Background

The Annona genus is named after the Latin phrase “annual harvest.” Among the Annonaceae families, this genus provides the most food. It contains approximately 162 species of trees and shrubs. These species are thin, 5 to 11 m tall, upright or slightly disseminated, and sometimes rough, with gray to brown bark [1]. With around 2400 species in 108 genera, Annonaceae are mainly pantropical, are a larger family than any other Magnoliidae group. The botanist Jussieu published his classification of the Annonaceae family in 1789 [2, 3]. Different analytical methods have documented terpenoids (mainly diterpenes) and alkaloids (isoquinoline alkaloids) in this family species [4]. The family has several plant species of economic value as they are edible worldwide, including tropical America, Australia, Africa, India, Europe, and the Mediterranean [5], which makes this genus economically the most important because of its foodstuffs and medicinal properties. The fruits of a number of Annona species are edible, including Annona crassiflora (araticum), Annona squamosa (Fruita do conde), and Annona muricata (Graviola). In Brazil, several of the Annonas’ fruits are highly prized. It is frequently consumed “naturally” or in the form of juice, cake, or ice cream [6]. Earlier molecular and medicinal studies of the species have shown substantial biological activities, such as cytotoxicity to various cell lines, anti-platelet, antiparasitic, antibiotics, and antimicrobial properties. The existence and reason for these activities is due to the presence of alkaloids, acetogens, and terpenes [7]. As a result, the purpose of this study was to examine the Annona genus species that have anti-diabetic and anti-oxidant capabilities.

Methods

We reviewed scientific articles published in journals by electronic databases (Google Scholar, PubMed, Medline, Web of Science, DOAJ, and Scopus) using specific keywords such as “Annona”; “Diabetes mellitus”; “Antioxidants”; “Medicinal plants”; “Antidiabetic”. We reviewed 76 articles that provided data on the use of Annona species to treat diabetes and oxidative damage. The synonyms, taxonomy, and several other botanical distribution and descriptions were retrieved from “The Plant List” (http://www.theplantlist.org/), “Flora of Bangladesh” (http://bnh-flora.gov.bd/species-list/), and “CABI” (https://www.cabi.org/isc/).

Main text

Botanical distribution

Nine species of the Annona genus were characterized in this study, whose botanical representation is summarized in Table 1.

Table 1 Botanical Information of the species
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Annona cherimola

Annona cherimola Miller belongs to the genus Annona in the Annonaceae family in magnolias order, which is also provides edible fruit species. It is a steep, semi momentary but low bunched tree. The plant, highly prevalent in Ecuador and Peru is widely distributed throughout the tropics and subtropics of America, Africa, Asia, and even South Europe [8, 9]. Alone or in combination with others, it has been used in Mexican Traditional medicine to treat several diseases like fever, cough, worms, headache, and inflammation. Currently, this is utilized in the treatment of diabetes [10,11,12].

Annona squamosa

Annona squamosa L., known as custard apple, generally is an endemic of the West Indies, and throughout India, it is well grown. Annona squamosa is renowned for its anti-diabetic properties among tribal men in and around Aligarh district’s village in Uttar Pradesh [13].. There, native people make a mixture of 4–5 newly emerged leaves with five grains of black pepper early in the morning to treat diabetes. Continuing the therapy ensured up to 80% positive results [13].

Annona macroprophyllata

Annona macroprophyllata Donn. Sm. is yet another species that is known to be classified under the genus Annona. It is referred to as “ilama,” a common tree in central Mexico. It is familiar by “papauce” or “anona blanca” in the Southeast [14, 15]. Its fruits are consumed as food, but its leaves are used as anticonvulsants [16]. In traditional medicine, it is also prescribed as an analgesic and anti-inflammatory agent [17].

Annona muricata

Annona muricata is a well-known member of the Annonaceae family and the Annona genus. It is commonly known as sour-sop. It is employed for treating diabetes, hypertension, fever, pain, and against worms and vomiting [18]. Several pharmacological studies showed that Annona muricata possess vasodilator, cardio-depressive, antispasmodic, antihypertensive, antimutagen, anticonvulsant antiviral, antidiabetic, and antioxidant properties [26,27,28,29,30].

