% to 19% for males ^[1]. Approximately 1 out of 11 people in the US are impacted, which results in high medical costs and more than a million-emergency room visits each year ^[2]. The pathophysiology of urolithiasis is complex and includes crystal nucleation, development, aggregation, retention in the kidneys, and supersaturation of urine with components that cause stones. Stone formation is affected by various factors, such metabolic disorders, genetic susceptibility, dietary habits, and dehydration ^[3]. The most prevalent kinds of stones include cystine, struvite, uric acid, calcium phosphate, and calcium oxalate ^[4].

Epidemiology and Socioeconomic Burden

Urolithiasis is a common condition that is becoming more common in many parts of the world. Despite a minor drop in age-adjusted incidence rates, the Global Burden of According to the 2019 Disease Study, there were 115.55 million annual cases in 2019 compared to 77.78 million in 1990 ^[5]. Its prevalence is largely caused by hot weather and inadequate fluid intake in regions like the Middle East and South Asia. About 8.4% of people in the US are impacted, and men are more vulnerable ^[6]. A significant financial burden is also imposed by urolithiasis because of recurrent episodes, numerous hospital stays, and surgical procedures, all of which raise direct and indirect medical expenses ^[7].

Etiology and Risk Factors

Urolithiasis is caused by a confluence of various factors such as environmental, metabolic, & hereditary. Urinary excretion of chemicals that create stones is increased by conditions such as cystinuria and hyperoxaluria ^[8]. Metabolic disorders including hypocitraturia and hypercalciuria also contribute to the development of stones by upsetting the equilibrium between inhibitors and promoters of crystallization ^[9]. Excessive ingestion of animal protein, sodium, and oxalate, along with dehydration, obesity, and alcohol use, are external risk factors that raise urine concentrations or acidity, which promotes the development of stones ^[10].

Types and Composition of Urinary Stones

The classification of urinary stones is based on their chemical makeup, which influences how they develop, are diagnosed, and are treated. Approximately 75–85% of cases are calcium stones, which are the most prevalent type. These mostly consist of calcium oxalate stones, which are associated with metabolic problems and arise in urine that is supersaturated with calcium and oxalate. Usually, these stones form in alkaline urine ^[11]. Gout, metabolic syndrome, and excessive purine intake are linked to uric acid stones, which make up 5–10% of all stones and develop in acidic urine ^[12]. Urease-producing bacteria cause struvite stones, also known as infection stones, to form in alkaline urine. These stones frequently form huge staghorn calculi that need to be surgically removed^[13]. Cysteinuria, a hereditary condition that causes excessive cystine excretion and repeated stone formation, is the cause of rare cystine stones ^[14].

Pathophysiology of Urolithiasis

Calcium oxalate is the most common type of kidney stone, and it forms along the surfaces of renal papillaries at Randall's plaque. Urinary stone components undergo a complex procedure of creation that includes physicochemical processes such as supersaturation, nucleation, aggregation, and retention inside tubular cells. These processes are impacted when the factors that promote or inhibit urine crystallization are out of balance. Furthermore, cellular injury has been demonstrated to promote particle retention on renal papillary surfaces ^[15]. In renal epithelial cells, exposure to oxalate sets off a series of signals that ultimately cause apoptosis through p38 MAP-kinase channels. There is currently no effective drug for treating kidney stones or prevent them from occurring in the future. Therefore, a better knowledge of the process underlying kidney stone formation is one field that is being studied for curing urolithiasis with new drugs. Therefore, the purpose of this study was to provide an extensive overview of the state of knowledge about kidney stone origin, pathophysiology, and prevention techniques. When lithogenic ions including Ca²⁺, oxalate, phosphate, and uric acid are supersaturated in urine, their solubility is exceeded and crystallization is allowed, which starts the formation of stones ^[16].

