Ethno-medicinal, phytochemistry, and pharmacological importance of Hunteria umbellate (K. Schum.) Hallier f. (Apocynaceae): a useful medicinal plant of sub-Saharan Africa

Hunteria umbellate (K. Schum.) Hallier f. (Apocynaceae) is a tropical rainforest tree commonly found in sub-Saharan region of Africa. It is a useful and very popular plant among the locals due to the outstanding anti-diabetic activity of the seeds. A comprehensive literature search on articles published on phytochemical analysis and various pharmacological activities of Hunteria umbellate was carried out using search engines such as Google Scholar, PubMed and Science Direct. In this review, it was deduced that H. umbellate is employed in folk medicine as an elixir for obesity, fever, leprosy sores, menstrual pain, infertility, yaws, intestinal worms, abdominal discomfort and stomach ache. Due to their durability and immunity against termites, the stems are coveted and desired as timbers in the construction of houses, while the bark has been reportedly exported to Europe for medicinal uses. Pharmacological activities such as fertility enhancing, aphrodisiac, hypoglycemic, anti-inflammatory, has been ascribed to the different morphological organs of H. umbellate. Moreover, compounds belonging to important classes of secondary metabolites with biological activities such as triterpenoids, flavonoids, tannins, alkaloids, quinic acids have been identified and characterized from the plant. From this review, it can be inferred that, numerous and bioactive principles with known biological usefulness are present in the extracts of H. umbellate and might be responsible for the observed biological and pharmacological activities.


Introduction
The African continent is blessed with about 5000-6000 species of important medicinal plants and flora [1,2]. Readily availability, cheapness and, presumed efficacy, coupled with ancestral practices and beliefs, have sustained the ceaseless usage of these plants as an elixir in the management of myriads of diseases [3]. Furthermore, some of these medicinal plants contribute to the economy of many countries, up millions of dollars in sales and export [4][5][6]. Moreover, there have been increasing pharmacological studies, evaluation, and validation of these plants based on their documented folkloric usage and ethnobotanical surveys [7]. To a large extent, scientific findings have documented many of these plants to elicit arrays of biological activities based on empirical evidence. Furthermore, the mechanism of action and active principles that might be attributed to the observed pharmacological activities have been elucidated. An important group of compounds known as secondary metabolites such as alkaloids, flavonoids, terpenoids, and saponins among others has been characterized and identified from many medicinal plants [8,9]. Some of these compounds have been included in the development of allopathic drugs against some infectious diseases such as malaria and metabolic syndromes [10,11]. In many third-world nations, developing countries and villages, they still rely largely on herbal preparation as a panacea for many ailments while it accounts for about 30-50% of medicinal consumption in China and some Asian countries [12,13,14]. Predominantly found in Sub-Saharan Africa, Huntera umbellate is a useful and beneficial medicinal plant, with a plethora of domestic and ethnomedicinal uses.

Botanical description, habitat and distribution of H. umbellate in Africa
H. umbellate belongs to the Apocynaceae plant family consisting of 4555 species of trees, shrubs, woody vines, and herbs. It is commonly found in West and Central African countries of Cameroon, Senegal, Ghana, Gabon, Congo, Liberia, Guinea Bissau, Sierra Leone, Ivory Coast, and Nigeria [15]. However, it has also been reported to grow in Angola (Fig. 1). H. umbellate is an all-year flowering and fruitful plant which is naturally located in secondary, rain, and gallery forests, 600 m above sea level. It grows as a shrub or small tree up to 15-22 m in height, with a dense leafy crown [16]. The trunk is greyish, which can be serpentine or straight with a diameter of 16 in., while the branches and branchlets have dark brown and pale green colours respectively [17]. The fruits ( Fig. 2) are yellowish, with a smooth texture and, can be as large as 31-60 × 40-50 mm in size [18]. The flowers have a strong pleasant smell, consisting of a creamy or pale yellow corolla and pale green sepals [17]. The leaves (Fig. 3) are hard in texture, elliptic or, oblong in shape, with a size of 10-20 cm × 3-10 cm, and petioles which are 8-25 mm long [19]. The peduncle and inflorescence axes in H. umbellate may appear swollen due to the exudation of resin from the young buds [17].

