Bioactive Peptides Derived from Edible Insects: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Silvia Caruso.

Novel foods, including edible insects, are emerging because of their nutritional characteristics and low environmental impacts and could represent a valid alternative source of food in a more sustainable way. Edible insects have been shown to have beneficial effects on human health. Insect-derived bioactive peptides exert antihypertensive, antioxidant, anti-inflammatory, and antimicrobial properties and have protective effects against common metabolic conditions. 

  • edible insects
  • nutrition
  • bioactive peptides
  • antihypertensive

1. Edible Insects and Human Health

Research suggests that insects’ proteins, after enzymatic proteolysis, may be a good source of bioactive peptides [5][1]. The positive impact of bioactive peptides on body functions and, thus, on human health is well acknowledged [25][2]. Indeed, bioactive peptides exert antioxidant, anticancer, antithrombotic, antihypertensive, antiobesity, anti-inflammatory, opioid, mineral binding, immunomodulatory, antiaging, and antimicrobial effects, with high organ specificity and low toxicity [26][3].

1.1. Antihypertensive Effects

High blood pressure is a major risk factor for cardiovascular diseases [27][4]. Globally, more than one billion people are considered hypertensive and hypertension is responsible for up to ten million deaths worldwide [28][5]. Interestingly, insect-derived bioactive peptides show antihypertensive properties. The best-characterized method of action consists in the inhibition of ACE. This enzyme is part of the renin–angiotensin–aldosterone system (RAAS), playing a pivotal role in blood pressure regulation. Indeed, the inhibition of ACE prevents the conversion of angiotensin I to angiotensin II and, for this reason, ACE inhibitors are commonly used as pharmacological therapies for patients with hypertension [29][6]. Many peptides show high affinity in binding ACE because of their C-terminal amino acid sequences [30][7]. For example, the peptide YETGNGIK, derived from locusts, includes amino acids like isoleucine and lysine, which bind ACE with high affinity, exerting a strong inhibition (half-maximal inhibitory concentration, IC50: 3.25 μg/mL) [31][8].
In an in vivo study of Yuan et al., a silk fibroin hydrolysate (SFH) exhibited blood pressure lowering and an improvement in endothelial functions in models of spontaneously hypertensive rats (SHRs) [32][9]. SFH, derived from alcalase hydrolysis with a hydrolysis degree of 17%, inhibits ACE [12][10], strictly correlated with the development of hypertension and atherosclerosis [33][11].
Vercruysse et al. studied the antihypertensive properties of cotton leafworm (Spodoptera littoralis) both in vitro and in vivo. The authors obtained a hydrolysate using pepsin, trypsin, and α-chymostrypsin to simulate the human gastrointestinal digestion process. Afterwards, the ACE inhibitory tripeptide Ala-Val-Phe was isolated by chromatography and RP-HPLC. This peptide showed good ACE inhibition activity in vitro, with an IC50 of 2123 μM [15][12]. Vercruysse et al. also evaluated the stability and activity of the tripeptide Ala-Val-Phe in vivo. The tripeptide was partially hydrolyzed by mucosal peptidases into the peptide Val-Phe, which showed a stronger ACE inhibition. Moreover, after a single oral administration (5 mg/kg body weight), the dipeptide induced a significant decrease in blood pressure in models of SHRs [34][13].
Also, the peptide GNPWM (603.7 Da; IC50 = 21.70 μM) and four modified peptides purified from silkworm pupae (Bombyx mori) directly inhibit ACE and could be beneficial as functional drugs or foods to treat hypertension [18][14]. Another study of Wu et al. investigated the antihypertensive activity of peptides derived from silkworm pupae. Peptides were hydrolyzed with three gastrointestinal peptidases (pepsin, trypsin, and α-chymostrypsin) to simulate digestion. Eventually, a novel tripeptide (Ala-Ser-Leu) was identified by mass spectrometry and was a competitive inhibitor of ACE, as suggested by Lineweaver–Burk plots [20][15].
Besides having protective effects against hypertension, bioactive peptides derived from yellow mealworms (Tenebrio molitor) may exert antithrombotic activities. The antihypertensive effects were reported by Dai et al. In their study, the novel peptide Tyr-Ala-Asn was purified and identified by RP-HPLC and mass spectrometry from a yellow mealworm larva hydrolysate. This tripeptide significantly decreased the blood pressure in in vivo models of SHsR [21][16]. Chen et al., instead, investigated the antithrombotic potential of enzymatic hydrolysates derived from Tenebrio molitor larvae, obtained after a treatment with pepsin and trypsin. After separation and purification processes, two peptides were identified (SLVDAIGMGP and AGFAGDDAPR), showing a strong antithrombotic activity, with values of thrombin inhibition activity of 40.87% and 65.61% at 8.0 mg/mL, respectively [35][17].
Thus, research suggests the important role of bioactive peptides derived from insects in the regulation of blood pressure and their protective cardiovascular effects.