Annona reticulata

Annona reticulata in India is typically known as “custard apple” or “heart bullock.” It is locally useful in the treatment of epilepsy, dysentery, cardiac problem, parasite and worm infection, constipation, and bacterial infection [19].

Annona carcans

Annona carcans is a member of the Annonaceae family, which comprises woody, arbustive, or arborist plants and many fruits [21, 31] and also known as Annona amambayensis Hassl. It is commonly known as “araticum-caga - reso” or “cortic - a reso.” It is used as purgative in folk medicine, and found in the Brazil [21].

Annona coriacea

Annona coriacea is a fruit tree native to Brazil. The ecoregions of Cerrado, Caatinga, and Pantanal are part of their original habitat. Buildings and toys are made from the wood. Synonyms of this plant are Annona coriacea var. cuneata R.E. Fr and Annona geraensis Barb. Rodr [32].

Annona cornifolia

Annona cornifolia is part of the family of Annonaceae and Annona walkeri S.Moore is used as a synonym of this plant. It is commonly referred to as “aratian-mirim.” The fruit pulp is mature, orange, and sweet and aromatic. The green fruit is well-known for its ability to treat ulcers [24].

Annona senegalensis

Annona senegalensis, referred to as sour soup (English), abo (Yoruba, Western Nigeria), and uburuocha (Igbo, Eastern Nigeria), is commonly found in Nigeria [25]. The bark of the stem is silvery gray or gray-brown. The leaves are simple, alternate, and oblong, and they're hairless on top with brownish hair on the underside. Leaves are used to treat diarrhea, joint disease, respiratory disease, conjunctivitis, burns, snakebite sores, trypanosomiasis, jaundice, bleeding, female barrenness, seizures, asthenia, and fever [25].

Phytochemicals

Nine species of the Annona genus were characterized in this study, whose phytochemical study is summarized in Table 2.

Table 2 Phytochemical constituents of the species
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Annona cherimola

From the ethanol leaf extract of Annona cherimola, four flavonoid compounds: kaempferol, quercetin, nicotinflorin, and rutin and phenolic compound caffeic acid was also identified using the TLC method [33]. Chen et al identified Aromin-A; squamocin from the stem extract of A. cherimola, along with Cherimolin; dihydrocherimolin; molvizarin;motrilin; itrabin; jetein; cherimolin-2; almunequin from the seeds [34]. In the ethanol extract of the Annona cherimola seeds, two new cytotoxic addictive acetogenins, anomolin and annocherimolin, were identified [35].

Annona squamosa

Annona squamosa is proven to have glycosides, alkaloids, saponins, flavonoids, tannins, carbohydrates, proteins, phytosterols, amino acids, and phenolic compounds. Different chemical components have been identified from the plant’s leaves, stems, and roots, including 15 alkaloids, 10 cyclopeptides, 39 acetogenins, and 8 diterpenoids [36].

Annona macroprophyllata

Seed extract of Annona macroprophyllata constitutes 3 compounds namely, Laherradurin (acetogenin), rolliniastin-2, and cherimolin-2 [47, 48].

Annona muricata

Several plant phytochemicals, such as alkaloids, flavonol, phenols, and essential oils, were evaluated from the A. muricata plant. However, acetogenin was found to be a rich source in A. muricata. The existence of several key minerals, including Potassium (K), Calcium (Ca), Sodium (Na), Copper (Cu), Iron (Fe), and Magnesium (Mg), demonstrate that the frequent intake of A. muricata fruit may assist in providing the human body with essential nutrients and elements [19, 47, 49,50,51,52,53,54,55]. According to research findings, Annona muricata reported 17 Alkaloids, 100 Annonaceae acetogenin, 10 phenolics, 13 flavonol triglycerides, 17 megastgmane, and 2 cyclopeptides from its fruits, leaves, seeds, and pericarp, respectively [38].

Annona reticulata

Various phytoconstituents from various parts of the A. reticulate have been described through identification of tannins, alkaloids, and phenolic compounds from the stem bark. Leaves are abundant in chemical constituents such as alkaloids, amino acids, carbohydrates, hormones, flavonoids, protein, tannins, glycosides, and phenolics. The root has been discovered to include acids, alkaloids, carbohydrates, proteins, flavonoids, and tannins. This species has also proven rich in Ca, Phosphorus (P), K, Mg, Na, Chlorine (Cl), Sulfur (S), Manganese (Mn), Zinc (Zn), Fe, Cu, Selinium (Se), Cobalt (Co), Nickel (Ni), and Chromium (Cr) [56,57,58].

