A systematic analysis of the ethnopharmacological relevance of an Indian traditional plant, Hemidesmus indicus (L.) R.Br. for the past 10 years

Botany

The plant possesses several narrow, slender, and terete stems. The top, larger leaves are dark green without any lines, while the lower leaves are thinner and frequently have white lines on the upper surface [2]. Leaves are opposite to each other with smooth, shiny, and firm petiolate. According to their age, the leaves vary in their size and shape. The flowers are small greenish on the outer area and deep purple in the inner parts crowded as tiny dense clusters at the axillary cymes [7]. Fruits or follicles are cylindrical, paired, slender, and pointed. The seeds are white, coated with tiny silver hairs. The roots of H. indicus are thick and hard with very few branches of rootlets. The roots are aromatic, bitter, astringent, and anthelmintic. The roots are dark brown externally whereas yellowish at the center enclosed by a white cortical layer. The plant has a brownish bark with longitudinal fissures and transverse cracks at the cork [7,9].

Distribution

Hemidesmus indicus is native to India, primarily in South Asian countries such as India, Pakistan, Sri Lanka, Bangladesh, Maldives, Iran, and Moluccas [10]. The plant has been found mostly throughout India from the Indo-Gangetic plains, eastern parts up to Assam, and across Southern India in mesophytic and semidry environments. It grows in moistened deciduous woods, shrubs, and deteriorated areas with untamed soils. Usually, they are cultivated at an altitude of 600 m [11].

Phytochemistry

Different secondary metabolites such as flavonoids, saponins, triterpenoids, and glycosides, were reported from the different parts of H. indicus. The phytochemical investigations report the presence of 2-hydroxy-4-methoxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, hexa-tricostate acid, lupeol acetate, β-amyrin acetate, lupeol-1-octacosanol, flavonoids, steroids, saponins, terpenoids, lignins, phenolic compounds, tannins, cardiac glycosides, insulins, carbohydrates, and proteins, from the roots [12]. Hemidesmol, lupeol, linalyl acetate, dihydrocarvyl acetate, camphor, borneol, sitosterol, hexadecanoic acid, ledol, nerolidol, and drevogenin were also isolated from the roots. Hemidesmus indicus stem contains hemidescine, hemidine, emidine, indicasin, hemisine, hindicusine, medidesmine, demicine, di-O-acetylhindicusine (pregnane glycoside), indicine, denicunine, desinine, heminine (pregnane glycoside), 3-keto-lup-12-ene-21 28-olide (triterpene lactone), 12-dehydrolupeol acetate, hexadecanoic acid, vanillin, and isovanillin [13]. Its leaves and flowers contain tannins, phenolics, flavonoids, and flavonoid glycosides (isoquercetin, rutin, and hyperoside), respectively. Flavonoids play a variety of biological activities and also impart color and aroma to the flowers [14]. The phytoconstituents isolated from H. indicus are listed in Table 1.

Figure 1. Methodology adopted for the systematic analysis. [Click here to view]

Commercial formulations of H. indicus

Various extracts of H. indicus roots are used against leukemia, breast, hepatic, colon, and skin cancers in traditional medicine. They also benefit from epileptic fits, diarrhea, arthralgia, leprosy, and burning sensations. The leaves help to cure vomiting, wounds, and leukoderma [15]. Due to the extensive traditional use of H. indicus, the plant is a major ingredient in many traditional formulations including Ayurveda. About 46 Ayurvedic formulations contain H. indicus alone or in combination with other herbal ingredients. Dhanwamthara Taila, Pinda Taila, Amrithadi Enna, Gandha Taila, Triphaladi Taila, Neelidaladi Taila, Chandanadi Taila, Anuthaila, and Aswagandhadi Yamaka are some of the Ayurvedic topical preparations containing H. indicus. Banyan botanicals commercialize H. indicus products like the Anantmul root powder, herbal skin care tablets, Mahanarayan oil, and Kidney formula tablets. Apart from this, the root powder of H. indicus is marketed as a hair care product [9,16].

