Natural Products as Mite Control Agents in Animals: A Review

Mites have been a persistent infectious disease affecting both humans and animals since ancient times. In veterinary clinics, the primary approach for treating and managing mite infestations has long been the use of chemical acaricides. However, the widespread use of these chemicals has resulted in significant problems, including drug resistance, drug residues, and environmental pollution, limiting their effectiveness. To address these challenges, researchers have shifted their focus towards natural products that have shown promise both in the laboratory and real-world settings against mite infestations. Natural products have a wide variety of chemical structures and biological activities, including acaricidal properties. This article offers a comprehensive review of the acaricidal capabilities and mechanisms of action of natural products like plant extracts, natural compounds, algae, and microbial metabolites against common animal mites.


Introduction
There are many kinds of mites, with more than ten species related to human and animal health. Common mites include Dermanyssus gallinae (D. gallinae), Posroptes cuniculi (P. cuniculi), Sarcoptes scabiei (S. scabiei), demodex, etc. D. gallinae (chicken mite), a bloodsucking ectoparasite, infests poultry worldwide, and its infestation leads to reduced food intake, weakened immune response, and, in severe cases, death of chickens [1]. Moreover, D. gallinae infestation causes a decline in laying percentage and reduces egg weights [2]. D. gallinae infestation is a significant threat to poultry farms due to its ability to transmit various diseases and pathogens, including fowl spirochetosis, Newcastle disease virus, pullorum disease, and fowl plague. This causes substantial losses to the poultry industry in terms of both economic value and animal health [3]. According to an estimate, the European Union egg industry incurs an annual economic loss of about EUR 130 million related to control measures and production losses from D. gallinae infestations [4]. P. cuniculi, a parasitic mite, targets the external auditory canal of rabbits and feeds on serous exudate, secretions, and blood. Due to its high transmission rate and rapid spread, P. cuniculi poses a serious threat to the healthy development of the rabbit farming industry, necessitating effective control measures to mitigate detrimental effects [5]. S. scabiei, another pathogenic organism, causes a highly contagious skin disease in humans and numerous domestic and wild mammals [6]. This disease, known as sarcoptic mange, is characterized by irritation, inflammation, hyperkeratosis, alopecia, and excessive itching and often accompanies secondary infections [7]. Modeling studies have estimated that the global prevalence of scabies is between 100 and 200 million cases, with approximately 4.55 million new cases annually [8]. Furthermore, Sarcoptes infections significantly impact animal health and extensive interest for its ability to handle diverse metabolites [24]. High-resolution liquid chromatography-mass spectrometry (LC-HRMS) [25] and nuclear magnetic resonance (NMR) spectroscopy [26] are some of the commonly used analytical tools in metabolomics. Natural products have been reported for various biological activities, including antiinflammatory [27], antioxidant [28], antibacterial [29], antiparasitic [30], antifungal [31], analgesic [32], anti-atherogenic [33], antidiabetic [34], and antiproliferative properties [35]. In recent years, several studies have reported that natural products also have anti-acaricidal activity with great application potential.
This article provides a summary of the current research status on various types of natural products that possess acaricidal properties, including single-flavor Chinese herbal extracts, Chinese herbal monomers, and natural products derived from microbial and algae sources. This compilation aims to offer valuable insights and references for the development of novel acaricidal drugs.

Acaricidal Activity of Plant Extracts
Owing to adverse effects associated with the excessive use of chemical agents, such as drug resistance, residues, and environmental pollution, their usage has been restricted. As a result, there has been a growing interest in seeking alternative and natural acaricides derived from plants. Plant secondary metabolites, with toxic, repellent, attractant, and growth regulator properties, have been widely investigated for potential applications [36]. This section discusses various plant extracts and a brief detail is provided in Table 1.

