INTRODUCTION:

A wide variety of medicinal plants possessing wound healing property contain compounds from the saponins class. Saponins are high molecular weight compounds having triterpenoid or steroidal aglycone. The glycone part of saponins consists of several oligosaccharide chain having glucose, galactose, rhamnose and even pentose sugars like arabinose, xylose etc.¹

Oleanolic acid (3β-hydroxy-olea-12-en-28-oic acid) is a compound which occurs widely in medicinal plants as aglycones in pentacyclic triterpenoid saponins. Saponins are highly bioactive compounds possess number of medicinal properties. The wide spectrum of saponins bioactivity includes antiinflammatory, antibacterial, antifungal, antidiabetic and anticancer properties.² It was observed that number of traditional herbs reported with wound healing activity contain saponins having oleanolic acid as aglycone. Apamarg, Jayanti-veda, Tulsi, Ginseng, Olives etc., are the examples of such plants containing oleanolic acid and its structural isomer namely ursolic acid. Earlier reviews on phytoconstituents of wound healing herbs have enlightened the common occurrence of tannins and flavonoids. But saponins were also found to be significant constituents in traditional wound healing herbs. Saponins have multidimensional activity like antibacterial, antiinflammatory and immunomodulatory which are all beneficial in process of wound healing. Hence the present review is an approach in emphasizing the occurrence of pentacyclic triterpenoid saponins specially containing oleanolic acid as aglycone in wound healing herbal drugs.³

Pentacyclic Triterpenoid Saponins:

Saponins constitute a vast group of glycosides which are ubiquitous in plants. They are characterized by their surface-active properties. They dissolve in water to form foamy solution. Most of the saponins have haemolytic activity and toxic to cold blooded animals especially for fish. Structurally saponins may be classified in to two groups based on the nature of their aglycones. Steroidal saponins (C27) have cyclopentanophenanthrene ring and triterpenoid saponins (C30) having pentacyclic ring. The majority of triterpenoids arise from the cyclization of (3S)-2, 3-epoxy-2, 3-dihydro-squalene. Triterpenoid sapogenins are most common in fact pentacyclic compounds found as oleananes (β-amyrin derivatives), ursanes (α-amyrin derivatives) and lupanes. Saponins are widespread among higher plants of families like Fabaceae, Asparagaceae, Aralicaeae, Cucurbitaceae, Oleaceae etc.⁴

Oleanolic Acid:

A natural compound oleanolic acid (3β-hydroxyolean-12-en-28-oic acid) is a biologically active pentacyclic triterpenoid compound that has been isolated from more than 1600 plant species, including many food and medicinal plants. The compound is especially prevalent in plants belonging to the family Oleaceae. Oleanolic acid is often present in combination with its structural isomer namely ursolic acid (3β-hydroxyurs-12-en-28-oic acid). Unconjugated triterpenoids such as free oleanolic acid are found in epicuticular tissue of the plants, serving as a first line defence barrier against pathogens. Researchers reported that oleanolic acid found in higher concentration in fruit peel as compared with the pulp. The most important source of oleanolic acid is Olives from which the compound derives its name.⁵

Process of Wound Healing:

Wound healing is essential for restoring the integrity of damaged tissues which involves four phases i.e., Haemostasis phase, Inflammation phase, Proliferation phase and Remodelling phase. The Haemostasis phase involves constriction of blood vessels to minimize the blood loss. Platelets adhere to the injury site then activate and release signalling molecules which promote platelet aggregation and vasoconstriction leading to the conversion of fibrinogen to fibrin which forms a stable clot.⁶

Inflammation phase is crucial during the process of wound healing for preventing infection. Inflammatory mediators cause vasodilatation and increase vascular permeability thereby favouring the defence mechanism. Body produces prostaglandins (PGE) from a fatty acid called arachidonic acid at the site of tissue damage or infection. Prostaglandins are hormone like properties trigger the inflammatory response, causing blood vessels to leak fluid into the tissue leads to swelling. They also attract white blood cells called phagocytes that engulf microbes and debris at the damage site. Prostaglandins are able to modulate the nuclear factor kappa B (NF-kB) which is further involved in increase of proinflammatory cytokines. The cytokines elevated are tumor necrosis factor-α (TNF-α), interleukins (IL)-1β, IL-6 and acute phase proteins namely C-reactive protein (CRP). Immune cells, neutrophils and macrophages perform phagocytosis to clear debris. They secrete growth factors and cytokines; this orchestrates the proliferation phase by promoting cell migration.

