PHYTOCHEMICAL CONSTITUENTS AND ANTI-ATHEROSCLEROTIC ACTIVITIES OF A POLYHERBAL FORMULATION –GSTC

PHYTOCHEMICAL CONSTITUENTS AND ANTI-ATHEROSCLEROTIC ACTIVITIES OF A POLYHERBAL FORMULATION –GSTC

G. Sathyapooja *, S. K. Arun, J. Aswin, N. Hariharan and K. Loganathan

Department of Pharmaceutical Chemistry, KMCH College of Pharmacy, Coimbatore, Tamil Nadu, India.

ABSTRACT: GSTC is a polyherbal formulation comprising Commiphora mukul, Salacia reticulata, Terminalia arjuna, and Curcuma longa, developed to address atherosclerosis through multi-targeted mechanisms. Its phytochemical constituents include guggulsterones, mangiferin, arjunolic acid, and curcuminoids, each offering diverse pharmacological actions. Guggulsterones from C. mukul are recognized for their hypolipidemic and anti-inflammatory effects, while mangiferin and salacinol from S. reticulata provide antidiabetic, anti-obesity, and cholesterol-lowering benefits. T. arjuna contributes arjunolic acid and phytosterols, known for cardioprotective, antioxidant, and anti-inflammatory properties. Curcuminoids and ar-turmerone from C. longa exhibit potent antioxidant, anti-inflammatory, and hypolipidemic actions. Pharmacological studies demonstrate GSTC’s efficacy in reducing cholesterol, triglycerides, LDL, and VLDL levels while elevating HDL in high-fat diet models. Its mechanisms include inhibition of lipid peroxidation, regulation of HMG-CoA reductase, and modulation of inflammatory pathways such as NF-κB and COX-2. The formulation also prevents fatty liver accumulation and enhances lipid metabolism, GSTC exhibits significant antioxidant activity and platelet peroxidation inhibition. GSTC’s unique composition and pharmacological profile suggest its potential as a safe and effective therapeutic agent for managing atherosclerosis and related cardiovascular conditions.

Keywords: GSTC, Atherosclerosis, Phytoconstituents, Hypolipidemic, Polyherbals

INTRODUCTION: Global health challenges are becoming increasingly urgent, with complex diseases like cancer, diabetes and atherosclerosis often caused by a complete regulatory network malfunction rather than a single gene malfunction ¹. To diagnose and treat these disorders, innovative approaches must be developed to target the entire biological networks underlying the disease. Understanding the molecular pathways governing disease prognosis is critical in the fight against complicated diseases ².

Natural products, such as Ayurveda, Unani, and Chinese, are used in pharmaceutical agents, particularly in disease treatments ³. High-throughput techniques have improved the screening of herbal medicines in drug discovery. The concept of developing multi-target drugs against complex diseases is rapidly growing in drug discovery ⁴. In an attempt to develop an anti-atherosclerotic drug candidate, a polyherbal formulation containing four different herbal plant materials were prepared, based on their scientifically proven efficacy in reducing atherosclerosis risks ⁵.

Atherosclerosis is a chronic degenerative disease that causes high morbidity and mortality due to its clinical repercussions, including angina pectoris, acute myocardial infarction, stroke, and peripheral vascular insufficiency ⁶.

In 2020, 28% of people aged 30–79 had abnormal carotid intima-media thickness (≥1.0 mm), over 21% had carotid plaque, and 1.5% had carotid stenosis affecting more than one billion, 816 million, and 58 million individuals, respectively. These conditions were more common in older adults and men ⁷. The disease is characterized by the accumulation of lipid materials in the arterial wall due to autoimmune and inflammation mechanisms. Hyperlipidemia, hypertension, and diabetes mellitus are important risk factors in atherogenesis. Current treatment strategies focus on lowering cholesterol using statins, but high doses present side effects such as muscle tissue breakdown ⁸.

The polyherbal formulation GSTC is a suspension made up of extracts from gum resin of Commiphora mukul, root bark of Salacia reticulata, bark of Terminalia arjuna and rhizome of Curcuma longa. Experimental evidence has revealed the antioxidant, hypercholesterolemic effect of C. mukul, which is used in medoroga and inflammatory conditions. T. arjuna has been well documented for its antithrombotic efficacy, with phytosterols and glycosides being the active component. S. reticulata is known as an antidiabetic plant, preventing intestinal absorption of sugars and interfering in sugar metabolism.

C. longa is a natural ingredient in culinary preparations, and the rhizome is known for its antioxidant, anti-inflammatory, and hypolipidemic properties ⁹.

