Medicinal Plants of Solanum Species: The Promising Sources of Phyto-Insecticidal Compounds

Several medicinal plants have the potential to be a promising alternative pharmacological therapy for a variety of human illnesses. Many insects, including mosquitoes, are important vectors of deadly pathogens and parasites, which in the world's growing human and animal populations can cause serious epidemics and pandemics. Medicinal plants continue to provide a large library of phytochemicals, which can be used to replace chemically synthesized insecticides, and utilization of herbal product-based insecticides is one of the best and safest alternatives for mosquito control. Identifying new effective phyto-derived insecticides is important to counter increasing insect resistance to synthetic compounds and provide a safer environment. Solanum genus (Solanaceae family or nightshades) comprises more than 2500 species, which are widely used as food and traditional medicine. All research publications on insecticidal properties of Solanaceae plants and their phytoconstituents against mosquitoes and other insects published up to July 2020 were systematically analyzed through PubMed/MEDLINE, Scopus, EBSCO, Europe PMC, and Google Scholar databases, with focus on species containing active phytoconstituents that are biodegradable and environmentally safe. The current state of knowledge on larvicidal plants of Solanum species, type of extracts, target insect species, type of effects, name of inhibiting bioactive compounds, and their lethal doses (LC50 and LC90) were reviewed in this study. These studies provide valuable information about the activity of various species of Solanum and their phytochemical diversity, as well as a roadmap for optimizing select compounds for botanical repellents against a variety of vectors that cause debilitating and life-threatening human diseases.


Introduction
Medicinal plants are traditionally used to treat numerous human infections, and their bioactive compounds have long been important in therapeutic development, particularly in cancer and infectious diseases. Medicinal plant-derived natural products have garnered much interest in recent years as potential bioactive agents for insect vector control. Vector control is threatened by the emergence of resistance to conventional synthetic insecticides in vectors, among which mosquitoes pose high threats to human and animal health and life, often leading to the transmission of serious diseases, such as dengue, Ebola, filariasis, and malaria, resulting in millions of deaths each year [1][2][3][4]. Because chemical control of mosquitoes has been linked to such detrimental outcomes as the development of insect resistance, it is urgently necessary to discover and develop reliable and environmentally sustainable alternatives to current synthetic chemical insecticides.
As an alternative to synthetic insecticides, plant-based insecticide preparations have the advantages of rapid biodegradability and low toxicity to humans and animals [5]. Several plants and their constituents, especially those in medicinal herbs, have been traditionally used as insecticides, due to being rich in various bioactive phytochemicals and providing potential sources of natural mosquito control agents [6][7][8][9]. Recently, attention has been given to preparations of mosquito-larvicidal compounds based on herbal origin to enhance insecticidal effects and reduce the probability of development of resistance by the target pest population [10,11]. While several plants from different families have been reported with mosquito-larvicidal properties, only a few species show promising effects and could be developed into natural insecticidal agents [12].
e Solanum family of plants is a large genus within the Solanaceae family that contains up to 2,000 species ranging from food crops to medicinal herbs. e genus Solanum has received much interest in chemical and biological studies over the last 30 years. Several steroidal saponins, steroidal alkaloids, disaccharides, flavonoids, and phenols have been implicated in the biological activities [13]. e genus Solanum appears to have a lot of potential, although most of the species are unknown or have had little research on their chemical contents. Several reviews of the Solanum genus and their phytochemistry have been published. ese compounds have been linked to various health-promoting activities in the fight against several noncommunicable diseases, which are the leading causes of death worldwide. Many species belonging to this genus present a huge range of pharmacological activities such as anticancer, hepatoprotective, antimalarial, anthelmintic, and other activities [14]. Plants in this family are recognized for having a wide spectrum of alkaloid compounds, some of which are therapeutically the most potent. Steroidal glycoalkaloids are the most common and important group of nitrogen-containing secondary metabolites identified in Solanaceae plants. More than 350 Solanum species have yielded more than 100 different forms of glycoalkaloids [15,16]. Many medicinal plants belonging to the Solanaceae family are promising therapeutic candidates to develop as bioinsecticidals against vector-borne human diseases such as malaria, leishmaniasis, and dengue fever due to the presence of different phytoconstituents. Various Solanum spp. provide a potential source of useful adulticidal drugs because of the presence of phytochemicals that can be used for the treatment of many diseases [17]. us, more scientific efforts should be made to identify and develop Solanum-based phyto-insecticides. Our literature review revealed 19 Solanum medicinal plants used in all parts (leaves, roots, bark, and flowers). e goal of this review is to compile most of the scientific literature on mosquito-larvicidal and insecticidal investigations of Solanum plants and their active bioactive chemicals from various scientific sources, including the types of extracts examined, dosages, and effect on target organisms.