Anti-inflammatory activity

Inflammation is a natural defensive response of the body against injury or pathogen invasion. However, chronic inflammation leads to various disorders like cancer, diabetes, rheumatoid arthritis, cardiovascular diseases, etc. [17]. Hemidesmus indicus roots exhibit anti-inflammatory action in human leukemia monocytic cell lines (THP-cell lines). The anti-inflammatory property of the alcoholic and water extracts of H. indicus roots was evaluated on lipopolysaccharide/ phorbol 12-myristate 13-acetate (LPS/PMA)induced human monocytic cells. The remarkable suppression of pro-inflammatory markers interleukin-6, macrophage inflammatory protein-1, tumor necrosis factor-α (IL-6, MIP-1, TNF-α) was noticed [18].

Anti-diabetic activity

Diabetes mellitus is a common, chronic metabolic disorder that leads to the dysfunction of various organ systems such as kidneys, heart, eyes, and blood vessels. In many countries, traditional medicinal systems are used to manage diabetes mellitus as it is cost-effective and non-toxic [19]. Senadheera et al. [20] investigated the potential of rice-based herbal porridges containing H. indicus leaf extracts in streptozotocin (STZ)-induced diabetic Wistar rat models. The study showed a marked decrease in the glucose level in the test group animals within 3 months [20]. Another research study investigated the influence of methanolic H. indicus root extracts on cataracts (a secondary complication of diabetes) in rats, where diabetes was induced by STZ. The results indicated that the methanolic H. indicus root extracts extract remarkably inhibits the aldose reductase enzyme activity. Aldose reductase converts glucose to sorbitol using nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) causing osmotic stress and cataractogenesis in a dose-dependent manner [21]. β-amyrin palmitate extracted from H. indicus roots showed anti-diabetic activity at 50 μg/kg body weight compared to 500 μg/kg glibenclamide (anti-diabetic drug in clinical use) in alloxan-induced and STZ-induced diabetic Wistar rat models [22,23]. Siraj et al. [24] studied the impact of ethanolic H. indicus root extract on intestinal glucose absorption. The results showed that the 500 mg/kg root extract of the plant steadily decreased the gastrointestinal tract (GIT) absorption of glucose compared to the control. These findings strongly suggested that the ethanolic root extract has remarkable anti-diabetic activity [24].

Table 1. The table illustrates the phytoconstituents of H. indicus reported till date. [Click here to view]

Anti-oxidant activity

Oxidative stress has been identified as the primary cause of various chronic disorders. However, increasing the endogenous antioxidant potential of the body limit the consequences of reactive oxygen species-induced oxidative damage. Since ancient times, herbal plants have been valued as good antioxidants. Hemidesmus indicus is used traditionally for several chronic diseases based on its antioxidant potential. Different extracts (hexane, ethyl acetate, and ethanol) of H. indicus root were used to determine the antioxidant activity using the 2,2-diphenylpicryl hydrazyl (DPPH) method. The hexane (IC₅₀ 14.53 g/ml), ethyl acetate (IC₅₀ 6.793 g/ml), and ethanolic (IC₅₀ 6.510 g/ml) extracts of the plant exhibited strong scavenging activity as compared to that of standard butylated hydroxytoluene (IC₅₀ 7.621 g/ml) [1,25]. The antioxidant properties of H. indicus crude extracts were evaluated using the phosphomolybdenum method. The antioxidant capacity was calculated as ascorbic acid equivalents. The IC₅₀ value of H. indicus was obtained as 190.09 g/ml compared to ascorbic acid (IC₅₀ values 18.80 g/ml) [26]. Kaffoor et al. [27] compared the antioxidant capability of various extracts of H. indicus (methanol, chloroform, petroleum ether, and water) root in which the methanol and aqueous extracts showed better antioxidant activity with IC₅₀ values of 51.92 ± 11.19 and 70.10 ± 8.28 μg/ml, respectively [27].

