Ethnomedicinal applications, phytochemistry, and pharmacological properties of Laggera aurita Linn (Asteraceae): A Review

The plant Laggera aurita (Asteraceae) is a commonly utilized medicinal plant growing as a weed in African countries used in the treatment of many diseases. Besides, several phytochemical and pharmacological studies were conducted to check its phytocompounds and therapeutic potentials. However, there is unavailable information on the plant documenting its ethnomedicinal uses and medicinal properties. Therefore, the current article aims to provide updated information on the ethnomedicinal values, phytochemical compounds, and therapeutic potentials of Laggera aurita for further studies to develop noble bioactive molecules. Studies regarding the plant Laggera aurita were sourced from online academic databases such as Google Scholar and PubMed. The search terms used include Laggera aurita, ethnomedicinal uses, phytochemistry, pharmacological activity, and toxicology. The plant has ethnomedicinal applications against epilepsy, cancer, atherosclerosis, thrombosis, malaria, fever, pain, stomatitis, asthma, bronchitis, nasal congestion, infections, rheumatism, dyspepsia, indigestion, constipation, dysentery, and many more. Several phytochemical agents were isolated from various plant parts. Besides, pharmacological studies have shown that the plant has antipyretic, analgesic, anti-inflammatory, anticonvulsant, anxiolytic, antimicrobial, antimalarial, and antioxidant effects. Various pharmacological evaluations conducted on the plant have validated the traditional values of the plant Laggera aurita. However, more research is paramount to validate many of the reported traditional uses. Also, the phytochemical molecules need to be screened for biological properties to develop potential therapeutic agents. The plant is relatively safe on sub-chronic administration and slightly toxic in acute studies. Hence, further toxicological studies on the plant are required to establish its safety. There is a need to also standardize doses to establish safety and efficacy.


Background
Medicinal plants are readily available sources of a wide range of phytochemical constituents for the prevention and treatment of various medical conditions (Dutra et al. 2016).These secondary metabolites have many biological actions, which give the scientific evidence for utilizing the herbal products in traditional medical practice in various communities (Kaur et al. 2021). Most people in developing nations rely on herbal medicines for basic treatment and other healthcare needs (Senthilkumar et al. 2018). About one-fourth of the world's population utilizes traditional treatments using herbs as a source of primary health care (Muhammad et al. 2021). In fact, herbal products are gaining more popularity due to their abundance, affordability, and presumed safety compared to orthodox medicines (Wada et al. 2019). So far, the pharmacological investigations on herbal products have encouraged the development of potent and efficient therapeutic agents for managing various diseases (Ahmad et al. 2020). The effective utilization of herbal products for medicinal purposes has obstacles, such as improper standardization, insufficient identification, characterization and isolation of the bioactive molecules, undiscovered pharmacological mechanisms, and clinical trials (Thomford et al. 2018). There have been efforts to explore alternative treatment options, particularly from natural products derived from plants due to the adverse effects of chemically synthesized drugs (Liu et al. 2020). Therefore, provision of documented information medicinal values and therapeutic potentials as a prerequisite for further development of valuable herbal products is paramount (Mao and He 2020).
Laggera aurita Linn (Asteraceae) is a shrub found around houses and farmlands (Olurishe and Mati 2014). It is an annual, erect, glutinous herbaceous plant with a pleasant aroma that grows up to 30-100 cm in height and is usually densely branched. The leaves of this plant are alternate, and the base is decurrent on the stem with glandulous points. The inflorescence reveals several involucres per head, with various white, yellow, or mauve-colored small flowers with narrow bract and usually flowers from December to February (Salisu et al. 2015;Shahwar et al. 2012). The plant grows as a weed in Nigeria and spreads throughout sub-Saharan Africa (Egharevba et al. 2010;Guragi et al. 2018). It is commonly utilized for medicinal reasons in African nations such as Senegal, Nigeria, and Ghana (Shehu et al. 2016). Laggera aurita is popularly known as ' Abanaadene' (meaning vulture's excrement) in Igbo (Awka), 'Eru-taba' (meaning slave of tobacco) in Yoruba (Ilorin), and 'Taba taba' in Hausa (Shehu et al. 2015). L. aurita (Asteraceae), also known as Blumea aurita Linn, belongs to the family Compositae (Olurishe and Mati 2014).
Currently, there are various documented traditional uses of the plant in the literature. Besides, many scientific investigations were conducted to investigate the bioactive molecules from L. aurita for therapeutic reasons. However, summarized information on the traditional values, phytochemical composition, pharmacology, and toxicology on the plant is lacking. Therefore, this review seeks to provide a comprehensive overview of the ethnomedicinal values, phytochemistry, isolated compounds, pharmacology, and toxicity of Laggera aurita to motivate further research for potential drug development.