Plant Extracts against P. cuniculi and S. scabiei
Many studies have demonstrated the high toxicity of certain plant extracts towards P. cuniculi and S. scabiei, including those from Syzygium aromaticum, Eupatorium adenophorum (E. adenophorum), Azadirachta indica, and Adonis coerulea. E. adenophorum has emerged as a significant weed in various agricultural settings, plantations, natural habitats, and forests across multiple regions globally. It is particularly considered the most impactful invasive species in China. Notably, AE derived from E. adenophorum exhibited potent toxicity against mites, effectively eliminating all S. scabiei at 0.5 and 1.0 g/mL (w/v). Furthermore, at 1 g/mL, the extract demonstrated complete eradication of P. cuniculi within a short span of 4 h, and the insecticidal effect of its 9β-hydroxy-ageraphorone compound ( Figure 1-(10)) was better than the insecticidal effect of fenvalerate and 9-oxo-ageraphorone compounds at 0.5% (Figure 1-(11)). Moreover, 9-oxo-10,11-dehydro-ageraphorone ( Figure 1-(12)) exhibited higher insecticidal effects than 9β-hydroxy-ageraphorone [43]. Origanum vulgare (Oregano, Labiateae family) oil showed remarkable acaricidal effects against P. cuniculi in a dose-and time-dependent manner, and it majorly contains carvacrol ( Figure 1-(13)), thymol, and p-cymene ( Figure 1- (14)). In vitro experiments demonstrated that at 0.05% and 0.02% (v/v), oregano oil resulted in complete eradication of P. cuniculi within 1 h and 6 h, respectively. Furthermore, a clinical evaluation was conducted using naturally infected rabbits to assess the efficacy of oregano oil. At 1% and 5%, oregano oil completely eliminated P. cuniculi infestation in rabbits, improving animal mental and physical conditions by the end of the study on the 20th day [44]. The EO extracts obtained from the shoots and leaves of Rhododendron nivale Hook.f. (R. nivale) exhibited potent in vitro acaricidal activity against adult P. cuniculi, with an LT50 value of up to 4.17 mg/mL. Following the EO treatment, P. cuniculi-infected rabbits showed a complete absence of scabs or secretions in the ear canal by the 20th day of treatment. The EO of R. nivale mainly contains δ-cadinene ( Figure 1-(15)) and displayed pronounced acaricidal activity against P. cuniculi in vitro [45]. Peganum harmala L., a perennial herbaceous plant, grows in semi-arid conditions, steppe areas, and sandy soils. Shang  The order of efficacy for the tested oils was: clove > palmarosa > geranium > tea tree > lavender > manuka > bitter orange > eucalyptus > Japanese cedar. Notably, cade oil exhibited no activity against S. scabiei [49]. The AE of Ligularia virgaurea demonstrated potent acaricidal activity against S. scabiei. Its LC50 values against mites at different time intervals were as follows: 1.388 g/mL at 1 h, 0.624 g/mL at 2 h, 0.310 g/mL at 4 h, and 0.213 g/mL at 6 h [50]. An in vitro study found a significant acaricidal activity of Elsholtzia densa (E. densa) Benth oil: its LC50 values against S. scabiei at different time intervals were as follows: 7.678 mg/mL at 1 h, 4.623 mg/mL at 2 h, 2.543 mg/mL at 4 h, 1.502 mg/mL at 8 h, 1.298 mg/mL at 16 h, and 0.981 mg/mL at 24 h. GC-MS analysis of the Benth oil revealed that it primarily contained 4-pyridinol ( Figure 1-(19); 28.16%) and thymol (26.58%) [51]. Lemongrass oil exhibited potent acaricidal activity against Sarcoptes mites. At 10% and 5% (v/v), it killed all mites within 10 and 25 min, respectively. Its LC50 values were 1.37%, 1.08%, 0.91%, 0.64%, and 0.48% at 1, 3, 6, 12, and 24 h, respectively. Moreover, lemongrass oil significantly reduced the hatching rate of Sarcoptes eggs at various concentrations (10%, 5%, 1%, 0.5%, and 0.1% v/v). Mass spectrometry analysis confirmed that the main component in lemongrass oil is citral (Figure 1- (20)) [52]. In a comparative study, three concentrations (5%, 10%, and 25% w/v) of aqueous neem fruit extract were assessed against commercial acaricide called 12.5% amitraz-based Triatix spray (used as the positive control) on pigs. The study found that the topical application of the 25% aqueous neem fruit extract demonstrated a higher efficacy against mites than a commercial acaricide [53]. Adonis coerulea Maxim. (A. coerulea) exhibited acaricidal activity in both in vitro and in vivo. It inhibited acetylcholinesterase (AchE) and Na + -K + -ATPase enzymes activities, and mainly contained isoorientin ( (31)). They found that silibinin, quercetin, and corilagin could inhibit AchE activity at the cellular level, with IC50 values of 40.11, 46.15, and 50.98 µg/mL, respectively [57]. The coconut seed extract was shown to have acaricidal activity against S. scabies in vitro and in vivo. In vitro, the mortality rate of mites reached 99% after 1 day, and the mRNA gene expression results showed that IL-6, IL-1β, IL-10, MMP-9, VEGF, and MCP-1 were inhibited, while I-CAM-1, KGF, and TIMP-1 were upregulated. The results of molecular docking analysis showed that the main substances in coconut seed extract that killed mites were gondoic acid (   The wide cultivation of the above-discussed natural products and their extensive use in foodstuffs and cosmetics as flavors and fragrances suggest that they could serve as a cost-effective and easily accessible eco-friendly alternative to the currently used pesticides in poultry farms. However, it is important to note that the extract composition is complex, and further studies are needed to identify and understand the specific medicinal substances present in these extracts. Future studies would provide a more comprehensive understanding of their potential as pesticides and facilitate their sustainable utilization in poultry farms.

