Review Article | Volume: 12, Issue: 7, July, 2022

Comprehensive study of secondary metabolite profile and pharmacological effects of medicinal plant Toddalia asiatica

Sathyamoorthy Jhansi Lakshmi Upendra Raje Siddiraju   

Open Access   

Published:  Jul 05, 2022

DOI: 10.7324/JAPS.2022.120704
Abstract

Toddalia asiatica (L) Lam is a liana commonly known as an orange climber and is a monotypic genus belonging to the family “Rutaceae.” It is one of the widely distributed medicinal plants in the countries, i.e., South Africa, north tropical regions of Africa, Asia, and also in Madagascar. Compounds that exhibit various pharmacological effects, isolated from the various parts of the plant Toddalia asiatica, such as root, root bark, stem, stem bark, flowers, fruits, and leaves have been of prime importance. Traditional medicinal practitioners of the Asian continent have been using this plant since ancient times to treat ailments such as pulmonary diseases and inflammation of joints known as rheumatism. The root and the root bark of the plant are said to be more potent and are used as a remedy for the conditions such as fever, malaria, cholera, diarrhea, neuralgia, sprains, and epilepsy. Fruits of the plant are used as a medication in the conditions, i.e., cough, digestive abnormalities, and viral influenza infection. The vital oil obtained from the root bark of the plant T. asiatica is known to produce strong larvicidal activity against the mosquito species Aedes. The present review emphasizes a variety of pharmacologically active secondary metabolites extracted from the medicinal plant T. asiatica such as coumarins, toddaculin, toddalactone, and their pharmacological effects such as in antiinflammatory, bactericidal, fungicidal, antimalarial, antidiabetic, antiviral, and antitumor activity


Keyword:     Toddalia asiatica traditional medicine root bark coumarins antimalarial activity antimicrobial activity antitumor activity


Citation:

Lakshmi SJ, Siddiraju UR. Comprehensive study of secondary metabolite profile and pharmacological effects of medicinal plant Toddalia asiatica. J Appl Pharm Sci, 2022; 12(07):042–052.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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INTRODUCTION

Plants are not only considered a food source but also supply an effective bioactive compound such as phytochemicals, which can be used as a drug to combat many disorders of mankind (Upendra and Khandelwal 2012). Bioactive compounds, known as phytoconstituents, are produced as secondary metabolites in plants that have beneficial effects on health when they are consumed as nutrients (Khandelwal et al., 2012). Phytochemicals play an important role in the development of the color, odor, and taste of the plants (Khandelwal et al., 2013). Traditionally used herbal (or) medicinal plants synthesize a range of phyto compounds of known therapeutic values. Presently significant members of researchers worldwide (Prithviraj et al., 2021; Upendra and Ahmed 2021) report on the pharmacological, healthcare, and antimicrobial activities of herbal plants. The bioactive phytocompounds originated from plant sources, i.e., alkaloids, flavonoids, phenolic compounds, and tannins have been used to treat various ailments caused by microorganisms (Upendra et al., 2011).

Toddalia asiatica L, widely known as the wild orange climber or orange climber, is a Rutaceae family evergreen woody liana. This plant is endemic to tropical Asia, from India to Sri Lanka to Malaysia; also, it has subsequently spread worldwide (Rajkumar et al., 2008). The plant is currently found in Africa’s tropical and sub-tropical regions, such as South Africa, East Africa, Mauritius, and Madagascar, where it thrives in forested riverine habitats (Nabwami et al., 2007). Toddalia asiatica can reach a height of 15 m when supported by other trees, and there is abundance of hooked thorns located inside its branches (Varsha et al., 2013). It produces little 5–7 mm citrus-like fruits that start green but turn orange as they develop. When crushed, both the fruits and the leaves emit a lemony odor, with the fruits having a texture and flavor similar to that of an orange rind (Balasubramaniam et al., 2012). Toddalia asiatica is a plant with a renowned history of medical applications and used as a medicinal herb across various regions of the globe. The plant and its derivatives, for example, are employed in the creation of folkloric medicines for a variety of maladies in East Africa, including pain and inflammation (Kariuki et al., 2013), malaria, stomach ache, sore throat (Amuka et al., 2014), and skin, respiratory, and urinary tract infections (Orwa et al., 2015).

Toddalia asiatica is a tracheophytic plant, belongs to Angiospermae and the class Magnoliopsida under sub class Rosidae, order Sapindales and a member of Rutaceae family (Chen et al., 2021). Toddalia asiatica has long been used in India for the ailments such as cough, fever, epilepsy, and dyspepsia and as an analgesic, expectorant, diaphoretic, and antiinflammatory drug. Furthermore, pharmacological studies have demonstrated interesting biological properties of the plant, including antimalarial, anticancer, antiviral, antifungal, and antibacterial behaviors. Toddalia asiatica is widely used in clinical therapy of traumatic injury, tumor, rheumatic discomfort, and knife wound hemorrhage among the minority Miao (Zeng et al., 2021). It exhibits hemostasis, anti-tumor, anti-inflammatory, and analgesic pharmacological properties. For hundreds of years, traditional Chinese medicine (TCM) theory has been employed therapeutically in the country of China. However, because of the complex chemical contents and unexplained pharmacological mechanisms of TCM, the theory has continuously been interrogated by scholars across the globe (Zhang et al., 2018). Scientifically elucidating the beneficial molecules and the formulations of TCM has become an imperative challenge that must be translated as modern medicine advances.

Animal model experiments conducted in proving the hemostatic action of compounds isolated from the root bark of the plant T. asiatica was available in the literature, the considerable number of natural compounds such as furocoumarins isolated from T. asiatica plant root bark had been studied successfully by the considerable number of researchers (Luo et al., 2021; Ma et al., 2021). However, there is no scientific document available on comparative studies on pharmacologically active molecules that were isolated from the different active parts of the plant T. asiatica. The present review discussed the medicinal application of different compounds that were isolated from all the possible active parts of the plant T. asiatica.


SECONDARY METABOLITES PROFILE OF TODDALIA ASIATICA

Benzophenanthridine alkaloids, protoberberine alkaloids, quinoline alkaloids, benzopyrans, terpenoids, cyclohexylamides, coumarins, furanocoumarins, biscoumarins, and other miscellaneous chemicals have all been identified from the active part extracts of the plant T. asiatica (Wang et al., 2009). Nitidine, chelerythrine, dihydronitidine, and dihydrochelerythrine are among the pharmacologically important benzophenanthridine alkaloids isolated from the plant T. asiatica were researched for various applications (Fig. 1).

The complete details about the active parts, their metabolites and their medicinal and pharmacological applications were presented in Table 1. The production of secondary metabolites from plant micropropagation is an intriguing method that has been proved to be effective in producing a wide range of simple and complex chemical compounds with potent pharmacological effects. When these secondary metabolites are present in trace amounts or underground parts of the plant, it is most advantageous to eliminate brutal plant exploitation. Toddalia asiatica callus cultures produced more Nitidine than a whole plant (Rajkumar et al., 2010).


