Ethnopharmacology and therapeutic potentials of Oxalis corniculata : an in-depth study

Background For centuries, plants have been used in the folk medicine of various cultures for their healing properties. It is amazing how nature has provided us with such powerful remedies. Oxalis corniculata ( O. corniculata ) has always been used traditionally for its medicinal attributes. In Asia, this herbaceous plant is used for treating many gastrointestinal disorders, such as diarrhea and dysentery. In African folk medicine, on the other hand, this herb is used for respiratory diseases, skin diseases, and fever. Main body Scientific research has revealed numerous pharmacological potentials of this plant, including antitumor, antimicrobial, antioxidant, anti-inflammatory, and hepatoprotective properties. In addition, studies have indicated that the extract of this plant protects against oxidative stress, inflammation, and various diseases, including cancer and diabetes. Phytochemical analysis of O. corniculata revealed various relevant compounds, including phenolic acids, flavonoids, and alkaloids, which are responsible for its therapeutic properties. Conclusion The various constituents of this plant have significant ethnomedicinal potential. The plant is a possible source of extracts and chemical compounds with pharmacological activity. In the future, O. corniculata could have an effective role in the development of modern drugs. The objective of this review is to summarize the current knowledge on the medicinal potential of O. corniculata , including its bioactive compounds, mechanisms of action, and therapeutic applications.


Graphical abstract 1 Background
Oxalis corniculata (O.corniculata) is an herbaceous perennial plant that belongs to the Oxalidaceae family [1] and is known for its clover-like leaves and yellow flowers [2].Taxonomic studies have placed O. corniculata in the section Corniculatae of the genus Oxalis.This section includes several other species, and taxonomic revisions have been conducted to better understand the morphological delimitation and relationships within this section [3].It is a cosmopolitan species which is extensively spread in tropical and temperate areas [4,5].In some areas, such as Japan, it is considered a non-native species, as it is thought to have been colonized there in prehistoric times [6].Its exact origin is still uncertain [7].The plant is often found in habitats such as roadsides and cultivated fields.Concerning its ecological interactions, the butterfly lays its eggs on the leaves of O. corniculata, as these serve as a host for its larvae [8].The use of this plant has been described in several researches owing to its medicinal possessions and biological activities [9].It is known to have antioxidant activities and antiradical potential due to its secondary metabolites [10].The flavonoids found in O. corniculata have been researched for their potential health benefits.These compounds have antioxidant properties, can scavenge free radicals, and may aid in the prevention of coronary heart disease [11].In addition, studies have investigated the antibacterial effect of the plant, particularly against Staphylococcus aureus biofilms, due to the presence of different bioactive constituents such as alkaloids, phenols, and flavonoids [12,13].These properties make this plant valuable in the arenas of medicine and pharmacy.
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Methods
This review on O. corniculata was compiled using literature from six databases: SciFinder, PubChem, Scien-ceDirect, Scopus, PubMed, Google Scholar, and Web of Science.The articles included in the review were published in English before August 2023 and focused on the various phytochemicals isolated from distinct parts of O. corniculata, the pharmacological activities of the extracts, and their therapeutic uses.The keywords used to retrieve related studies were in vitro systems, virtual screening and animal studies, O. corniculata, creeping wood sorrel, ethnopharmacology, phytochemical constituents, traditional medicine, pharmacological properties, and phytochemistry.

Traditional uses
O. corniculata is used in folk medicine to alleviate various ailments [27].In India, this plant is considered astringent, antiscorbutic, cooling, and helpful in the treatment of rectal prolapse, dysentery, fever, and biliousness [28].In rural parts of Pakistan, Jammu & Kashmir, O. corniculata is one of the most commonly mentioned species used for the treatment of diabetes [29].The herb is also recognized in folk medicine schemes viz.Siddha, Unani, and Ayurveda [30].The plant is widely distributed and has been recorded as a common weed in various regions, including Southeast Asia, Tanzania, Egypt, and India [4,7,31,32].The plant is native to inhabitants of Southeast Asia and is commonly utilized as a remedy in this region [7].The plant has acclimatized in Japan and other regions of the world [4].Its versatility and broad spectrum of biological activity make it a valuable medicinal plant [33].
Traditionally, it is also used for the treatment of complications like diarrhea, ulcers in the stomach, toothache, and tonsillitis [13,28,34,35].In Tanzania, extracts of the plant are used traditionally for medicines [13].The plant is also commonly used as medicine in Southeast Asia, indicating a long association with the society in the region [7].Ethnobotanical studies in the Balasore district of Odisha, India, have shown that this plant is consumed as a leafy vegetable by the local communities and reportedly has ethnomedicinal uses against gastrointestinal ailments, especially gastrointestinal disorders and diarrhea [32].This herb is also used as livestock feed [36].The plant has been found to have gastroprotective effects, with significant antisecretory and antiulcer properties, supporting its traditional use as a remedy for peptic ulcers [35].The traditional use and bioactivity of this plant suggest its potential as a source of dietary supplements and pharmaceuticals [10].

