Helichrysum Genus in Management of Diabetes Mellitus: History
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Contributor:
Akeem Akinfenwa
,
Idowu Sagbo
,
MASIXOLE MAKHABA
,
Wilfred Mabusela
,
Ahmed Hussein

Diabetes mellitus (DM) is a very prevalent disease affecting both developed and developing countries. Concerted efforts by the International Diabetes Federation (IDF) and the American Diabetes Association (ADA) to reduce the spike in global diabetes cases and mortality have witnessed different advocacies over the past years. The IDF report shows that 463 million (9.3%) adults worldwide are suffering from diabetes, and this number is projected to increase by 51% in 2030 (578 million) and 2045 (700 million). The prevalence of diabetes varies according to geographical region, with more than 80% of diabetic patients living in low-to-middle-income countries, which poses additional challenges with ineffective treatment. Despite the success recorded from these synthetic drugs, the traditional method of treatment using medicinal plants is increasingly accepted by the locals due to its low cost and the perceived no side effects. Helichrysum species are used in folk medicine and are documented for the treatment of DM in different regions of the world. 

  • antidiabetic drugs
  • Helichrysum species
  • medicinal plants

Ethnobotanical and Pharmacological Relevance of Helichrysum Genus

The Helichrysum genus encompasses typically aromatic herbs and shrubs with dense leaves that belong to the family of Asteraceae. The genus is widely distributed worldwide but is mostly found in Africa, with its highest diversity in South Africa, where about 500 known species occur. The plants belonging to this genus are well-known as everlasting flowers with leaves oblong to lanceolate. They have been in use for more than 3000 years for various folkloric purposes. In traditional medicine, some Helichrysum plant parts are either drunk as teas or prepared as “burnt offering” smoke to appeal for blessings from the ancestors and are used to purify the home of the sick patients [1]. In addition, the plant from the Helichrysum genus has also been reported in traditional medicine for the treatment of several ailments, including stomach pain, gall bladder problems, jaundice, colds, wound healing, diabetes mellitus, skin infections, and asthma [2][3][4]. Nevertheless, with the emergence of scientific data on the use of Helichrysum species in the last few decades, some of the reported traditional claims have been scientifically supported. To mention a few, Tirillini et al. [5] reported the antioxidant activity of methanol extract of Helichrysum foetidum from east Africa. Additionally, research conducted by Matić et al. [6] revealed the antitumor potential of Helichrysum zivojinii extract. Another study conducted by Süzgeç-Selçuk and Birteksöz [7] reported the antimicrobial actions of flavonoids isolated from Helichrysum chasmolycicum. Ranaivoarisoa et al. [8] also reported the anti-plasmodial effect of Helichrysum gymnocephalum from Southern Africa. The anti-inflammatory activity of Helichrysum stoechas extracts from north Africa has also been reported [9] among others. It is imperative to note that several plants belonging to the Helichrysum genus have been more extensively researched for various bioactivities than their role as antidiabetic agents.

Antidiabetic Potentials of Helichrysum Species and Metabolites in Folk Medicine

Several Helichrysum species used for the treatment of diabetes have been identified in the literature. Despite this, not all have been scientifically investigated for their antidiabetic activity. In addition, only a few compounds obtained from these Helichrysum species have been shown to exhibit antidiabetic activity. Thus, in this section, a comprehensive description of plant species belonging to the genus Helichrysum used in the management of diabetes along with the compounds displaying antidiabetic activity will be elaborated.

 Helichrysum arenarium

Description and Ethnobotanical Usage

Helichrysum arenarium perennial herb that grows up to 50 cm in height with a robust and short rhizome [10]. The stem of the plant is generally branched at the upper part and carries alternate leaves of about 2 to 5 cm in length. H. arenarium is widely dispersed in Europe, Central Asia, and China [10]. The plant is well known in traditional medicine. The decoction from the aerial parts of H. arenarium is used for the treatment of diabetes [10]. The flowers are also reported to contain constituents and bitter substances used to promote gastric and pancreatic secretion. In addition, the infusions of the H. arenarium inflorescence are also used in the treatment of gallbladder disorders (rheumatism, cystitis, gout, arthritis) [11].