Folkloric and ethno-medicinal uses of H. umbellate
Vernacularly, the plant is known as "Osu", "Npokiri" and "Abeere" or "Erin" among the Edo, Igbo and, Yoruba people of Nigeria respectively [20,21]. H. umbellate has been documented to possess numerous local and folkloric medicinal uses. The seed and bark, which are prepared as infusions and decoction are effective against fever, leprosy sores, menstrual disturbance, infertility, yaws, intestinal worms, abdominal colic, discomfort, and stomach ache [22][23][24]. The seeds are used in the local management of Diabetes mellitus by herbalists, while the  leaves and pulp are employed by traditional obstetric and midwives to prevent dystocia and unwanted abortion [20,21,25,26]. The roots are blended and macerated as a bitter tonic in Cameroon and Nigeria, while the wood and stems are durable and considered immune to termites. They are used for making household furniture, carving of small tools, and carpenters planes [17]. The bark is also sold to Europe for different medicinal uses [27].
Pharmacological properties of H. umbellate Anti-diabetic and hypoglycemic property The hypoglycemic activity of water extract of H. umbellate seed was evaluated in streptozotocin (50 mg/kg i.p) induced diabetic rats [28]. The extract at 400, 800, 1000 mg/kg exhibited a significant non-concentrationdependent blood glucose reduction which was stronger than glibenclamide. Moreover, glycogen concentration in the extract-treated diabetic rats was also significantly buoyed thus indicating the glycogen storage enhancing activity of the plant [28]. Pretreatment with aqueous seed extract (20-200 mg/kg) significantly attenuated oral glucose (3 g/kg) and nicotine (50 μg/kg i.p) induced hyperglycemia in rats. It was suggested that the antihyperglycemic mechanism of the extract was mediated through intestinal inhibition of glucose uptake [62]. Momodu et al. [29] demonstrated that 250 mg/kg H. umbellate aqueous seed extract significantly diminished streptozotocin-induced diabetes with an observed hypoglycemic fasting blood glucose value. A concomitant restoration in the cytoarchitecture of the pancreatic cell was noticed in the treated rats. In a dose (50-200 μg/ml) dependent pattern, H. umbellate aqueous seeds extract inhibited 50% hog pancreatic α-amylase (IC 50 = 221.30 μg/ml) and α-glucosidase (IC 50 = 184.35 μg/ml) respectively. The enzymes' inhibitory properties of the extract could be attributed to its phenolics and flavonoids constituents [31,32]. As established by Adeneye et al. [63], butanol fraction (200 mg/ kg) of aqueous seed extract exhibited a significant timedependent hypoglycemic effect in alloxan-induced hyperglycemic rats. The fasting blood glucose concentration (FBG) of 116 mg/dl recorded in the extract-treated animals was comparable to 114 mg/kg observed in glibenclamide treated. From the same study, a similar blood lowering glucose activity was demonstrated by the alkaloids fraction of the seed extract. Longe and Momoh [44] and Longe et al. [30] demonstrated that 100 and 250 mg/kg methanol seed extract significantly abated buoyed blood glucose in alloxan-induced diabetic male rats. Aqueous seed extract (100-400 mg/kg) significantly reduced blood glucose concentration in high fructose (600 g) diet-fed rats with a tandem decrease in plasma insulin, basal insulin resistance, and leptin reduction [39]. From the same study, an increased adiponectin activity exhibited in the extract-treated animals can be linked to increased insulin sensitivity and fatty acid oxidation which simultaneously can reduce the risk of myocardial infarction and cardiovascular derangement [64][65][66]. A 14 day oral treatment of alloxan monohydrate (120 mg/kg) induced diabetic rats with 50-200 mg/kg aqueous seed extract revealed an ascending dosedependent hypoglycemic activity of the seed extract. Furthermore, high circulating plasma insulin, FBG, glycosylated hemoglobin (HbA1c) in response to daily oral fructose (66.7 g/kg), and subcutaneous dexamethasone sodium phosphate (10 mg/kg) load was significantly ameliorated in the extract treatment group [67]. Erinidine, a light yellow, an amorphous solid alkaloid isolated from the seed extract demonstrated considerable invitro α-glucosidase and dipeptidylpeptidase inhibition, but lacked in-vitro aldolase reductase, glycogen  phosphorylase inhibitory activity and was unable to stimulate insulin release and glucose uptake by HIT-T15 cells and 3 T3-L1 adipocyte respectively. Nonetheless, a significant hypoglycemic effect was observed from the in-vivo studies [59]. In-silico study reported that GC-MS identified compound (3-methylbenzofuran) from H. umbellate methanol seed extract exhibited strong binding energy to peroxisome proliferator-activated receptor gamma (PPAR-γ). Peroxisome proliferator-activated receptors are key regulators of glucose metabolism. Thus, compounds showing agonistic tendencies are being developed as anti-diabetic agents. With a good molecular docking score of this protein, 3-methylbenzofuran has a promising prospect as an anti-diabetic agent [49].