Pharmacological activities of Oxalis corniculata
The leaf and whole plant of O. corniculata have been studied for their pharmacological properties.An overview of these activities is presented in Table 1.

Antimicrobial activity
Recent research has revealed that different organic solvents can extract other phytochemicals from plants [71], each with varying antimicrobial activity [72].The Ethanol and Methanol fractions of O. corniculata have shown notable effectiveness in combating Staphylococcus aureus [48] and its biofilm formation ability [12], along with some clinical isolates of Vibrio cholerae [49] Staphylococci species, Salmonella typhi [50] and some Multi-Drug Resistant (MDR) strains of Citrobacter koseri, Salmonella typhi, and Klebsiella pneumoniae [51].n-butanol and n-hexane soluble fractions also had significant antimicrobial activity for bacterial strains Shigella dysenteriae, Bacillus subtilis, Salmonella typhi, and strains of fungus, Fusarium solani, Aspergillus flavus, and Aspergillus flexneri [52].Apart from organic extracts, water extract was also effective against Candida albicans [13].The cream made out of oil in a water-based emulsion and a 20% fresh leaf extract was also effective against bacterial strains of Escherichia coli and Staphylococcus aureus [53].

Anticancer activity
Several studies have investigated the anticancer potential of O. corniculata.One study suggested that the ethanolic extract may cause apoptosis in the MCF7, a breast cancer cell line, by inducing oxidative stress and can exhibit significant anticancer and antitumor activity in Swiss albino mice [41,42].The hydroalcoholic extract and ethyl acetate fraction have demonstrated the ability to inhibit the growth of the Hep-G2 cancer cell line; further molecular docking study with phytoconstituents of O. corniculata demonstrated that among different compounds, apigenin possesses strong binding energy of − 7.90 kcal/mol compared to the standard drug doxorubicin, which possesses − 7.63 kcal/mol against the epidermal growth factor receptor tyrosine kinase [27].Another in silico study identified isovitexin as a potential Human Papillomavirus (HPV-18) inhibitor that could help treat cervical cancer [73].Furthermore, a study in Uganda reported different plants with anticancer activity used locally in Uganda.O. corniculata was among the plant species identified for its potential anticancer properties [74].The exact mechanisms of the anticancer activity of O. corniculata have yet to be fully understood.However, it has been suggested that bioactive constituents, such as quassinoids and flavonoids, may contribute to its anticancer effects [75,76].
Overall, the available studies suggest that O. corniculata   CCl4-induced hepatotoxic model in male rats [59] exhibits potential anticancer activity, possibly through its antioxidant properties and induction of apoptosis.The phytochemical composition and biological activities of O. corniculata make it a promising candidate for further investigation and development of novel anticancer agents [5].However, additional research is warranted to elucidate the underlying mechanisms and potential therapeutic applications of O. corniculata in cancer treatment.