Toxicity

Kramberger et al. [12] documented the toxicity of H. arenarium. In the study, the authors revealed that the aqueous extract was only toxic at the highest concentration (5%, v/v) against lymphoma (U937) cells, while the same extract displayed toxicity even at 1% (v/v) concentration in both the human colorectal adenocarcinoma (Caco-2) and primary colon fibroblast (CCD112CoN) cell lines.

Antidiabetic Activity of Isolated Compounds

Two compounds, chalconaringenin 2′-O-β-D-glucopyranoside (isosalipurposide, 1) and aureusidin 6-O-β-d-glucopyranoside (2), obtained from the methanol flower extract of H. arenarium have been reported to exhibit strong inhibition against DPP4 enzyme activity, with IC50 values of 23.1 and 24.3 μM, respectively [13]. The percentage composition of compounds 1 and 2 was reported to be 0.013% and 0.0025%, respectively [13].

Helichrysum aureum

Description and Ethnobotanical Usage

Helichrysum aureum is a perennial plant with a woody rootstock and rosette of radical leaves. It has flowering stems of 0.1–0.6 m in height with small leaves. H. aureum is native to Swaziland, Zimbabwe, Angola, South Africa, and Mozambique. In South Africa, it is broadly dispersed in the Cape provinces, KwaZulu-Natal, and Free State. Traditionally, H. aureum is used by the people of Basotho for the treatment of diabetes [14].

Toxicity

The cytotoxicity study reported by Lourens et al. [15] revealed that the chloroform:methanol (1:1) extract of H. aureum displayed cytotoxic effects toward transformed human kidney epithelial (Graham) cells, breast adenocarcinoma (MCF-7), and glioblastoma (SF-268) cells at the tested concentration (0.1 mg/mL) with inhibition of 5%, 7%, and 35%, respectively.

Antidiabetic Activity of Isolated Compounds

Literature survey revealed no reports on the antidiabetic activity of compounds from H. aureum.

Helichrysum caespititium

Description and Ethnobotanical Usage

Helichrysum caespititium is a perennial creeping plant of 10 to 20 cm in height. The leaves of the plant are linear, clutching at the base and hairy on both sides, while its flowers are white to yellow [16]. H. caespititium is broadly distributed in Lesotho, Zimbabwe, South Africa, and Swaziland [17]. In South Africa, the whole plant of H. caespititium is cooked and then used to alleviate diabetes mellitus [18]. Additionally, the plant is also used for the treatment of some medical conditions such as wounds, ulceration, skin infection diseases, nausea, tuberculosis, bronco-pneumonia, and sexually transmitted infections [4].

Toxicity

Research conducted by Mamabolo et al. [19] reported the toxicity of H. caespititium. The findings of the study showed that the whole plant extracts (hexane, dichloromethane, methanol, and aqueous extracts) of H. caespititium had low-to-high toxic effects in rat hepatoma (H411E) cell lines. In the study, the highest toxicity was reported for the dichloromethane whole plant extract of H. caespititium with a lethal concentration 50 (LC50) value of 82.86 μg/mL compared to the standard control, doxorubicin (LC50 = 10.80 μg/mL).

Antidiabetic Activity of Isolated Compounds

Presently, information on the antidiabetic activity of isolated compound from H. caespititium is very scanty in the literature.

Helichrysum graveolens

Description and Ethnobotanical Usage

Helichrysum graveolens is an herbaceous plant belonging to the Helichrysum genus, with grey-bushy foliage and thin everlasting flower-heads. The plant is native to Eastern Europe, Caucasus, Turkey, Iran, and South Africa [20]. Traditionally, the decoction from H. graveolens has been reported to be active in the treatment of diabetes mellitus in several regions of South Africa, Anatolia, and Turkey [20]. The capitulums of the plant are also reported to be consumed for the treatment of jaundice, diuretic, and wound healing in the rural districts of Anatolia [20].

