A SYNTHESIS AND REVIEW OF MEDICINAL USES, PHYTOCHEMISTRY AND BIOLOGICAL ACTIVITIES OF HELICHRYSUM ODORATISSIMUM (L.) SWEET

Helichrysum odoratissimum is an important medicinal plant species in tropical Africa. The current study critically reviewed the medicinal uses, phytochemistry and biological activities of H. odoratissimum . Information on medicinal uses, phytochemistry and biological activities of H. odoratissimum were collected from multiple internet sources which included Scopus, Google Scholar, Elsevier, Science Direct, Web of Science, PubMed, SciFinder, and BMC. Additional information was gathered from pre-electronic sources such as journal articles, scientific reports, theses, books, and book chapters obtained from the university library. This study showed that H. odoratissimum is mainly used as an herbal medicine for insomnia, menstrual pain and sterility, and wounds and respiratory problems. Pharmacological research revealed that H. odoratissimum extracts and compounds isolated from the species have antibacterial, antimycobacterial, antifungal, anti-inflammatory, antioxidant, hepatoprotection, and hypoglycemic and cytotoxicity activities. There is a need to validate the documented ethnomedicinal uses of H. odoratissimum through phytochemical and pharmacological studies. Therefore, future studies should address these knowledge gaps through experimental animal studies, randomized clinical trials, and target-organ toxicity studies involving H. odoratissimum crude extracts and compounds isolated from the species.

The aerial parts, flowers, leaves, roots, stems, twigs and whole plant parts of H. odoratissimum are primary sources of herbal medicines in tropical Africa. A patented extract of H. odoratissimum is used in the prevention of and treatment of skin cancer in South Africa [8]. Moreover, the leaves, stems, and twigs of H. odoratissimum are sold as herbal medicines in the informal herbal medicine markets in Gauteng and the Western Cape provinces in South Africa [9][10][11][12][13]. Research by Van Wyk [14][15][16] showed that the leaves of H. odoratissimum have commercial potential as ritual incense and sedative, while essential oils isolated from the species have commercial potential as an inhalant and aromatherapy in South Africa. Research carried out so far on H. odoratissimum and other plant species showed that these resources are an integral part of traditional pharmacopeia in tropical Africa with a potential contribution to primary health care of local communities in the region [11][12][13][14][15][16][17][18]. Therefore, the current study is aimed at providing a critical appraisal of the existing ethnomedicinal value, phytochemistry and biological activities of H. odoratissimum as well as exploring the potential of the species as herbal medicine in tropical Africa.

Antibacterial activities
Boily and Van Puyvelde [85]  showed potential antibacterial activities against tested microorganisms with mean zones of inhibition and MIC values ranging from 6.7 mm to 17.0 mm and 1.3 mg/mL to 10.0 mg/mL, respectively. These antibacterial activities were comparable to the zone of inhibition of 6.0 mm to 23.7 mm and MIC values of 1.3 mg/mL to 10.0 mg/mL exhibited by the controls [42].

Antimycobacterial activities
Lall and Meyer [88] evaluated antimycobacterial activities of acetone and waterleaf extracts of H. odoratissimum against the drug-sensitive strain of Mycobacterium tuberculosis using the agar plate method and screened the activities of drug-resistant and drug-sensitive strains of M. tuberculosis using rapid radiometric method to confirm the inhibitory activities. The MIC values of acetone extracts against all the strains by both methods were 0.5 mg/ml [88]. Seaman [61] evaluated the antimycobacterial activities of acetone and waterleaf extracts of H. odoratissimum against M. smegmatis and Mycobacterium aurum using broth microdilution technique and M. tuberculosis using BACTEC susceptibility testing with rifampicin and ciprofloxacin as positive controls. The extracts exhibited activities with MIC values ranging from 0.3 mg/ml to 2.0 mg/ml [61].  [86]. Seaman [61] evaluated the antibacterial activities of acetone and methanol leaf extracts of H. odoratissimum against C. albicans using disc diffusion and broth microdilution methods with neomycin and ciprofloxacin as positive controls. The extract showed activities with MIC values ranging from 2.0 mg/ml to 8.0 mg/ml [61]. Reddy [38] evaluated antifungal activities of acetone and methanol extracts of aerial parts of H. odoratissimum as well as essential oils isolated from the species against Cryptococcus neoformans, C. albicans, and Alternaria alternata using disc diffusion assay with nystatin (30 µg) as a positive control. The acetone extract exhibited activities with a zone of inhibition of 2 mm and 3 mm against Cryptococcus neoformans and C. albicans, respectively [38].

