PHARMACOLOGICAL EFFECTS OF VITIS VINIFERA SUBSP. VINIFERA: A REVIEW

PHARMACOLOGICAL EFFECTS OF VITIS VINIFERA SUBSP. VINIFERA: A REVIEW

Ashok Kumar *, Amit Sharma, Pragi and Varun Kumar

Department of Pharmacy, Faculty of Medical/Para Medical & Allied Health Sciences, Jagannath University, Jaipur, Rajasthan, India.

ABSTRACT: Grapes are one of the most widely grown fruits and have been used for winemaking since the ancient Greek and Roman civilizations. Grapes are rich in proanthocyanidins which have been shown to possess potent free radical scavenging activity. Grape seeds are a complex matrix containing 40% fiber, 16% oil, 11% proteins, and 7% complex phenols such as tannins, in addition to abundant quantities of gallic acid, p-coumaric, caffeic and ferulic acids etc. also present. Roots contain resveratrol, vitisins A & B and other stilbenoid compounds. Leaves of grapes include gallocatechin, catechins, procyanidins, epicatechins, hydroxybenzoic acid, syringic acid and coumarin. Grapes are rich sources of flavonoids and contain monomers, dimers, trimers, oligomers and polymers. The monomeric compounds includes (+)-catechins, (-)-epicatechin, and epicatechin-3-O-gallate. Grapes have pharmacological activities, like anti-inflammatory, antidiabetic, antioxidant, anti-aging, anti-cataract, antibacterial, antifungal, antiacne, antiobesity, antispasmodic, spasmolytic, anti-virus, wound-healing, antihypertension and antiplatelet and antihyperpigmentation. Studies have reported that grapefruit exhibit a broad spectrum of pharmacological properties against Alzheimer, tumor, leishmanial, Low-Density Lipoprotein, viral, oxidative stress, and had hepatoprotective activity. Their potential health benefits include protection against oxidative damage and anti-diabetic, anti-cholesterol, and anti-platelet functions. Recognition of such health benefits of proanthocyanidins and resveratrol has led consumers to use grapes as a dietary supplement. This paper summarizes the studies of grape fruit's phytochemical compounds and pharmacological properties.

Keywords: Vitis vinifera, Resveratrol, Proanthocyanidins, Flavonoids, Polyphenols, Catechins, Syringic acid

INTRODUCTION: There are significant economic benefits from the development of native medicines and use of medicinal plants to treat various diseases ¹. The use of natural remedies to treat liver diseases has a long history. Plants which exhibits hepatoprotective activity contain number of chemical constituents such as phenols, coumarins, lignins, essential oils, monoterpenes, carotenoids, glycosides, flavonoids, organic acids, lipids, alkaloids and xanthenes ².

Recent studies has shown that herbal preparations are relatively non-toxic, safe and no series complications ^3-4. Oxidative stress affects the progression of liver diseases ⁵. Grapes (Vitis vinifera Subsp. Vitaceae) are used as a drug therapy for many ailments grown globally ⁶. It produces more than 67 million tons of fruit annually, making it the greatest fruit production in the world ⁷.

In recent years, several significant reviews have concluded the phytochemical and pharmacological effects of grapes and their active components in various portions of the fruit, including the skin, seeds, pomace, and stems ^8-13. Grapes are traditionally used as medicine in Pakistan, Italy, and Turkey for the treatment of bronchitis, allergies, colds & flu, anemia, wound care, and laxatives ^14-18. They classify into edible seeds, seedless, grape wine, table grapes and raisin. North American and European Grapes varieties knowledge as Vitis labrusca, Vitis rotundifolia and Vitis vinifera respectively ¹⁹.

In India, the Grape is evaluated as one of the most important commercially prominent fruit crops, mainly in Maharashtra, Andhra Pradesh, Karnataka, Tamil Nadu, Punjab, Haryana, and Uttar Pradesh, due to its higher yields. In India, grape cultivation is about 40,000 hectare in Maharashtra shares about 20,000 hectare with production >5 lakhtones / year and an approximate turnover above 500 crores. Cultivation in Haryana increases progressively. The main grape-growing districts are Sirsa, Hisar, Bhivani, Jind and Gurgaon. They are cultivated as a temperate crop in Kinnaur (Himachal Pradesh) ²⁰.