Anti-microbial property
Employing the agar well diffusion method, 50% aqueous leaf and seed extract in-significantly inhibited methicillin-resistant Staphylococcus aureus (MRSA) with zones of 10 mm and 6.30 mm respectively [34].  [35]. The activity index of the ethanol extract versus commercial antibiotics (nalidixic acid and ciprofloxacin), revealed the plant extract as a potential candidate against food pathogens [35]. Aqueous seed extract (25-200 mg/ml) exhibited a dosedependent anti-microbial activity against gram-positive (Staphylococcus aureus, Escherichia coli) gram-negative (Pseudomonas aeruginosa and Bacillus subtilis) bacteria [28]. The anti-fungi potential was also observed tandemly in Candida albicans, Penicillium notatum, and Aspergillus niger [28]. The highest bacteria inhibition zone of 22 mm at 200 mg/ml was detected for Bacillus subtilis and 19 mm for fungi (Candida albicans). Nonetheless, very low and insignificant inhibitory activities of the aqueous fruit pulp extract were observed against Staphylococcus aureus, Klebsiella pnuemoniae, Escherichia coli, and Psuedomonas aeruginosa [28]. The antagonistic effect of methanol stem and seed extracts (15-150 μg/ml) on two clinical bacteria isolates (Escherichia coli and Staphylococcus aureus) was determined by Chimechefulma et al. [53]. Minimum inhibition of both microorganisms by stem bark and leaves extract respectively was detected at 50 and 150 mg/ml. In a separate study, Ajala et al. [61] submitted that ikirydinium, an isolated alkaloid from the seed extract exhibited an IC 50 of (0.6 μg) against Bacillus subtilis ATCC 6051. Dismayingly, no significant inhibition was observed on the growth of Candida albicans (ATCC 90028), Escherichia coli ATCC 11775, Staphylococcus aureus ATCC 9144 and ATCC 25923, and Bacillus subtilis ATCC 6633.

Anti-inflammatory property
In a 9 weeks study, the palliative effect of the aqueous seed extract (100-400 mg/kg) against pro-inflammatory mediators expression was observed in a high fructose diet-induced metabolic syndrome model. Compared to the untreated groups, a significant reduction in the activity of tumor necrosis factor-α (13.72 ng/ml), interleukin-6 (4.03 ng/ml), and interleukin-8 (4.53 ng/ml) were observed at 400 mg/kg extract-treated groups [39]. The anti-inflammatory mechanism of action of aqueous fruit pulp extract was reported by [37]. The plant was hypothesized to block the release of inflammatory mediators such as prostaglandins and histamine. The extract at 250 mg/kg and 500 mg/kg attenuated xylene and carrageenan-induced ear and paw edema which compared favourably with dexamethasone and indomethacin [37]. A more effective (6.00 mm) ameliorative activity of the extract (500 mg/kg) on dextran induced paw edema which was significant (p < 0.01) to the control (7.6 mm) and stronger than diphenhydramine (6.5 mm), treated animals after 6 h was observed. However, an insignificant formalin-induced arthritis abating potential of the extract was noticed [37]. A notable reduction in formalin (0.2 ml of 2%), and carrageenan (0.1 ml of 0.5%) induced paw swelling was caused by administration of 50 mg/kg alkaloid and butanol fractions [36].