Proliferation phase involves formation of new tissue to replace the damage. Fibroblasts are recruited to the wound site and begin to proliferate. They synthesize and secret certain molecules like collagen for forming new extracellular matrix. New blood vessels are formed from pre-existing cells where vascular endothelial growth factor helps in stimulating endothelial cells to form new capillaries for supply of oxygen and nutrients. Granulation tissue fills the wound bed which is essential for regeneration.

Remodelling occurs by maturation and reorganization of newly formed tissues. Collagen fibers deposited during the proliferation phase are reoriented, cross linked, aliened to increase tensile strength. Matrix metalloproteinase helps in reorganization of tissue. Excess cells undergo apoptosis and tissue regains its normal architecture.⁷

Therapeutic potential of saponins in wound healing

Saponins have been reported for number of medicinal properties which include antiinflammatory, antibacterial, antifungal, immunomodulatory, antidiabetic, cardioprotective, neuroprotective and antitumor activities. The potential therapeutic effect especially antimicrobial, antiinflammatory, immunomodulatory and rejuvenation of saponins are more prevalent in the process of wound healing.⁸

Antibacterial:

Many saponins have inhibitory effect on both gram-positive and gram-negative organisms. They are effective against the most causative organisms associated with wound infections that include Staphylococcus aureus, S. pyogenes, Pseudomonas aeruginosa, Clostridium botulinum, Listeria monocytogene, Bacillus subtilis, Escherichia coli etc. Saponins are able to modulate the microbial growth in natural and artificial fermenters. They are able to show a synergistic effect with antibiotics such as tetracycline, erythromycin, ciprofloxacin, which sometimes considered ineffective due to the resistance of pathogens. The antibacterial mechanism of action of saponins is generally related to the disruption of cell wall and membrane proteins of microorganisms.⁹

Antifungal:

Minor wound or cuts that come in contact with fungus enriched soil and plant matter can lead to severe infections. Dermatophytes are the fungi that need keratin for their growth. Therefore, when a fungus cell invades the skin, it produces keratinase an enzyme that feeds on the skin layer keratin due to which keratin tissue degradation occurs and causes skin inflammation. The most common fungi are Candida albicans, Trichophyton rubrum, T. violaceum, Microsporum distortum, M. fulvum, M. Gypseum, Aspergillus niger, that affect the dermal tissue. When recent scenario regarding fungal diseases and antifungal drugs are taken into consideration it has been noted that the development of resistance of fungus towards presently used synthetic antifungal drugs has increased. Plants enriched with terpenoids and saponins like Rubia tinctorum, Tithonia diversifolia, Zingiber officinale, Olinia ventosa, Bucida buceras (black olive tree) are characterized by promising antifungal activity.¹⁰

Antiinflammatory:

Inflammation is a major reactive defence mechanism in the battle against infective agents like microbes. Saponins exhibit their antiinflammatory effect by inhibiting Cyclooxygenase-2 (COX-2), thus reducing the synthesis of prostaglandins specially PGE2. Saponins were found to be inhibitory effect on inflammatory mediators such as cytokines, IL-1β, IL-6 and down regulating NF-kB. This process reduces the cardinal signs of inflammation like redness, oedema and pain. The herbs like Glycyrrhiza glabra, Panax ginseng, Olea europaea etc., are rich in saponins have wonderful antiinflammatory activity by the above stated mechanism of actions.³

Immunomodulatory:

Research has shown that saponins can augment the phagocytic activity of macrophages and cytotoxicity of natural killer cells, thereby modulating the innate immune responses. Furthermore, saponins can enhance the antigen-presenting capacity of dendritic cells, activates various subsets of T-lymphocytes, induce B-lymphocytes to differentiate into plasma cells and stimulate the production of specific antibodies. These effects collectively contribute to the reinforcement of adaptive immune response. In conclusion, plant saponins possess immunomodulatory activity and can regulate the immune functions of the body through different pathways.^11,12

Rejuvenation:

The final stage of wound healing involves the reconstruction of granulation tissue and its maturation into a connective tissue. Remodelling process consists of the proper deposition of collagen fibers. A series of key events in the process of wound healing is the effective differentiation of fibroblasts and myofibroblasts. Triterpenoid saponins are renowned for their ability to rejuvenate the skin. Saponins can promote vascular regeneration and shorten the wound healing time.