Annona coriacea

Gomes et al. 2019 reported, leaves extract of Annona coriacea has been found to contain palmitic acid, oleic acid, asitrocinone, annonacin, trilobalicin, annomuricin E, asimicin, bullatacin, annohexocin, murihexocin, goniotriocin, bullatalicinone, annoglaucin, ginsenoside Rh5, salzmanolin, annoheptocin A, annoheptocin B, squamocin glycosylated using analysis of the electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry [40].

Annona cornifolia

The assessment of phytochemicals from various plant parts led to numerous bioactive constituents being found among different Annona species. Acetogenins, alkaloids, essential oils, phenolic compounds, cyclopeptides, amino acids, pigments, and vitamins are among the principal phytochemical components [48]. The study found acetogenins namely 9-Hydroxyfolianain, annofolin, folianin B, 4-desoxylongimicin, folianin A, squamocin M, squamocin L from seed extract of Annona cornifolia [41].

Annona senegalensis

The study identified acetogenin and annosenegalin from the seed extract of Annona senegalansis and annogalene; gigantetronenine; squamocine; glaucanisine; glaucanetine; goniothalamicine from the root extract. Six alkaloids were also found out, namely roemerine; anonaine; nornuciferine; liriodenine; coclaurine; isoboldine, from the leave extract of Annona senegalensis [42,43,44,45,46].

Biological activity

Antidiabetic activity

Annona cherimola

Ethanol extract of Annona cherimola was tested in alloxan-induced type-2 diabetic rats to study the antidiabetic effect of the leaves of Annona cherimola. Plant extract administered at dose 300 mg/kg on alloxan-induced anti-hyperglycemic rats decreased blood glucose level 331.5 mg/dl to 149.2 mg/dl 4 h after the administration (P < 0.05) compared to the acarbose (151.3 mg/dl), an alpha glucosidase inhibitor. The above study proved that rutin, a flavonal glucoside present at the ethanol extract, acts as an alpha glucosidase inhibitor like acarbose, which contributes significantly to the decrease of blood glucose level [59] (Table 3).

Table 3 Result and methods of antidiabetic and antioxidant activity
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Annona squamosa

A research study was conducted using the aqueous extract of Annona squamosa in streptozotocin-nicotinamide type 2 diabetic rats where symptomatic decrease in plasma glucose level was seen for oral glucose tolerance test from 30 min onwards compared to 250 mg/kg and 500 mg/kg doses administered in normal rats. The result ensured that, aqueous extract of A. squamosa has significant potential of anti-hypoglycemic effect. In that study, the anti-hyperglycemic effect of that aqueous extract was independent of the dose since no significant difference in results were observed between 250 and 500 mg/kg extract [61].

Annona macroprophyllata

A study in Mexico stated that Annona muricata, Annona glabra, and Annona cherimola are used as antidiabetic plants. Based on their research, another study is carried out on Annona macroprophyllata as it is a similar species of the Annona genus.

Kamalakkannan, N., & Prince, P. S. M. (2006) isolated a flavonol compound rutin from Annona microprophyllata extract which was tested on hyperglycemic rats, and was found to inhibit fasting plasma glucose level, while the insulin and the antioxidant levels were increased [70, 71]. Rutin also reduced the alpha-glucosidase activity in both in vivo and in vitro studies [72]. They demonstrated the same yeast alpha-glucosidase behavior as Annona macroprophyllata, whereas a low IC50 (1.18 μg/ml) was observed [63].