Analgesic and antipyretic property
Employing different experimental procedures, [38] evaluated the analgesic potential and activity of the seed (50-200 mg/kg) in aqueous extract pretreated rats. It was revealed that the treated rats had significant tolerance to cold (0-1°C) and hot water (55°C). The highest reduction (76%) in the rate of writhes in 200 mg/kg extract-treated mice in response to acetic acid injection was also noticed. Furthermore, a considerable decrease in formalin-induced biphasic nociceptive responses (frequency in paw licking and biting) in extract-treated rats was observed. The extract at the highest dose (200 mg/ kg) was significant to the un-treated group and compared favourably with aspirin (100 mg/kg) and morphine (10 mg/kg). Sixty minutes pretreatment with stem bark extract (150, 300, 600 mg/kg) significantly reduced the frequency of abdominal constriction in response to intraperitoneal administration of 0.6% acetic acid (10 ml/ kg) at all extract doses. The 150 mg/kg extract group demonstrated 68.2% inhibition which is higher than the acetylsalicylic acid (66.9%) treated group. An observable increased reaction time of the extract-treated groups to hot plate test was exhibited 300 and 600 mg/kg [33]. The percentage (79.9 and 72.3%) reduction paw licking interval in response formalin (to 20 μl of 1%) was highest at 150 mg/kg and 300 mg/kg respectively. The study thus suggests that the extract's antinociceptive action might be through modulation of the dopaminergic system [33]. Within 30 min of the experiment, the induction of writhes by acetic acid was significantly less pronounced in fruit pulp aqueous extract (250 and 500 mg/kg) and aspirin-treated mice relatively to normal saline-treated mice [68]. Fever reducing activity of the fruit pulp aqueous extract (250-500 mg/kg) was observed in E.coli induced pyrexia rabbits [28]. Relatively to aspirin, a statistically significant and reduced basal rectal temperature, 90 min post extract treatment was noticed [68].

Effect on weight
A significant dose-dependent weight-reducing effect was observed in rats pretreated with alkaloids fractions (25 and 50 mg/kg) of H. umbellate seed for 14 days before intraperitoneal triton WR-1339 (200 mg/kg i.p) exposure [40]. The lowest percentage weight increase of 12.08% and 15.85% was noticed in 50 and 25 mg/kg alkaloid fractions treated groups respectively, while triton only induced group showed the highest weight increase (21.42%). In another 14 days study, the impact of alkaloid fractions on weight increase was evaluated. The smallest but significant average body weight of 144 g amounting to a 10.45% increase was noticed in the 50 mg/kg treated group while the simvastatin (10 mg/kg) and 25 mg/kg alkaloid treated group of rats showed 13.47% and 16.67% weight increase respectively [40]. In the same period, the control group of animals on normal rat chow, without the extract or simvastatin exhibited a weight increase from 127.30 g -161.80 g equating to 27.12% [40]. As established by Adeneye et al. [42], a 60day study with 6 experimental groups revealed that the set of animals treated with 100, 200 and 400 mg/kg aqueous seed extract exhibited a dose-dependent weight reduction of 280 g, 279.20 g, and 243.70 g respectively vis-à-vis Vitamin C (20 mg/kg), distilled water (10 ml/ kg), clomiphene (0.3 mg/kg) treated groups with average body weights of 307.80 g, 290 g, and 315.30 g respectively. Ajiboye et al. [39] reported that abdominal circumference which was hitherto increased in rats on high fructose diet for 9 weeks was dose-dependently reduced after 3 weeks of administration of aqueous seed extract (100, 200, and 400 mg/kg). Respective mean abdominal sizes of 12.5 cm, 15 cm, 19 cm, and 27 cm were recorded in 400, 200, 100 mg/kg extract group and untreated rats respectively. A body mass index (BMI) of 0.9 g/cm 3 significantly higher than 0.65 g/cm 3 and 0.60 g/cm 3 of metformin and 400 mg/kg seed extract groups respectively was calculated in the high fructose diet animals [39]. Body mass index is the measure of body fat and risk of obesity based on weight (kg) to height (m 2 ) ratio. The low BMI of the extract-treated group thus implicates H. umbellate seed as a potential anti-obesity agent. Worth noting, an opposing effect on weight gain was also dosedependently demonstrated by all extract doses (100, 200, and 400 mg/kg) but the highest activity of 16% weight gain by the 400 mg/kg extract was statistically significant to the 65% weight gain observed in the untreated high fructose dieted animals [39]. Weight loss has been associated with alloxan-induced diabetes models in rats due to the loss of muscle adipose tissue protein and fatty acids [69][70][71]. This phenomenon was considerably ameliorated by 100 and 250 mg/kg methanol seed extract. A 150 g average weight documented in glibenclamide treated diabetic animals was similar to 170 g and 155 g mean weights that were recorded in 250 and 100 mg/kg extract treated groups. However, the above results were statistically significant and higher than 90 g average weight of the diabetic untreated animals [30]. Vis-à-vis the control animals, 28 days of oral consumption of aqueous seed extract showed that the animals on all extract dose exhibited lower weight increment [72]. In ascending order, 200, 400 and 800 mg/kg extract exhibited 5.30%, 6.25%, and 14% weight increase which were nonetheless lower than 16% documented for the control animals. However, no observable changes in the weight of the liver, kidney, spleen, and heart were noticed [72].