Disadvantages of saponins such as varying degrees of haemolysis, cytotoxicity, poor solubility of triterpenoid aglycones need to take precaution in therapeutic use of saponins. Even the tissue irritations greatly limit the clinical use of saponins.¹³

Figure 1: Wound Healing Herbal Drugs Containing Triterpenoid Saponins:

1) Dronapushpi:

Dronapushpi scientifically known as Leucas aspera Spreng. of Lamiaceae family is found as a weed throughout the country. Traditionally it is named as Dronapushpi. The leaves of L. aspera contain significant bioactive components. Studies revealed the presence of various phytochemical constituents mainly triterpenoids, oleanolic acid, ursolic acid and β-sitosterol, diterpenes and phenolics compounds in the plant. Even it contains alkaloids, tannins and flavonoids as minor constituents. Traditionally the plant is used as an antiseptic and insecticide. Methanolic extract of the leaves showed inhibitory effect on bacterial strains like Staphylococcus aureus, Salmonella typhi, Pseudomonas pyocya etc., and fungi.¹⁴ Leaves are used to treat psoriasis and other chronic skin eruptions. The whole plant is used to cure many human ailments. Antiinflammatory activity of the herb is mainly due to the inhibition of prostaglandins i.e., PEG-1 and PEG-2. In process of wound healing, it reduces the scar area, increase in collagen deposition and more fibroblasts.¹⁵

2) Apamarg:

Achyranthes aspera Linn. commonly called prickly chaff flower in English is found throughout India, tropical Asian countries and other parts of the world. Certain Ayurvedic and Unani practitioners use various parts of this plant to treat wound, insect bites, skin disorders and parasitic infections etc.¹⁶ This plant has been reported to treat microbial infections and low blood sugar level also. The herb possesses significant antiinflammatory, analgesic, antipyretic and antispasmodic activity in various animal models. Phytochemical research on A. aspera revealed the presence of alkaloids, saponins containing pentacyclic triterpenoid compounds namely ursolic acid as aglycone. Phytosterols were also reported from various parts of this plant¹⁷. Antiinflammatory activity of A. aspera has shown to suppress the release of various inflammatory mediators in both early and late phases of inflammation. However, the ethanolic fraction decreased the release of inflammatory mediators in early phase but effects on chronic inflammation were not satisfactory. It has been reported with potential wound healing activity. Improvement in protein profile of granulation tissue of diabetic wounds was observed when treated with the ointment of A. Aspera extract.¹⁸

3) Olives:

The Mediterranean diet is associated with a lower incidence of chronic degenerative diseases and higher life expectancy. These health benefits are due to the dietary consumption of virgin olive oil. Olives are small fruits that grow on olive trees scientifically known as Olea europaea Linn. belonging to the family Oleaceae. Olive oil has strong antiinflammatory properties. Oil is rich in polyunsaturated fatty acids along with oleanolic acid. It also contains antioxidants like vitamin E and phenolic compounds. The mechanism of antiinflammatory effects has been attributed by the inhibition of histamine release from mast cells followed by inhibition of both lipooxygenase and cyclooxygenase enzyme activity. Overall, the oil reduces the inflammatory factors produced during arachidonic acid cascade in process of inflammation. The synthesis and release of prostaglandins and leukotriene were suppressed.¹⁹

4) Jayanti-veda:

Tridax procumbens, commonly known as coat buttons is a species of flowering plant in the family Asteraceae. It is best known as a widespread weed and pest plant. The plant is usually found in tropical, sub-tropical and mild temperate regions around the world²⁰. In Ayurveda it is used in treatment for boils, cuts, blisters and wounds. The drug has well reported antifungal and insect repellent activity. The leaves and other parts of T. procumbens are reported to have flavonoids, alkaloids, carotenoids, hydroxycinnamates, lignans, benzoic acid derivatives, phytosterols and tannins. Pentacyclic triterpenoid compound i.e., oleanolic acid has been reported in significant concentration in this plant. Flower extract of the plant contains flavonoids namely quercetin and isoquercetin. Traditionally the juice from the leaves has been used for healing dermal wounds. The aqueous and ethanolic extracts of T. procumbens increase the tensile strength of dermal tissue in wound healing. Further wound healing biomarkers such as hydroxyl-proline, collagen and hexosamine were also increased. The leaf extract improved cell proliferation and wound remodelling.²¹

5) Brahmi:

In Indian system of medicine Bacopa monnieri is known as Jala Brahmi belonging to the family Scrophulariaceae. The isolated saponin namely bacoside-A showed a significant wound healing activity on excision, incision and dead space wound healing models in Swiss albino rats. Brahmi inhibits the release of inflammatory cytokines, TNF-α, IL-6 and also inhibits the activity of enzymes associated with inflammation. In Ayurveda where it is recognized as medhya rasayana a botanical entity believed to enhance intellect and mental abilities. Research findings showed the immunomodulatory role of Brahmi in augmenting the action of T-helper 1 cells which in turn activates cytotoxic T-lymphocytes. Brahmi has potential antimicrobial activity against clinical isolates of multi-drug resistant bacterial strains. Varieties of microorganisms including S. aureus, Pseudomonas aeruginosa, P. Mirabilis, E. coli, were inhibited by the extracts of Brahmi. Major constituents of Brahmi are saponins namely bacosides, saponins containing pentacyclic terpenoid aglycones namely betulinic acid and brahmic acid. The herb is also a rich source of flavonoids like apigenin found to be a rejuvenator of damaged tissues.²²

Figure 3: Images of medicinal plants.

6) Mandukaparni:

It consists of the dried aerial parts preferably the leaves of Centella asiatica belonging to the family Apiaceae. The extract showed significant wound healing process in both incision and burn wounds by inhibiting inflammation, inducing collagen synthesis, inducing vasodilation and promoting angiogenesis. Histological examinations of the granuloma tissue showed the increased cross-linking of collagen fibers. Traditionally leaves have antiinflammatory properties and used to treat skin problems like eczema and psoriasis. The leaves of C. asiatica are thought to have pain-relieving qualities. The chief constituents are pentacyclic triterpenoid saponins viz., madecassoside and asiaticoside and their aglycones namely madecassic acid and asiatic acid respectively. Other triterpenic acids namely betulinic acid, brahmic acid, centoic acid etc., were also found in C. asiatica. Flavonoids and alkaloids are the minor constituents present in the herb Mandukaparni.^6,23

7) Myrobalan

Terminalia chebula Retzius., commonly known as myrobalan is a species of Terminalia, belonging to the family combretaceae. The plant is native to south Asia from India to Nepal to south-west China, Malaysia and Vietnam. In Ayurvedic Materia Medica, Myrobalan is mentioned as king of medicines. Its leaves and fruits have been employed to improve the process of wound healing. It has been reported that the drug possess wound healing property by improving the rate of contraction of dermal tissue during healing. The main chemical constituents are tannins, phenolic acids, triterpenoid saponins, flavonoids and volatile oils. The drug has significant inhibitory effect on COX-2 which is a key enzyme in process of inflammation. It is hypothesized that the presence of gallic acid and tannic acid in the drug were also found to be significant in wound healing ^24.

8) Yastimadhu:

Yastimadhu scientifically named as Glycyrrhiza glabra is the most popular medicinal plant belonging to Fabaceae family. It is commonly known as liquorice. It is a perennial herb, occurs widely in Asia but now cultivated worldwide. The chemical composition of G. glabra are triterpenoid saponins namely glycyrrhizin, glabranin, isoglabrolide; flavonoids viz., liquiritin, isoliquiritin and their derivatives, coumarins, triterpene sterols etc. Extract of the drug has been reported for several pharmacological activities. Potential activities of the drug reported are expectorant, antiinflammatory and antiulcer. Roots and stolons are the most important medicinal parts used in liquorice. Glycyrrhizin, the main active component of G. glabra has shown potential antiviral efficiency, as viral cell binding was inhibited. Glycyrrhizin is also used in reducing the cardinal signs of inflammation i.e., redness, irritation, swelling in skin conditions like atopic dermatitis and eczema. It enhances fibroblast proliferation, granulation tissue formation and collagen deposition in cutaneous wound healing.²⁵

9) Holy Basil:

Ocimum sanctum is native throughout the world tropics and widely cultivating for its medicinal use. Commonly it is called as tulsi, an erect much branched shrub belonging to the family of Lamiaceae. The main chemical constituents present in Holy Basil are volatile oil containing eugenol, carvacrol, β-caryophyllene, followed by flavonoids, saponins with oleanolic acid or ursolic acid as aglycones. The leaf extract of O. Sanctum by disc diffusion method showed a wide range of antibacterial activity against both gram positive and gram-negative bacterial pathogens. Total phenolic content estimated in stem and leaf extracts, the leaf extract showed significant biological activity compared to stem extract. The aqueous extract of O. Sanctum exhibited antiinflammatory activity in various animal models. Oleanolic acid present in the plant has ability to block cyclooxygenase and lipooxygenase pathways of arachidonic acid metabolism, showing antiinflammatory activity against prostaglandins.²⁶

Table 1: Wound Healing Plants Containing Oleanolic Acid and Related Pentacyclic Triterpenoid Saponins