1.2. Antidiabetes, Antiobesity, and Hepatoprotective Effects

Over the past few decades, the prevalence of diabetes has risen significantly, representing a burden in worldwide healthcare [36][18]. Also, obesity remains the main risk factor for the development of diabetes [37][19]. Surprisingly, bioactive peptides derived from many insects show antidiabetic properties both in vitro and in vivo. The main targets of those peptides investigated so far are α-amylase, α-glucosidase, and dipeptidyl peptidase IV (DDP-IV) inhibition. Both α-glucosidase and α-amylase enzyme inhibitors can suppress peaks of postprandial glucose, counteracting hyperglycemia, as previously demonstrated by studies conducted on botanical compounds including polyphenols [38][20]. Alternatively, DDP-IV is responsible for the degradation of glucagon-like peptide-1 (GLP-1), decreasing its insulinotropic effect and worsening diabetes conditions [39][21].
Bioactive peptides derived from edible crickets (Gryllodes sigillatus) show both antihypertensive and antidiabetic properties targeting ACE, α-glucosidase, and α-amylase.
This multiple protective effect is particularly interesting since diabetes and hypertension are two closely related conditions, sharing common mechanisms, such as upregulation of the renin–angiotensin–aldosterone system, oxidative stress, and inflammation [40][22].
The hydrolysated peptides LPDQWDWR and APPDGGFWEWGD from Tenebrio molitor, instead, show good inhibitory effects on DDP-IV, with IC50 values of 0.15 and 1.03 mg/mL, respectively [17][23]. An in vivo study of Han et al. showed the hypoglycemic effects of the tripeptides Gly-Glu-Tyr (GEY) and Gly-Tyr-Gly (GYG), isolated from the silk peptide E5K6 in a model of steptozotocin (STZ)-induced diabetic mice in a dose-dependent manner [41][24]. Indeed, the hydrolysated E5K6 protein exerts many protective functions, lowering not only glucose levels but also total cholesterol and low-density lipoprotein (LDL) plasma levels in vivo [42][25].
Bioactive peptides isolated from edible insects have also shown antiobesity properties. The prevalence of obesity has increased globally in recent decades. This heterogeneous condition also causes concern due to the associated comorbidities (cardiovascular conditions, type 2 diabetes, etc.), causing millions of deaths worldwide [43][26].
Chemically synthetized fractions derived from the peptide sequence of edible insects target lipases, thus reducing lipidic absorption and accumulation. The fractions IIAPPER from Gryllodes sigillatur and AIGVGAIER from Schistocerca gregaria showed high lipase inhibition, with an IC50 of 49.44 and 49.95 μg/mL, respectively [31][8].
Obesity is often characterized by a hormonal dysregulation and, in this context, the hormone leptin has a pivotal role, leading to reduced satiety, increased body mass, and overconsumption of nutrients [44][27]. However, the feeling of satiety also depends on the chemical composition of foods [45][28]. Being rich in proteins, edible insects have highly satiating properties as discussed in a recent work of Skotnicka et al. [46][29]. In this study, pancakes were prepared with flour derived from Tenebrio molitor, Alphitobius domesticus, and Acheta domesticus in three different proportions. The physico-chemical composition of the pancakes was characterized and the satiating potential of this food in a population of seventy-one volunteers was assessed using a visual analogue scale (VAS). As a result, the products richer in protein best suppressed hunger and promoted satiety, supporting the idea of introducing edible insects in antiobesity diets [46][29].
As well as antiobesity properties, edible insects also have hepatoprotective effects. Fan et al. investigated the potential role of AGL9, the enzymatic hydrolysate of the beetle larva of Allomyrina dichotoma, in moderating hepatic steatosis in a non-alcoholic fatty liver disease (NAFLD) murine model. After administration of AGL9 for five weeks, mice showed normalized levels of alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol, high-density lipoprotein, very low-density lipoprotein (VLDL), adiponectin, and leptin. Indeed, AGL9 inhibits the AMPK/Nrf2 signaling pathway, thus decreasing lipid accumulation and the production of proinflammatory mediators [47][30].
Collectively, all these findings highlight the protective properties of bioactive peptides derived from edible insects against complex metabolic conditions that represent a burden on health nowadays.