Methods
A detailed search of information about the plant Laggera aurita was carried out and retrieved from online academic databases such as PubMed and Google Scholar from inception to April 2022. The search terms used include Laggera aurita, ethnomedicinal uses, phytochemistry, pharmacological activity, and toxicology.

Traditional uses
The Laggera aurita leaves are employed in Nigeria to manage epilepsy (Malami et al. 2016). The plant's essential oils are used to treat cancer, atherosclerosis, and thrombosis. They also serve as antispasmodics and diuretic (Edris 2007;Guragi et al. 2018;Magaji and Malami 2018;Malami et al. 2016). The plant is used traditionally to treat pediatric, fever, malaria, stomatitis, pain, asthma, nasal congestion, bronchitis, and bacterial infections in Burkina Faso, Cameroon, and Nigeria. It serves as a preservative in cereal grains (Egharevba et al. 2010). It is also reported to be used traditionally in treating inflammation, rheumatic pain, dyspepsia, indigestion, constipation, and dysentery and aiding wound healing (Diabala et al. 2014). The reported ethnomedicinal uses of the plant L. aurita are presented in Table 1.

Analgesic and anti-inflammatory studies
Pain is a disturbing and unpleasant sensation elicited after the activation of peripheral pain receptors, which is associated with real or possible tissue damage (Fan et al. 2014;Kaliyaperumal et al. 2020). Inflammation is an adaptive physiological response that happens in a particular tissue in response to tissue injury, cell death, cancer, degeneration, and ischemia (Azab et al. 2016).
Even though progress has been achieved substantially in treating pain and inflammatory conditions with efficacious drugs, the conditions remain among the highest health burdens in the global healthcare system (Khan et al. 2020). The herbal products' utilization against pain and inflammation has been well reported (Borges et al. 2018;Saleh et al. 2015). In a previous experiment by Olurishe and Mati (2014), the methanol extract of L. aurita at 200 and 400 mg/kg elicited analgesic action against mechanically and chemically induced hyperalgesia via peripheral and central mechanisms in mice as compared with the piroxicam (5 mg/kg) (Olurishe and Mati 2014). A similar finding was documented by Shehu and team members on the acetic acid-elicited writhing test and hot plate test method (Shehu et al. 2016). The result showed an effective and dose-dependent decline in the number of acetic acid-elicited writhes than piroxicam administered at a dose of 20 mg/kg and a significant elevation in the mean reaction time at 800 mg/kg than morphine (5 mg/kg) (Shehu et al. 2016). Furthermore, the extract unveiled a remarkable and dose-dependent decrease in the mean reaction time when it was co-administered with naloxone, as suggestive of possible participation of the opioidergic system in its antinociceptive effects (Shehu et al. 2016). The saponins-and flavonoids-rich constituents of the plant also showcased analgesic potentials in the acetic acid and thermally induced nociception (Shehu et al. 2016). The same study documented the anti-inflammatory actions of the plant in formalin-induced inflammation at 200, 400, and 800 mg/kg (Shehu et al. 2016).

Anticonvulsant properties
Epilepsy is a common serious neurological pathological condition accompanied by recurrent spontaneous seizures due to complicated neurochemical processes involving several neurotransmitters (Almeida et al. 2011). The currently available antiepileptic compounds have adverse effects and limited efficiency, necessitating alternative, potent, clinically efficacious, and safe therapeutic options against the disorder (Fisseha et al. 2021). Several herbal preparations have medicinal use against epilepsy in traditional practice (Aghamiri et al. 2020), including L. aurita (Malami et al. 2016). Various herbal products with potential antiepileptic effects have been documented (Zhu et al. 2014).
As per the study by Malami et al. (2016), the leaf extract of L. aurita at 600 mg/kg produced 40% protection against tonic hind limb extension and a significant decline in the mean recovery time in maximal electroshock (MEST)-elicited seizures. Besides, the extract  (2014) (2020) Valencene Essential oil from leaf Not mentioned Not mentioned Mevy et al. (2006) α-Himachalene Essential oil from leaf Not mentioned Not mentioned Mevy et al. (2006) α-Methyl-3-phenylallyl alcohol Essential oil from leaf Not mentioned Not mentioned Mevy et al. (2006) α-Terpineol Essential oil from leaf Not mentioned Not mentioned Mevy et al. (2006) α-Bourbonene Essential oil Not mentioned Not mentioned Dantanko and Malann (2020) α-Phellandrene Essential oil Not mentioned Not mentioned Dantanko and Malann (2020) α-Amorphene Essential oil from leaf Not mentioned Not mentioned Mevy et al. (2006) (2020), Mevy et al. (2006) β-Linalool Essential oil Not mentioned Not mentioned Dantanko and Malann (2020) β-Caryophyllene Volatile oil from leaf Not mentioned Larvicidal and insecticidal activity Dantanko and Malann (2020)  conferred 50% protection against pentylenetetrazol (PTZ)-produced seizures and significantly elevated the seizures onset. In the strychnine-provoked seizure model, the highest protection of 50% against seizure was seen when the animal was administered 300 mg/kg of the extract (Malami et al. 2016). In fact, a remarkable elevation in the seizure's latency was observed at all the tested doses. About 33.3% protection was recorded against the clonic convulsion in the picrotoxin-elicited seizure (Malami et al. 2016). When subjected to a chronic model of epilepsy, the extract significantly produced a dose-dependent delay in the seizure for all the treatment days, showcasing its action at 600 mg/kg comparable to sodium valproate at 100 mg/kg in the PTZ-induced kindling test (Malami et al. 2016). When the extract (600 mg/kg) was coadministered with flufenamic acid (5 mg/kg), there was a 70% synergistic effect as against the respective 40% and 20% protection recorded when the individual agents were administered, respectively (Malami et al. 2016). About 80% protection was also observed when the extract was administered together with phenytoin against respective 40% and 60% protection recorded with individual administrations (Malami et al. 2016). It was postulated that the possible mechanisms of antiepileptic actions of the extract could be attributed to its interaction with serotonergic and histaminergic pathways following pretreatment with cyproheptadine before the extract administration (Malami et al. 2016).