Anti-hyperlipidemic property
As observed by Adeneye and crooks [42], elevated levels of serum triacylglyceride (TG), total cholesterol (TC), low and very-low-density lipoprotein cholesterol (LDL-C and VLDL-C) in rats exposed to a single dose of 200 mg/kg triton WR-1339 (i.p) were considerably reduced by oral infusion of seed alkaloid fractions (25 and 25.00 mg/dl to 60.33 mg/dl after alkaloid therapy. Besides, a significantly reduced value for the predictor of cardiovascular disease such as atherogenic index (AI) and cardiovascular risk index (CRI) of 0.4 and 1.8 was observed in the alkaloids treated animals compared to 3.0 and 5.0 of hyperlipidemic untreated rats [40]. This development might be due to the increased activity of HDL-C which is referred to as good cholesterol. HDL-C is involved in reverse cholesterol transport from peripheral tissue to the liver, which can subsequently redistribute cholesterol to other tissues or excreted from the body by the gallbladder [73]. CCL 4 exposure has been implicated in the aetiology of dyslipidemia by triggering increased entry of acetate into liver cells, thereby leading to a rise in fatty acids and triglycerides production. Ogunlana [62]. As documented by Longe and Momoh [41], the methanol seed extract at 250 mg/ kg elicited stronger total cholesterol, plasma triacylglyceride, LDL-C reducing and a formidable HDL-C increasing activity than glibenclamide in alloxan exposed treated animals. The activity of the extract at all doses was significantly better than control (untreated animals).

Sexual, aphrodisiac and oxytocic property
H. umbellate has been reported to improve sexual activities and related enzyme markers in male rats [31]. The aqueous seed extract (50 and 100 mg/kg) administered orally for 28 days was observed to increase mounting prevalence, copulation, and intromission urge in the male rats. Moreover, a decrease in post-ejaculatory, climbing, and intromission latency was observed. These are relevant feelings, indexes, and a sense of sexual performance and gratification. Biochemical analysis revealed that the extract at 100 mg/kg elicited the highest decrease in arginase activity (0.22 μmol/min/mg protein) of the penile tissue homogenate in comparison with 0.39 and 0.58 observed in the viagra (5 mg/kg) treated and control animals respectively [31]. The 50 mg/kg extract dosage significantly (p < 0.05) reduced serum arginase activity (0.19 μmol/min/mg protein), which was lower than the 0.22 μmol/min/mg protein and 0.39 μmol/min/ mg protein exhibited by 100 mg/kg extract and sildenafil citrate (5 ml/kg) treated groups respectively. Conversely, penile nitric oxide activity was significantly raised by 50% in 100 mg/kg extract-treated animals relative to the control group [31]. Reduced arginase and increased nitric oxide play a vital biochemical role in initiating, maintaining an erection, and preventing