Source of Data
A comprehensive systematic review of the literature up to July 2020 on Solanaceae plants with larvicidal effects present in standard electronic databases, such as EBSCO, Europe PMC, Google Scholar, MEDLINE, PubMed, Scopus, and Web of Science, was conducted using various keywords (adulticidal, botanical, essential oil, insecticidal, larvicidal, repellency, Solanaceae, Solanum, and steroidal alkaloids). e search was restricted to publications having English titles. In addition, a manual search was performed to categorize related articles using references from the retrieved literature.
A total of 51 full-text original research articles published in peer-reviewed journals on Solanaceae plants were retrieved, and data were culled for larvicidal effects. Roles of larvicidal activities were assessed in Solanaceae plant solvent extracts, such as acetone, chloroform, ethyl acetate, hexane, and methanol from seventeen different medicinal plants.
Other parts of these plants with significant larvicidal properties against various mosquito vectors were highlighted.

Solanaceae Family
Solanum L genus is the largest of the Solanaceae family or nightshades containing approximately 85-90 genera and 2,500-3000 species distributed in tropical and subtropical regions (Table 1) [12,13]. Local names are given in various languages to describe a specific species for a particular local use. In Saudi Arabia, some species of Solanaceae are found primarily in the Asir Region and Jizan Region of Abha ( Figure 1). A recent ethnobotanical study recorded three new collections of Solanum spp. in the southwest regions of Saudi Arabia [18].