MEDICINAL APPLICATIONS OF THE PLANT TODDALIA ASIATICA

Anti-inflammatory activity

The experimental rat models showing condition such as arthritis induced with wind-chill, and dampness were evaluated against the isolated compounds of the plant T. asiatica for the anti-inflammatory activity screening. Screened compounds of plant T. asiatica evidenced with the balanced inflammatory activity of Th17 and Treg response in arthritis-induced rat models (Liu et al., 2018). Feeding of arthritis-induced mice model along with collagen-infused T. asiatica plant extracts such as ethanol and ethyl acetate solvents containing active compounds, has shown remarkable progress in releasing the paw and other joints pain, inflammation, and edema (Yang et al., 2013). The histopathological examination of rat fed with the isolated compounds of the plant T. asiatica in comparison with control groups showed increased protection for the condition such as knee joint pains, reduced erosion of bone and cartilage, and also the deformation in the tested animal model (Tian et al., 2018), examined animal models also exhibited much decreased levels of tumor necrosis factor-α (TNF-α), the lesser concentration of interleukin-1β (IL-1β), and interleukin-6 (IL-6) cytokines and also shown a significant increase in the concentration of cytokine interleukin-10 (IL-10). Aqueous and mild organic solvents such as alcohol and n-butanol extracts of T. asiatica plant roots had shown analgesic effects (Zeng et al., 2021). Mechanism of action of these molecules connected with rise in the levels of serum b-endorphin (b-EP) levels by up-regulating the b-EP receptor expression and cause significant downfall in the concentration of prostaglandin E2 (PGE2), nitric oxide (NO) levels, while suppressing PGE2 receptor expression.

A research group conducted a hot plate test and explained that the rhizome extracts of the plant T. asiatica are evidenced to possess a strong antiinflammatory activity and analgesic property. The study also revealed that the tested extracts were efficient in reducing the writhing numbers in the glacial acetic acid-induced mice animal model. In another study, 1:1 dilution of ethanol extracts of the plant T. asiatica exhibited improved analgesic behavior and antiinflammatory activity in the mice model denoting the conditions of foot swelling and granuloma condition (Wang et al., 2007). Kariuki et al. (2013) examined the analgesic property and anti-inflammatory mechanism of an organic extract of the plant T. asiatica in the mice model developed with formalin-induced pain condition and carrageenan-induced condition of foot swelling. Results explained that the tested organic extract (methane/methanol in equal ratio) shown much improved property of analgesic activity and the mechanism of antiinflammatory.

Hu et al. (2000) stated that an ethanol extract from the plant T. asiatica in dose-dependent manner found to reduce the acetic acid-induced writhing times and agar-induced foot edema in the animal model (mice) evaluated. It is evidenced from the study that the bioactive molecules isolated from the root bark of the plant T. asiatica reduce the condition of ear swelling and foot swelling by inhibiting the action of xylene. The mice models assessed with the alkaloids isolated from the plant T. asiatica also found to inhibit migration of hemameba in the abdominal cavity primarily due to sodium carboxymethyl cellulose and writhing effects exhibited due to the exposure of acetic acid in the mice model screened. The tested mice model has shown no liver damage, which certainly indicate the non-toxic effects of the screened biomolecules of plant T. asiatica (Hu et al., 2000).

Figure 1. Structures representing medicinally significant phytocompounds of the plant Toddalia asiatica. 1. Flindersine, 2. Chelerythrine, 3. Nitidine, 4. Toddalolactone, 5. 8-methoxynorchelerythrine, 6. Isointegriamide, 7. Oxynitidine, 8. Oxysanguinarine, 9. Artanin, 10. Benzophenanthridine alkaloids, 11. Ulopterol, 12. Arnottianamide.

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Bioactive compounds of the plant T. asiatica named coumarin and omphalocarpin were assessed for their anti-inflammatory behaviors in the in vitro cell culture of RAW264.7 cell lines. Results explained that screened biomolecules were reported to suppress the synthesis and adverse activity of iNOS and COX-2 due to the release of “TNF-α” and “IL-6” cytokines and also found to facilitate the transfer of NF-KB molecules into the cell nucleus by reducing the NO gas release (Tong et al., 2014). Another study revealed that an ethanol extracts from the plant T. asiatica reported to inhibit the migration of macrophages in the tested mice animal model (Qin et al., 2020). These findings evidenced antiinflammatory effects of bioactive compounds of T. asiatica medicinal plant.

Table 1. Secondary metabolites profile of the plant T. asiatica.

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Anti-oxidant activity

Balasubramaniam et al. (2012) discovered that a 50% of ethanol extract content of T. asiatica stem part could scavenge diphenylpicryl hydrazide radicals, hydroxyl radicals, and nitric oxide radicals in vitro while also chelating divalent iron ions, indicating anti-oxidant behaviors. In the tested diabetic induced rats, catalase, glutathione peroxidase, and superoxide dismutase enzyme activity were reported low. All the three enzymes evaluated were shown normal activity after the intragastric region injection of 50% ethyl acetate crude extracts of leaves of T. asiatica, in turn indicating stronger anti-oxidant efficacies of the plant T. asiatica (Balasubramaniam et al., 2012).

Ding et al. (2007) investigated the antioxidant activity of T. asiatica stem extract using the Fenton method, 1, 1-Diphenyl-2-picrylhydrazine (DPPH) screening method, and the Fe2+- cysteine reaction method. The study reported that n-butanol based extracts exhibited noticeable hydroxyl radical scavenging property and the ethyl acetate extract possess much stronger ability to scavenge DPPH. Further study also reported the potent antioxidant activity of 70% ethanol and n-butanol extracts of T. asiatica (Ding et al., 2007). Using the Fenton and DPPH methods, Tian et al. (2018) revealed that polysaccharide compounds of the root part of T. asiatica could scavenge hydroxyl and DPPH free radicals at a concentration range of 0.2–0.4 g/l and 5 (103–101) g/l, correspondingly. The capacity to scavenge hydroxyl radicals at concentrations ranging from 0.1 to 500 mg/l was proportional to IC50 values shown 5.69, 2.19, and 0.745 mg/l individually. When polysaccharides were present in concentrations of up to 500 mg/l, the free radical scavenging activity rates were reached to 94% and the photostability property was superior comparison to Vitamin C and tea polyphenols (Tian et al., 2018).

Anti-bacterial effects

A study showed that chelerythrine has anti-bacterial properties. According to HPLC data, the highest concentration of chelerythrine was identified in the ethyl acetate fraction, while the lowest concentration was found in the petroleum ether fraction. However, the petroleum ether fraction had higher antibacterial activity than the ethyl acetate fraction, which could be due to other fraction ingredients contributing to anti-bacterial functions, and the exact causes for this need to be researched further. The content of AKP can be used to determine the integrity of the bacterial cell wall. AKP is typically found between the cell wall and the cell membrane of bacteria. When the permeability of the bacterial cell wall rises, AKP leaks into the extracellular area in an indirect way. AKP results can reflect bacterial cell wall integrity (He et al., 2018).

Antifungal activity

According to a detailed investigation, only the ethyl acetate extract of T. asiatica demonstrated potential efficacy against tested bacteria and fungus. Flindersine, an active metabolite isolated from ethyl acetate extract with antibacterial activity comparable to or greater than crude extract. Toddalia asiatica-derived compound demonstrated good antibacterial activity in vitro and could treat infectious diseases caused by dangerous germs. A related molecule, flindersine has previously been effective against fungus. Rahmani et al. (2004) discovered that Glycosmis calcicola and Glycosmis rubestris extracts have antifungal activity, identifying the anti-fungal molecule as Flindersine and testing it against infections. The chemical treatment suppressed Trichophyton rubrum 296, Trichophyton mentagrophytes, T. rubrum, Trichophyton simii, Epidermophyton floccosum, Magnaporthe grisea, and Candida albicans.

Antinociceptive activity

Toddalia asiatica extracts exhibited a significant amount of antinociceptive efficacies in all the phases of the formalin test (Fig. 2).

Dosage of screened T. asiatica extract equivalent to 200 mg/kg body weight exhibited enhanced antinociceptive effects in the early phase, while the dosage of extract at 100 mg/kg body weight represented high impact antinociceptive effect in late phase of the employed formalin test. The impact of the antinociceptive effect of the tested extracts was equivalent standard reference medicine range, i.e., indomethacin (50 mg/kg) and ASA (100 mg/kg). But root bark extract of the plant at a dosage of 200 mg/kg has not shown any effects at the late stage of the formalin test. With these findings, it is evident that root bark extract of the plant T. asiatica shown both PNS and CNS activities. At a lower dose of 100 mg/kg of body weight, antinociceptive efficacies were shown at later phase, while at a higher dosage 200 mg/kg body weight antinociceptive efficacies were represented at early phases of the formalin test (Njoroge and Bussmann, 2006).