erectile dysfunction [74]. Thus, the observed activity by the extracts hence validates the folkloric and ethno-medicinal usage as an aphrodisiac. In a bid to analyze the erectogenic potential of H. umbellate seed on popular enzymes implicated in male erectile dysfunction, phosphodiesterase 5 (PDE5), and arginase inhibitory activity of the aqueous seed extract was investigated [32]. It was disclosed that the extract in a dose (50-250 μg/ml) dependent manner inhibited these enzymes. The highest inhibitory activity of 23% and 78% of phosphodiesterase (IC 50 539.72 μg/ml) and arginase (IC 50 41.53 μg/ml) respectively was demonstrated by 250 μg/ml. In a 60-day study, Adeneye et al. [36] comprehensively evaluated the male fertility enhancing the ability of the aqueous extract (100-400 mg/kg) of the seed. Radioimmunoassay analysis revealed that serum testosterone activity of 4.70 ng/ml and 6.39 ng/ml exhibited by 200 and 400 mg/kg extract fed animals was significantly higher than 2.53 ng/ml and 2.59 ng/ml observed in control and Vitamin C treated animals. The same trend was discerned in the serum immuneradiometric assay of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [36]. Although clomiphene (0.3 mg/kg) had the strongest activity in upregulating the pro-fertility hormones in male rats, however, the 400 mg/kg extract-treated group manifested a higher LH and FSH activity of 1.42 ng/ml and 3.25 ng/ ml respectively, which was better than 0.64 ng/ml and 2.29 ng/ml in Vitamin C (20 mg/kg) and control animals. Conversely, the concentration of prolactin and estrogen which has been reported to interfere negatively with the function of the testicles, testosterone, and sperm production was significantly diminished by the extract at 400 mg/kg [36]. Compared to the control, the average weight of the testes was slightly bigger in the extract fed groups. A significantly (p < 0.05) improved gonadosomatic and sexual developmental indices (GSI) was reported in the quintessence groups. Also, analysis of semen showed that the most elevated sperm quantity (47.38 total sperm/g cauda epi × 10 7 ) and percentage sperm motility (87.17%) was found in the 400 mg/kg extract group. Juxtaposing with the control group value of 22.97%, significantly diminished dead sperm cells of 16.83% was exhibited at the highest concentration of extract treatment [36]. Corroborative, 7.67% of abnormal sperm cells found in the 400 mg/kg were statistically smaller than 10.86% and 14.03% displayed by ascorbic acid and clomiphene medicated groups respectively [36]. The oxytocic activity of the pulp extract (10 mg/kg) was assessed in the uterus of non-pregnant rats. As reported by [48], there was a 77.60% uterine contraction in response to the extract administration, and a subsequent significantly (p < 0.05) augmented and potentiated tonic response was noted when the extract was in synergy with oxytocin [48].