Anticancer activity

Cancer is a chronic disease marked by the spread of abnormally growing cells to different body parts. According to GLOBOCAN reports, mortality due to cancer will increase from 9.96 to 1.63 million by 2040 [28]. Natural products possess an excellent capacity to prevent the spread or risk of acquiring various forms of cancer. Hemidesmus indicus also possess efficient anticancer potential which is validated through various preclinical studies. The anticancer potentials of ethanolic H. indicus root extracts on hepatoblastoma cell lines (HepG2 cell lines) were compared with Vero cell lines. The cytotoxicity study results indicated that the maximal cell death of HepG2 cells with the extracts was 72.110% ± 004% at 160 g/ml concentration. The IC₅₀ of the root extract of the plant was 65.58 g/ml. The maximal cell death of Vero cells with root extracts was found to be 20.690% ± 003% at 160 g/ml concentrations, and the IC₅₀ was found to be 386.66 g/ml. The microscopic observations revealed the H. indicus extract exhibited significant anti-tumor activity against HepG2 cells [29].

Another in vitro study showed that rhizomes of H. indicus exhibit cytotoxic effects on the HT-29 colon cancer cell lines. Similarly, the methanolic extract of H. indicus significantly exhibit cytotoxicity to Ehrlich ascites tumor (EAT) at the IC₅₀ of 274.83 μg [1]. Another study indicated that the decoction of the roots of H. indicus exhibits chemopreventive effects against HL-60 (Human promyelocytic leukemia) cell lines. Hemidesmus indicus decoction inhibited the G0/G1 phase of the cell cycle, thus altering the cell cycle progression. Moreover, it increased the differentiation of the cancer cells [30]. Another research study examined the chemopreventive efficacy of the hydro-alcoholic root extract of H. indicus on the acute lymphoblastic leukemia cell line. The phytochemical analysis of the extract revealed the presence of 2-hydroxy-4-methoxybenzaldehyde (2H4MB), 2-hydroxy-4-methoxybenzoic acid (2H4MBA), and 3-hydroxy-4-methoxybenzaldehyde (3H4MB) as bioactive compounds. The extract induced apoptosis in a dose-dependent manner. It was also analyzed for its anti-tumor action on DLD1 cells (colorectal adenocarcinoma cells). The extract showed a cytostatic effect on the cells by inhibiting the G2/M phase (growth 2/mitosis) of the cell cycle [31].

Anti-venom activity

Snake bites are considered a major health concern in India that causes mortality. The only effective treatment available for snake bites is antivenom. However, the use of antivenom has been hampered by several drawbacks, such as allergic reactions, high cost, and scarcity, which makes it challenging. Since ancient times, H. indicus was shown to be highly effective at neutralizing snake bite venom. An ethnobotanical study of traditional herbs used to treat snakebites in southern Tamil Nadu, India exhibited the effective potential of Sariva as an antivenom. It is revealed that 2-hydroxy-4-methoxybenzoic acid isolated from H. indicus suppressed the free radical production brought on by viper venom-induced inflammation and antagonized fatal, hemorrhagic and coagulant action in experimental rodents [16].

Another study investigating the anti-venom property of “lupeol acetate,” a component isolated from the roots of Sariva neutralizes the venom of Daboiarussellii and Najakaouthia. The results indicate that lupeol acetate significantly inhibits the lethality, bleeding, defibrinogenation, and edema brought on by Daboiarussellii venom [32]. Additionally, it reversed the cardiotoxicity, neurotoxicity, and respiratory problems that Najakaouthia venom caused in Swiss albino mice [7,33,34]. The mortality caused by viper venom (Viperarussellii) and hemorrhage in albino rats and mice were significantly neutralized by the methanolic extract of H. indicus [8]. Another research study established the anti-scorpion venom property of an aromatic compound isolated from methanolic H. indicus root extracts in Swiss albino mice and Wistar albino rats. The antivenom activity was assessed by various tests like qualitative analysis of urine, levels of alanine transaminase and aspartate transaminase (hepatotoxicity markers), urea and creatinine (renal toxicity markers), creatine phosphokinase and lactic dehydrogenase (myotoxic markers) and oxidative stress markers lipid peroxidation (LPO), glutathione peroxidase, glutathione. The results indicated that the compound isolated from H. indicus exhibits significant antioxidant potential [35].