Analgesic effects

The analgesic activity of an ethanolic solvent extract of T. asiatica was assessed using a test named hot plate method and positive control used was 100 mg/kg dose of acetylsalicylate. Toddalia asiatica crude extract has a higher analgesic activity than positive control acetylsalicylate. The effects of T. asiatica extract on some blood indicators revealed significant changes in cholesterol, alanine transaminase, and gamma-glutamyl transpeptidase levels after 14 days. The levels of aspartate transaminase and alkaline phosphatase (ALP) in the treated and untreated groups, however, did not change significantly. Total cholesterol (TC) and low-density lipoprotein (LDL) levels are linked to a condition of coronary heart disease (Sblendorio and Palmieri 2008). A study examines the activity of herbal extracts on blood and also on selected biochemical markers in Sri Lankan male of adult age, who has lived in Switzerland for 15 years. The patient went to the emergency room with constipation and stomach pain that he had been experiencing on and off for several weeks. Physical examination revealed a soft abdomen with no discomfort or organomegaly. Stool retention was confirmed by an abdominal X-ray, which revealed neither perforation nor intestinal obstruction. Increased alkaline phosphatase or gamma-glutamyl transferase activity in the liver shows that specific hepatobiliary damage markers may be induced directly or indirectly. This occurs in the absence of liver tissue damage and the mainly due to the activity of hepatic drug metabolizing enzyme (DME). Significant serum/plasma activity changes and other indications usually indicate hepatobiliary damage rather than DME induction.

Nelson et al. (1995) previously reported a case of aplastic anemia linked to a 12-year-old child’s herbal medicine usage. A component of herbal medication, phenylbutazone, has been linked to the development of comparable hematologic abnormalities. Anisocytosis was observed in the blood smears of Wistar rat’s model fed with the crude ethanolic extracts of T. asiatica. Anisocytosis is a medical term that refers to the presence of red blood cells of varying sizes. This symptom is known to be caused by anemia and other blood illnesses. Anisocytosis is assessed using the red cell distribution width. Laboratory tests of blood film revealed that 9.1 g dl−1 hemoglobin level indicate the condition such as reticulocytes enlargement, liver enzymes, such as bilirubin and LDH levels were increased slightly. The Coombs test resulted negative, and haptoglobin levels were undetectable (Nelson et al., 1995).

At the Official Food Law Enforcement Authority, leftover pills were found to trace amounts of lead per pill, as well as arsenic, mercury, and chromium. Heavy metal poisoning is becoming more common due to “herbal treatments,” particularly in the Asian countries. The lead level in the blood was connected to the symptoms at the time of presentation. Lead levels less than 50 g dl−1 might produce symptoms like asthenia, arthralgia, hypertension, headaches, and even infertility (Doumouchtsis et al., 2009). Toddalia asiatica exhibits analgesic effects that are superior to aspirin. Despite this promising finding, crude extracts harm blood and liver functioning. In order to avoid overdose, it is prudent to suggest that T. asiatica should be used with caution to treat pain. There are no guidelines for standardized doses in herbal therapy because the evidence is scarce on pharmacogenetics and pharmacodynamics of herbal medicines. In addition, the possible toxicity of consuming T. asiatica should be considered.

Figure 2. Mice model representing the Antinociceptive effect of extracts tested from the T. asiatica.

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HEALTHCARE BENEFITS OF TODDALIA ASIATICA

Antidiabetic effects

For generations, T. asiatica has been used to treat diabetes mellitus. A study aimed to treat the T. streptozotocin (STZ)-induced diabetic rats fed with leaves of plant T. asiatica to screen the antidiabetic and antioxidant characteristics. STZ was used routinely to induce the condition diabetes mellitus in the tested experimental rat models. When administered intraperitoneally, STZ breaks the DNA strand of insulin hormone secreting pancreatic beta-cells, resulting in the reduction in the levels of insulin secretion. In STZ-induced diabetic mice, ethyl acetate extract of leaf part of the plant T. asiatica, injection resulted a noteworthy reduction in blood plasma glucose quantities, while simultaneously boosting the hormone insulin levels. Toddalia asiatica may improve glycemic control and stimulate insulin production from a remnant or regenerated pancreatic beta-cell population in diabetic mice, according to one idea (Fig. 3) (Punitha et al., 2006). Different metabolic and renal problems are detected in experimental diabetes, resulting in a negative nitrogen balance, increased proteolysis, and decreased protein synthesis. Toddalia asiatica ethanol extract therapy raised plasma protein levels in diabetic induced rat model. Further urea and creatine levels in the tested rat model reported much higher quantities, both are critical indicators of renal function and failure.

The extract showed course of kidney impairment in diabetic induced rats, as demonstrated by a substantial reduction in blood urea concentration and serum creatinine levels in TALEe-treated diabetic rats. A considerable drop in body weight distinguishes STZ-induced diabetes. Weight loss is assumed to be caused by accelerated muscle breakdown or structural protein degradation. TALEe administration improved the body weight of diabetic induced rats in comparison with diabetic induced control rat model and standard glibenclamide-treated groups, demonstrating that it has a preventive effect against muscle wasting, i.e., gluconeogenesis reversal (Salahuddin and Jalalpure, 2010)

Furthermore, it indicates that its capacity to maintain body weight loss is attributable to lower blood sugar levels. Insulin promotes intracellular glycogen formation by increasing glycogen synthase and inhibiting glycogen phosphorylase. Glycogen is the most prevalent muscle storage form of glucose and its content in many organs reflects insulin activity directly. Diabetic mice had considerably lower hepatic glycogen stores, indicating insulin insufficiency. TALEe therapy improved liver glycogen stores to normal levels in diabetic rats by increasing the secretion of insulin. Serum glutamatic-oxaloacetic transaminase (SGOT), Serum glutamic pyruvic transaminase (SGPT), and ALP are all reliable liver function indicators. The liver of diabetic rats caused by STZ were necrotized. As a result, an increase in SGOT, SGPT, and ALP activity in plasma could be attributable to enzyme leakage from the liver’s cytosol into the bloodstream, confirming STZ’s hepatotoxic action. TALEe therapy suppress the activity of liver functional enzymes in blood plasma compared to the diabetes control group (Kasetti et al., 2010).

Antimalarial effects

Toddalia asiatica root bark extracts compounds i.e isopimpinellin, geraniol, and D-limonene were shown in Figure 4, to have anti-malarial and insecticidal properties.

Figure 3. Flow diagram explaining the Anti-Diabetic Effects of Toddalia asiatica.

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Figure 4. Flow diagram depicting the Anti-Malarial effects of Toddalia asiatica plant extract.

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Treatment for cardiovascular diseases

Fei Long 1 (F01), an aqueous phase extract of the plant T. asiatica, protects against pituitrin-induced coronary artery-based contraction, isoproterenol-induced condition of myocardial muscle overexcitation and also the condition known as acute phase myocardial ischemia developed due to the obstructions of the coronary artery. F01 extract inhibits block of peripheral blood vessels connect to the heart and widens, decreases cardiac after load, myocardial exertion, and oxygen consumption rates connected to the cardiac function in the studied experimental animal domestic cats. F01 also found to reduce the oxygen consumption rates of acutely ischemic myocardium in New Zealand rabbits without showing the ligation of pleural coronary (He et al., 2000).

