REVIEW Doi: 10.12032/TMR20200603189

REVIEW doi: 10.12032/TMR20200603189

Traditional Medicine in Sri Lanka

South Asian medicinal plants and chronic kidney disease

Sachinthi Sandaruwani Amarasiri1, Anoja Priyadarshani Attanayake2*, Kamani Ayoma Perera Wijewardana Jayatilaka2, Lakmini Kumari Boralugoda Mudduwa3

1Department of Medical Laboratory Science, Faculty of Allied Health Sciences, University of Ruhuna, Galle 80000, Sri Lanka; 2Department of Biochemistry, Faculty of Medicine, University of Ruhuna, Galle 80000, Sri Lanka; 3Department of Pathology, Faculty of Medicine, University of Ruhuna, Galle 80000, Sri Lanka.

*Corresponding to: Anoja Priyadarshani Attanayakeb. Department of Biochemistry, Faculty of Medicine, University of Ruhuna, Karapitiya, Galle 80000, Sri Lanka. E-mail: [email protected].

Highlights

This review focuses on the use of South Asian medicinal plants in the therapy for kidney disease in traditional systems of medicine and on the nephroprotective activity of medicinal plant extracts in animal models.

Traditionality

The potential threat to quality of life and the chronic nature of kidney disease have led many patients with chronic kidney disease to turn to complementary and alternative medicine practices to help them manage their disease. Several complementary and alternative medicine systems have been used in South Asian countries, including Ayurveda, Siddha, Unani, and Dhivehi beys. Ayurveda is the oldest system of medicine, originating in 1500 B.C.E.–2000 B.C.E. The classical Indian Ayurvedic texts, such as Rigveda (unknown author, written in 1500 B.C.E.–900 B.C.E.), Atharvaveda (unknown author, written in 600 B.C.E.), Charak Samhita (written by Charaka in 120 C.E–162 C.E.), and Sushruta Samhita (written by Divodasa Dhanvantari, Susruta and Nagarjuna in 1500 B.C.E.–4th century C.E.), may have originated centuries ago as well and guide this approach to health. In 1997, the National Center for Complementary and Alternative Medicine of the National Institutes of Health in United States defined the complementary and alternative medicine as the practices that are not categorized as a part of the current conventional medical system for managing health and disease. The use of herbal therapeutics is the most common form of complementary and alternative medicine used by chronic kidney disease patients worldwide.

OH HO S

O OH O C OH O CH3 CH3 O O OH

HO O O OH N OH O O CH3 CH3 HO

HO O

OH HO OH

O OH HO OH

HO O

HO OH OH

O O

H3C CH3

OH O

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 389 doi: 10.12032/TMR20200603189 REVIEW

Abstract Chronic kidney disease remains as one of the serious health issues in South Asia. The paucity of effective pharmacotherapy targeting the management of chronic kidney disease has led to a search for alternative pharmacologic therapies. The traditional knowledge of medicinal plants plays a key role in the discovery of novel nephroprotective agents. This review aims to present the use of such South Asian ethnomedicinal plants that have sufficient therapeutic potency for the management of kidney diseases. Medicinal plants are rich sources of bioactive compounds that have been reported to exert nephroprotective mechanisms, such as antioxidant, anti-inflammation, diuretic, and immunomodulation. Many South Asian medicinal plants have been detailed in traditional medicinal pharmacopoeias for the management of kidney-related diseases. Some have shown promising effects to address nephropathy in animal models and in vitro research. This information can be beneficial in the development of novel pharmaceutical agents targeting the management of kidney diseases and improvement of quality of life for chronic kidney disease patients by fulfilling the requirements for disease management unmet by modern allopathic medicine. Keywords: Chronic kidney disease, Medicinal plants, Nephroprotective agents, South Asia, Antioxidant, Anti- inflammation

Author contributions: Sachinthi Sandaruwani Amarasiria contributed to the acquisition of data and writing the manuscript; Anoja Priyadarshani Attanayakeb contributed to conception of the manuscript, critical reviewing and revisions to the article; Kamani Ayoma Perera Wijewardana Jayatilakab and Lakmini Kumari Boralugoda Mudduwac contributed to revisions to the article. Competing interests: The authors declare no conflicts of interest. Abbreviations: AGE, aged garlic extract; CAM, complementary and alternative medicine; CKD, chronic kidney disease; CKDu, chronic kidney disease of unknown origin; ESRD, end stage renal disease. Citation: Sachinthi Sandaruwani Amarasiria, Anoja Priyadarshani Attanayakeb, Kamani Ayoma Perera Wijewardana Jayatilakab, et al. Nephroprotective South Asian medicinal plants in the treatment of chronic kidney disease: a review. Traditional Medicine Research 2020, 5 (5): 389–412. Executive editor: Yu-Ping Shi. Submitted: 17 April 2020, Accepted: 04 June 2020, Online: 01 August 2020.