Acaricidal Activity of Natural Compounds
Various compounds from natural sources with acaricidal activity are discussed in this section and a brief description of the chemicals is listed in Table 2. The acaricidal mechanisms of the compounds are listed in Figure 2.

Acaricidal Activity of Natural Compounds
Various compounds from natural sources with acaricidal activity are discussed in this section and a brief description of the chemicals is listed in Table 2. The acaricidal mechanisms of the compounds are listed in Figure 2.

Phenylpropanoids
Among the phytochemicals found in EOs, cinnamaldehyde, an α,β-unsaturated aldehyde, has been noted for its remarkable antimicrobial properties and its ability to enhance the effectiveness of antibiotics. Cinnamic acid (Figure 1-(34)) and its esters, which are widely distributed in plants, have garnered significant attention due to their diverse pharmacological activities. Trans-cinnamaldehyde and ethyl cinnamate, analogs of cinnamic acid, have also been reported for acaricidal activity. Cinnamaldehyde is particularly abundant in EOs from Cinnamomum species. Notably, it is widely used as a food additive, and its antimicrobial activity makes it a valuable component for potential applications in both the medical and food industries [59]. In vitro studies were performed to assess the acaricidal activity of trans-cinnamaldehyde against P. cuniculi, and the results showed that trans-cinnamaldehyde up to 8 μg/mL exhibited significant mites mortality