1.3. Antioxidant and Anti-Inflammatory Effects

The antioxidant effects of insects’ bioactive peptides have been widely investigated, although the precise mechanisms are still poorly understood. Many edible insects showed antioxidant potential, including crickets, mealworms, and locusts [22][31].
One of the most powerful antioxidant peptides isolated so far is FDPFPK, derived from Gryllodes sigillatur. The peptides were obtained by in vitro digestion and separated by gel filtration chromatography. Eventually, proteins were identified with mass spectrometry methods and antioxidant potential was assessed with both 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays. As a result, the peptide FDPFPK showed a high antiradical activity with IC50 values of 0.08 and 0.35 mg/mL for ABTS and DPPH, respectively [22][31].
Moreover, a study of Mudd at al. showed the antioxidant effects of simulated gastrointestinally digested (SGD) peptides from Gryllodes sigillatus, both in vitro and in vivo, on a model of Caenorhabditis elegans. SGD peptides increased Caenorhabditis elegans lifespan under oxidative stress conditions, reducing reactive oxygen species (ROS) levels. Also, SGD peptides increased gene glutathione S-transferase alpha 4 (gsta-4) expression through the activation of the epidermal growth factor (EGF) pathway [16][32].
Larvae and pupae of Asian weaver ants (Oecophylla smaragdina) exert both antihypertensive and antioxidants effects. In particular, the fraction CTKKHKPNC showed radical-scavenging activity (ABTS assay: IC50, 38.4 μg/mL) and antioxidant activity (DPPH assay: 48.2 μg/mL) [19][33].
Studies of Zhang et al. and Li et al. highlighted the antioxidant properties of peptides derived from houseflies’ larvae (Musca domestica). Zhang et al. compared the antioxidant activities of hydrolysates obtained either with alcalase or neutral proteinase. In both cases, hydrolysates showed up to 50% superoxide anion radical-scavenging activity [13][34]. Li et al. evaluated the amino acidic composition of housefly larvae. Interestingly, according to the authors, the presence of hydrophobic and aromatic amino acids in the water extract of horseflies may contribute to the radical-scavenging activity [48][35].
Hydrolysates from silkworm pupae (Bombyx mori) have been investigated for their antioxidant potential [14,49][36][37]. FKGPACA and SVLGTGC fractions showed radical-scavenging activity in vitro (ABTS assay: IC50, 0.312 mM and 0.181 mM, respectively) [49][37]. Furthermore, SWFVTPF and NDVLFF fractions showed high superoxide dismutase (SOD) activity with values of 36.96 ± 7.31 and 30.43 ± 7.90% SO inhibition on a culture of HepG2 cells, and all peptide-treated cells also showed significantly high glutathione (GSH) levels [14][36].
Inflammation is one of the major risk factors for the progression of several chronic diseases, including cancer, diabetes, and cardiovascular disorders [50][38]. In addition to immune response cells, which are the main actors in the inflammatory process, several mediators play a pivotal role in inflammation. The enzymes belonging to the family of cyclooxygenase (COX) and lipoxygenase (LOX) are implicated in the production of prostaglandins and leukotrienes, respectively, from arachidonic acid [51][39]. Both eicosanoids can be powerful mediators of inflammation and, for this reason, COX and LOX enzymes are the target of many drugs for the treatment of inflammation [51,52][39][40].
Bioactive peptides identified from edible insects showed promising anti-inflammatory effects by inhibiting COX and LOX enzymes.
As well as displaying strong antioxidant properties, peptide fractions obtained from Gryllodes sigillatus were shown to have anti-inflammatory effects in vitro. These peptides are effective inhibitors of COX-2 (IC50: 0.26 µg/mL) and LOX (IC50: 0.13 µg/mL) as shown by a cyclooxygenase inhibitory activity assay and lipoxygenase inhibitory activity assay, respectively [22][31].
Tang et al. isolated thirteen non-peptide nitrogen-containing compounds from Chinese black ants (Polyrhachis dives) and tested their anti-inflammatory activity on murine macrophage cells (RAW264.7 cells) treated with lipopolysaccharides (LPSs). These compounds inhibited not only the production of tumor necrosis factor-α (TNF-α) and COX-1 but also Jak3 kinase activity and T lymphocytes, but no significant inhibition was detected for B-cells as shown by T- and B-lymphocyte proliferation assays [53][41].
Baek et al. obtained an aqueous fraction of Lycorma delicatula and tested the anti-inflammatory properties in LPS-treated RAW264.7 cells. The fraction inhibited nitric oxide production at a concentration of 300 μg/mL. Moreover, interleukin (IL)-13 induced by LPS and matrix metalloproteinase (MMP)-7, -9, -14, and -17 levels were significantly decreased [54][42].
Collectively, all these results support the idea that edible insects could ameliorate the severity of the inflammatory process, although the mechanisms of action must be better understood.