Antioxidant activity
Free radicals can cause damage to the body, but antioxidants offer protection against this by reducing oxidative stress [10].The antioxidant activity of O. corniculata has been studied from different parts of this plant., including leaves, whole plants, and extracts obtained using other solvents [56].O. corniculata has been found to contain various phytochemicals that possess antioxidant activity, such as glycosides, phytosterols, tannins, flavonoids, and polyphenols [77,78].These compounds have been shown to scavenge free radicals and reduce oxidative stress [79][80][81][82].Several studies have supported the antioxidant activity of O. corniculata.In one study, the extract from methanol and their sub-fractions of different solvents demonstrated strong antioxidant capabilities when compared to ascorbic acid used as the reference standard [56,83].The plant's methanolic extract showed significant in vivo antioxidant activity in rat paw edema and cotton pellet-induced granuloma formation [55].In another study, oxidative stress induced by carbon tetrachloride (CCl 4 ) in rats was significantly attenuated by treatment with methanolic extract, as evidenced by a decrease in the levels of liver enzymes [59].Apart from methanol, ethyl acetate and ethanol fractions also showed the highest antioxidant activity [56,57].The acidic polysaccharide, b.w.body weight

Wound healing activity
The petroleum ether and alcohol extracts of O. corniculata, when administered to rats in different models of experimental wounds, showed potential wound-healing activity, as evidenced by their ability to promote granulation tissue formation, collagen synthesis, and wound closure.However, it is essential to note that these findings are based on animal models, and further research is needed to validate these results in human subjects [70].

Antidiarrheal activity
In a study of diarrhea induced by the administration of castor oil in rats, the water extract displayed greater efficacy than the methanolic extract at all doses [44].
In the evaluation of anti-colonization properties, an infant mouse model was exposed to an intragastric challenge with S. flexneri 2a and S. dysenteriae 1. Methanolic extract showed higher efficacy against S. dysenteriae 1 as compared to S. flexneri 2a.Examination of the methanolic extract of the leaf by High-performance Liquid Chromatography (HPLC) revealed the presence of various flavonoids and phenolic acids, such as rutin, p-hydroxybenzoic acid, ferulic acid, which are responsible for the antidiarrheal activity [45].

Anti-inflammatory activity
An experimentally induced in vivo inflammatory bowel disease model showed significant anti-inflammatory activity when treated with ethanolic extract of O. corniculata leaves in rats [46].In another animal model, ethanolic extract demonstrated anti-inflammatory and analgesic effects in mice with acute peritonitis induced by acetic acid [38].Apart from ethanolic extract, β-sitosterol isolated using petroleum ether extraction demonstrated dose-dependent anti-inflammatory activity, reducing paw edema in the rat model of carrageenan-induced hind paw edema [47].

Nootropic activity
The ethanolic extract showed potential neuroprotective effects and improved cognitive and motor performance in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model of Parkinson's disease.The potential improvement in memory performance by ethanolic extract might possibly be ascribed due to the occurrence of flavonoids, coumarins, tocopherols, and phenolic acids [69].

Hepatoprotective activity
The liver of rats treated with aqueous leaf extract significantly reduced CCl 4 -induced increases in serum levels of bilirubin, AST, ALT, and ALP.It only showed less damage than the livers of rats treated with CCl4 [66].Another study with ethanolic extract showed a membrane-stabilizing effect, which helped protect the liver cells from damage caused by thioacetamide (TAA) in rats [67].In an in silico study, active compounds of O. corniculata and 30 potential targets, like TP53, AKT1, ALB, and IL6, were employed in network pharmacology and constructed a "drug-active ingredient-target-disease" network.The study identified several biological processes and signaling pathways potentially involved in the antihepatic effects [85].

Analgesic activity
The ethanol-derived extract had a remarkable effect on reducing acetic acid-induced twitching in mice, indicating potential analgesic properties compared to the control group [39].In addition, ethanol extract showed a significant decrease in body torsions and a noticeable reduction in abdominal capillary permeability in mice with acute peritonitis induced by acetic acid [38].β-Sitosterol, an isolated phytochemical compound from the petroleum ether extract of O. corniculata, exhibits significant analgesic properties in acetic acid-induced twitching in mice.Analgesic properties of β-sitosterol might be because of its capability to either hinder pain perception at nerve terminals or to regulate pain-inducing mediators [47].

Anthelmintic activity
In vitro studies have shown that O. corniculata has potential anthelmintic activity.All three extracts (petroleum ether, methanol, and ethyl acetate) showed significant anthelmintic activity at 400 mg/mL, with the most potent methanol extract.The methanolic extract caused paralysis and death of earthworms in 11.33 and 41.33 min, respectively [40].