Antimicrobial properties
Infectious diseases form part of the top 10 causes of global death, disability, and morbidity (Etame et al. 2019;Nair et al. 2017). Even though there has been advancement in antimicrobial therapy, resistance causes serious drawbacks in curtailing infectious diseases (Etame et al. 2019). Natural products, including plants, form a new hub for treating infectious diseases (Blondeau et al. 2020). The crude extract of L. aurita and its fractions were reported to have anti-tubercular activity in the broth micro-dilution method (BMM) (Egharevba et al. 2010). The crude extract's minimum inhibitory concentration (MIC) was determined to be625u/ml compared to several fractions ranging between 1000-3000u/ ml (Egharevba et al. 2010). It was proposed that the observed antimicrobial effect shown by the crude extract might result from several compounds' synergistic action (Egharevba et al. 2010). In another experiment by Shahwar and c0-researchers, the antibacterial properties of the volatile oil of L. aurita elicited the effective antimicrobial actions against Proteus mirabilis as compared to Bacillus subtilis, Escherichia coli, and Nocardia asteroides using the agar well diffusion test (Shahwar et al. 2012).
The antibacterial action of L. aurita was further supported by Diabala et al. (2014), where the MIC and minimum bactericidal concentration (MBC) of the bioactive fractions revealed the highest efficacy in the ethyl acetate fraction (EAF) than dichloromethane fraction (DCMF) in the broth microdilution method. The inhibitory effects of the ethyl acetate containing-flavonoid fractions combined with gentamycin against the food bacterial strain multi-resistant showed a synergistic and additive effect (Diabala et al. 2014;Salisu et al. 2015).

Antiplasmodial properties
Malaria is a disease that causes rampant death and complications globally, where more than 50% of the population is affected by the disease. The most affected region is sub-Saharan Africa (Habte and Assefa 2020). Besides, the Plasmodium species, notably P. falciparum, have developed resistance to the currently available antimalarial agents, posing obstacles to malaria prevention and treatment (Fenta and Kahaliw 2019). In developing areas, people rely on herbal preparations for treating malaria (Okokon et al. 2017). The plant L. aurita exhibited significant repellent properties against A. stephensi and oviposition deterrence against A. stephensi vector of malaria (Singh and Mittal 2015). It was reported by Dantanko and Malann (2020) that the essential oil of L. aurita possesses potential larvicidal activity against Anopheles gambiae (Dantanko and Malann 2020). The L. aurita extract unveiled an effective and dose-dependent decline in the elevated parasitemia level in 4-day suppressive, prophylactic, and curative in vivo test models against chloroquine-sensitive Plasmodium berghei in mice (Magaji and Malami 2018).