Phenylpropanoids
Among the phytochemicals found in EOs, cinnamaldehyde, an α,β-unsaturated aldehyde, has been noted for its remarkable antimicrobial properties and its ability to enhance the effectiveness of antibiotics. Cinnamic acid (Figure 1-(34)) and its esters, which are widely distributed in plants, have garnered significant attention due to their diverse pharmacological activities. Trans-cinnamaldehyde and ethyl cinnamate, analogs of cinnamic acid, have also been reported for acaricidal activity. Cinnamaldehyde is particularly abundant in EOs from Cinnamomum species. Notably, it is widely used as a food additive, and its antimicrobial activity makes it a valuable component for potential applications in both the medical and food industries [59]. In vitro studies were performed to assess the acaricidal activity of trans-cinnamaldehyde against P. cuniculi, and the results showed that transcinnamaldehyde up to 8 µg/mL exhibited significant mites mortality rate (p < 0.01) [60]. Ethyl cinnamate derivatives have been identified as promising and highly efficient acaricides against P. cuniculi. The structure-activity relationship (SAR) analysis revealed that the presence of o-NO 2 or m-NO 2 on their benzene ring significantly enhanced their activity. On the other hand, the introduction of a hydroxy, methoxy, acetoxy, methylenedioxy, bromo, or chloro group reduced the activity [61]. Chen et al. [62] synthesized cinnamic acid derivatives and isoaromatic ring analogs to evaluate their in vitro acaricidal activities against P. cuniculi. Among them, eight compounds exhibited higher activity. Structureactivity relationship (SAR) analysis revealed the crucial role of the carbonyl group in the activity. Also, the type and chain length of the alkoxy group in the ester moiety, as well as the steric hindrance near the ester group, significantly influenced the activity. Ester derivatives demonstrated greater activity compared to thiol esters, amides, ketones, or acids. Substituting the phenyl group of cinnamic esters with a-pyridyl or a-furanyl groups led to a significant increase in activity. Shang et al. investigated the anti-pruritus activity of 18 coumarins and found that among the coumarins, 4-methoxy-coumarin ( Figure 1-(35)) exhibited the highest anti-mite activity, with an LC50 value of 34.00 µg/mL. Importantly, 4-methoxy-coumarin demonstrated minimal to no toxicity towards normal human hepatocytes and keratinocytes, with an LC50 value of greater than 100 µg/mL. This finding suggested that 4-methoxy-coumarin holds great potential for further research and development, particularly in the context of managing pruritus [63]. Eugenol (Figure 1-(36)), a naturally occurring phenolic monoterpenoid, has bioactive properties and belongs to the phenylpropanoids class of natural products. It is commonly found in various aromatic herbal plants, including clove, tulsi, cinnamon, nutmeg, and pepper. However, it is primarily isolated from the clove plant (Syzygium aromaticum). Eugenol has a broad range of applications in various industries such as pharmaceuticals, food, flavors, cosmetics, agriculture, and many others. Eugenol is well-known for its diverse pharmacological properties, including antimicrobial, anticancer, antioxidant, anti-inflammatory, and analgesic effects [64]. Ma et al. showed that eugenol can completely eradicate P. cuniculi mites at 4 mg/mL for 8 h. The median lethal dose (LD50) of eugenol ranged from 1.564 ± 0.023 to 1.039 ± 0.009 mg/mL at 1 to 24 h after treatment. The study suggested that several signaling pathways, including PPAR (peroxisome proliferator-activated receptor), NF-kappa B, TNF (tumor necrosis factor), Rap1, and Ras pathways, might play significant roles in mite killing by eugenol [5]. For instance, eugenol inhibited complex I activity of the mitochondrial respiratory chain in the oxidative phosphorylation pathway by binding to NADH dehydrogenase chain 2, causing the death of mites [55]. The mite's inhibitory activity of five compounds, terpine-4-ol (Figure 1-(37)), citral, linalool, eugenol, and geranyl ( Figure 1-(38)) on eggs and eggs of naturally infected rabbits, was determined. The results showed that the median effect concentration (EC50) of eugenol, geranyl, citral, terpine-4-ol, and linalool were 0.65%, 0.66%, 0.85%, 1.47%, and 2.87%, respectively [65].

Terpenoids
Thymol, a monoterpene found in many natural plant EOs, has been discovered to possess strong toxicity against the scabies mites. In a study, the LC50 value of thymol against scabies mites was determined to be 3.829 mg/mL within a 4 h exposure. The mechanism of thymol's acaricidal activity involves interference with the energy metabolism and nerve conduction of the mites [66]. 1,8-Cineole, a monoterpene, is found in many EOs and can change the activity of superoxide dismutase (SOD), nitric oxide synthase (NOS), and GSTs in the nervous system of S. scabies [67]. The acaricidal activity of 9oxo-10,11-dehydroageraphorone (euptox A), a cadinane sesquiterpene derived from E. adenophorum, was tested against S. scabiei and P. cuniculi both in vitro and in vivo. In vitro studies revealed that euptox A killed all S. scabiei mites at 3-4 mg/mL and demonstrated complete lethality against P. cuniculi at 4 mg/mL within 4 h of the treatment [68]. In vivo, euptox A exhibited superior clinical acaricidal efficacy against P. cuniculi at 2 mg/mL. Concisely, euptox A has strong potential as an acaricidal agent against both S. scabiei and P. cuniculi [69]. Tabari et al. evaluated the efficacy of different combinations of terpenes, such as carvacrol, thymol, and menthol ( Figure 1-(39)) against D. gallinae and found that the combination of all three was most effective compared to other combinations. This particular combination successfully killed 100% of the mites at 0.5 µg/mL. Additionally, the terpene-based combination exhibited promising miticidal activity in field conditions resulting in residue-free eggs, indicating its potential in environmentally friendly pest management practices [70]. Li et al. evaluated the activity of six commonly found terpenes in EOs (carvacrol, eugenol, geraniol, citral, terpine-4-ol, and linalool) against S. scabies adults and eggs. The EC50 values of carvacrol, eugenol, geranyl, citral, terpine-4-ol, and linalool were 0.5, 0.9, 2.0, 4.8, 5.1, and 9.8% (w/v), respectively. These terpenoids may act by penetrating the aerogen membrane on the egg surface. Importantly, carvacrol, eugenol, and geraniol showed significant ovicidal activity [71]. The LC50 values of carvacrol, eugenol, and geraniol at 30 min were 0.24%, 0.79%, and 0.91% (w/v), respectively [9].