Grapes are known in India since the 11th century BC. But much of its information was unknown until the Muslim infiltration. Muslim introduced grape fruits from Iran and Afghanistan by the end of 12th century, and later, these grapes were shifted to South India by them²⁰. The formerly earlier varieties they introduced are Abi (Bhokri), Fakhri and Sahebi. Several reports show to have the cultivation of grapes during the times of Susrata and Charaka (1356 B.C.). The Grape cultivation in India has been restrained to one of kind states along with Andhra Pradesh, Haryana, Karnataka, Maharashtra, Punjab and Tamil Nadu. It is also suggested to be grown on a restricted scale in the western part of Uttar Pradesh, Rajasthan, and Himachal Pradesh ²⁰. Grapes had pharmacological activities like anti-inflammatory, antidiabetic, antioxidant, anti-aging, anti-cataract, antibacterial, antifungal, anti-acne, anti-obesity, antispasmodic, spasmolytic, anti-virus, wound-healing ^21-22, antihypertension, antiplatelet and anti-hyper pigmentation ^23-24.

Fresh fruits, dried fruits, and juice are the next most common uses for grapes, which account for 50-75% of their total consumption and significantly use in wine production ²⁵.

DESCRIPTION: The grapevine (Vitis vinifera) is endemic to southern Europe and Western Asia and nowadays cultivated in all temperature areas of the world ²³, which comprises approximately 60 inter-fertile wild Vitis species dispersed in Asia, North America, and Europe below subtropical, Mediterranean and continental temperate climatic conditions ¹.

North American V. rupestris, V. riparia or V. berlandieri are used as breeding rootstock because of their resistance to grapevine pathogens, including Phylloxera, Oidium , and mildews. Indeed, a high volume of cultivars is widely cultivated for fruit, juice, and specifically for wine ²⁶. V. vinifera and American bunch grapes have hanging, flaky bark on older wood and have massive (up to 8-10" in width) cordate to orbicular leaves, which can be lobed. Grapes are extensively used in digestive issues such as constipation, jaundice, and thirst. The berries act as cardiac tonic. They improve the heart muscles and enhance blood's nutrient components (haemoglobin). Grapes assist in strengthening the lungs; grapes are used as primary ingredients in ayurvedic preparations, which can be administered for breathing complications like tuberculosis, cough, bronchitis, etc. Grapes help to improve fertility in men and women, and decrease inflammation.

In India, grapes are grown underneath semi-irrigated regions in north India. The temperature ranging from 35°C to 40°C, and 80-110 cm rainfall is required. These conditions favor growing colored grapes because hot days and cold nights support the developing coloured pigment viz. anthocyanin ^27-28. V. vinifera comes in seedless as well as non-seedless varieties, and they contain red, black, and white colour fruits ²⁴. Unripen fruits performa vital role to treat sore throat, dried fruit (raisins) constipation and thirst. The ripe, sweet grapes were used to treat more than a range of ailments involving cancer, cholera, smallpox, nausea, eye infections, and skin, kidney, and liver diseases. Furthermore, grapes are useful in bilious dyspepsia, dysuria, haemorrhage, chronic bronchitis, gout, and heart disorders ²⁹.

Red grapes are basically less in calories and lack of fats and cholesterol. One serving (approx. 150 grams) of red grapes carries104 calories, 27 gm carbs, 1 gm protein, 0 gm fat, 23.4 gm sugar and 1.4 gm fiber. Grapes are high in vitamin K, a fat-soluble vitamin reserved in body tissues and the liver. The human body requires adequate vitamin K to construct strong bones and synthesize several proteins required for blood coagulation. If someone diets less in ingredients rich in vitamin K, a deficiency might lead to osteoporosis ^30-31. The current review provides an update on the pharmacological effects on which recent work was done and includes more recently published research.