Ren et al. (1993) conducted a comprehensive study on T. asiatica cardiovascular preventative properties. Long Jing 1 (L01, T. asiatica extract) reduced anaesthetized rats’ blood pressure and relaxed smooth contractile muscle produced by KCl in vitro, with the mechanism probably connected to calcium influx inhibition. The iso-anise coumarin (Isopimpinellin) present in T. asiatica ethanol extract may protect the rat aortic ring against KCl-induced contraction (Guo et al., 2014; Ren et al., 1993). After the 4-week therapy, rats tested were fed a high-fat diet and given isoprenaline hydrochloride once a day for three days. According to the findings of Liu et al. (2018), T. asiatica extract may significantly alleviate Iso-induced ECG alterations in rats, reduce heart, liver and fat indices and lower TC, triglyceride, LDL.

Inhibition of Alzheimer’s disease

Alzheimer’s is a neurological disease that commonly leads to conditions such as dementia, chronic and progressive neurodegenerative disorders, marked significantly with symptoms such as the loss of memory, causing mental impairment, decreased learning ability, and emotional loss. Since there is no specific drug available to treat the condition, the number of AD patients increases as the world’s population ages. This adds to the stress on families and medical treatment. As a result, traditional Chinese herb has grabbed the curiosity of medical experts as another promising technique that could provide a novel treatment for people living with Alzheimer’s. According to Takomthong et al. (2020), seven of nine coumarins derived from the medicinal plant T. asiatica were found to be multifunctional that might prevent the pathogenesis of AD, particularly phellopterin, which demonstrated a strong protecting effect against neuronal cell damage produced by H2O2 and Ab1-42 toxicity.

Antitumor effects

The antitumor properties of medicinal components of plant T. asiatica, i.e., root bark, root core region, stem bark, stem core region, near-leaf stem part, and leaf parts were investigated applying the standard 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay method. The antitumor activity mean inhibitory rate of different medicinal components of T. asiatica were tested on MCF-7 cells at 100 g/ml following a pharmacodynamic action principle. From the study, it is evidenced that active parts such as root, stem bark, root & stem core, near-leaf stem, and whole leaf had shown increased inhibition rate in the tested in vitro cell model (MCF-7). Toddalia asiatica root bark active part and root core region can reduce the growth and proliferation of screened MCF-7 breast cancer cells lines in comparison with other parts of the plant evaluated. Bivariate analysis was used to establish a relationship between nineteen distinct peaks and the anti-tumor inhibition rate of different T. asiatica medicinal components, which was reflected in the form of peak correlation coefficients. Statistical investigations revealed that various compounds in T. asiatica exhibited anticancer activities, including toddalolactone, 4-methoxycinnamic acid, pimpinellin, isopimpinellin, and hesperidin appearing in that order (Luo et al., 2021).


DISCUSSION

Toddalia asiatica (L.) Lam., a member of the Toddalia genus in the Rutaceae family, has been used as a traditional medicine in China (Zeng et al., 2021). The entire plant can be used as medication, particularly the roots were utilized in traditional folk medicine (Arul and Veerappa, 2019). With extensive investigation from both local and foreign experts in recent decades, it has gradually been established that the chemical components of T. asiatica are primarily coumarins and alkaloids (Zhu et al., 2019). Its pharmacological activities include antiinflammatory and analgesic properties, hemostatic coagulation, antitumor properties, therapy of cardiovascular illnesses, etc. (Alagaraj et al., 2020). It has numerous clinical applications and substantially impacts rheumatism, discomfort, wound bleeding, and bruising discomforts (Qiu et al., 2022). Recent studies highlight the importance of T. asiatica phytochemical research, in view, the present review discussed chemical compositions, and pharmacological effects of different extracts of the plant T. asiatica to give a reference for relevant research and uses of medicinal phytochemicals of the plant T. asiatica. Although herbs are frequently viewed as “natural” and safe, many adverse effects have been observed.

Herbal pharmaceuticals play a significant role in healthcare systems worldwide and there is a renewed interest in herbal medicines for the treatment of a variety of disorders, including hepatopathy. Furthermore, there is a lack of scientific evidence to support the safety and efficacy of most herbal products. Toddalia asiatica is a vital medicinal plant with a broad pharmacological spectrum. The most common ingredients the plant T. asiatica have been identified as benzo[c]phenanthridine, secobenzo[c]phenantridine, aporphine, berberine, and indole alkaloids (Singh et al., 2022). Benzo[c] phenan-thridine alkaloids show a broad spectrum of biological activity compared to other alkaloids. Many cancers cell lines, including human promyelocytic leukemia HL-60 cells, have mostly antiproliferative and cytotoxic effects (Fialova et al., 2017). In reaction to stress, benzo[c]phenanthridine alkaloids are generated and employed as a phytoalexin against fungal and bacterial diseases (Roshan et al., 2022). This plant’s root bark is also used to treat diarrhoea, gonorrhoea, cough, influenza, and toothache (Hu et al., 2014). The fresh leaves cure respiratory disorders and intestinal problems (Hirunwong et al., 2016). The fruits are thought to help treat malaria and cough (Ngarivhume et al., 2015). Rheumatism has been treated with an ointment made from the roots and unripe fruits (Ye et al., 2021). There have been numerous studies conducted on this plant’s chemical contents and biological activity, including prenylated and geranylated coumarins, triterpenes, phenanthridine alkaloids, and volatile oils (Saxena and Sharma, 1999). Compounds from this plant have been studied for their biological effects, including anticancer activity against the U-937 cell line (Önder, 2020), antidiabetic, antioxidant (Irudayaraj et al., 2022), and antibacterial activity. The analgesic potential of T. asiatica (L.) was astounding. However, compared to the untreated negative controls, the crude extract of T. asiatica (L.) triggered nephrotoxicity, liver enzyme modulation, and increased TC in the test organisms.

The ethyl acetate extracts effectively reduced plasma, and hepatic lipid levels in hyperlipidemic rats fed a high-fat diet. Oxidative stress contributes significantly to the pathophysiology of many clinical illnesses, including cardiovascular dysfunction, atherosclerosis, inflammation, carcinogenesis, medication toxicity, reperfusion injury, and neurodegenerative disease (Liguori et al, 2018). Numerous studies support the use of antioxidant supplements in lowering oxidative stress and decreasing or preventing the development of disease-related consequences. Furthermore, by scavenging free radicals, antioxidants may aid in preventing diseases such as cancer, cardiovascular disease, Alzheimer’s disease, and muscle degeneration (Akbari et al., 2022). The reducing power assay was first performed to explore the Fe3+ to Fe2+ transformation in the presence of T. asiatica ethyl acetate extract. The reducing power of T. asiatica ethyl acetate extract increased with increasing concentration (Irudayaraj et al., 2022).

Monoclonal medications’ pharmacological mechanisms are still inaccurate, and further research is needed in the future. Toddalia asiatica is also plentiful. However, the medicinal component of the plant is the root and stem, which has resulted in a decline in the quantity of wild T. asiatica. As a result, additional magnificent work is required to close gaps in the preservation of medicinal resources.


CONCLUSION

Toddalia asiatica plant as a whole and its various extracts were widely used as a traditional medicine in the mountain regions of Wuling province of southwest China. Toddalia asiatica plant was reported scientifically with significant clinical application, most notably anti-inflammatory properties, and used as a medicine in the condition of analgesia, hemostasis, and the condition of coagulation disorders. Few new active natural compounds, as well as novel pharmacology formulations of the plant T. asiatica, is yet to be explored along with this, there is a scarcity of data on its safety which could be explored and scientifically proved to improve the possibilities of developing novel biomolecules and formulation from this unexplored medicinal plant. Present work finds its importance in studying the plant T. asiatica as one of the most important medicinal resources.


ABBREVIATIONS

ALP: Alkaline phosphatise

b-EP: Endorphin

DME: Drug metabolizing enzymes

DPPH: 1,1-Diphenyl 1-2-Picrylhydrazine

IL: Interleukin

LDL: Low-density lipoprotein

NO: Nitric oxide

PGE2: Prostaglandin E2

SGOT: Serum glutamatic-oxaloacetic transaminase

SGPT: Serum glutamic pyruvic transaminase

STZ: Streptozotocin

TC: Total cholestrol

TNF-α: Tumor necrosis factor-α


AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.