Anti-hyperlipidemic activity

Hyperlipidemia is a chronic condition caused by aberrant lipid metabolism which leads to various diseases such as diabetes, obesity, atherosclerosis, hypertension, and coronary heart disease. Low-density lipoprotein (LDL), total cholesterol, and triglycerides are higher in the blood indicating hyperlipidemia. A research study investigating the protective effect of H. indicus root extracts in Wistar rats indicated that methanolic root extract produced significant dose-dependent protection against oxidative stress-induced through a high-fat diet. Significant differences in the levels of triglycerides, phospholipids, free cholesterol, total cholesterol, ester cholesterol, atherogenic index, and the body weight of the treatment group and the control group animals were observed. Moreover, intake of H. indicus extracts protected the rats from fat-induced hepatic damage [36,37]. Choudhury et al. [18] investigated the anti-hyperlipidemic property of alcoholic and aqueous extracts of H. indicus roots in Wistar rats. The extracts administered at 200 mg/kg bw/day showed that serum lipid markers induced by high-fat diet consumption (total triglycerides, LDL, and total cholesterol) are reduced significantly. Moreover, the treatment with extracts of H. indicus roots maintained a healthy level of High density lipoprotein (HDL) in the test group [18].

Anti-ulcer activity

An ulcer is caused by the imbalanced production of digestive juices and the protective elements of the stomach lining. Anti-ulcer medications work by inhibiting the generation of stomach acid, neutralizing the acid, or protecting the gastrointestinal mucosa from damage. One of the research studies investigated the potential of ethanolic extract of H. indicus (whole plant) against ulcers (induced by indomethacin) in Wistar rats. The results indicated that oral consumption of the extracts (at 200 and 400 mg/kg) exhibited remarkable antiulcer activity by strengthening the gastric mucosa [38]. Another research study compared the potential of the aqueous root extracts (500 mg/kg) and alcohol root extracts (100 mg/kg) of H. indicus in protecting the gastrointestinal mucosa of indomethacin-induced peptic ulcers in Wister Albino rats. The results showed an efficient ulcer healing action for alcohol root extracts than aqueous extracts [39].

Another study revealed that the ulcer index significantly decreased with the alcoholic extract of H. indicus roots at doses, 200 and 400 mg/kg in Wistar rats with indomethacin-induced gastric ulcers. Omeprazole 20 mg/kg provided ulcer protection of 78.91%, whereas H. indicus root extract offered 73.59% and 76.82% protection, at 200 and 400 mg/kg, respectively [8,40]. Anti-ulcerogenic property of ethanolic H. indicus root extract was investigated in pyloric ligated Wistar rats. The aqueous ethanolic extract of the H. indicus roots decreased the destructive factors such as pepsin and proteins whereas subsequently increased the defensive factors of pH, hexosamine, fucose, hexose, and sialic acid. The results showed an increased carbohydrate-to-protein ratio, indicating high mucin action [41].

Hepatoprotective activity

The liver, the most essential organ in the body, is responsible for many physiological processes like metabolism and detoxification. Hepatic disorders are a major concern to public health worldwide. Despite the advancements in modern medicine, there are still no specific therapeutic agents to enhance hepatic function, protect the whole organ, or support liver cell regeneration [42]. Das et al. [5] reported that ethanolic extract of H. indicus roots (100 mg/kg, for 15 days) administered orally prevented isoniazid (INH) and rifampicin (RMP) induced hepatotoxicity in Wistar rats. The results showed that in comparison to control rats, INH and RMP-intoxicated rats possessed significantly lesser levels of the mitochondrial protein in the liver, iso-citrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, α-ketoglutarate dehydrogenase, NADH dehydrogenase, and cytochrome c oxidase. The antiperoxidative enzymes chloramphenicol acetyltransferase and superoxide dismutases exhibited a considerable decline in activity after intraperitoneal treatment of INH and RMP, which also caused an inclination in LPO in the mitochondria [5].