Antioxidant properties
Antioxidants moderate the generation of reactive oxygen species (ROS) such as free radicals from various bodily metabolic activities. However, an irregularity that increases the ROS level and oxidative stress results in many disorders, including cardiovascular diseases, diabetes mellitus, inflammation, and neurodegenerative disorders associated with oxidative stress (Aldoghaci et al. 2021). Medicinal plants are a great source of antioxidant compounds (Link et al. 2016).
The antioxidant effect of the volatile oils obtained from L. aurita elicited significant xanthine oxidase inhibitory effects against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities comparable to allopurinol (Shahwar et al. 2012). In another work by Diabala et al. (2014), the DPPH radical method, 2,2-Azino-bis-3-ethylbenzothiazoline-6-sulfonic Acid (ABTS) radical cation decolorization assay and the ferric reducing antioxidant power (FRAP) assay were carried out on ethyl  (Diabala et al. 2014). The strongest scavenging actions against DPPH radicals were observed in the EAF fraction, followed by the DCMF, and the lowest activity was seen in the OEF fraction (Diabala et al. 2014). The strongest ABTS activity was seen in EAF, followed by DCMF, and the lowest activity in OEF (Diabala et al. 2014).In addition, the strongest FRAP activity was obtained by DCMF, followed by EAF and the lowest activity was obtained by OEF (Diabala et al. 2014).
According to the study, the EAF and DCMF have the highest polyphenol than other fractions and, therefore, might be the reason for the high antioxidant activities seen in the two fractions (Diabala et al. 2014).

Antipyretic activity
Pyrexia is an elevation in the body temperature beyond the physiological level due to conditions including ovulation, increased thyroid hormone secretion, strenuous exercise, and microbial agents (Sultana et al. 2015). The body's immune is stimulated to remove the microbes in case of infections (Sultana et al. 2015). Various medicinal plants were reported to have antipyretic actions (Nock et al. 2022;Rauf et al. 2014). Another research unveiled a significant (p < 0.05) reduction in the Brewers' yeastinduced fever model as an indication of the antipyretic effect of the plant (Magaji and Malami 2018).

Anxiolytic activities
Anxiety is a severe psychological situation associated with negative emotional experiences (Mani et al. 2021). This disorder is one of the most common community illnesses affecting about 2-6% of the world population (Mani et al. 2021). Previous studies reported the anxiolytic actions of medicinal plants (Doukkali et al. 2015;Elakhal et al. 2021;Lobina et al. 2018). The methanol leaf extract of L. aurita (150, 300, and 600 mg/kg) exhibited anxiolytic potentials in the hole-board, elevated plus maze, staircase, beam walk assay, open field, and diazepam-induced sleep models (Guragi et al. 2018).

Toxicological studies
Traditional medicine has been getting attention globally with medicinal plant products to treat diseases and improve health (Joung et al. 2019). Because herbal products are obtained from natural sources and utilized for prevention and disease curation, they are generally presumed safe (Abraham and Ahmad 2021). Nevertheless, studies have cautioned about the safety of the herbal preparations, particularly their possible liver and kidney toxicity Teschke et al. 2014).
Therefore, scientific documentation on plant safety information is necessary for drug development (Reduan et al. 2020). An experiment by Shehu et al. (2016) reported the acute toxicological effects of the L. aurita extract at 2000 and 5000 mg/kg (Shehu et al. 2016). The histopathological result showed specific toxicity of the extract on the kidney and liver at 2000 mg/kg. The liver, kidney, spleen, lungs, and stomach were all affected at 5000 mg/kg, except for the heart (Shehu et al. 2016).
Evaluation of the serum biomarker of Wistar rats following the 28-day oral treatment of the L. aurita showcased that the extract has some level of safety (Julde et al. 2017). However, there was an elevation in alkaline phosphatase (ALP) level at the tested doses (75, 150, 300, and 600 mg/kg), while aspartate transaminase (AST) and alanine transaminase (ALT) levels were lowered (Julde et al. 2017). The results of the kidney parameters showed no significant alteration in creatinine concentration at all the doses. Besides, a substantial reduction in the urea level was observed at 600 mg/kg. The study also showed no significant change in the oxidative stress markers (superoxide dismutase, catalase, and malondialdehyde) except in glutathione peroxidase, where a remarkable increase was observed at 300 and 75 mg/kg (Julde et al. 2017). Besides, there were no substantial changes in the food and water consumption, weights of the animals, organ weight, and blood glucose level. The hematological indices evaluated were also not affected by the extract (Julde et al. 2017).

Conclusions
The plant Laggera aurita possesses promising therapeutic values. Previous experiments on the plant have established some of its ethnopharmacological indications in traditional medicine as evidence for its potential therapeutic activity against various disorders. However, more research is needed to provide documented proof for many of its traditional uses. The literature has shown that several compounds have been isolated and identified from Laggera aurita from different locations, although there are variations in the compounds isolated. Therefore, there is a need to screen the compounds responsible for potential pharmacological effects and toxicities. The toxicological evaluation of Laggera aurita has also shown relative safety in sub-chronic administration and signs of toxicity in acute studies. In addition, there is a need for further detailed long-term toxicological evaluation, such as chronic, mutagenic, teratogenic, and genotoxic toxicity studies of the plant, to establish its safety fully. Furthermore, there is a need to standardize doses that could be used for subsequent clinical trials in humans. This will