Annona muricata

Research has shown that a single dose of 100 mg/kg and 200 mg/kg of an aqueous extract of Annona muricata did not significantly affect blood glucose levels in regular rats. The extract administration of single dosing effectively lowered the blood glucose levels in hyperglycemic rats after 2 h of dosing. Plant extracts at 100 mg/kg and 200 mg/kg reduced blood glucose levels by 31.77% and 45.77% after injection of streptozotocin for 14 days, respectively. Repetitive administering of Annona muricata aqueous extract at all doses led to a substantial decline of near-normal blood glucose levels on day 7. Also, 76.56% and 58.3% reductions were shown at doses 100 mg/kg and 200 mg/kg, respectively, compared to the initial value. The result also showed that before streptozotocin injection, plant extract’s daily administration did not inhibit streptozotocin-induced hyperglycemia during 3 days. However, a significant drop in blood glucose levels during 14 days without treatment has shown that plant extract can work long. The findings also indicate decreased bodyweight loss, fluid and water intake in streptozotocin-induced rats, and blood glucose levels decreased during the four weeks of daily extract administration within one week. The presence of tannins and flavonoids in the phytochemistry of Annona muricata confirmed their hypoglycemic activity [64].

Annona reticulata

Various fractions of 100 mg/kg of ethyl acetate, methanol, and residual fractions were obtained from Annona reticulata leaves hydro-alcoholic extract and was examined to determine its reduction of blood glucose level potential in streptozotocin-induced diabetic rats. After 14 days of treatment, fasting blood glucose levels decreased in hyperglycemic rats. Fasting blood glucose level decreased by 3.67%, 14.03%, 47.69%, and 50.93% for treatment with residual fraction, methanol fraction, ethyl acetate fraction, and standard drug. The study exhibited a significant (P < 0.001) decreased blood glucose level in comparison to the diabetic control group.

The blood glucose levels decreased by a residual fraction and methanol fraction from 417.83 to 402.50 mg/dl and 432.33 to 371.67 mg/dl. Compared to diabetic control groups, these levels were not substantial and the fraction of ethyl acetate was capable of controlling the increase in blood glucose and also attenuating secondary variables with hyperglycemia due to streptozotocin [73].

Antioxidant activity

Annona cherimola

The cherimoya skin, flesh, and juice were isolated from Annona cherimola and analyzed for antioxidant content using the oxygen radical absorbance capacity (ORAC) assay. The juice showed the highest antioxidant activity, while the flesh exhibited the lowest [60]. Gupta-Elera et al. stated that the cherimoya juice extract enhanced the antioxidant uptake against the burkitt’s lymphoma and colon cancer cell lines [60].

Annona crassiflora

Ethanol and aqueous extract of Annona crassiflora peel, seed, and pulp were screened for in vitro antioxidant activity, whereas antioxidants were measured using DPPH and lipid peroxidation assay. The ethanol extract exhibited substantial and concentration-based scavenging activity in DPPH, together with lipid peroxidation activity inhibition in mice’s model. Furthermore, the in-vitro antioxidant activity of peel, seed, and pulp exposed noticeable total phenolic content (TPC), whereas the ethanol peel extract contains the maximum TPC [67].

Annona muricate, A. squamosa, A. reticulata

Using different in vitro models (DPPH, ABTS, nitric oxide, superoxide, hydroxyl radical, and lipid peroxidation), the antioxidant potential of leaves of three other species of Annona (Annona muricata, Annona. squamosa, Annona reticulata) were studied. Annona muricata ethanol extract displayed a maximum scavenging activity (90.05%) at 500 μg/ml for ABTS, followed by hydroxyl radical scavenging (85.88%) and nitric oxide scavenging (72.60%), whereas a moderate action observed for lipid peroxidation assay. Annona squamosa extract showed the least inhibition in all in vitro antioxidant models. The ethanol extract of Annona reticulata showed maximum inhibition of 89.37% in DPPH, 89.05% in ABTS, 71.10% in nitric oxide, 77.72% in hydroxyl radical, 80.88% in superoxide radical, and 35.54% in lipid peroxidation at 500 μg/ml. The ethanol extract of Annona squamosa showed maximum inhibition of 88.77% in DPPH, 88.06% in ABTS, 68.03% in nitric oxide, 79.79% in hydroxyl radical, 77.21% in superoxide radical, and 50.83% in lipid peroxidation at 500 μg/ml. These findings indicate that Annona muricata extracts have strong in-vitro antioxidants efficacy compared to Annona squamosa and Annona reticulata leaves, which show the function as an effective, free radical scavenger, increasing its therapeutic value [62, 65].