Ethnopharmacological Use.
Solanaceae is the most economically important family in the genus Solanum (Table 2). Solanaceae family offers a diversity of medicinal, culinary, and ornamental applications. e genus Solanum has attracted much interest in chemical and biological investigations over the last 30 years. Biologically important products for medicine and food include atropine, hyoscine, solasodine, and withanolide [19][20][21]. Although rich in alkaloids of medical importance, Solanaceae plants contain alkaloids with toxicity to humans and animals, ranging from mild irritation to fatal outcomes [22][23][24][25]. In addition, Solanaceae spp. have potential importance as food supplements worldwide [22,26]. S. nigrum, S. xanthocarpum, S. tuberosum, and S. lycopersicum are a few economically important species of the Solanum genus. Various species in this genus have completed various pharmacological research to verify and validate their ethnopharmacological usage. However, various reviews of the Solanum genus have been published, most of which focused on a single species [14,[27][28][29][30]. Table 3 summarizes the scientific literature and reveals a variety of ethnopharmacologically based traditional insect repellents derived from Solanum plants utilized by local ethnic communities in various countries to avoid mosquito bites.
Solanum genus has several species found in tropical and subtropical areas and is used in folk medicine and dietary supplements. Among them, S. nigrum has been considered ethnobotanically important due to its use in the traditional healthcare system to cure various ailments. e leaves and bitter berries with pungent have been traditionally used against severe ulcers, heart diseases, piles, dysentery, gastritis, and stomachache [27]. S. sisymbriifolium, known as "wild tomato," is a traditional medicine used by indigenous people of Central and South America to treat veterinary and human diseases. Various parts of the wild tomato have been widely used to prevent and treat numerous diseases, including hypertension, diarrhea, and respiratory and urinary tract infections [31].
S. tuberosum is used in folk medicine to treat burns, constipation, hemorrhoids, corns, cough, tumors, scurvy, and warts and to prevent wrinkles on the face [32]. S. integrifolium is native to Africa; its unripe fruits are eaten daily to check high blood pressure, inflammation, pain remedy to alleviate edema or cure stomach pain, lymphadenopathy, or sore armpits in indigenous medicine [34]. S. villosum is a traditionally important plant used in various systems of medicine for the treatment of leucorrhea, nappy rash, wounds, and cold sores, and as an ointment for sores and abscesses. A well-known traditional herb S. xanthocarpum is widely used in India to manage different ailments, including urolithiasis [35]. S. trilobatum is a widely used plant in the Indian indigenous systems of medicine. It is mainly used to treat respiratory diseases such as bronchial asthma [37]. S. virginianum L. has been used to manage fever, bronchial asthma, and cough for thousands of years [48].
In traditional medicine in Peru, S. mammosum is used to treat fungal infections and respiratory disorders via topical application. S. incanum is commonly found in Africa and is used as a folklore remedy for sore throat, angina, stomachache, colic, headache, wounds, pain relief in toothache, cure of snake bites, and sexually transmitted disease in wounds [49]. S. elaeagnifolium is called silverleaf nightshade and traditionally is used for the treatment of sore throats as an antiseptic agent, toothaches, and gastrointestinal disorders.      Journal of Tropical Medicine

Leaves and roots
Pentanone and c-sitosterol India and China [47] Journal of Tropical Medicine 5 Phytochemical analysis of berry extracts S. elaeagnifolium revealed the presence of kaempferol 8-C-β-galactoside that possesses medicinal proprieties [50]. S. verbascifolium is used in Chinese folklore for diarrhea, dysentery, eczema, edema, gout, headaches, ulcers, fever, hematuria, and toothache [45]. Despite being a poisonous plant, S. pseudocapsicum is used in traditional medicine to treat boils and gonorrhea and relieve abdominal pain, and as a male tonic [47]. S. torvum is another commonly used Solanaceae herb in traditional medicine. e plant extracts have been widely used to treat fever, wounds, tooth decay, reproductive problems, and arterial hypertension [46]. us, leaves, fruits, roots, and aerial parts of Solanum plants can benefit humans by enhancing their health when consumed as part of a daily diet, nutraceutical, or biopharmaceutical.