FUNDING

There is no funding to report.


CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.


ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.


DATA AVAILABILITY

All data generated and analyzed are included within this research article.


PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.


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Akbari B, Baghaei-Yazdi N, Bahmaie M, Mahdavi Abhari F. The role of plant-derived natural antioxidants in reduction of oxidative stress. BioFactors, 2022; doi: 10.1002/biof.1831 CrossRef

Alagaraj P, Muthukrishnan S. Toddalia asiatica L.—a rich source of phytoconstituents with potential pharmacological actions, an appropriate plant for recent global arena. Cardiovasc Hematol Agents Med Chem. 2020; 18(2):104–10. CrossRef

Amuka O, Machocho AK, Okemo PO, Mbugua PK. Antibacterial and antifungal activities of essential oils from Satureiabiflora D. Don, Benth, Speng (Chepsagitiet). Lippiajavanica Burm.F. (Labotuet) and Toddalia asiatica (L) Lam. Rutaceae (Chepindoruet). Glob J Sci Front Res B Chem, 2014; 14:133.

Arul M, Veerappa NS. Pharmacognostical analysis of Fruit of Toddalia asiatica (L.) Lam. (Rutaceae). Res J Pharmacogn Phytochem, 2019; 11(3):193–6. CrossRef

Balasubramaniam A, Manivannan R, Paramaguru R, Mazumder PM, Vijayakumar M. Evaluation of anti-inflammatory and antioxidant activities of stem bark of Toddalia asiatica (L) lam. using different experimental models. Pharmacologia, 2012; 3(5):144–9. CrossRef

Chen SS, Xie TZ, He YJ, Liu YY, Li L, Zhao LX, Luo XD. Alkaloids of Toddalia asiatica (Rutaceae). Biochem Syst Ecol, 2021; 95:104244. CrossRef

Ding W, Wen CF, Chen JH, Huang KX, Dong AW. Primary study on antibacterial activity of extracts from Toddalia asiatica (Linn.) lam. Biomass. Chem Eng, 2007; 41(5):33–5.

Doumouchtsis KK, Doumouchtsis SK, Doumouchtsis EK, Perrea DN. The effect of lead intoxication on endocrine functions. J Endocrinol Invest, 2009; 32:175–83. CrossRef

Duraipandiyan V, Ignacimuthu S. Antibacterial and antifungal activity of Flindersine isolated from the traditional medicinal plant, Toddalia asiatica (L.) Lam. J Ethnopharmacol, 2009; 123(3):494–8. CrossRef

Fialova S, Rendekova K, Mucaji P, Slobodnikova, L. Plant natural agents: polyphenols, alkaloids and essential oils as perspective solution of microbial resistance. Curr Organ Chem, 2017; 21(18):1875–84. CrossRef

Guo JY, Sun Y, Wang YK, Liu X. Study on isolation of endophytic fungi from Toddalia asiatica and their antimicrobial activity. J Guangdong Pharm Univ, 2014; 30:422–6.

He N, Wang P, Wang P, Ma C, Kang W. Antibacterial mechanism of chelerythrine isolated from root of Toddalia asiatica (Linn) Lam. BMC Complement Altern Med, 2018; 18(1):1–9. CrossRef

He YK, Da RX, Hua XA, Xiu YY. Effects of aqueous extract from Toddalia asiatica on cardiac function and hemodynamics in myocardial ischemic rabbits. Chinese J Pathophysiol, 2000; 16(606–609).

Hirunwong C, Sukieum S, Phatchana R, Yenjai C. Cytotoxic and antimalarial constituents from the roots of Toddalia asiatica. Phytochem Lett, 2016; 17:242–6. CrossRef

Hu J, Shi X, Chen J, Mao X, Zhu L, Yu L, Shi J. Alkaloids from Toddalia asiatica and their cytotoxic, antimicrobial, and antifungal activities. Food Chem, 2014; 148:437-44. CrossRef

Hu XY, Zeng FB, Cui XR, Li YR. Studies on analgesic and anti-inflammatory effects and toxicity of ethanol extract from Toddalia asiatica. Chinese J Trad Med Sci Technol, 2000; 7:231–2.

Irudayaraj SS, Jincy J, Sunil C, Duraipandiyan V, Ignacimuthu S, Chandramohan G, Packiam SM. Antidiabetic with antilipidemic and antioxidant effects of flindersine by enhanced glucose uptake through GLUT4 translocation and PPARγ agonism in type 2 diabetic rats. J Ethnopharmacol, 2022; 285(1):114883. CrossRef

Jain SC, Pandey MK, Upadhyay RK, Kumar R, Hundal G, Hundal MS. Alkaloids from Toddalia aculeata. Phytochemistry, 2006; 67(10):1005–10. CrossRef

Kariuki HN, Kanui TI, Yenesew A, Patel N, Mbugua PM. Antinociceptive and anti-inflammatory effects of Toddalia asiatica (L) Lam. (Rutaceae) root extract in Swiss albino mice. Pan Afr Med J, 2013; 14:133. CrossRef

Kasetti RB, Rajasekhar MD, Kondeti VK, Fatima SS, Kumar EGT, Swapna S, Bellamkonda R, Chippada Appa R. Antihyperglycemic and antihyper- lipidemic activities of methanol: water (4:1) fraction isolated from aqueous extract of Syzgiumalternifolium seeds in streptozotocin induced diabetic rats. Food Chem Toxicol, 2010; 48:1078–84. CrossRef

Khandelwal P, Upendra R. S, Raftani amiri Z, Ramachandra GG. Assessment of biotherapeutic potential of Pimenta dioica (Allspice) leaf extract. Int J Pharm Sci Res, 2012; 3(9):1000–4.

Khandelwal Pratima, Upendra RS, Yashaswini R, Subha B, Sneha G, Ramachandra GG. Comparative studies on biotherapeutic potentials of two selected medicinal plants—Pimenta dioica and Epiphyllum oxypetalum. World J Pharm Pharm Sci, 2013; 2(4):1789–801.

Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della-Morte D, Abete P. Oxidative stress, aging, and diseases. Clin Interv Aging, 2018; 13:757. CrossRef

Liu M, Liu Y, Deng Y, Zulin HU. Effects of Toddalia asiatica extract on inflammatory cytokines in rats with myocardial ischemia and hyperlipidemia. Chinese J Comp Med, 2018; 28(2):64–8.

Luo C, Liu J, Liang Y, Shen X, Zhang X, Zhou W. Antitumor chemical constituents of Toddalia asiatica (Linn) Lam root bark and its rational alternative medicinal parts by multivariate statistical analysis. Acta Chromatogr, 2021; 33(2):153–61. CrossRef

Ma W, Ali I, Li Y, Hussain H, Zhao H, Sun X, Wang D. A simple and efficient two-dimensional high-speed counter-current chromatography linear gradient and isocratic elution modes for the preparative separation of coumarins from roots of Toddalia asiatica (Linn.) Lam. Molecules, 2021; 26(19):5986. CrossRef

Nabwami J, Tabuti J, Bekundai MA. Characterization of the natural habitat of Toddalia asiatica in the Lake Victoria basin: soil characteristics and seedling establishment. Afr Crop Sci Conf Proc, 2007; 8:2057–61.

Nattudurai G, Paulraj MG, Ignacimuthu S. Toddalia asiatica (L.) Lam. essential oil: a potential natural fumigant and repellent against three coleopteran pests of stored products. Int J Pure Appl Zool, 2014; 2(3):246–55.