Anti-inflammatory activities
Frum and Viljoen [89] evaluated anti-inflammatory activities of aqueous and methanol leaf extracts of H. odoratissimum as well as essential oils isolated from the species through the assessment of the 5-lipoxygenase inhibitory activities using a three-fold stepwise dilution method with dimethyl sulfoxide and Tween ® 20 as negative controls and nordihydroguaiaretic acid as a positive control. The essential oils displayed 5-lipoxygenase inhibitory activities with half maximal inhibitory concentration (IC 50 ) values of 22.5 ppm-35.9 ppm [89].

Hepatoprotection activities
Twilley et al. [65] evaluated the in vitro hepatoprotection activities of the ethanol leaf and stem extracts of H. odoratissimum on the liver hepatocellular carcinoma (HepG2) cells before the hepatoprotective assay to determine the appropriate doses to be tested in the assay. The extract showed significant hepatoprotection at 25 µg/ml on HepG2 cells exposed to D-galactosamine [65].

Hypoglycemic activities
Njagi et al. [90] evaluated hypoglycemic activities of aqueous leaf extracts of H. odoratissimum by administering 50 mg/kg body weight, 100 mg/kg body weight, and 150 mg/kg body weight in alloxan-induced diabetic Swiss albino mice. The extract exhibited a non-dose dependent response by lowering blood glucose levels in diabetic mice [90].

Cytotoxicity and toxicity activities
Lourens et al. [87] evaluated in vitro cytotoxicity activities of chloroform:methanol (1:1) leaf and stem extracts of H. odoratissimum against transformed human kidney epithelial (Graham) cells, MCF-7 breast adenocarcinoma, and SF-268 glioblastoma cells at a concentration of 0.1 mg/ml using the sulforhodamine B assay. The extract exhibited Graham cell growth ranging from 7.4% to 48.2% at the tested concentration [87], implying that the species may be toxic against Graham cells. Lawal et al. [42] evaluated the cytotoxicity of essential oils isolated from H. odoratissimum using the brine shrimp assay. The essential oil of H. odoratissimum showed significant cytotoxicity against the brine shrimp with median lethal concentration value of 31.62 µg/mL [42]. Twilley and Lall [8] evaluated the cytotoxicity activities of ethanol leaf extracts of H. odoratissimum against human epidermoid carcinoma (A431) and non-cancerous cell lines such as Chang liver cells, human embryonic kidney cells (Hek293), and mouse melanocyte cells (B16F10) using the 2,3-Bis-(2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5carboxyanilide salt (XTT) method. The extracts exhibited activities with IC 50 values ranging from 15.5 µg/ml to 57.4 µg/ml against the tested line cell [8]. Twilley et al. [65] evaluated the cytotoxicity activities of the ethanol leaf and stem extracts of H. odoratissimum against human epidermoid carcinoma (A431), malignant melanoma (A375), cervical epithelial carcinoma (HeLa), and human embryonic kidney (HEK-293) cells using the XTT method. The extracts showed inhibitory activities with IC 50 values ranging from 15.5 µg/ml to 55.5 µg/ml with a selectivity index value of 2.4 [65]. Njagi et al. [90] evaluated acute toxicity of the leaf aqueous extract of H. odoratissimum using Swiss albino mice by administering orally to mice a dose of 450 mg/kg body weight of the extract for 30 days. The animals were observed for any signs of acute toxicity such as hypoactivity, piloerection, and salivation. The animals showed mild perihepatitis and perivascular inflammation in the kidneys, while the renal cells, hepatocytes, and spleen tissue cells were intact, and the liver and heart muscle had no signs of pathology [90]. Therefore, the species showed no discernible toxicity on the major organs of the studied animals.

CONCLUSION
In this review, the medicinal uses, phytochemistry, biological activities, and toxicity of different extracts and compounds of H. odoratissimum have been summarized. The diverse medicinal uses of H. odoratissimum and the preliminary phytochemical and ethnopharmacological studies carried so far indicates that the species has potential as herbal medicine. Therefore, there is a need to validate the documented ethnomedicinal uses of H. odoratissimum through phytochemical and pharmacological studies. Although contemporary ethnopharmacological research involving H. odoratissimum is promising, it is too preliminary and sometimes too general to be used to explain and support some of the medicinal uses of the species. Therefore, future studies should address these knowledge gaps through experimental animal studies, randomized clinical trials, and target-organ toxicity studies involving H. odoratissimum crude extracts and compounds isolated from the species.

ACKNOWLEDGMENTS
I would like to express my gratitude to the National Research Foundation, South Africa and Govan Mbeki Research and Development Centre, University of Fort Hare for financial support to conduct this study.

AUTHOR'S CONTRIBUTIONS
The author declares that this work was done by the author named in this article.

CONFLICTS OF INTEREST
The author declares that they have no conflicts of interest.