Toxicological property
The hepatoprotective activity of water extract of the seed was evaluated in-vivo against carbon tetrachloride (CCl 4 )(2 ml/kg i.p) induced toxicity in rats [35]. It was documented that the concentration of important liver toxicity biomarkers such as alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total protein was increased in CCl 4 induced untreated animals. However, 28 days of oral exposure of the rats to 500 mg/ kg of the extract significantly reduced the values of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein to 678 U/L, 42.40 U/L, 25.70 U/L and 6.88 (g/dl) respectively. The result suggests that the extract prevented haloakylation and lipid peroxidation of the liver tissue [35]. Short term toxicity study in rabbits depicts that, the seed alcohol and water extracts did not elicit liver toxicity [39]. This was inferred from the insignificant changes in the values of liver function markers viz. ALP, AST, ALT, total bilirubin, and conjugated bilirubin of the extracttreated animals [39]. The result of the tissue histology showed no observable distortion in the architectural integrity of the liver vis-à-vis the control group [41]. In another 21 days study, Ajiboye et al. [39] established that a near-normal liver histo-architecture was found in high fructose-induced metabolic syndrome rats, treated with aqueous seed extract (400 mg/kg). A full lustre appearance, sparkling eyes, and normal fecal droppings are the few physical parameters that corroborated the biochemical and physiological wellness of the extract fed animals [75]. Morphometric analysis and histology revealed that the aqueous seed and leaves extract (250 mg/kg) reversed streptozotocin-induced uneven distribution, distortion, vacuolation of pancreatic islet cell in rats [29]. Congruently, 14 days of oral pretreatment with 25 and 50 mg/kg alkaloid fraction of H. umbellate markedly improved the histological lesions of fatty hepatic degeneration induced by triton WR-1339 (200 mg/kg i.p) [71]. The possibility of the fruit pulp to elicit sub-acute toxicity was evaluated by Igbe et al. [37].  [72]. Further histological assessment of the kidney, liver, and lungs revealed a protective effect of 800 mg/kg extract on the tissues. The data from the study concluded that sub-acute administration of aqueous fruit pulp extract is nontoxic, and no observable changes in the values of hematological parameters such as hemoglobin, hematocrit, red blood cells, white blood cells, platelets, mean platelet volume, granulocytes count, monocytes/eosinophil, lymphocytes, mean corpuscular volume, mean corpuscular hemoglobin concentration, red cell distribution width was detected [37]. Nonetheless, Edosuyi et al. [33] observed an increased platelet aggregation, suggesting that prolonged usage of the aqueous stem bark extract might be a risk factor for thrombotic complications. In 28 days sub-acute toxicity study, the aqueous stem bark extract (150, 300, and 600 mg/kg) was observed to be toxic [33]. Histological examination revealed changes such as irregular glomeruli in the kidneys and the architectural configuration were not observed in control but seen in the heart, liver at 300 and 600 mg/kg water extract-treated animals. Alveolar hemorrhage and edema mild vascular congestion observed in the lungs and spleen respectively were not present in the control animals. A significantly increased creatinine value in 300 and 600 mg/kg extract exposed rat which was significantly greater than control animals is suggestive of damaged functioning nephrons [33]. Increased mean corpuscular hemoglobin, reduced lymphocyte and red blood cells observed in the study are characteristic of macrocytic anemia. The extract significantly increased the activity of aspartate aminotransferase at 300 and 600 mg/kg which corroborated the mild liver inflammation observed in the histopathology diagnosis [33]. Contrastingly, a 24-h acute toxicity study by Igbe et al. [28] established that no adverse effect on hematological parameters such as white blood cell count and hematocrit values or mortality was detected in all aqueous seed extract (10, 12.5, 15 and 17.5 g/kg) treated group. As reported by Longe et al. [30], extensive treatment of alloxan-induced diabetic rats with methanol seed extract (100 and 250 mg/kg), revealed that the extract at 100 mg/kg conferred a more potent hepatic protection in the diabetic rats. Comparatively, elevated values of AST, ALT, ALP, and total bilirubin were abrogated in the untreated animals from 15.60 U/L, 14.10 U/ L, 92.10 U/L, and 0.76 mg/dl to 10.10 U/L, 11.10 U/L, 78.10 U/L and 0.59 mg/dl in the treated rats [30]. As demonstrated Edosuyi et al. [67], 14 days acute toxicity examination of 1000, 2000, 4000, and 8000 mg/kg stem bark water extract showed zero mortality of the treated mice. Toxicity signs and allergic reactions such as convulsion, diarrhea, Curtis anserina, sedation, horripilation, increased urination, and tremors were not exhibited by any animals in the different dosage groups. Intraperitoneal administration of the aqueous seed extract was analyzed for acute toxicity using Weibull and Probit mathematical tests. The result suggests that the mean lethal dose of extract was 1660 mg/kg and 1614 mg/kg respectively for the two mathematical models [76]. Dismayingly, a very high mortality rate of 80 and 100% was observed at 1.8 and 2.0 g/kg extract-treated animals. Probit scores of 3.04, 5.25, 5.84, and 6.90 were recorded at 1.4 g/kg, 1.6 g/kg, 1.8 g/kg 2.0 g/kg extract dose respectively, indicating the slight toxicity of the extract considering the route of administration [76]. On the other hand, an acute oral toxicity study in Swiss albino mice showed no mortality after 24 h of exposure to aqueous seed extract (1, 5, 10, and 15 g/kg), and no signs of delayed toxicity were exhibited 2 weeks posttreatment [37].