Annona coriacea

Seeds and pulp extracts of fruit Annona coriacea and Annona sylvatica were tested for antioxidant potential. DPPH, Beta-carotene bleaching, and ABTS methods were applied to determine the antioxidant activity. The pulp and seeds of the fruits were extracted by using methanol/water (8:2) for maceration. An excellent extraction yield was shown in the seeds and pulp extracts of fruit Annona coriacea (14.5 and 20.5%) and Annona sylvatica (8.7 and 5.2%). A moderate antioxidant effect and exhibited free radical scavenging activity of 31.53% by DPPH test was demonstrated by the seed extracts of Annona coriacea. By the Beta-carotene bleaching test, the seed further showed 51.59% antioxidant activity. Besides, the ABTS assay afforded 159.50 μM Trolox/g antioxidant activity. Seed extracts of Annona coriacea showed significant antioxidant activity. On the other hand, the antioxidant activity of seeds and pulp extract of Annona sylvatica was not significant [68].

Annona carcans

A research study was done to evaluate the antioxidant effect of the hydro-methanol extract of the leaves, pulp, and seeds of Annona carcans. Antioxidant activity was determined by a different model (DPPH, ABTS, and beta-carotene/linoleic acid methods). These three different extracts demonstrated that all of them possess prominent free radical scavenging activity with IC50 estimating between 89.67 μg and 26.25 μg/ml, especially the pulp extract with IC50 44.08 μg/ml (DPPH) and 39.32 μg/ml (ABTS). The pulp fraction displayed promising activity in multiple assays with IC50 = 47.11 μg/ml (DPPH) and IC50 = 26.25 μg/ml (ABTS), relatable to the positive control ascorbic acid. The lipid peroxidation assay also revealed good antioxidant effects of both hydro methanol (51.51 μg/ml) and ethyl acetate (34.34 μg/ml) fractions of pulp. It is observed that due to the presence of quercetin and kaempferol derivative, the pulp extract of Annona carcans probably showed antioxidant effects [21].

Annona cornifolia

Annona cornifolia has been tested for its antioxidant potential against DPPH using seed ethanol extract fractions containing acetogenins, and these compounds exhibited a robust antioxidant activity at 10–100 μg/ml in DPPH assay with a lower IC50 [41].

Annona senegalensis

The aqueous extract of the Annona senegalensis leaves were assessed for in-vitro antioxidant activities using DPPH, H2O2, superoxide, 2,2′-azo-(3-ethylbenzthiazoline-6-sulfonate), and ferric ion models, while the in vivo antioxidant activities were evaluated at the doses of 100 mg/kg, 200 mg/kg, and 400 mg/kg by enzymes and ion levels. In vitro antioxidant activity of the aqueous plant extract of Annona senegalansis demonstrated concentration-dependent activity (0.2–1 mg/ml) in 2,2 diphenyl-1 picrylhydration (DPPH), H2O2 superoxide ion, 2,2′-azo-(3-ethylbenzthiazoline-6-sulfonate), and ferric ion models. The extract produced maximum inhibitory scavenging activity of DPPH and H2O2 which was 96.9% and 77.54% at higher concentration, respectively, while superoxide ion inhibitory activity was 97.4%. Furthermore, the in-vitro antioxidant activity of leaves extract exhibited noticeable total phenolic content (TPC), total flavonoids contents, and proanthocyanidins [69].

Conclusion

This review involves nine of the Annonaceae species and highlights the antidiabetic and antioxidant ability of Annona plants. Annona species are widely distributed worldwide, while many species are used for both medicinal and food use. As the global scenario is now heading toward non-toxic herbal products with therapeutic applications, comprehensive research into this gold mine of centuries-old expertise should be emphasized. The majority of the plants in this study demonstrated that their antidiabetic and antioxidant activity was potent. Five species were reviewed as having antidiabetic activity, and they demonstrated potent antihyperglycemic effect. Furthermore, antioxidant activity was reviewed from ten species, and they showed potent antioxidant activity with different in vitro models. Though several in vitro studies have confirmed the antioxidant and antidiabetic potential of the species of the Annona genus, still only a few in vivo and clinical trials were performed to date to validate the in vitro outcomes. So their potential in animal and human models should be assessed in the future. Furthermore, the mechanism of action by which they confer antidiabetic and antioxidant activities is still not developed elaborately. This should also be developed in further studies. Moreover, it can be concluded that, since natural medicines have the least side effects and are considered safe for human health, they can substantially substitute synthetic drugs in the future.