Phytopharmacology and Insecticidal Properties of Solanaceae spp.
Medicinal Solanaceae plants have traditionally been used as insecticidal, anti-infectious, and antimicrobial agents [51,52]. Table 4 shows the different types of test organisms, bioassays, and doses applied to investigate the mosquitocidal activity of crude plant extracts from the Solanum genus. Crude and chloroform-methanol extracts of S. tuberosum at very low concentrations are effective in mosquito control [54]. Volatile oils of S. xanthocarpum were effective as insect repellents, giving rise to >5 hours of protection against Culex quinquefasciatus without apparent dermal irritation to human skin [72]. Chloroform-methanol extract of S. villosum green berries was used as a biocontrol agent against Aedes aegypti [90]. S. villosum green berries had the greatest biocidal activity against St. aegypti. aegypti, and Cx. quinquefasciatus in chloroform and methanol extracts. As a result, crude extracts or protein fractions/isolated bioactive phytochemicals from S. villosum could be utilized as a possible biocontrol agent against these mosquitoes, especially because of its larvicidal impact [58,59,90]. S. integrifolium chitin-binding lectins (CBLs) inhibit Spodoptera frugiperda (sf21) insect cell growth by binding to carbohydrates and depolarizing mitochondrial membrane potential [60]. Table 5 summarizes detailed investigations of the mosquito-larvicidal efficiency of various Solanum species. Some examples are highlighted (according to the author's viewpoint) as follows: S. xanthocarpum extracts show various larvicidal and pupicidal activity against Cx's first-tofourth instars. Cx. quinquefasciatus fruit aqueous extract exhibits 100% killing after 48-hour exposure compared with its root extract [61,62]. e previous study has reported that the fruit extract of S. xanthocarpum and copepod Mesocyclops thermocyclopoides could serve as a potential highest mortality rate against dengue vector Ae. aegypti [63]. is mosquitocidal efficiency may be caused by detrimental effects of the S. xanthocarpum active principle compounds (solanocarpine and solanocarpidine) on the mosquito larvae. Similarly, S. xanthocarpum fruit extracts had larvicidal action against An. stephensi and Cx. quinquefasciatus, as well as one culicine species, Ae. aegypti. e toxic concentrations of fruit extract against An. culicifacies, An. stephensi, and Ae.
aegypti were found to be 0.112 and 0.258%, 0.058 and 0.289%, and 0.052 and 0.218%, respectively, at the LC 50 and LC 90 levels. It was discovered that crude extracts have larvicidal capability due to their volatile oil content, implying that they could be used as an environmentally friendly, effective larvicidal in managing various vector-borne epidemics [66,97]. Methanol leaf extract of S. trilobatum is effective against Ae. aegypti, Cx. quinquefasciatus, and An. stephensi pupae and larvae with an LC 50 value of 125, 128, and 117 ppm, respectively [73]. Chloroform: methanol (1 : 1 v/v) extract of S. nigrum mature leaves is toxic against Cx's early 3rd instar larvae of the Cx. vishnui group and An. subpictus [56].
e seed hexane extract of S. trilobatum exhibited (38%) acaricidal and insecticidal activities against the adult of H. bispinosa (Ixodidae) and hematophagous fly H. maculata Leach (Hippoboscidae). erefore, this study provides the first report on the parasitic activities of plant extracts from southern India [75]. e leaf extract of S. trilobatum was found to have an oviposition deterrent effect, reducing egglaying by An. stephensi by 18 to 99% and providing 70 to 120 minutes of mosquito bite protection skin repellent activities. S. trilobatum leaf extract had dose-dependent oviposition deterrent and skin repellent effects. Several solvent extracts of S. trilobatum were tested against the filarial vector Cx. quinquefasciatus; petroleum ether had the highest larvicidal activity, with LC 50 values of 203.87 and 165.04, respectively, after 24 and 48 hours, followed by acetone and chloroform extracts [96]. According to the findings, S. trilobatum leaf extract is an efficient oviposition preventive and cutaneous repellent against A. stephensi [72]. e crude extract of the leaves or fruits of S. incanum and W. somnifera has an equal effect on the A. messinae mortality (96% mortality). However, the percentage mortality of the termite was 100% with 135 µg from the crude extract of S. incanum leaves. Based on findings, both crude extracts have the potential to be used as termite control agents in termite breeding areas in the field or infested homes [80]. e larvicidal efficacy of S. torvum was tested against An. stephensi and Cx. quinquefasciatus, with the results indicating that the leaf methanol extract of S. torvum had the highest LC 90 , ranging from 70.38 to 210.68 ppm. As a result, isolated plant metabolites from S. torvum from southern India have the potential to be used as environmentally safe and long-lasting mosquito repellents [85]. e mosquito repellant effect of S. lycopersicum esculentum leaf hydroethanolic extract on the larvae of multiple mosquito species was tested at varied concentrations of 50, 100, 150, 200, and 250 ppm, with larva mortality seen within 24 hours. e hydro-ethanolic extract caused complete mortality in mosquitoes at 200 ppm in 18-19 hours, and the study found that S. lycopersicum esculentum may kill mosquitoes at a lower concentration [77]. e insecticidal effects of methanolic extracts of S. elaeagnifolium seeds were investigated further against S. littoralis, and 100% larval mortality was observed with the strongest growth inhibition (59.68%) compared to leaves [110]. Methanolic extracts from the leaves and seeds of S. elaeagnifolium also showed insecticidal efficacy against P. operculella and T. castaneum. Seed extract   [92] 8 Journal of Tropical Medicine Journal of Tropical Medicine 9 10 Journal of Tropical Medicine Journal of Tropical Medicine 11