Alkaloid Compounds
Alkaloids are important nitrogen-containing natural organic compounds that are widely distributed in plants. Shang et al. evaluated the acaricidal activity of three bioactive alkaloids from Peganum harmala L., namely, vasicine, harmaline, and harmine, against P. cuniculi in vitro. The LT50 values of vasicine, harmaline, and harmine against P. cuniculi at 2.5 mg/mL were 9.791, 10.095, and 9.273 h, respectively [46]. Sanguinarine (Figure 1-(40)) and chelerythrine (Figure 1-(41)) are two quaternary benzo[c]phenanthridine alkaloids that are widely present in several plant species of the Fumariaceae, Papaveraceae, and Rutaceae families. Miao et al. synthesized derivatives by modifying the C=N + bonds of sanguinarine and chelerythrine, and then evaluated their in vitro acaricidal activity against P. cuniculi. A derivative, named 6-alkoxy dihydrosanguinarines, exhibited strong acaricidal activity against P. cuniculi at 5.0 mg/mL, which was comparable to the commercial acaricide ivermectin. The modification at the C=N + double bond in sanguinarine and chelerythrine determined the acaricidal properties of the derivatives, and quaternary benzo[c] phenanthridine alkaloids showed promise for the development of new isoquinoline acaricidal agents [72].

Other Active Substances
A study investigated the efficacy of the ivermectin-allicin (Figure 1-(42)) combination against D. gallinae. Specifically, 0.5 mg/mL each of ivermectin and allicin completely eliminated D. gallinae within 5 days of treatment. The most effective combination was 0.25 mg/mL ivermectin with 1.00 mg/mL allicin [73]. Kang et al. evaluated the efficacy of ivermectin and allicin combinations against D. gallinae in vivo. A solution containing 0.25 mg/mL ivermectin and 1 mg/mL allicin (IA) was sprayed on hens housed in isolators that were infested with D. gallinae. The researchers found that IA exhibited insecticidal rates of 98.7%, 98.4%, 99.4%, and 99.9% at 7, 14, 21, and 28 days of treatment, respectively. Importantly, no clinical symptoms related to IA compounds or residues of ivermectin were observed in the treated hens [74]. Octadecanoic acid-3,4-tetrahydrofuran diester (Figure 1-(43)) is a newly identified compound from neem oil. Its acaricidal activity against S. scabiei is significantly higher compared to pyrethrins and abamectin. Its LC50 value (0.1 mg/mL) is approximately 1/33 of the neem oil. Mechanistically, this compound significantly changes the activity of mite enzymes, such as superoxide dismutase, peroxidase, Ca 2+ -ATPase, glutathione-s-transferases, and peroxidase. This suggests that octadecanoic acid-3,4-tetrahydrofuran diester may regulate the energy metabolism in mites [75,76]. Song et al. [77] conducted transcriptome and proteomics studies to investigate the acaricidal mechanism of octadecanoic acid-3,4-tetrahydrofuran diester. They identified several target proteins of the compound, including NADH dehydrogenase, ubiquinol-cytochrome c reductase, cytochrome c oxidase, ATP synthase, enolase, and su-peroxide dismutase. These findings suggest that the acaricidal mechanism of octadecanoic acid-3,4-tetrahydrofuran diester involves the interference with energy metabolism, particularly the oxidative phosphorylation pathway. Li et al. [78] modified the structure of octadecanoic acid-3,4-tetrahydrofuran diester to enhance its acaricidal activity, specifically by introducing benzyloxy substitution at the 2-position of the furan ring and forming a benzoate at the 3,4-position of the furan ring (benzoic acid-2-benzyloxy-3,4-tetrahydrofuran diester). Transcriptome sequencing analysis revealed that the acaricidal mechanism of this derivative involves interfering with energy metabolism in S. scabiei, particularly the citric acid cycle, oxidative phosphorylation pathway, and fatty acid metabolism. This finding was further confirmed through the activity detection of mitochondrial complexes. Naphthoquinone is an important secondary metabolite in plants with diverse biological activities. Shang et al. investigated the acaricidal activity of naphthoquinones against P. cuniculi both in vitro and in vivo. They found that juglone (Figure 1-(44)) and plumbagin (Figure 1-(45)) exhibited the strongest acaricidal activities against P. cuniculi, with LC50 values of 20.53 ppm and 17.96 ppm, respectively at 24 h. In the in vivo experiments, after three treatments, both juglone and plumbagin completely cured naturally infested rabbits within 15 days. Importantly, no skin irritation was observed in any of the treated rabbits, indicating the safety of these chemicals. Furthermore, the researchers discovered that juglone and plumbagin significantly inhibited the activity of AchE and GST, highlighting their mechanism [79].