Toxicity

Studies on the toxicity of H. graveolens revealed no toxicity activity displayed by the plant against the tested cells [21][22]. Kutluk et al. [21] investigated and reported that the whole plant aqueous and ethanol extracts were not toxic to Vero African green monkey kidney cell lines, even at the highest tested concentration of 64 µg/mL. Yazdi et al. [22] supported these results, whereby they reported no toxicity effects of the aerial parts aqueous extract of H. graveolens in C26 colon carcinoma cells up to 5.0 µg/mL concentration.

In Vitro Antidiabetic Study

Several reports have confirmed the antidiabetic activities of H. graveolens. Orhan et al. [23] revealed that the hydroethanolic extract from H. graveolens exhibited 55.7% inhibition at a concentration of 3000 µg/mL against alpha-amylase enzyme. In the same study, the authors also showed that the same extract demonstrated significant inhibition against the alpha-glucosidase enzyme with IC50 values of 0.7129 mg/mL.

In Vivo Antidiabetic Study

A study by Aslan et al. [20] showed that the aqueous and ethanol extracts of H. graveolens significantly reduced blood glucose levels in streptozotocin-induced diabetic rats at a 500 mg/kg dose concentration.

Antidiabetic Activity of Isolated Compounds

A literature search revealed no report of antidiabetic compounds from H. graveolens.

Helichrysum gymnocomum

Description and Ethnobotanical Usage

Helichrysum gymnocomum is a straggling aromatic perennial herb with pleasantly scented flowers. The stems of the plant are often decumbent and rooting at the base while the leaves are very variable and pleasantly scented [1]. H. gymnocomum grows abundantly in the Eastern Cape and KwaZulu-Natal provinces of South Africa [24]. In addition, the plant is also native to Lesotho. Traditionally, the decoction of the fresh leaves of the plant is taken orally for the treatment of diabetes [25].

Toxicity

An extensive search of the literature at the time of compiling this review revealed no scientific report on the toxicity activity of H. gymnocomum.

In Vitro Antidiabetic Study

No reported in vitro studies were found in the literature.

In vivo antidiabetic study

No reported in vivo studies were found in the literature.

Antidiabetic activity of isolated compounds

Bioactive constituents in diabetes from H. gymnocomum are yet to be reported.

Helichrysum italicum

Description and Ethnobotanical Usage

Helichrysum italicum is a small evergreen shrub that grows on dry, rocky, and sandy ground. It has small leaves with a revolute margin and woody stems at the base and is 60 cm or more in height. H. italicum is native to Mediterranean countries such as Turkey, Portugal, Italy, and Greece [26]. The infusion or decoction of the plant is traditionally used for the treatment of diabetes [27]. In addition, infusion and decoction are also used to treat dermatologic, digestive, and respiratory disorders.

Toxicity

Toxicity studies involving H. italicum have mainly been concerted in vitro [28]. Kramberger et al. [12] evaluated cell viability on lymphoma cell line (U937), adenocarcinoma cell line (Caco-2), and primary colon fibroblasts (CCD112CoN) after exposure to the aerial parts infusion of H. italicum. The study reported that the infusion was not toxic up to 5% v/v concentration in U937 cells, whereas for Caco-2 it was toxic at 1% v/v. A higher concentration (2% v/v) was toxic for CCD112CoN cells than for cancerous cell line Caco-2. Staver et al. [29] and Gismondi et al. [30] independently showed that H. italicum essential oil exhibited toxicity effects against HeLa human cervix adenocarcinoma (IC50 = 0.075 mg/mL) and MCF-7 human breast cancer (IC50 = 0.057 mg/mL) cells, as well as B16F10 murine melanoma, respectively, in a dose-dependent manner. Nostro et al. [31], in their research study assessing the genotoxicity of H. italicum, found that the diethyl ether extract of the plant exhibited no DNA damaging activity, even at the highest concentration (2000 g/disc).