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Journal of Tropical Medicine inhibited oviposition and egg hatching the most (95.9% and 98.6%, respectively), with an aphid mortality rate of 23.6% [79]. ese findings suggested that numerous Solanum species might be used as plant-based mosquitocidal. ey could be a valuable source for developing novel natural repellents as an alternative to chemical repellents in the future.
e structure of phytochemicals with promising mosquitocidal and insecticidal effects from Solanum species is summarized in Figure 2.

Solanaceae spp. Phytochemicals with Insecticidal
Properties. For decades, Solanum species have been widely used in healthcare systems as a source for various phytochemicals, including steroidal alkaloids. Solanum is distinguished by the presence of the steroidal alkaloid solasodine, which is a potential starting material for the manufacture of steroid hormones. Because of the wide spectrum of biological activities such as antibacterial, anti-inflammatory, antioxidant, and anticancer, Solanum alkaloids have been a topic of interest in pharmacological and therapeutical investigations. Because of metabolites such glycoalkaloids, some of the Solanum species are poisonous. Several pharmacologically important lead compounds are found in Solanum species, including steroidal alkaloids such as solasodine, solasonine, solamargine, and other medicinally important alkaloids; solasodine and its glycosylated derivatives, such as solamargine and solanine; and other chemicals with medicinal potential for developing new drugs against various human diseases.
β-Solamarine isolated from the methanolic extract of seeds of S. elaeagnifolium was found to have molluscicidal activity against G. truncatula and F. hepatica. e median lethal concentration of β-solamarine in molluscicidal activity (LC 50 ) was of 0.49, and the study emphasizes that this glycoalkaloid may be used as molluscicides [101]. Another mosquitocidal investigation revealed that the leaf extract of S. trilobatum possesses oviposition deterrent and skin repellent activity against An. stephensi. Both oviposition deterrent and skin repellent activity were dose-dependent [112]. Two major compounds of steroidal glycoalkaloids were isolated from the fraction C MeOH extract of S. sisymbriifolium and were identified as solamargine (1) and β-solamarine. e toxicity of fraction C is 10-fold higher than that of Anophelinae larvae. ese two steroidal alkaloids were known to possess molluscicidal activity where they could be used as a molluscicide in the future [53].
Luciamin, a spirostanol saponin, was isolated from the ethanolic extract of the aerial parts of S. laxum and was tested against the aphid S. graminum by incorporation in artificial diets. Luciamin showed a deterrent (toxic) activity against the insect and is the first spirostanol glycoside reported to have this activity. Luciamin's aphid repelling effect deserves further exploration to determine its biological and economic effects against viral vectors [81]. Two Solanum glycosides isolated from S. laxum were found to have insecticidal effects against S. graminum with LC 50 4.3 µM (laxumin A) and LC 50 6.1 µM (laxumin B), respectively [82]. e insecticidal effect of the isolated steroidal alkaloids fraction B from S. sisymbriifolium was investigated on Anophelinae larvae (A. gambia, A. funestus). Compared with other extracts and fractions, fraction B, which contains solamargine and β-solamarine, appears less hazardous to larvae. As a result, fraction B could potentially be employed as an insecticide in the future [53]. Solanum species steroidal alkaloids are unique in their pharmacological properties and are important lead molecules for drug development [113].
Glucosisaustrin, a glucosinolate group of bioactive compounds from S. nigrum, was responsible for larval mortality. Glucosinolate is a plant-derived secondary metabolite and hydrophilic, having potent mosquito-larvicidal properties against Cx. quinquefasciatus and found to be safe for the environment [87]. For several decades, N. glauca has been known for its content of the pyridine alkaloids, such as anabasine, nicotine, and nornicotine. In the P. rapae larval bioassay, the median effective concentrations of anabasine were 0.572 mg/larva. Despite this, the insecticidal activities of the N. glauca extract are likely related to anabasine, as several phytochemical experiments and bioassays have shown [88]. is review intended to collect all of the scientific data on mosquitocidal, insecticidal, and larvicidal investigations on medicinally important Solanum compounds including steroidal alkaloids. Because most of the studies are laboratory-based and do not meet clinical standards, this comprehensive review is expected to bolster investigators in furthering their research into this field, which could lead to the development of plant-based mosquito repellents with significant economic benefits.