Acaricidal Activity of Lichens and Algae
Algae contain natural active substances that are absent in terrestrial plants. In recent years, numerous studies have reported various active substances derived from algae with a wide range of biological activities, including antioxidant, anti-inflammatory, antimicrobial, antiviral, anticancer, neuroprotective activities, etc. The bioactive compounds found in algae, such as polysaccharides, polyphenols, pigments, and fatty acids, exert these biological effects [80]. Lectins are widely distributed in nature and can be found in plants, animals, and microorganisms. Among microorganisms, algae, particularly red algae, are known to be a potent source of lectins with unique properties [81]. The lectin derived from Gracilaria ornata, a type of red algae, has been found to possess acaricidal activity. Exposure of this lectin to female cattle ticks (Boophilus microplus) significantly reduced tick weight after the oviposition period, egg mass weight, hatching period, and mean larvae survival time [82]. A study reported the inhibitory effects of water-soluble Moringa oleifera (M. oleifera) lectin on egg hatching and larval development of gastrointestinal nematodes in goats, which function by interfering with the activity of parasites proteases and making potential interactions with intestinal receptors and larval cuticles [83]. Medeiros et al. demonstrated that proteins from M. oleifera, specifically water-soluble M. oleifera lectin and coagulant M. oleifera lectin, have inhibitory effects on infective larvae and adult male and female worms of Haemonchus contortus, a hematophagous parasite in ruminant animals. These lectins induce morphological changes in the worms and increase proteolytic activity [84].
Lichens are a rich source of natural products, including a wide variety of unique polyketides and polyphenols [85]. Usnic acid (Figure 1-(46)), a major active compound found in lichens, was first isolated in 1884 and is considered one of the best-studied lichen metabolites. Usnic acid has a wide range of biological activities, including antiinflammatory, antibacterial, antiviral, immunostimulating, antifungal, and antiparasitic properties [86]. Shang et al. conducted an in vitro investigation on the acaricidal activity of usnic acid against P. cuniculi. They found that at 250, 125, and 62.5 mg/mL, usnic acid exhibited mite mortality rates of 91.67%, 85.00%, and 55.00%, respectively after a 24 h treatment period: the LT50 values of usnic acid were 4.208, 8.249, and 16.950 h at the respective doses [87]. Although usnic acid presents important biological activities, its low solubility is a limiting factor. Alternatively, its potassium salt has better solubility without compromising its biological potential [88]. The potassium salt usnic acid has been reported for promising schistosomicidal activity, causing mortality, motility changes, and tegument alterations in Schistosoma mansoni. Also, it has low toxicity to human cells, and therefore has high potential as a new anthelmintic drug for the control of schistosomiasis [89,90].
Numerous studies have investigated the potential of natural metabolites derived from algae and lichen for their anthelmintic activity against nematodes and schistosomiasis. However, there is limited research on their efficacy in acaricidal activity.