S. No	Name of the Plant	Family	Parts used	Phytoconstituents of interest
1	Leucas aspera Spreng.	Lamiaceace	leaves and areial parts	saponins, oleanolic acid, ursolic acid
2	Achyranthes aspera Linn.	Amaranthaceae	leaves and roots	saponins, ursolic acid
3	Olea europaea Linn.	Oleaceace	fruits	saponins, oleanolic acid
4	Tridax procumbens Linn.	Asteraceae	leaves	saponins, oleanolic acid, quercetin
5	Bacopa monnieri Linn.	Scrophulariaceae	leaves	saponins, betulinic acid, brahmic acid
6	Centella asiatica Linn.	Apiaceae	leaves	saponins, madecassoside, asiaticoside
7	Terminalia chebula Retzuis.	Combretaceae	leaves and fruits	saponins, tannins
8	Glycyrrhiza glabra Linn.	Fabaceae	roots and stolons	saponins, glycyrrhizin, flavonoids
9	Ocimum sanctum Linn.	Lamiaceae	leaves	saponins, oleanolic acid, ursolic acid
10	Nerium oleander Linn.	Apocynaceae	leaves and flowers	saponins, oleanolic acid
11	Calendula officinalis Linn.	Asteraceae	Flowers	saponins, oleanolic acid
12	Spindus trifoliatus Linn.	Sapindaceae	fruits	saponins, tannins
13	Panax ginseng Linn.	Araliaceae	roots	saponins, oleanolic acid

10) Oleander:

Nerium oleander of Apocynaceae family commonly known as rosebay is a shrub cultivated worldwide in temperate and subtropical areas. The leaves and flower extract of N. oleander contain active compounds such as tannins, flavonoids, triterpenes, Saponins, coumarins, sterols and alkaloids which are known to exhibit medicinal properties. The important pharmacological activities are antifungal, antiinflammatory, antibacterial and antitermite effect. N. oleander is used in the treatment of external wounds, infected areas, ring worms, tumours etc., in traditional system of medicine. The process of wound healing in plant involves continuous cell-cell interactions and cell-matrix interactions that allow the process to proceed in different overlapping phases and processes including inflammation, wound contraction, re-epithelialisation and tissue remodelling.²⁷

11) Gandhapushpa

Calendula officinalis is an aromatic, erect, annual herb belonging to the family Asteraceae. It is commonly known as pot marigold. Pot marigold is a plant native to southern Europe and eastern Mediterranean countries. A wide range of pharmacological activities are described to C. officinalis including antiinflammatory, antioxidant, antibacterial, antiviral and antifungal activities. It contains chemical constituents which include saponins, triterpenes, flavonoids, steroids, tannins, quinines, coumarins, amino acids and polysaccharides. C. officinalis flower petals are used to treat variety of skin conditions such as wounds, burns and dermatitis. It facilitate wound healing by increasing both wound angiogenesis and collagen metabolism leading to improvement in both local granulation tissue formation and blood circulation.²⁸

12) Soap nut:

There are more than 40 species in the genus Sapindus belonging to the family Sapindaceae. Among these species, Sapindus trifoliatus and Sapindus mukorossi have gained the attention of investigators because of their various pharmacological applications. Both the species were found to be significant antibacterial, antifungal and antioxidant activities and hence revealed benefits for wound healing. The drug is rich in phytoconstituents namely fatty acids, mucilage, minerals, tannins and saponins. It is reported that the saponins present in the drug plays an important role in reducing skin inflammation and could serve as a potential herbal drug treatment for skin and soft tissue infections.²⁹

13) Ginseng:

Panax ginseng of Araliaceae family also commonly known as Korean ginseng is an herb that is distributed throughout China, Japan, Korea and Eastern Siberia. P. ginseng includes different pharmacological activities such as anti-inflammatory, antioxidant, antiallergic and antiaging. The drug contains many bioactive substances like ginsenosides which are basically saponin glycosides containing oleanolic acid as aglycone. Other constituents of Ginseng are polysaccharides, peptides and fatty acids. Among these bioactive substances class of saponins (ginsenosides) represent the most potent active constituents of P. ginseng. The root extracts of P. ginseng have been shown to protect skin and also stimulate proliferation followed by collagen synthesis in human dermal tissue.³⁰

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Received on 07.11.2024 Revised on 20.01.2025

Accepted on 10.03.2025 Published on 10.05.2025

Available online from May 14, 2025

Res. J. Pharmacognosy and Phytochem. 2025; 17(2):123-129.

DOI: 10.52711/0975-4385.2025.00021

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