Table 2. The table summarizes the in-vitro studies of H. indicus reported over the past 10 years. [Click here to view]

Hydroalcoholic extract of H. indicus roots (400 mg/kg, orally) was effective against carbon tetrachloride (CCl₄)-induced liver damage. In a similar study, methanolic extract of the roots of H. indicus showed hepatoprotective activity against CCl₄-induced liver damage. The oral administration of the extract rats significantly reduced the elevated levels of serum glutamate pyruvate transaminase, alkaline phosphatase, glutamate oxaloacetate transaminase, and bilirubin [5,34]. In another research study, the influence of ethanolic H. indicus extract and 2-hydroxy 4-methoxy benzoic acid (HMBA) against liver fibrosis was evaluated in ethanol-fed rats. The extract and the compound remarkably reduced LPO and the levels of hepatic collagen and hydroxyproline content. It was also noticed that the ascorbic acid level and the solubility of hepatic collagen were increased in the treatment group. The levels of matrix metalloproteinases (MMP-2 and MMP-9) relevant during the extracellular matrix degradation on ethanol intoxication were found to be less in the extract and HMBA-treated group [34,43].

Anti-microbial activity

“Microbial infections” is a collective term for the infections caused by bacteria, parasites, viruses fungi, etc. The infectious agents invade an organism, grow, and are confronted by the host tissue leading to microbial infection [44]. Phytochemicals are reported to be effective antimicrobials with negligible toxicity. Aqueous extracts of the H. indicus roots (0.04–0.1 mg) exhibited anti-microbial activity against Staphylococcus aureus, Klebsila pneumonia, and Pseudomonas aeruginosa [5]. Hemidesmus indicus roots extracted using methanol were formulated as an ointment to check its wound-healing activity in Wistar rats. The herbal formulation exhibited remarkable wound healing action by promoting the proliferation of the cells, stimulating granulation tissue formation, and enhancing the healing index [45]. Another study investigated the effects of various solvent fractions of the roots of H. indicus (methanol, chloroform, petroleum benzene, acetone) against some of the uropathogenic bacteria, including S. aureus, Escherichia coli, and Enterococcus faecalis. Among these strains, S. aureus is a multi-drug resistant strain. The results indicate the effectiveness of the methanolic extract of H. indicus roots for the treatment of urinary tract infections [46].

Table 3. The table illustrates the summary of in-vivo studies of H. indicus reported in the last 10 years. [Click here to view]

Another research study investigated the anti-microbial efficacy of hexane, ethanol, and ethyl acetate extracts of H. indicus roots by disk diffusion method against Bacillus megaterium, P. aeruginosa, S. aureus, and K. pneumonia. It was observed that in the extract-treated group, there was a marked decrease in the bacterial load [25]. Saritha et al. [47] studied the efficacy of ethanolic extract of H. indicus against E. coli. The extract showed its activity through cellular content leakage, inner membrane permeabilization, blebbing, and membrane potential disruption [47]. Purohit and Bais [48] studied the anti-bacterial activity of ethanol and aqueous extracts of H. indicus roots against E. coli, Bacillus subtilis, S. aureus, and P. aeruginosa compared to those of the standard drug, ciprofloxacin. The results showed that the ethanol extract was highly efficient against Gram-positive bacteria (E. coli and B. subtilis) whereas moderately active against Gram-negative (P. aeruginosa and S. aureus). The aqueous extract was comparatively efficient against B. subtilis and S. aureus whereas moderately efficient against P. aeruginosa and E. coli [48].