Acaricidal Activity of Microbial Metabolites
Many secondary metabolites produced by fungi and bacteria have been utilized in medicine and agriculture due to their diverse biological effects, including insecticidal, hypoglycemic, lipid-lowering, antitumor, anti-diabetic, antibacterial, and antifungal activities. Beauveria bassiana (B. bassiana) is a fungus that produces beauvericin (Figure 1-(47)), a secondary metabolite from the enniatin family [91]. B. bassiana toxins include various secondary metabolites and small molecular compounds, such as bassianin, beauvericin, bassianolide, tenellin, beauverolides, oxalic acid, oosporein, calcium oxalate crystals, and several beauvericin analogs [92]. Al Khoury et al. [22] assessed the potential acaricidal activity of beauvericin against various life stages of S. scabiei. They reported the first evidence of B. bassiana's activity against S. scabiei eggs, with a hatching inhibition rate of 28.75%. Mechanistically, they found fungal genomic material within the surface-cleaned eggs that demonstrated the ability of B. bassiana to penetrate and proliferate within the eggshell of S. scabiei [93]. Chitinase (Figure 1-(48)) was induced in Streptomyces mutabilis IMA8 using chitin from Charybdis smithii, which exhibited potent miticidal activity (LC50, 24.2 ppm) against D. gallinae [94]. In vitro, Metarhizium anisopliae (M. anisopliae) CQMa128 demonstrated significant acaricidal activity against P. cuniculi in a time-and dose-dependent manner. Applying 6.14 × 10 9 conidia/mL of M. anisopliae resulted in 83.33% mortality at 9 d, with an LT50 value of 6.1 d. In vivo, M. anisopliae achieved a 100% therapeutic effect after 3 d, compared to only 62.21% for ivermectin. The acaricidal activity of M. anisopliae was attributed to changes in enzyme activities within the detoxification and antioxidant system of P. cuniculi [95]. Emmanuel et al. [96] reported the in vitro acaricidal effect of Bacillus thuringiensis GP532 on P. cuniculi mites, with LC50 values of 1.3 mg/mL and 68 h. Furthermore, protein extracts from B. thuringiensis were shown to induce histological changes in P. cuniculi, including the enlargement of the basal membrane space, detachment of the peripheral nutrient matrix membrane, and morphological alterations in intestinal columnar cells.

Conclusions and Future Research Direction
Plant extracts, as one of the main sources of natural products, are eco-friendly and sustainable. They are readily available, biodegradable, and have high volatility, lowecological toxicity, and low-environmental residual activity, with a huge development potential in controlling mites [97,98]. However, the current research mainly focuses on their in vitro acaricidal activity and only a few attempts have been made to their actual production. Meanwhile, the complex composition of these products limits the research on the acaricidal mechanism and it is difficult to establish a system standard for the extract [99]. The key mechanism of action of natural products is modification of the mite's enzyme and interference with energy metabolism and nerve conduction (Figure 2). In the future, the application of multi-omics techniques, such as transcriptomics, proteomics, and metabolomics, can help to further explore the mechanism of mite killing by natural products at the molecular level [77,100].
Whether derived from plants, bacteria, or fungi, metabolite compositions are inherently complex. Though metabolomics is still in its developing stage, in the coming 10 years, there can be an impactful integration of LC-HRMS and NMR, allowing for the direct comparison and correlation of metabolite data [24]. While there are many studies on the biological activities of endophytic metabolites [101,102], such as antitumor [103][104][105], antibacterial [106], and insecticidal [107,108] activities, they lack in terms of acaricidal activities. This research area is believed to get the attention of scholars in the future.
Presently, it seems that natural products have limited anti-mite activity. However, structural modification and semi-synthesis of natural products can improve the anti-mite effect. Overall, natural products are promising molecular scaffolds for the development of new drugs, such as cinnamic acid [61,62,78,109], sanguinarine, chelerythrine [72,110], etc. Also, combining natural products with existing chemical drugs can reduce their resistance, decrease drug residue, and improve the therapeutic effect [111].