Antidiabetic activity
Treatment with ethanolic and aqueous extract showed a rectification in the final body weight and level of blood glucose in streptozotocin (STZ) induced hyperglycemia in rats compared to the untreated control group of diabetics [14,43].

Abortifacient activity
The petroleum ether extract of the whole plant showed more activity than the ethanol extract regarding antiimplantation and abortifacient effects.A 100 mg/kg body weight dose of the extract from petroleum ether in all six rats resulted in complete pregnancy inhibition [37].

Anti-ulcer activity
Administration of the methanolic extract in an indomethacin-induced ulcer model in rats at doses of 125, 250, and 500 mg/kg b. w. decreased ulcer score, ulcer index, and number of ulcers in a dose-dependent manner.The presence of flavonoids in the methanolic extract could be the reason for its anti-ulcer effect [35].

Nephroprotective activity
An aqueous extract effectively suppresses the growth of struvite stones grown in a gel medium using the in vitro single diffusion gel growth assay, leading to the stones' dissolution [68].

Anxiolytic activity
The ethanolic extract showed an anxiolytic effect, as evidenced by improved locomotor activity in the open field test, improved entries into the open arms of the elevated plus-maze test, and decreased fighting episodes [62].Another study indicated a reduction in anxiety-like behavior in the ethanolic extract-treated groups.Treatments increased the time spent in the open arm of the elevated plus maze and decreased the number of head dips in the hole board test compared to the control group [63].The methanolic extract also showed neuroprotective activity in mice models of depression in the tail suspension test and the swimming test; methanolic extract-treated groups showed a substantial decline in immobility time compared to the control group [65].Since 1970, angiotensin-converting enzymes (ACE) have been targeted for hypertension control [86].The aqueous extract was found to have dose-dependent ACE inhibitory activity in vitro more effectively than the standard ACE inhibitor, captopril, at all doses tested ranging from 10 to 50 mg/mL [64].

Anti-pyretic activity
The efficacy of the extracts in reducing fever was tested by inducing pyrexia in rats using Brewer's yeast.The administration of a 200 mg/kg body weight dose of ethanolic extract resulted in a significant reduction in pyrexia from 1 to 4 h compared to the initial measurement (0 h) in the same group of animals [39].

Cardioprotective activity
In a study, the potential protective effect of an aqueous extract was investigated in isoproterenol-induced myocardial infarction in rats.Histopathological analysis of cardiac tissue after pretreatment with the aqueous extract showed normal myocardial fibers with mild inflammatory changes in comparison with isoproterenoltreated rats [60].

Phytochemistry
We have collected information on several phytoconstituents extracted from O. corniculata and provided comprehensive information on their pharmacological activities, chemical structures, IUPAC names, and corresponding references in Table 2. "ChemDraw JS 19.0" was used to create the chemical structures of the phytochemicals found in O. corniculata.https:// chemd rawdi rect.perki nelmer.cloud/ js.PubChem database was used to retrieve the International Union of Pure and Applied Chemistry (IUPAC) chemical names.

Toxicology of O. corniculata
An acute oral toxicity test was conducted in male and female mice with the methanol extract of O. corniculata in accordance with Organisation for Economic Co-operation and Development (OECD) guideline 425.No signs of toxicity, mortality, and behavioral changes were observed following administration of 2000 mg/kg b. w.The extract was, therefore, reported safe up to 2000 mg/kg b. w. [35,65].OECD guidelines 423 and 425 were followed to test the acute toxicity of the ethanolic extract, and the animals survived at 2000 mg/kg body weight, demonstrating the safety of the extract up to this dose [43,46,63].

Conclusion
Oxalis corniculata is a promising plant for future research as it combines traditional ethnomedicinal knowledge with modern scientific findings.The traditional use of the is supported by scientific evidence of its pharmacological activities.

Table 1
Pharmacological activities of Oxalis corniculata extracts

Table 1
[84]an et al. (2019)ry active ingredient in aqueous extract, significantly reduced oxidative damage in the HEK-293 cell line and Caenorhabditis elegans[58].Moreover, O. corniculata has been traditionally used for various medicinal purposes.According to a study byRahman et al. (2019), local inhabitants in Pakistan use O. corniculata to treat Vitamin C deficiency and bad mouth smell[84].