In Vitro Antidiabetic Study

Research on the in vitro antidiabetic activity of H. italicum has been investigated [27][32][33]. The study conducted by Pereira et al. [27] revealed that the water-based preparation (infusion and decoction) from H. italicum flowers exhibited moderate inhibition of alpha-glucosidase activity compared to the control at 10 mg/mL. In the research study by de la Garza et al. [32], the methanol:water (1:1) extract of H. italicum was reported to exhibit significant inhibitory activity against both alpha-glucosidase and alpha-amylase enzymes, with IC50 values of 0.19 and 0.83 mg/mL, respectively. Aćimović et al. [33], in their research study, showed that H. italicum essential oil had strong inhibitory activity on alpha-glucosidase enzyme (62.02%) at the tested concentration (250 mg/mL).

In Vivo Antidiabetic Study

The in vivo study reported by de la Garza et al. [32] demonstrated that H. italicum methanol:water (1:1) extract reduced blood glucose levels, thereby improving postprandial glycemic control in rats. In a separate study [34], it was shown by the authors that the methanol:water (3:1) extract of H. italicum ameliorated hyperglycaemia in db/db mice. Another research study [35] revealed that the methanol:water (3:1) extract of H. italicum markedly reduced hyperinsulinemia and insulin resistance induced by high-fat sucrose (HFS) diet in insulin-resistant rats (at 2 g/kg concentration).

Antidiabetic Activity of Isolated Compounds

Presently, no studies have been reported on the antidiabetic activity of isolated compounds from H. italicum.

Helichrysum nudifolium

Description and Ethnobotanical Usage

Helichrysum nudifolium is a fast-growing plant with a light-yellow inflorescence and shiny green leaves. The plant’s flowering stalks can reach 1.5 m in height. It is very easy to grow in the garden and is widely found in South Africa. In South Africa, it is one of the most important species culturally, medicinally, and historically [36]. Traditionally, the fresh leaves or roots of H. nudifolium are boiled and taken orally for the treatment of diabetes [37]. Additionally, the leaves and roots are also used as traditional medicine for wound dressing, internal sores, and chest complaints [36].

Toxicity

The study conducted by Lourens et al. [15] showed that the chloroform: methanol (1:1) extract of the plant displayed cytotoxicity activity with 73%, 83%, and 35% inhibitions, respectively, against transformed human kidney epithelial (Graham) cells, glioblastoma (SF-268) cells, and breast adenocarcinoma (MCF-7) at the tested concentration (0.1 mg/mL). Mokoka et al. [38], however, revealed that the whole plant dichloromethane:methanol (1:1) extract of H. nudifolium had low toxicity in rat myoblast L6 cells with a reported IC50 value of 47.7 µg/mL.

In Vitro Antidiabetic Study

The literature search revealed no reported in vitro antidiabetic activity of H. nudifolium.

In Vivo Antidiabetic Study

To date, there are no reported in vivo antidiabetic activities of H. nudifolium.

Antidiabetic activity of isolated compounds

Regrettably, there are no reports on the antidiabetic activity of the isolated compounds from H. nudifolium.

Helichrysum odoratissimum

Description and Ethnobotanical Usage

Helichrysum odoratissimum is an aromatic, branched perennial plant with small grey leaves [39]. The leaves of the H. odoratissimum vary from linear-oblong, lingulate, to lanceolate. This plant has a yellow flowerhead borne in clusters at the tips of the twigs. H. odoratissimum is broadly found in South Africa, Mozambique, Zimbabwe, Lesotho, and Malawi [39]. In South Africa, it is found in the Eastern Cape across the mountains and coastal areas. In traditional medicine, the infusion from the whole plant is taken orally to treat diabetes [37]. In Lesotho, the whole plant part is mixed with other plants as herbal medicine to treat backache [39].

Toxicity

Studies on the toxicity of H. odoratissimum were documented by Lourens et al. [15] and Twilley et al. [40]. Lourens et al. [15] found the leaf and stem chloroform:methanol (1:1) extract of H. odoratissimum to be toxic against glioblastoma (SF-268) cells, transformed human kidney epithelial (Graham) cells, and breast adenocarcinoma (MCF-7) at 0.1 mg/mL, thereby displaying 48%, 17%, and 7.4% toxicity, respectively. While research conducted by Twilley et al. [40] revealed that the ethanol (100%) leaf and stem extract of H. odoratissimum exhibits toxicity against malignant melanoma (A 375), human embryonic kidney (HEK-293), human epidermoid carcinoma (A 431), and cervical epithelial carcinoma (HeLa) cell lines, with IC50 values at 55.5, 37.1, 33.1, and 15.5 µg/mL, respectively.