Nelson L, Shih R, Hoffman R. Aplastic anaemia induced by an adulterated herbal medication. J Toxicol Clin Toxicol, 1995; 33(5):467–70. CrossRef

Ngarivhume T, van’t Klooster CI, de Jong JT, Van der Westhuizen JH. Medicinal plants used by traditional healers for the treatment of malaria in the Chipinge district in Zimbabwe. J Ethnopharmacol, 2015; 159:224–37. CrossRef

Ni J, Zhao Y, Su J, Liu Z, Fang S, Li L, Deng J, Fan G. Toddalolactone protects lipopolysaccharide-induced sepsis and attenuates lipopolysaccharide-induced inflammatory response by modulating HMGB1-NF-κB translocation. Front Pharmacol, 2020; 21(11):109. CrossRef

Njoroge GN, Bussmann RW. Diversity and utilization of antimalarial ethnophytotherapeutic remedies among the Kikuyus (Central Kenya). J Ethnobiol Ethnomed, 2006; 2:1–8. CrossRef

Önder, A. Anticancer activity of natural coumarins for biological targets. Stud Nat Prod Chem, 2020; 64:85–109. CrossRef

Orwa JA, Jondiko IJ, Bii C. Antimicrobial activity of aqueous and organic solvent extracts from a Kenyan medicinal plant, Toddalia asiatica (L) Lam. J Afr Health Sci, 2015; 28(1):80–6.

Praveena C, Veeresham C. Benzophenanthridine alkaloids from callus cultures of Toddalia asiatica. Int J Pharm Sci Nano Technol, 2015; 8:3003–8. CrossRef

Prithviraj SR, Nitesh Kumar T, Shahid Khan A, Upendra RS, Ahmed MR. The role of immunity and immune boosting food in combating covid-19 global pandemic. Int J Pharm Res, 2021; 13(2):2816. CrossRef

Punitha R, Manohara S. Antihyperglycemic and antilipidperoxidative effects of Pongamia pinnata (Linn.) Pierre flowers in alloxan induced diabetic rats. J Ethnopharmacol, 2006; 105:39–46. CrossRef

Qin S, Zhang YP, Chen X, Xia JY, Chen YD, Kong DM. Research on high throughput screening of drugs to inhibit macrophage migration (in Chinese). J. Guizhou Univ Tradit Chinese Medicine. 2020; 42, 87–90.

Qiu J, Zhu M, Wang Y, Chen B, Bai R, Chen F, Zhang L. Pharmacokinetic and excretion study of eight active constituents in rat by LC-MS/MS after oral administration of the Toddalia asiatica extract. Anal Biochem, 2022; 640:114407. CrossRef

Rahmani M, Ling CY, Meon S, Ismail HBM, Sukari MA. The antifungal activity of Glycosmis calcicola and G. rupestris extracts. Pharm Biol, 2004; 42:430–3. CrossRef

Raj MK, Balachandran C, Duraipandiyan V, Agastian P, Ignacimuthu S. Antimicrobial activity of Ulopterol isolated from Toddalia asiatica (L.) Lam.: a traditional medicinal plant. J Ethnopharmacol, 2012; 140(1):161–5. CrossRef

Rajkumar M, Chandra RH, Veeresham C. Production of nitidine from callus cultures of Toddalia asiatica. Int J Pharm Sci Nanotechnol, 2010; 3(2):1028–33. CrossRef

Rajkumar M, Chandra RH, Asres K, Veeresham C. Toddalia asiatica (Linn.) Lam.—a comprehensive review. Pharmacogn Rev, 2008; 2(4):386–97.

Ren XD, Wang DW, Zhong L, Li SM, Guo SY. Effects of Long Jing 1 on isolated rat thoracic aortic rings. Chinese J Pathophysiol, 1993; 9:129–32.

Roshan, A. B., Venkatesh, H. N., Dubey, N. K., & Mohana, D. C. (2022). Chitosan-based nanoencapsulation of Toddalia asiatica (L.) Lam. essential oil to enhance antifungal and aflatoxin B1 inhibitory activities for safe storage of maize. Int J Biol Macromol, 2022; 204:476–84. CrossRef

Salahuddin M, Jalalpure SS. Antidiabetic activity of aqueous fruit extract of Cucumis trigonusRoxb. in streptozotocin-induced diabetic rats. J Ethnopharmacol, 2010; 127:565–7. CrossRef

Sblendorio V, Palmieri B. Accuracy of analyses for lipid profile parameters as measured with the CR3000 system. Eur Rev Med Pharmacol Sci, 2008; 12:191–6.

Singh VK, Chaurasia H, Mishra R, Srivastava R, Chaturvedi VK, Singh RK. Role of plant-based anti-hiv agents in hiv-associated neurocognitive disorders (Hand). In: Goyal MR, Birwal P, Mishra SK (eds.). Phytochemicals and medicinal plants in food design (pp. 25–44). Apple Academic Press, New York, 2022. CrossRef

Takomthong P, Waiwut P, Yenjai C, Sripanidkulchai B, Reubroycharoen P, Lai R, Kamau P, Boonyarat C. Structure-activity analysis and molecular docking studies of coumarins from Toddalia asiatica as multifunctional agents for Alzheimer’s disease. Biomedicines, 2020; 8(5):107. CrossRef

Thirugnanasampandan R, Jayakumar R, Prabhakaran M. Analysis of chemical composition and evaluation of antigenotoxic, cytotoxic and antioxidant activities of essential oil of Toddalia asiatica (L.) Lam. Asian Pac J Trop Biomed, 2012; 2(3):S1276–9. CrossRef

Tian PY, Yu YS, Deng ZG, Chen YK, Zhu X. Effects of Miao medicine Toddalia asiatica on acute gouty arthris in rats. Chinese J Gerontol, 2018; 3019–22.

Tong L, Chen T, Chen Z, Zhang P, Pi H, Ruan H, Wu J. Anti-inflammatory activity of omphalocarpin isolated from Radix Toddalia asiatica. J Ethnopharmacol, 2014; 155:1553–60. CrossRef

Upendra RS, Ahmed MR. Healthcare prominence and immune boosting activity of ashwagandha against various clinical conditions and covid 19 disease outbreak. Int J Pharm Res, 2021; 489–97.

Upendra RS, Khandelwal P. Assessment of nutritive values, phytochemical constituents and biotherapeutic potentials of Epiphyllum oxypetalum. Int J Pharm Pharm Sci, 2012; 4(5):421–5.

Upendra RS, Khandelwal P, Manjunatha RAH. Turmeric powder (Curcuma longa Linn.) as an antifungal agent in plant tissue culture studies. Int J Eng Sci Technol, 2011; 3(11):7899–904.

Varsha DJ, Patil AV, Patil PC. Ethnomedicinal and pharmacognostical studies on leaves of Toddalia asiatica L. Der Pharmacia Sin, 2013; 4(4):76–80.

Vázquez R, Riveiro ME, Vermeulen M, Mondillo C, Coombes PH, Crouch NR, Ismail F, Mulholland DA, Baldi A, Shayo C, Davio C. Toddaculin, a natural coumarin from Toddalia asiatica, induces differentiation and apoptosis in U-937 leukemic cells. Phytomedicine, 2012; 19(8–9):737–46. CrossRef

Wang F, Xu Y, Liu JK. New geranyloxycoumarins from Toddalia asiatica. J Asian Nat Prod Res, 2009; 11(8):752–6. CrossRef

Wang QJ, Lu H, Lv WW, Liu F, Liu J. The experimental research on analgesia and anti-inflammation of aqueous extract from Toddalia asiatica Lam. Chinese J Exp Tradit Med Formulae, 2007; 13:35–7.