GSTC has been found to be a good antioxidant and ant-inflammatory agent, as well as anti-atherosclerotic potential, preventing serum oxidation, platelet peroxidation, and hypolipidemic activity in high fat-diet (hfd) fed rats. Based on these anti-atherosclerotic activities and nontoxic nature, GSTC could prove to be a fruitful drug candidate against atherosclerosis. GSTC has showed the most potent activity, with an IC₅₀ of 50 µg/mL, indicating strong inhibition of platelet peroxidation and the cyclooxygenase pathway. GSTC was effective in preventing serum lipid oxidation and lowering cholesterol, triglycerides, LDL, and VLDL levels in rats fed a high-fat diet, similar to atorvastatin. Unlike atorvastatin, GSTC also reduced lipid peroxidation and fatty liver accumulation, suggesting enhanced lipid metabolism. Additionally, GSTC improved HMG-CoA reductase regulation, indicating cholesterol biosynthesis inhibition. It exhibited antioxidant, anti-inflammatory, and non-toxic properties, making it a promising candidate for future atherosclerotic drug development ¹⁰.

FIG. 1: POLYHERBAL FORMULATION COMPRISING COMMIPHORA MUKUL, SALACIA RETICULATA, TERMINALIA ARJUNA AND CURCUMA LONGA

Phytoconstituents and its Therapeutic Potential:

Commiphora mukul: Guggul, derived from the resin of Commiphora wightii (also known as Commiphora mukul) belonging to the Burseraceae family, characterized by its prostrate growth, whitish bark, and serrated, non-hairy, trifoliate leaves, is highly valued in Ayurvedic medicine ^{11, 12}. Indigenous to India, it also thrives in the wild across various states of India, Afghanistan, Arabia, and northeastern Africa. The Atharva Veda, refers to Guggul as 'Krimighna,' praised for its fragrant properties that repel parasites. This ancient text, along with other significant Ayurvedic works such as the Charaka Samhita, Sushruta Samhita, and writings by Vagbhata, detail the drug's applications and benefits ¹³. The gum resin of Guggul, obtained by drying the white sap of the Balsamodendron mukul tree, is utilized in Indian folk medicine for alleviating inflammation ¹⁴, arthritis ¹⁵, reducing fat, mending bone fractures ¹⁶, atherosclerosis, obesity, and hyperlipidemia ¹⁷. It is traditionally administered as 'Yog,' combined with other substances and often accompanied by castor oil or Indian spices ¹⁸. The sesquiterpene elements present in Myrrh (akin to Guggul), furanoeudesma-1,3-diene and curzarene, exhibit analgesic properties ¹⁹. However, due to its toxicity, myrrh is seldom used in modern medicine, except as a mouthwash in India. The Ethiopian resin "agarsu" is used to protect livestock from ticks and has medicinal properties like antimalarial, cold prevention, and wound healing ²⁰. Guggulsterone, a component of Guggul, is known to stimulate fat-breaking enzymes, inhibits the cholesterol production in the liver, and lowers the serum LDL and cholesterol levels ²¹. The major chemical compounds of Commiphora mukul are listed in Table 1 ^22-26.

TABLE 1: PHYTOCONSTITUENTS OF COMMIPHORA MUKUL

FIG. 2: CHEMICAL CONSTITUENTS OF COMMIPHORA MUKUL

TABLE 2: POTENTIAL ACTIVITIES OF COMMIPHORA MUKUL

Salacia reticulata: Kothala himbatu (Salacia reticulata Wight) is a substantial woody climbing shrub characterised by greenish-brown bark, belonging to the Hippocrateaceae family. It is indigenous to Sri Lanka and the southern region of India, with other species such as S. chinensis and S. oblonga also distributed across Asia and various global regions ^{47, 48}. In Ayurvedic medicine, it is sometimes referred to as "Ponkoranti". Species of Salacia, including S. oblonga, S. prinoides, and S. reticulata, have been utilised for millennia in traditional medicine, especially for diabetes management ^{49, 50}. Salacia species have recently been utilised in Japan, the United States, and other nations as a dietary supplement for the prevention of obesity and diabetes ^{51, 52}. In the Ayurvedic system of traditional medicine, the roots and stems of S. reticulata and S. oblonga have been extensively employed to treat rheumatism, gonorrhoea, skin maladies, and as a specific remedy for the initial stages of diabetes. Decoctions of S. reticulata and extracts from other Salacia species have been utilised for centuries to treat asthma, rheumatism, haemorrhoids, pruritus and oedema, gonorrhoea, dermatological conditions, and amenorrhoea ^{53, 54, 55}. The roots possess acrid, bitter, thermogenic, diuretic, astringent, analgesic, and anti-inflammatory properties ^{56, 57}. The interest in Salacia extracts has surged recently due to the escalating prevalence of diabetes and pre-diabetes, the demand for safe and effective pharmaceuticals and functional foods that aid in regulating blood sugar and lipid levels, and the diverse mechanisms of action exhibited by Salacia extracts ⁵⁸. The principal chemical elements of Salacia reticulata root are shown in Table 3 ^59-66.

TABLE 3: PHYTOCONSTITUENTS OF SALACIA RETICULATA

FIG. 3: CHEMICAL CONSTITUENTS OF SALACIA RETICULATA

TABLE 4: POTENTIAL ACTIVITIES OF SALACIA RETICULATA

Terminalia arjuna: T. arjuna is often described as Arjuna, Indradru, Partha, and Veeravriksha. It belongs to Combretaceae family, having 200 species found all around the world ⁸².  The arjuna tree, which reaches a height of 60 to 80 feet, is found in the Indo-Himalayan regions. Although it can thrive in about any kind of soil, it prefers red lateritic and damp loam soils. It is propagated by seeds ⁸³. Indigenous medical systems employ plant components including T. arjuna's fruits, leaves, and stem bark to address a range of ailments. It has been discovered that the powdered bark has the following benefits: it is hypocholesterolemic, hypo-ischemic, antioxidant, antibacterial, anti-inflammatory, immunomodulatory, and antinociceptive ⁸⁴.