Figure 1: Pathophysiology of Urolithiasis

Limitations of Current Therapies

Surgical and conservative methods are used to treat urolithiasis, depending on the patient's unique circumstances, the size and placement of the stone, and other considerations. Conservative treatment involves dietary changes like cutting back on sodium and animal protein, increasing fluid intake to keep urine output above 2.5 liters per day, and using medications like potassium citrate, thiazide diuretics, or allopurinol to help correct metabolic abnormalities and stop recurrence ^[17]. Surgical options are taken into consideration when the stones are big, symptomatic, or obstructive. Percutaneous nephrolithotomy (PCNL) is appropriate for big or complex renal calculi, ureteroscopy (URS) works well for mid-to-distal ureteral stones, and extracorporeal shock wave lithotripsy (ESWL) is recommended for renal stones smaller than 2 cm ^[18]. Treatment-associated problems, recurrence risk, and inconsistent clinical standards are among the issues that persist despite technological advancements.

Potential of Medicinal Plants in Urolithiasis

The investigation of medicinal plants for the treatment of urolithiasis has attracted interest because of their diverse therapeutic qualities and minimal adverse impact profiles. Numerous facets of stone development and advancement can be addressed by phytotherapeutic substances' anti-inflammatory, antioxidant, diuretic, and litholytic properties ^[19]. In experimental models, a number of plants, including Coriandrum sativum (coriander) and Spinacia oleracea (spinach), have shown antiurolithiatic properties. These plants work through processes such as diuresis augmentation, urinary pH regulation, and suppression of crystal aggregation. Such herbal therapies could provide accessible and economical alternatives for the prevention  treatment of urolithiasis if they are incorporated into clinical practice ^[20].

Tagetes Erecta

Tagetes erecta, a blooming plant in the Asteraceae family, is also referred to as marigold. Its therapeutic qualities have historically been utilized in many cultures to treat infections, inflammation, and digestive issues ^[21]. Phytochemical studies have revealed bioactive compounds such as flavonoids, carotenoids, and essential oils, that increases the plant's potential for medicinal application ^[22]. T. erecta extracts have been shown in recent research to have diuretic and natriuretic actions in animal models, indicating a possible function in encouraging urine evacuation and avoiding the formation of stones. In light of its pharmacological characteristics and historical application in treating renal conditions, T. erecta shows promise as a subject for additional research in the treatment of urolithiasis ^[23].

Botanical Description

The aromatic herb T. erecta can reach a height of 120 cm and is erect and branching. It has big, solitary flower heads made of ray and disc florets, as well as pinnately split leaves with serrated edges. The inflorescences might be rich orange or golden yellow in hue. An achene is the fruit, and the essential oil in the plant gives it a powerful aroma. Mostly found in tropical and subtropical areas, it can flourish in a range of soil types and climates and is spread by seeds ^[24].

Figure 2: Tagetes erecta plant and its botanical description

Geographical Distribution

Originally indigenous to Mexico and Central America, T. erecta is now grown all over the world, particularly in the southern United States, China, India, and Africa. It is an essential part of these areas' traditional medicinal systems as well as commercial agriculture ^[25].

Traditional and Medicinal Uses

Tagetes erecta has been used traditionally for therapeutic purposes in many cultures, according to ethnopharmacological archives. Because of its remarkable antibacterial and wound-healing qualities, plant has been used extensively to treat wounds and skin infections. Additionally, it has long been used to treat eye conditions, especially conjunctivitis. T. erecta has been used in the field of gastrointestinal health to treat conditions like diarrhea ^[26].