1.4. Insects’ Antimicrobial Peptides

Most living organisms, ranging from fungi to plants and animals, can produce antimicrobial peptides (AMPs). These small (15–30 amino acids) and positively charged peptides play a significant role in killing pathogens (bacteria, fungi, viruses, and some parasites) through the modulation of the host’s innate response and are particularly effective against biofilms. Interestingly, since the purification of cecropin, the first insect AMP from Hyalophora cecropia in 1980 [55][43], about 150 AMPs have been isolated from Acalolepta luxuriosa, Apis mellifera, Bombyx mori, Galleria mellonella, Heterometrus spinifer, and Holotrichia diomphalia [56,57][44][45].
According to their amino acidic components, insect AMPs can be classified in four groups: the α-helical peptides (e.g., cecropin and moricin), cysteine-rich peptides (e.g., insect defensin and drosomycin), proline-rich peptides (e.g., apidaecin, drosocin, and lebocin), and glycine-rich proteins (e.g., attacin and gloverin). Among them, defensins, cecropins, proline-rich peptides, and attacins are probably the most common insects’ AMPs [57][45].
Insect defensins are probably the best-characterized AMPs and are active in particular against Gram-positive bacteria, for example Bacillus subtilis, Bacillus thuringiensis, and Staphylococcus aureus, although antibacterial effects have also been shown on Gram-negatives such as Escherichia coli [58][46]. In a study of Kaneko et al., a defensin sequence was isolated from Bombyx mori. Interestingly, the expression of the defensin gene was stimulated by the infection of E. coli and B. subtilis, showing an implication of this AMP in the immune response against these bacteria [59][47].
Many cysteine-rich peptides with different names may be considered defensin-like proteins, including coprisins. In a study of Hwang et al., coprisin was isolated from a dung beetle (Copris tripartitus). In vitro studies showed an upregulation of coprisin genes after infection with bacteria, followed by strong antimicrobial activity against S. aureus and E. coli [60][48]. Moreover, coprisin shows a synergistic activity with common antibiotics like ampicillin and vancomycin against many bacteria (Enterococcus faecium, Streptococcus mutans, E. coli O-157, and Pseudomonas aeruginosa) and inhibits biofilm formation [61][49].
The ability of AMPs to inhibit biofilm formation deserves a special mention, since the matrix surrounding bacteria makes them more resistant to antibacterial treatments and responsible for a wide range of chronic diseases [62][50]. In addition to coprisin, many are further examples of AMPs involved in biofilm inhibition. Defensin-1, the recombinant form derived from European honeybee defensin, showed antibiofilm efficacy against S. aureus, Streptococcus agalactiae, and P. aeruginosa (minimum inhibitory concentration, MIC: 0.009–0.09 μM) [63][51], and melittin, which is the principal component of the venom of honeybees, showed high MIC values against P. aeruginosa and a synergic activity with antibiotics against E. coli and Klebsiella pneumoniae [64][52]. Notably, mauriporin derived from Androctonus mauritanicus and Mastoparan-1 derived from Polybia paulista are significantly effective against methicillin-resistant S. aureus (MRSA), with a MIC of 5–10 and 0.001–0.019 μM, respectively [65,66][53][54].
In recent years, the focus on the application of AMPs in clinical practice has increased notably because of their interesting characteristics, such as the broad spectrum of antimicrobial activity, the small size, and the low chance for development of resistances [67][55]. For these reasons, some insect-derived AMPs (i.e., ETD151, thanatin) have been optimized by genetic manipulation and have been tested in in vivo models with promising antibacterial properties [68,69,70][56][57][58]. These observations support the idea of extending the experimentation and study of these molecules to various fields of medicine, including dentistry.