Solanum Plant-Mediated
Nanoparticles. Plant extractbased silver nanoparticles have recently been developed to improve the control of mosquitoes without causing any significant harm to humans [114,115]      demonstrated adulticidal and insecticidal activity against Ae. aegypti, implying that AgNPs produced from plant extracts have higher levels of toxicity than the extracts alone [55,76].
us, these herbal-based AgNPs hold great promise as potent larvicides, but their environmental impact requires further investigation for controlling target vector mosquitoes.

Conclusion
Mosquito control is an important public health policy in tropical areas. Mosquitoes constitute a part of natural biodiversity, and their total eradication is not necessary, but only the diseases they transmit need to be eradicated. Nevertheless, bites from disease-bearing insects can be minimized and even avoided altogether. Inappropriate application of chemical insecticides in insect pest control can lead to insect resistance and pose environmental hazards and raises pest resistance to insecticides. Plants contain a variety of larvicidal secondary metabolites, and given their low environmental impact and minimal toxicity to humans, medicinal plants present a promising alternative to synthetic pesticides [116,117]. Solanum spp. constitute a large and diverse genus (∼2,000 species) of flowering plants, which provide food sources, eggplant, potato and tomato, ornamental flowers and fruits, and herbal medications. Solanum species grow in various habitats and can be annuals and perennials, vines, subshrubs, shrubs, and small trees.
Solanum spp. contain a diversity of phytochemicals that can be culled for their insecticidal properties, particularly mosquito larvicide, adulticide, and repellent. Although crude extracts have higher insecticidal potency than pure components, probably due to synergy among their bioactive constituents, optimal utilization of crude extracts is limited by an inability to control their contents, which can vary depending on plant species, cultivation conditions, the season of harvest, and extraction methods and solvents used.
us, an understanding of the mechanism of insecticidal activity of the major bioactive compounds can lead to consistent and optimal formulation and adjustment to match the target insect pests of interest. e review highlights current knowledge of phytocompounds (glycoalkaloids, phytosteroids, plant proteins, and volatile oils) reported as larvicides, adulticides, and repellents against a variety of insect pests, against vectors of important human diseases (dengue, filaria, and malaria). e exquisitely low larvicidal activity of silver nanoparticles formed from plant fruit and aqueous leaf extracts indicates the synergism between traditional medicinal herbal knowledge and modern (nano)technology. As a result, the usage of environmentally beneficial and cost-free plant-based products for insect/mosquito control is now unavoidable. Although the evaluation of phytochemicals is still in its early stages, with much more research needed to characterize promising agents and discover new ones, some of the findings presented in this review suggest that Solanum genus-based botanical phytochemicals should not be dismissed as a potential future alternative to synthetic insecticides. Hence, Solanaceae plants should be mined for their inexpensive, eco-friendly, safe, and effective alternatives to current chemical larvicides.

Data Availability
e data used to support the findings of the study can be obtained from the corresponding author upon request.

Conflicts of Interest
e authors declare no conflicts of interest.