Phytochemical Investigations of Tagetes erecta

The therapeutic benefits of Tagetes erecta are attributed to its abundance of various bioactive substances. One of T. erecta's most prevalent secondary metabolites are flavonoids, which are especially prevalent in the petals. Patuletin, kaempferol, isorhamnetin, quercetagetin, and its glycosides have all been found using sophisticated analytical methods including LC-MS and HPLC-DAD ^[27]. Total flavonoid concentration has been observed to vary between 15 and 25 mg QE/g dry extract, depending upon the solvent used and the maturation stage of the plant. These flavonoids have a substantial role in both pigmentation as well as antioxidant activity ^[28,29]. Reverse-phase HPLC is used to quantify the presence of phenolic acids, such as gallic acid, chlorogenic acids, caffeic acid, ellagic acid, and syringic acid, at about 8–12 mg GAE/g dry extract. The DPPH and ABTS tests show that these substances improve the plant's ability to scavenge free radicals ^[30,31]. Using GC-MS, terpenoids and phytosterols like stigmasterol, erythrodiol, lupeol, and β-amyrin have been found. The leaves and stems are very rich in these; the total terpenoid content is estimated to be 20–30 mg/g, and GC–FID is used to quantify specific sterols, such as stigmasterol, between 0.5 and 1.2 mg/g ^[32]. Petal chromoplasts have been shown to include carotenoids such as lutein (15mg/100g), zeaxanthin (5-8mg/100g), violaxanthin, and β-carotene (in negligible levels) that are important for colour and eye health. Their concentrations are affected by environmental elements including light exposure and reach their maximum during full bloom ^[33]. Mono- and sesquiterpenes make up the majority of T. erecta's essential oil makeup, according to GC-MS analysis. The main components are limonene (6–10%), (E)-ocimenone (5–7%), β-caryophyllene (3–5%), dihydrotagetone (12–15%), (Z)-β-ocimene (35–42%), and (Z)-tagetone (7–8%). Fresh leaves and flowers can generate 0.3–0.6% essential oil (w/w) using hydrodistillation. These six volatile chemicals consistently make up more than 80% of the overall oil content, according to studies conducted in different geographical areas^[26]. The traditional and contemporary therapeutic usage of Tagetes erecta is justified by the combination of these phytochemicals, which support a wide variety of pharmacological potentials, especially anti-inflammatory, antioxidant, hepatoprotective, diuretic, antibacterial, and antiurolithiatic characteristics.

Figure 3: Phytochemical Profile of Tagetes erecta

Pharmacological Properties of Tagetes erecta

Antioxidant Activity

Tagetes erecta's high concentration of phenolics and flavonoids, including quercetagetin and patulitrin, gives it potent antioxidant qualities. Because oxidative stress is a major contributor to many degenerative diseases, these bioactive chemicals help the plant scavenge free radicals and lessen it. The strong antioxidant capacity of T. erecta extracts was confirmed by a recent investigation that showed significant DPPH and ABTS radical scavenging activities ^[24]. Additionally, it has been demonstrated that the antioxidant-rich extract stabilizes oils against oxidation, confirming its usefulness in pharmaceutical and food preservation applications ^[27].

Anti-inflammatory Activity

Studies conducted in vitro and in vivo shown that T. erecta has anti-inflammatory properties. According to one study, the plant's extract effectively decreased inflammation by modifying important inflammatory indicators and reducing neutrophil migration²¹. Furthermore, in a rat model of ulcerative colitis T. erecta extract enhanced with lutein dramatically decreased inflammatory cytokine levels while simultaneously enhancing indicators for oxidative stress. These results bolster its possible application in the treatment of inflammatory conditions ^[28].

Antimicrobial Activity

Broad-spectrum antibacterial activity has been demonstrated by T. erecta extracts. Ethanolic floral extracts demonstrated efficacy against a number of bacterial and fungal species, such as Candida albicans, Staphylococcus aureus, and E. coli, in a preliminary study³⁴. When combined with traditional antibiotics, solvent-based extracts showed synergistic action, according to another study assessing them ^[35]. This demonstrates its potential for creating substitute antibacterial agents.