Terminalia arjuna's bark is smooth, pinkish-grey on the exterior, curved, roughly flat. Each piece can vary in length by up to 15 cm, in breadth by up to 10 cm, and in thickness by up to 10 mm. Heartwood is brown, while sapwood is reddish-white. The bark has a uni-layered epidermis with hair-like projections and a few dispersed lenticels, as revealed by histopathological analysis. Epidermis is covered with a thin layered cortex. The bark contains secondary phloem and periderm ⁸⁵. Traditional methods of using the stem bark (asava) for cardiac diseases involve either making an alcoholic preparation of it or giving it along with purified boiled milk (kshirpak) or butter (ghrita). There are other formulations on the market with suggested dose of bark juice, notably Arjunarishta, Shankara vati, and Kakubhadi kshira ⁸⁶.

When T. arjuna bark was initially recorded, it had 34% ash value and composed of calcium carbonate. While only colouring matter and tannins were present in the alcoholic extract, the aqueous extract showed calcium salts (23%) and tannins (16%). Subsequent analysis of the bark revealed the presence of sugar, colouring materials, a glycoside and calcium carbonates, and trace amounts of alkali metal chloride. Subsequently, the existence of a glycoside and an alkaloid was verified. Glycoside isolation produced a high melting point organic acid, phytosterols, 12% tannins, calcium concentrations, trace amounts of magnesium and aluminium salts, sugars ⁸⁷. The primary chemical components of T.arjuna are listed in Table 5 ^88-95.

TABLE 5: PHYTOCONSTITUENTS OF TERMINALIA ARJUNA

FIG. 4: CHEMICAL CONSTITUENTS OF TERMINALIA ARJUNA

TABLE 6: POTENTIAL ACTIVITIES OF TERMINALIA ARJUNA

Curcuma longa: A ubiquitous spice used in Asian cuisine; turmeric (Curcuma longa L.) belongs to the Zingiberaceae family ¹⁰⁹. The yellow-orange, oblong, aromatic, coarsely segmented rhizomes of turmeric plants are 2.5–7.0 cm in length and about 2.5 cm in diameter ¹¹⁰. Originating in Southeast Asia, this plant is widely cultivated in tropical and subtropical climates worldwide. In India and numerous other nations, it stands as one of the most significant spices. It is also utilized in herbal medicine and as a natural yellow food colour ¹¹¹. Owing to its striking yellow coloration, it is frequently named as "Indian Saffron" ¹¹².  Active ingredients found in turmeric include polyphenols, sterols, alkaloids, sesquiterpenes, diterpenes, and triterpenoids and its yellow colour is due to the presence curcuminoids ¹¹³. Ayurvedic and traditional Chinese medicine have utilized Curcuma longa extract, which contains Biological attributes including the inhibition of platelet aggregation, management of diabetes, tumor suppression, reduction of inflammation, antioxidant properties, protection of the gastrointestinal tract, lowering of lipid levels, effects associated with Alzheimer's, and more ^114,115. Among them curcumin shows greater biological activity and its capacity to interact with diverse proteins enables the specific control of many cellular signaling pathways linked to a range of chronic illnesses ¹¹⁶. The main chemical constituents of the rhizome of Cucuma longa are displayed in Table 7 ^117-131.

TABLE 7: PHYTOCONSTITUENTS OF CURCUMA LONGA

FIG. 5: CHEMICAL CONSTITUENTS OF CURCUMA LONGA

TABLE 8: POTENTIAL ACTIVITIES OF CURCUMA LONGA

CONCLUSION: GSTC is a unique poly-herbal formulation with multi-targeted activity based on the scientific data mentioned above. Together, they control several stages of atherogenesis.

A multicentric clinical study of GSTC is necessary, even if these individual plants are already being used clinically. A deeper understanding of its harmful or useful constituents may be obtained by bioactive screening, raising GSTC's present quality standard and offering fresh perspectives on designing bioactive lead compounds.

ACKNOWLEDGEMENT: Nil

Data Availability Statement: Data sharing is not applicable to this article as it is a review of previously published studies. All data cited are available in the original articles referenced within the manuscript.

CONFLICT OF INTEREST: None of the authors of the above manuscript has declared any conflict of interest which may arise from being named as an author on the manuscript.

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     Sathyapooja G, Arun SK, Aswin J, Hariharan N and Loganathan K: Phytochemical constituents and anti-atherosclerotic activities of a polyherbal formulation –GSTC. Int J Pharmacognosy 2025; 12(2): 58-74. doi link: http://dx.doi.org/10.13040/IJPSR.0975-8232.IJP.12(2).58-74.

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