Phyto-constituents: Several scientific studies regarding grape processing by-products have been revealed so far, it mainly specializes in grapes’ seeds, stems, and skin, but a few research have been reported on leaves and tendrils of V. vinifera. The uncommon information regarding grape leaves shows the presence of organic acids, phenolic acids, flavonols, tannins, procyanidins, anthocyanins, enzymes, vitamins, and carotenoids, consequently high in nutritional and biological potential ³². One of the few research-emphasized tendrils’ composition reports flavonoids, polyphenols, and anthocyanins as important constituents with promising in-vitro anti-inflammatory consequences ³³. The principle constituents of grapes are phenolic compounds ⁹. In 2009, A mico et al. suggested that the main ingredients of the grape stem ethanolic extract are: triterpenoid acids, oleanolic and betulinic acids; astilbenoid, daucosterol; E-resveratrol and its dimer E-viniferin; gallic acid as a simple phenol; catech in and gallo-catechin (flavanols); four 6′-O-acyldaucosterols and five 1, 2-di-O-acyl-3-O-β-D-galactopyranosylglycerols ³⁴. Stilbene derivatives: Trans-Resveratrol (trans-3, 5, 40-trihy-droxystilbene) has also been stated in grapes ²³. Anthocyanins and proanthocyanidins have an important role in the stability, taste, and colour of red grape varieties ³⁵.V. vinifera seeds were found to contain a bund antquantities of gallic acid in addition to small eramounts of p-coumaric, caffeic and ferulic acids ³⁶. They contained higher amounts of bothgallic and p-coumaric acids than the seeds of other fruit species ³⁷.

Five anthocyanidin-3-O-glucosides, including malvidin-3-O-glucoside, peonidin-3-O-glucoside, and cyanidin-3-O-glucoside, were identified and quantified in Corinthian currants (V. vinifera L., var. Apyrena) ³⁸. The (+)-catechin and (-)-epicatechin flavanols were the probable flavanols in red grape pomace extract (V. vinifera L. cv. Malbec), with malvidin-3-glucoside being the most potent anthocyanin. Additionally, piceatannol, a stilbene counterpart to resveratrol, were identified and measured for the first time in grape pomace ³⁹. It was suggested that the grape variety has a strong phenolic composition ⁴⁰ similar to that of V. vinifera L. fruits ⁴¹.

According to Esatbeyoglu et al., ⁴² grape root extract is made up of stilbenoid compounds such resveratrol, vitisins A and B, picaetannol and miyabenol ⁴². Trans-piecid, cis-piecid, vitisinol B, viniferether A, and viniferether B are additional stilbenoid chemicals in the grape root, as are ampelopsin C, ampelopsin E, hopeaphenol and isohopeaphenol ⁴³. The flavan-3-ol compounds in grape leave include gallocatechin, catechins, procyanidins, procyanidin B1, procyanidin A1 and epicatechins. Grape leaves also contain hydroxybenzoic acid (quinic acid, gallic acid, vanilic acid, and syringic acid), hydroxycinnamic acid (caftaric acid, caffeic acid, and fertaric acid), coumarin, dihydrochalcon ⁴⁴. The flavonol substances were myricetin, kaempferol, quercetin and quercetin-3-O-glucoside.

Anthocyanins, coumarin (aesculin, fraxin, aesculutin and umbelliferone), flavone (apigenin-7-O-glucoside and luteolin-7-O-glucoside) and flavanone (taxifolin, naringenin and hesperetin) ⁴³ condensed tannin, also be found in leaves ⁴⁵. Grape seeds are rich in phenolic compounds and have likely beneficial effects on human health as peptic ulcer protective ^46-47 and expressed to exhibit scavenged superoxide radicals ⁴⁸. Grape seed extract is composed of the following: procyanidin, gallic acid, epicatechin, catechin, and Quercetin ⁴⁹. Other ingredients like protein, fiber, minerals, and water are 11%, 35%, 3% & 7%, respectively. Additionally, 7 to 20% of lipid content also present ⁵⁰.

Flavonol glycosides were found in the white grape seed extract after being examined by ultra-high-performance liquid chromatography-tandem mass spectrometry ⁴⁵. In the context of the black grape, the seed was exposed to resveratrol, anthocyanidins, and flavonol glycosides ^51-52. Sochorova et al., added caffeic acid, coumaric acid, coutaric acid, ferulic acid, and fertaric acid, also claimed that grape seed extract also had other phenolic components, including quercetin-3-D-glucoside, quercitrin, myricetin, catechin, and epicatechin ⁵³. Using gas chromatography-mass spectrometry (GC-MS), Felhi discovered that grape seed extract contain higher amount of linoleic acid, primaric acid, caffeic acid, p-hydroxy-phenylacetic acid, and gallic acid compared to the seeds of other fruit species ³⁷.