Antidiabetic Activity of Isolated Compounds

To date, there are no reported studies involving the antidiabetic activity of the compounds from H. odoratissimum.

Helichrysum platicum

Description and Ethnobotanical Usage

Helichrysum plicatum is a species belonging to the Helichrysum genus with simple and broad leaves. It is an herbaceous perennial plant that grows up to 0.24 m in height. H. platicum is widely found in Balkan, Iran, and Anatolian Peninsulas [41]. The infusion prepared from the plant is used to suppress diabetes symptoms [42].

Toxicity

Eroglu et al. [43] reported that the methanol (100%) flower extract of H. platicum exhibits toxicity properties in human lymphocytes at 0.5 mg/mL concentration. A separate study conducted by Bigović et al. [44] documented moderate toxicity of the ethanol (100%) and ethyl acetate: ethanol (100:0) flower extracts of the plant against human cervix adenocarcinoma cells (HeLa), prostate cancer (PC3) cells, and myelogenous leukemia (K562) cells, with IC50 values at 42.1 ± 0.05, 39.2 ± 1.1, and 25.9 ± 1.5 µg/mL, respectively.

In Vitro Antidiabetic Study

To the best of our knowledge, there are no reported of in vitro antidiabetic studies of H. plicatum.

In Vivo Antidiabetic Study

A research study indicated by Aslan et al. [45] revealed the in vivo antidiabetic activity of H. plicatum aqueous and ethanol extracts in normal and streptozotocin-induced diabetic rats. In the study, the results showed that the aqueous and ethanol extracts demonstrated significant antihyperglycemic activity at a concentration of 500 mg/kg body weight as compared with tolbutamide used as a positive control.

Antidiabetic Activity of Isolated Compounds

A comprehensive literature search showed that compounds such as isosalipurposide (102 mg), helichrysin A (87 mg), helichrysin B (220 mg), apigenin (300 mg), astragalin (28 mg), β-sitosterol (35 mg), β-sitosterol-3-O-β-d-glucopyranoside (25 mg), and nonacosanoic acid (15 mg), isolated from H. platicum methanol extract have been reported to exhibit alpha-glucosidase activity [46].

Helichrysum petiolare

Description and Ethnobotanical Usage

Helichrysum petiolare is a vigorous shrub with silver-gray hair covering the aromatic round-shaped leaf [47]. It is one of the well-known and most used members of the Helichrysum genus. The plant grows to about 0.5 to 1 m in height with its flower whitish-cream in color. H. petiolare is found in the drier inland parts of South African provinces, such as the Eastern Cape and KwaZulu-Natal [48]. In South African traditional medicine, the infusion of the whole plant is taken orally to treat diabetes [37]. In addition, the decoction of the leaves of H. petiolare is used to improve skin texture and for wound healing [49].

Toxicity

An extensive search of the literature revealed at least three documented studies investigating the toxicity of H. petiolare [15][50][51]. Lourens et al. [15] reported that the chloroform:methanol (1:1) extract of H. petiolare had toxic effects on glioblastoma (SF-268), transformed human kidney epithelial (Graham), and breast adenocarcinoma (MCF-7) cells at 0.1 mg/mL, showing 76%, 59%, and 33% activity, respectively. The work of Aladejana et al. [50] revealed that the whole plant ethanol extract of H. petiolare demonstrated significant toxicity in L6 myocytes cells and HepG2 (C3A) hepatocytes at 100 μg/mL concentration. Sagbo and Otang-Mbeng [51] in their toxicity assessment of the methanol extract of H petiolare also reported that the extract was toxic against B16F10 mouse melanoma cells and MeWo human melanoma cells in a dose-dependent manner. The same group [51] also reported the genotoxicity of the plant extract (methanol) against the Vero cell line at the highest three concentrations tested (50, 100, and 200 µg/mL).

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