Yang K, Tong L, Chen C, Zhang P, Pi H, Ruan H, Wu J. Therapeutic effects of extracts from Radix Toddalia asiatica on collagen-induced arthritis in Balb/c mice. J Ethnopharmacol, 2013; 146:355–62. CrossRef

Ye H, Li C, Ye W, Zeng F, Liu F, Liu Y, Li J. Medicinal Angiosperms of Rutaceae. In Common Chinese Materia Medica (pp. 519–622). Springer, Singapore, 2021. CrossRef

Zeng Z, Tian R, Feng J, Yang NA, Yuan L. A systematic review on traditional medicine Toddalia asiatica (L.) Lam.: chemistry and medicinal potential. Saudi Pharm J, 2021; 29(8):781–98. CrossRef

Zhang C, Zheng X, Ni H, Li P, & Li, H. J. Discovery of quality control markers from traditional Chinese medicines by fingerprint-efficacy modeling: Current status and future perspectives. J Pharm Biomed Anal, 2018; 159:296–304. CrossRef

Zhu M, Wei P, Peng Q, Qin S, Zhou Y, Zhang R, Zhang L. Simultaneous qualitative and quantitative evaluation of Toddalia asiatica root by using HPLC-DAD and UPLC-QTOF-MS/MS. Phytochem Anal, 2019; 30(2):164–81. CrossRef

Reference

Akbari B, Baghaei-Yazdi N, Bahmaie M, Mahdavi Abhari F. The role of plant-derived natural antioxidants in reduction of oxidative stress. BioFactors, 2022. https://doi.org/10.1002/biof.1831

Alagaraj P, Muthukrishnan S. Toddalia asiatica L.-a rich source of phytoconstituents with potential pharmacological actions, an appropriate plant for recent global arena. Cardiovasc Hematol Agents Med Chem. 2020; 18(2):104-10. https://doi.org/10.2174/1871525718666200212095756

Amuka O, Machocho AK, Okemo PO, Mbugua PK. Antibacterial and antifungal activities of essential oils from Satureiabiflora D. Don, Benth, Speng (Chepsagitiet). Lippiajavanica Burm.F. (Labotuet) and Toddalia asiatica (L) Lam. Rutaceae (Chepindoruet). Glob J Sci Front Res B Chem, 2014; 14:133.

Arul M, Veerappa NS. Pharmacognostical analysis of Fruit of Toddalia asiatica (L.) Lam. (Rutaceae). Res J Pharmacogn Phytochem, 2019; 11(3):193-6. https://doi.org/10.5958/0975-4385.2019.00033.5

Balasubramaniam A, Manivannan R, Paramaguru R, Mazumder PM, Vijayakumar M. Evaluation of anti-inflammatory and antioxidant activities of stem bark of Toddalia asiatica (L) lam. using different experimental models. Pharmacologia, 2012; 3(5):144-9. https://doi.org/10.5567/pharmacologia.2012.144.149

Chen SS, Xie TZ, He YJ, Liu YY, Li L, Zhao LX, Luo XD. Alkaloids of Toddalia asiatica (Rutaceae). Biochem Syst Ecol, 2021; 95:104244. https://doi.org/10.1016/j.bse.2021.104244

Ding W, Wen CF, Chen JH, Huang KX, Dong AW. Primary study on antibacterial activity of extracts from Toddalia asiatica (Linn.) lam. Biomass. Chem Eng, 2007; 41(5):33-5.

Doumouchtsis KK, Doumouchtsis SK, Doumouchtsis EK, Perrea DN. The effect of lead intoxication on endocrine functions. J Endocrinol Invest, 2009; 32:175-83. https://doi.org/10.1007/BF03345710

Duraipandiyan V, Ignacimuthu S. Antibacterial and antifungal activity of Flindersine isolated from the traditional medicinal plant, Toddalia asiatica (L.) Lam. J Ethnopharmacol, 2009; 123(3):494-8. https://doi.org/10.1016/j.jep.2009.02.020

Fialova S, Rendekova K, Mucaji P, Slobodnikova, L. Plant natural agents: polyphenols, alkaloids and essential oils as perspective solution of microbial resistance. Curr Organ Chem, 2017; 21(18):1875-84. https://doi.org/10.2174/1385272821666170127161321

Guo JY, Sun Y, Wang YK, Liu X. Study on isolation of endophytic fungi from Toddalia asiatica and their antimicrobial activity. J Guangdong Pharm Univ, 2014; 30:422-6.

He N, Wang P, Wang P, Ma C, Kang W. Antibacterial mechanism of chelerythrine isolated from root of Toddalia asiatica (Linn) Lam. BMC Complement Altern Med, 2018; 18(1):1-9. https://doi.org/10.1186/s12906-018-2317-3

He YK, Da RX, Hua XA, Xiu YY. Effects of aqueous extract from Toddalia asiatica on cardiac function and hemodynamics in myocardial ischemic rabbits. Chinese J Pathophysiol, 2000; 16(606-609).

Hirunwong C, Sukieum S, Phatchana R, Yenjai C. Cytotoxic and antimalarial constituents from the roots of Toddalia asiatica. Phytochem Lett, 2016; 17:242-6. https://doi.org/10.1016/j.phytol.2016.08.008

Hu J, Shi X, Chen J, Mao X, Zhu L, Yu L, Shi J. Alkaloids from Toddalia asiatica and their cytotoxic, antimicrobial, and antifungal activities. Food Chem, 2014; 148:437-44. https://doi.org/10.1016/j.foodchem.2012.12.058

Hu XY, Zeng FB, Cui XR, Li YR. Studies on analgesic and antiinflammatory effects and toxicity of ethanol extract from Toddalia asiatica. Chinese J Trad Med Sci Technol, 2000; 7:231-2.

Irudayaraj SS, Jincy J, Sunil C, Duraipandiyan V, Ignacimuthu S, Chandramohan G, Packiam SM. Antidiabetic with antilipidemic and antioxidant effects of flindersine by enhanced glucose uptake through GLUT4 translocation and PPARγ agonism in type 2 diabetic rats. J Ethnopharmacol, 2022; 285(1):114883. https://doi.org/10.1016/j.jep.2021.114883

Jain SC, Pandey MK, Upadhyay RK, Kumar R, Hundal G, Hundal MS. Alkaloids from Toddalia aculeata. Phytochemistry, 2006; 67(10):1005-10. https://doi.org/10.1016/j.phytochem.2006.03.012

Kariuki HN, Kanui TI, Yenesew A, Patel N, Mbugua PM. Antinociceptive and anti-inflammatory effects of Toddalia asiatica (L) Lam. (Rutaceae) root extract in Swiss albino mice. Pan Afr Med J, 2013; 14:133. https://doi.org/10.11604/pamj.2013.14.133.2130

Kasetti RB, Rajasekhar MD, Kondeti VK, Fatima SS, Kumar EGT, Swapna S, Bellamkonda R, Chippada Appa R. Antihyperglycemic and antihyper- lipidemic activities of methanol: water (4:1) fraction isolated from aqueous extract of Syzgiumalternifolium seeds in streptozotocin induced diabetic rats. Food Chem Toxicol, 2010; 48:1078-84. https://doi.org/10.1016/j.fct.2010.01.029

Khandelwal P, Upendra R. S, Raftani amiri Z, Ramachandra GG. Assessment of biotherapeutic potential of Pimenta dioica (Allspice) leaf extract. Int J Pharm Sci Res, 2012; 3(9):1000-4.

Khandelwal Pratima, Upendra RS, Yashaswini R, Subha B, Sneha G, Ramachandra GG. Comparative studies on biotherapeutic potentials of two selected medicinal plants-Pimenta dioica and Epiphyllum oxypetalum. World J Pharm Pharm Sci, 2013; 2(4):1789-801.

Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della-Morte D, Abete P. Oxidative stress, aging, and diseases. Clin Interv Aging, 2018; 13:757. https://doi.org/10.2147/CIA.S158513

Liu M, Liu Y, Deng Y, Zulin HU. Effects of Toddalia asiatica extract on inflammatory cytokines in rats with myocardial ischemia and hyperlipidemia. Chinese J Comp Med, 2018; 28(2):64-8.