Grape skin contained flavonols, anthocyanins ⁵⁴, flavan-3-ols, stilbenes, and phenolic acid ⁵⁵. While quercetin, vanillic acid, kaempferol, syringic acid, and gallic acid were identified in the grape pomace extract of V. vinifera L. var. Chilean ⁵⁶. By using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), researchers were able to identify the flavonols quercetin, rutin, kaempferol, caftaric acid, caftaric acid, ferulic acid, (-) epicatechin, (+) catechin, resveratrol and procyanidin in the grape juice from V. vinifera L. var. Sangiovese ⁵⁷. Gallic acid, syringic acid, caffeic acid, chioric acid, gallocatechin, ferulic acid, procyanidin B1, procyanidin A1, procyanidin C1, epicatechin, catechin, catechingallate, anthocyanin, flavanone, flavone, and flavonol were all present in the grape stem (quercetin, quercetin-3-O-glucoside, and kaempferol). Additionally, stilbenic substances such as transastringin, trans-resveratrol side, ampelopsin A, D and F, vitisin A, B, and C and miyabenol C are present in stem sections ⁴³. The different chemical groups of polyphenols identified in different fruit parts are carbohydrates, alkaloids, flavonoids, glycosides, saponins, tannins and sterols ⁵⁸.

In order of significance, the phytochemicals found in V. vinifera L. are as follows:

(a) Resveratrol; (b) Pterostilbene; (c) Gallic acid; (d) Ferulic acid; (e) Caffeic acid; (f) Caftaric acid; (g) Syringic acid; (h) Quercetin; (i) Kaempferol; (j) (+) Catechin; (k) Epicatechin; (l) Anthocyanin; (m) Proanthocyanidin; (n) Ampelopsin A; (o) Vitisin A; (p) Vitisin B.

The proanthocyanidins with a DP higher than eight that are present in ripe fruits showed more potent inhibition of α-amylase and α -glucosidase than the less-polymerized proanthocyanidins present in unripe fruits ⁵⁹.

Pharmacological Effects: When the total antioxidant activity of the extracted tendril was tested on NCTC 2544 cells and increased concentration to 25, 50, 62.5 and 100 mg/mL of V. vinifera tendril aqueous extract in DMEM for 24 h at 37°C. To increase the GSH levels and increase the reduced glutathione level at 25 mg/mL. Membrane integrity was assessed by the lactate dehydrogenase release in the medium ⁴⁴.

Polyphenols are effective in periodontal disease mainly due to their effects on inflammation signals, antioxidant and antibacterial activity ⁶⁰. Polyphenols, such as epigallocatechin, quercetin, and caffeic acid, have already been confirmed by their in-vitro cytoprotective action on the cells exposed to nicotine or lip polysaccharides ⁶¹. Grape seed extract contains oligomeric proanthocyanidins (PACs), which show strong antioxidant activity. PACs have been able to control high levels of malondialdehyde (MDA) and carboxymethyllysine, reduce superoxide dismutase, and reduce glutathione (GSH) activity in mice with induced diabetes mellitus ⁶².

Anti-Alzheimer Activity: The causes of Alzheimer's disease (AD) are oxidative stress and inflammation as triggers, leading to increased levels of Reactive Oxygen Species (ROS) and minimizing the energy to the brain ⁶³. AD progression reflects the gene expression of Amyloid Precursor Protein (APP) & Tau. Vitis vinifera fruit contains antioxidants play a vital role in AD therapy to minimize /slow down the disease progression by the formation of amyloid plaques, Tau tangles, and reduced oxidative stress ⁶⁴.

Anti-tumour Activity: In several human clinical studies Vitis vinifera seed extracts have been shown effective in human colorectal carcinoma ⁶⁵, head and neck squamous cell carcinoma ⁶⁶ and prostate cancer cells ⁶⁷. So, daily supplementation of extract might be effective as an anti-tumour agent.

Anti-leishmanial Activity: The ethanolic extract of V. vinifera L. leaves showed a prominent activity against L. infantum promastigotes ⁶⁸.

Antidiabetic Activity: When Vitisvinifera seeds extract given at dose of 100 mg/kg through oral route, for 20 days to diabetics rats, show antioxidant effects against produced Reactive Oxygen Species and protect liver cells ⁶⁹.

Muscat Variety seeds Ethanolic Extract at a dose of 250, 500 mg/kg, ingested orally for 28 days to diabetic rats at a concentration of 55 mg/kg. Which resulting in decreased Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and Thiobarbituric acid reactive substances (TBARS) and prevent histopathological changes in liver prevented the decrease in malate dehydrogenase (MDH), succinic dehydrogenase (SDH) while increased LDH ⁷⁰.