2. Potential Applications of Edible Insects’ AMPs in Dentistry

Previous studies investigated the role of functional food in prevention and management of oral diseases. Notably, cyanobacteria and microalgae are receiving attention for the richness of high-value compounds (i.e., carotenoids, vitamins, and proteins) and for their beneficial effects on human health, being a source of anti-inflammatory and antioxidant molecules [71,72,73][59][60][61]. In the specific case of oral health, cyanobacteria and microalgae may find application as promising drugs in oral cancer prevention, oral submucosal fibrosis treatment, and in the management of chronic periodontitis [74,75,76,77][62][63][64][65]. Furthermore, as for insects, these functional foods have antimicrobial activity against microorganisms like Herpes labialis, Streptococcus mutans, and Candida albicans, representing a potential application in oral infection prevention [77][65].
In fact, one of the most important challenges that dentistry faces is the onset of oral infections, which may lead to serious clinical outcomes. The case of infective endocarditis (IE) is emblematic. Indeed, an antibiotic prophylaxis (AP) is recommended before orthodontic procedures in order to lower the risk of infection, especially in patients at high risk [78][66]. AP, that has been widely used in the past, is now controversial because of the emergence of multidrug-resistant strains of bacteria, mostly Staphylococci, Streptococci, and P. aeruginosa [79][67]. As discussed above, AMPs derived from edible insects display a broad spectrum of antimicrobial activities, both against Gram-positive and Gram-negative bacteria, representing a potential tool to treat oral infections with a low chance of developing resistances. For this reason, AMPs might be manipulated, optimized, and introduced into dental practice as substitutes for the common antibiotics used to date. Further studies may focus on the possible effects of the combined administration of AMPs derived from edible insects and molecules with antimicrobial activity extracted from other functional foods (i.e., cyanobacteria and microalgae) to investigate possible synergistic effects. The manipulation and transformation of edible insects deserve a special mention, allowing a better tolerance of insect intake and palatability. Previous studies investigating the role of functional foods (e.g., algae) in dentistry usually employed local gels or tablets [74,80,81][62][68][69]. Also, an interesting study of Rashad et al. synthesized silver nanoparticles against oral pathogens [82][70]. Silver nanoparticles are well documented as antibacterial, antifungal, and antiviral agents and are employed in different fields, including drug delivery and diagnosis [83][71]. In addition to the above-mentioned administration methods, novel drug delivery systems could be considered, including chewing gums or toothpastes for topical effects. Flours extracted from edible insects could be processed to make foods like pancakes, biscuits, or bread [46,84][29][72]. These foods based on insect flours may be better tolerated, even by pediatric patients.
Despite AMPs appearing to be promising candidates for the treatment of different infections and as an interesting tool to solve the problem of microbial resistance, there are many limitations for drug development. The process of induction, extraction, and optimization of these molecules is far from easy and requires expertise and has high costs, despite the high availability of insects.

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