Diuretic and Natriuretic Effects

Recent pharmacological studies have substantiated the traditional usage of T. erecta as a diuretic. Both hypertension and normotensive rats' sodium excretion and urine volume were markedly elevated by a hydroethanolic floral extract. Bioactive substances may interact with muscarinic acetylcholine receptors to enhance renal fluid excretion and provide this diuretic action ^[23].

Antidiabetic Activity

T. erecta has shown to have antidiabetic properties through α-glucosidase inhibition, which helps regulate blood glucose levels after meals. Flower extracts were found to strongly block enzymes that hydrolyze carbohydrates in one research ^[36]. Furthermore, in diabetic mice administered T. erecta extract, an in vivo investigation showed decreased blood glucose and enhanced insulin sensitivity ^[37].

Hepatoprotective Activity

It is also well known that T. erecta has hepatoprotective properties. In models of hepatotoxicity caused by CCl?, the extract restored liver histology, strengthened antioxidant defenses, and dramatically decreased liver enzyme levels. An additional investigation employing ethanol-induced liver damage validated the plant's ability to restore biochemical markers and hepatic architecture ^[38].

Mechanistic Relevance to Urolithiasis

Oxidative Stress role in Urolithiasis

The pathophysiology of urolithiasis is significantly influenced by oxidative stress. One important step in the growth of kidney stones is the adhesion and retention of calcium oxalate crystals, which might be facilitated by reactive oxygen species (ROS) and free radicals damaging renal tubular epithelial cells. Additionally, oxidative injury raises inflammation and lipid peroxidation, which encourages crystal aggregation and the formation of stones ^[24]. Strong antioxidants like phenolic acids, carotenoids (lutein, zeaxanthin), & flavonoids (quercetagetin, patuletin) are abundant in Tagetes erecta. These substances may shield renal tissues from damage brought on by crystals by reducing oxidative stress and neutralizing ROS. Through tests like DPPH and ABTS, research has confirmed the antioxidant potential of T. erecta extracts, thereby bolstering their application in conditions like urolithiasis that are linked to oxidative stress ^[39].

Anti-inflammatory Effects and Renal Protection

Inflammation aggravates kidney damage caused by crystals. Further epithelium damage and fibrosis result from calcium oxalate crystals activating NLRP3 inflammasomes and stimulating the production of inflammatory cytokines such IL-1β, TNF- α, and IL- 6. By inhibiting inflammatory mediators, Tagetes erecta demonstrates potent anti-inflammatory properties. The plant's flavonoids inhibit the release of pro-inflammatory cytokines, COX-2 expression, and NF-κB activation. These exercises can lessen renal inflammation brought on by crystals, preventing tissue damage and delaying the course of urolithiasis^[40].

Diuresis and Urinary Stone Prevention

By diluting urine and lowering the supersaturation of lithogenic salts like calcium and oxalate, diuresis is a basic treatment approach for preventing kidney stones ^[41]. Aqueous and hydroalcoholic Tagetes erecta extracts have been demonstrated in numerous investigations to enhance electrolyte excretion and urine production. Because its flavonoids and essential oils alter renal tubular transit, they are thought to have a diuretic impact. In order to reduce the danger of stone formation, increased urine flow which can  help in the removal of tiny crystals and lessen their aggregation ^[23].

Synergistic Action of Bioactive Compounds

Tagetes erecta's diverse defensive benefits are the result of the complex phytochemical profile's synergistic activity rather than a single molecule. Collectively, flavonoids, phenolic acids, carotenoids, and essential oils have the following effects: they have antioxidant properties by neutralizing free radicals; they have anti-inflammatory properties by suppressing inflammatory pathways; and they have a diuretic effect by encouraging urine production and solute excretion. Its status as a viable antiurolithiatic option is greatly enhanced by this combination. Studies indicate that plant-based remedies with several active ingredients frequently provide better protective outcomes, mostly as a result of the elements' additive or synergistic interactions ^[42].

Figure 4: Proposed Mechanisms of Antiurolithiatic Action of Tagetes erecta.