Luo C, Liu J, Liang Y, Shen X, Zhang X, Zhou W. Antitumor chemical constituents of Toddalia asiatica (Linn) Lam root bark and its rational alternative medicinal parts by multivariate statistical analysis. Acta Chromatogr, 2021; 33(2):153-61. https://doi.org/10.1556/1326.2020.00762

Ma W, Ali I, Li Y, Hussain H, Zhao H, Sun X, Wang D. A simple and efficient two-dimensional high-speed counter-current chromatography linear gradient and isocratic elution modes for the preparative separation of coumarins from roots of Toddalia asiatica (Linn.) Lam. Molecules, 2021; 26(19):5986. https://doi.org/10.3390/molecules26195986

Nabwami J, Tabuti J, Bekundai MA. Characterization of the natural habitat of Toddalia asiatica in the Lake Victoria basin: soil characteristics and seedling establishment. Afr Crop Sci Conf Proc, 2007; 8:2057-61.

Nattudurai G, Paulraj MG, Ignacimuthu S. Toddalia asiatica (L.) Lam. essential oil: a potential natural fumigant and repellent against three coleopteran pests of stored products. Int J Pure Appl Zool, 2014; 2(3):246-55.

Nelson L, Shih R, Hoffman R. Aplastic anaemia induced by an adulterated herbal medication. J Toxicol Clin Toxicol, 1995; 33(5):467-70. https://doi.org/10.3109/15563659509013756

Ngarivhume T, van't Klooster CI, de Jong JT, Van der Westhuizen JH. Medicinal plants used by traditional healers for the treatment of malaria in the Chipinge district in Zimbabwe. J Ethnopharmacol, 2015; 159:224-37. https://doi.org/10.1016/j.jep.2014.11.011

Ni J, Zhao Y, Su J, Liu Z, Fang S, Li L, Deng J, Fan G. Toddalolactone protects lipopolysaccharide-induced sepsis and attenuates lipopolysaccharide-induced inflammatory response by modulating HMGB1-NF-κB translocation. Front Pharmacol, 2020; 21(11):109. https://doi.org/10.3389/fphar.2020.00109

Njoroge GN, Bussmann RW. Diversity and utilization of antimalarial ethnophytotherapeutic remedies among the Kikuyus (Central Kenya). J Ethnobiol Ethnomed, 2006; 2:1-8. https://doi.org/10.1186/1746-4269-2-8

Önder, A. Anticancer activity of natural coumarins for biological targets. Stud Nat Prod Chem, 2020; 64:85-109. https://doi.org/10.1016/B978-0-12-817903-1.00003-6

Orwa JA, Jondiko IJ, Bii C. Antimicrobial activity of aqueous and organic solvent extracts from a Kenyan medicinal plant, Toddalia asiatica (L) Lam. J Afr Health Sci, 2015; 28(1):80-6.

Praveena C, Veeresham C. Benzophenanthridine alkaloids from callus cultures of Toddalia asiatica. Int J Pharm Sci Nano Technol, 2015; 8:3003-8. https://doi.org/10.37285/ijpsn.2015.8.4.2

Prithviraj SR, Nitesh Kumar T, Shahid Khan A, Upendra RS, Ahmed MR. The role of immunity and immune boosting food in combating covid-19 global pandemic. Int J Pharm Res, 2021; 13(2):2816. https://doi.org/10.31838/ijpr/2021.13.02.323

Punitha R, Manohara S. Antihyperglycemic and antilipidperoxidative effects of Pongamia pinnata (Linn.) Pierre flowers in alloxan induced diabetic rats. J Ethnopharmacol, 2006; 105:39-46. https://doi.org/10.1016/j.jep.2005.09.037

Qin S, Zhang YP, Chen X, Xia JY, Chen YD, Kong DM. Research on high throughput screening of drugs to inhibit macrophage migration (in Chinese). J. Guizhou Univ Tradit Chinese Medicine. 2020; 42, 87-90.

Qiu J, Zhu M, Wang Y, Chen B, Bai R, Chen F, Zhang L. Pharmacokinetic and excretion study of eight active constituents in rat by LC-MS/MS after oral administration of the Toddalia asiatica extract. Anal Biochem, 2022; 640:114407. https://doi.org/10.1016/j.ab.2021.114407

Rahmani M, Ling CY, Meon S, Ismail HBM, Sukari MA. The antifungal activity of Glycosmis calcicola and G. rupestris extracts. Pharm Biol, 2004; 42:430-3. https://doi.org/10.1080/13880200490886085

Raj MK, Balachandran C, Duraipandiyan V, Agastian P, Ignacimuthu S. Antimicrobial activity of Ulopterol isolated from Toddalia asiatica (L.) Lam.: a traditional medicinal plant. J Ethnopharmacol, 2012; 140(1):161-5. https://doi.org/10.1016/j.jep.2012.01.005

Rajkumar M, Chandra RH, Veeresham C. Production of nitidine from callus cultures of Toddalia asiatica. Int J Pharm Sci Nanotechnol, 2010; 3(2):1028-33. https://doi.org/10.37285/ijpsn.2010.3.2.18

Rajkumar M, Chandra RH, Asres K, Veeresham C. Toddalia asiatica (Linn.) Lam.-a comprehensive review. Pharmacogn Rev, 2008; 2(4):386-97.

Ren XD, Wang DW, Zhong L, Li SM, Guo SY. Effects of Long Jing 1 on isolated rat thoracic aortic rings. Chinese J Pathophysiol, 1993; 9:129-32.

Roshan, A. B., Venkatesh, H. N., Dubey, N. K., & Mohana, D. C. (2022). Chitosan-based nanoencapsulation of Toddalia asiatica (L.) Lam. essential oil to enhance antifungal and aflatoxin B1 inhibitory activities for safe storage of maize. Int J Biol Macromol, 2022; 204:476-84. https://doi.org/10.1016/j.ijbiomac.2022.02.026

Salahuddin M, Jalalpure SS. Antidiabetic activity of aqueous fruit extract of Cucumis trigonusRoxb. in streptozotocin-induced diabetic rats. J Ethnopharmacol, 2010; 127:565-7. https://doi.org/10.1016/j.jep.2009.10.018

Sblendorio V, Palmieri B. Accuracy of analyses for lipid profile parameters as measured with the CR3000 system. Eur Rev Med Pharmacol Sci, 2008; 12:191-6.

Singh VK, Chaurasia H, Mishra R, Srivastava R, Chaturvedi VK, Singh RK. Role of plant-based anti-hiv agents in hiv-associated neurocognitive disorders (Hand). In: Goyal MR, Birwal P, Mishra SK (eds.). Phytochemicals and medicinal plants in food design (pp. 25-44). Apple Academic Press, New York, 2022. https://doi.org/10.1201/9781003150336-3

Takomthong P, Waiwut P, Yenjai C, Sripanidkulchai B, Reubroycharoen P, Lai R, Kamau P, Boonyarat C. Structure-activity analysis and molecular docking studies of coumarins from Toddalia asiatica as multifunctional agents for Alzheimer's disease. Biomedicines, 2020; 8(5):107. https://doi.org/10.3390/biomedicines8050107

Thirugnanasampandan R, Jayakumar R, Prabhakaran M. Analysis of chemical composition and evaluation of antigenotoxic, cytotoxic and antioxidant activities of essential oil of Toddalia asiatica (L.) Lam. Asian Pac J Trop Biomed, 2012; 2(3):S1276-9. https://doi.org/10.1016/S2221-1691(12)60399-2

Tian PY, Yu YS, Deng ZG, Chen YK, Zhu X. Effects of Miao medicine Toddalia asiatica on acute gouty arthris in rats. Chinese J Gerontol, 2018; 3019-22.

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