Grape Skin Aqueous extract at a dose of 200 mg/kg/d to diabetics ‘mice, increased glucose transporter (GLUT-4)/ glucose did not change secretion of insulin ⁷¹. Investigation on the anti-inflammatory, anti apoptotic and pro-proliferative effects of Vitis vinifera L. seed extract on the livers of rats with induced type 2 diabetes mellitus ⁷². Consumption of vine seeds has been found to improve the overall liver condition inrats with diabetes mellitus ⁷³.

Cardiovascular Effects: Grapes Skin (V. vinifera L.) have polygalloyl polyflavan-3-ols are very effective to stop the human platelet aggregation and low-density lipoprotein oxidation in-vitro ^74-75.

Antimicrobial and Antiviral Effects: Antimicrobial activity has been reported in several components of grapes, including gallic acid, hydroxycinnamic acids, flavanols, trans-resveratrol, and tannins. Moreover, antilisterial activity has been reported for grape seed extract (1%). The seed and skin of Ribier grapes extracts decreased L. monocytogenes numbers from 106.107 CFU/ml to node tectable colonies within 10 minutes ⁷⁶. Polyphenols can form complexes with metal ions and macromolecules such as polysaccharides and proteins ⁷⁷. They are an attractive option for developing Nutraceuticals and functional food ingredients ⁷⁸. In particular, proanthocyanidins have been shown to inhibit the key enzymes (α-amylase and α-glucosidase) related to Type 2 Diabetes Mellitus (T2DM), being a natural alternative to the synthetic drug Acarbose ^79-81. Acarbose has been validated to exert an anti-postprandial hyperglycaemia effect. However, it causes undesirable side effects such as flatulence and diarrhoea, with corresponding abdominal pain and a loss of nutrient absorption ⁸².

Hepatoprotective Activity: Hepatotherapeutic potency of the isolated polyphenols from seedless (pulp and skin) black Vitisvinifera against CCl₄-induced hepatotoxicity in-vitro and in-vivo. Further, the test sample had highest content of phenolics showing in-vitro synergistic antioxidant and anti-hepatotoxic activities resveratrol-enriched and phenolics-enriched and silymarin. Though, it exhibited multiple in-vivo regulatory functions via reducing oxidative stress and inflammation, which in turn decreased necroptosis and pro-fibrotic mediators (mixed lineage kinase domain-like protein (MLKL), collagen type I alpha 1 chain and transforming growth factor (TGF)-β1) ⁸³.

Clinical Studies: In this study, supercritical fluid extraction (SFE) technique was used and is designed for temperature, CO, pressure and ethanol concentration using orthogonal array design as well as the yield system, whole phenols and antioxidants from grape seeds (Vitis labrusca B.). The effects of output temperatures and pressures were found to be significant in all of these response changes in the SFE process. They found that the antiradical assay showed that SFE extracts of grape seeds could consume more than 85% of 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radicals. Grape seed extracts were also analyzed for hydroxybenzoic acid containing gallic acid (1.21 ~ 3.84 μg/ml), protocatechuic acid (3.57 ~ 11.78 μg/ml) and    p-hydroxybenzoic acid (206.72 ~ 688.18 μg/ml) ⁸⁴.

CONCLUSION: The data presented here indicate that the marked antioxidant activity of grapes extracts that contain large amounts of flavonoids and phenolic compounds may act similarly as reductones by donating the electrons and reacting with free radicals to convert them into more stable products and terminate free radical chain reaction. Grape leaves. Skin and roots have many phytoconstituents which produce potential pharmacological effects against- Alzheimer, carcinoma L. leishmanial, diabetes, cardiovascular disorder, hepatoprotective, antimicrobial and antiviral activity antioxidant activities as well. Due to its wide range of chemical constituents, furthermore, studies could be performed in the future to get good results.

ACKNOWLEDGEMENT: The authors thank Jagannath University NCR Bahadurgarh for providing the necessary facilities and support.

CONFLICTS OF INTEREST: The authors declare no conflict of interest.

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    Kumar A, Sharma A, Pragi and Kumar V: Pharmacological effects of Vitis vinifera Subsp. Vinifera: a review. Int J Pharm Sci & Res 2023; 14(6): 2670-77. doi: 10.13040/IJPSR.0975-8232.14(6).2670-77.

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