Cytotoxic and anti-carcinogenic property
As reported by Engel et al. [43], H. umbellate methanol leave extract (10 g/ml) showed a 6% proliferative effect on breast cancer cell line BT-20. However, no in-vitro effect on breast cell line MCF-7, osteocarcinoma cell lines MG-63 and Saos-2 were demonstrated.

Anxiolytic and anti-angiogenic property
The efficacy of H. umbellate aqueous seed extract to reduce and relieve anxiety in rats using the open field and dark-light box tests was carried out by Adeneye et al. [42]. It was recorded that the animal given 100 mg/kg extract spent more time in the compartment and less time in the dark compartment which was significant (p < 0.05) than the control animals. Moreover, extracttreated animals showed more confidence by expressing less aversion for open spaces. The extract treated animals exhibited significantly (p < 0.05) enthusiastic, explorative, less anxious tendency by entering into more squares, and this was more significant than the control animals. Adeneye et al. [42] credited the observed antianxiogenic activity to phytochemical compounds contained in the plant extract.

Hematopoietic property
The potential of aqueous seed extract (50, 100, 200 mg/ kg) to improve hematological profile in rats was evaluated by Adeneye et al. [45]. In the 28 days study, 200 mg/kg extract-treated rats recorded the highest immuno-stimulatory and positive increase in some blood parameters. Significant (p < 0.05) increase in hemoglobin (Hb) (15.2 g/dl), pack cell volume (PCV) (47.9%), platelet count (764.30 × 10 3 μl), total leucocyte count (18.5 × 10 3 μl) and lymphocyte differential (90.6%) were noticed. Furthermore, it was observed that co-administration of cyclophosphamide (30 mg/kg i.p) and aqueous seed extract significantly increased red blood cell (RBC), Hb, PCV in rats. A non-significant increase in mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) was also noticed [45]. Cyclophosphamide is a known anti-cancer drug, albeit deleterious effect on proliferating tissues such as the bone marrow, thereby indirectly lowering the formation and division of blood cells [77,78]. Based on the elicited activity, it was concluded that the seed extract can be handy in preventing drug-induced anemia [45]. Corroborative, it was extrapolated from 14 days experiment by Longe and Momoh [44] and Longe et al. [41] that methanol seed extract exhibited significant hematopoietic effect by increasing RBC, PCV, and Hb values in diabetic rats.

Non-pharmacological activity
Alamneme et al. [81] extensively reported that sulfuric (H 2 SO 4 ) and hydrochloric acid (HCl) extracts (0.1-0.5% v/v) of H. umbellate seed husk inhibited steel rod (Fe = 98.3%, C = 0.133%, P = 0.0061%, Mn = 0.82%, Cr = 0.08%) corrosion. There was a significant reduction in the loss of the metal mass in presence of the extracts compared to the control. Moreover, scanning electron micrograph (SEM) and surface morphology observation indicated that mild steel immersed in the acid media in the absence of the extracts showed corrosion pits and a high degree of localized corrosion attack. Adsorption spectroscopy depicts that the amount of Fe 2+ dissolved in the electrolyte was inversely proportional to extract concentration. This further suggests that the mechanism of corrosion inhibition of H. umbellate was through adsorption of the extract molecules and formation of protective film on the metal surface, consequently leading to a reduction in the rate of metal dissolution. However, HCl extracts showed better activity than the H 2 SO 4 counterpart. Fourier transform infrared spectroscopy (FTIS) of the extracts and corrosion by-products showed the presence of oxygen and nitrogen atoms in the functional groups which mimic the structures and features of known anti-rust agents [82].

Clinical studies
There is a dearth of literature on clinical studies on the biological and pharmacological activity of morphological organs of H. umbellate. Notwithstanding, the antidiabetic efficacy of H. umbellate aqueous seed extract was observed in 5 patients with Type 1 diabetes mellitus. An average fasting blood sugar (FBS) of 180 mg/dl was recorded in the first week of the experiment. It was deduced that treatment with 1 oz. shot of the extract, twice per day for 21 days attenuated the average FBS to 88 mg/ dl in diabetic patients. The researchers inferred from the result that the extract is twice potent as metformin (500 mg) in the treatment of diabetes mellitus. Data interpretation from the study concluded that metformin cures diabetes mellitus in 8 weeks, while H. umbellate aqueous seed extract attains a more effective result in about 3 weeks. Biometric analysis of the study concluded that the extract was better than metformin by a factor of 2.67 [83].

Conclusion
From the review, it can be inferred that numerous and bioactive principles with known biological usefulness are present in the extracts of H. umbellate. There is no paucity of scientific information on the plant as seen from the arrays of documented and reported pharmacological activity elicited by the plant, which can be attributed to many of these active compounds acting singly or synergistically. Amongst the morphological organs, it was deduced that the aqueous extract of the seed is non-toxic, with potent and widest range of biological activities. On the other hand, the stem extracts were noted to be more toxic and caution should be taken in its consumption. Conclusively, more clinical research and studies should be carried out to explore the seed for its arrays of biological potential, especially the hypoglycemic activity. Authors' contributions OSO and OSF conceived the idea, OSF and PIA outlined the content, PIA and OSF searched the internet. AZA and OSF wrote the manuscript, OSF and DOA edited the manuscript. All authors read and approved the final manuscript for submission. All authors reviewed and approved the final manuscript.

Funding
No funding was received from any source.