TMR | September 2020 | vol. 5 | no. 5 | 390 Submit a manuscript: https://www.tmrjournals.com/tmr

REVIEW doi: 10.12032/TMR20200603189 disease. Background Disease burden in South Asia Reports on traditional systems of medicine provide several effective therapeutic approaches to address the CKD remains one of the leading public health issues diverse pathologic conditions related to kidney disease. worldwide [12, 13, 14]. It is characterized mainly by In general, medicinal plants are the key element in most progressive loss of kidney function [15]. The complex of the therapeutic remedies used in traditional systems nature and the risks associated with the progression of of medicine. Ethnomedicinal plants used in the the disease to a severe state—called the end-stage renal management of chronic kidney disease (CKD) are disease (ESRD)—make the management of CKD quite effective in diuresis and renal detoxification, and thus critical [9]. The disease burden is massive in developing are beneficial to reduce the adverse effects of dialysis countries, as described later in text [12]. In addition, treatment [1, 2, 3, 4]. The ease of availability, low cost, CKD is a major contributor to increased morbidity and efficacy, and safety of these plants available as herbal mortality in South Asia, where the disease is most medicines to the general public make their use common frequently present as ESRD [16]. Thus, CKD has in this population [5, 6, 7, 8]. Use of ethnomedicinal become a devastating health problem in the South Asia, plants is further supported with the fact that they have which directly affects the social and economic growth shown promising effects in the treatment of diseases throughout the region [16]. that allopathic systems of medicine have failed to Glomerular nephritis and interstitial disease have manage [5, 9]. Therefore, these plants are of utmost been considered to be the most common causes of importance to protect renal function and slow the ESRD in South Asia. Prevalent infections and occurrence and the progression of CKD, thus environmental toxins are identified as the risk factors forestalling the need for end-stage treatment options for glomerular nephritis and interstitial disease, such as renal replacement therapy [9]. respectively [12, 17]. However, diabetes mellitus and Most of the South Asian population continue to rely hypertension have drawn increasing research attention on traditional systems of medicine, especially for the and are currently the leading causes of CKD [12, 18]. treatment of chronic diseases. Several systems of The oxidative stress associated with these two diseases complementary and alternative medicine (CAM) are leads to the progression of CKD. A high prevalence of used in South Asia, with different approaches among diabetes mellitus and hypertension among the South the countries in the region, including Ayurveda, Siddha, Asian population may be the reason for an increase in Unani, and Dhivehi beys, for example. Ayurveda is the the prevalence of CKD [1, 19, 20]. Furthermore, oldest system of medicine, originating in 1500–2000 individuals with a positive family history of kidney B.C.E. The classical Indian Ayurvedic texts, such as the disease are more prone to develop diabetic renal disease Rigveda (unknown author, written in 1500 B.C.E.–900 or glomerulonephritis associated with CKD [14]. B.C.E.), Atharvaveda (unknown author, written in 600 However, the primary cause of CKD may vary B.C.E.), Charak Samhita (written by Charaka in 120 depending on the socioeconomic status of patients and C.E–162 C.E.), and Sushruta Samhita (written by their environmental factors as well [18]. Divodasa Dhanvantari, Susruta and Nagarjuna in 1500 Chronic kidney disease of unknown origin (CKDu) is B.C.E.–4th century C.E.), likewise may have originated a condition in which the etiology and the exact thousands of years ago. In the modern era, in 1997, the prevalence of the disease remain unknown. This type of National Center for Complementary and Alternative CKD has become a major health issue throughout South Medicine of the National Institutes of Health in United Asia, especially in countries such as Sri Lanka, where States (renamed the National Center for most CKDu patients are in the north central and north Complementary and Integrative Health in 2014) defined western provinces of the island, and in the Uva and CAM as the practices that are not categorized as a part Eastern provinces as well. Exposure to heavy metals of the current conventional medical system for (Cd, As, Pb), ﬂuoride, pesticide residues, glyphosate managing health and disease. The use of ethnomedicinal from herbicides, and cyanogens from algae present in plants, also referred to as herbal therapeutics, is the most contaminated water sources have been identified as common form of CAM used by CKD patients possible predisposing factors for CKDu [17, 18, 21]. worldwide. The mean age of CKD patients in South Asian Although several studies to date have focused on the countries is lower compared with those in other nephroprotective medicinal plants used in traditional countries globally. This age discrepancy may be the Indian medicine, there is no comprehensive review of result of exposure to environmental toxins at a young the medicinal plants grown in other countries within the age and poor access to health care, which delays South Asia region, to the best knowledge of these diagnosis. In general, South Asian countries perform authors [2, 3]. Therefore, this current review focuses on poorly on health care indices [16, 17]. Therefore, the use of ethnomedicinal plants of South Asian origin, providing sufficient health care for patient with CKD is with a potential therapeutic application in kidney a major challenge within this region. Moreover,

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 391 doi: 10.12032/TMR20200603189 REVIEW although the prevalence of CKD is high among South disease progression is a critical factor in the appropriate Asian countries, no accurate data are currently management of CKD [23]. available. Most of the reported data are hospital-based The implementation of measures to preserve renal records or individual approximations [16]. Therefore, function is considered as one of the best options there is a large gap between the reported prevalence of available to slow the progression of CKD and to delay CKD and the actual value because many patients with the need of renal replacement therapy [28]. In this CKD never seek or receive medical attention [17]. regard, the use of nephroprotective agents at the earlier Furthermore, CKD is often asymptomatic until the stages of the disease play an important role in the disease reaches its advanced stages; thus, these patients management of CKD [14]. already have one or more disease complications or comorbidities by the time they seek medical attention Complementary and alternative practices in South [14]. Therefore, it is critical to implement a strategy so Asia that measures can be taken for prevention as well as The potential threat to quality of life and the chronic management of the disease before the progression to nature of kidney disease have led many South Asian ESRD [17]. patients with CKD to turn to CAM practices to help them manage their disease [29]. In addition, the Management strategies available treatment options in allopathic medicine for CKD are in most cases unaffordable for low- and Management of CKD is mainly based on early middle-income patients in South Asia, and this cost diagnosis, pharmacologic intervention, and strategies to factor further directs these patients toward the preserve renal function [14]. Early diagnosis permits traditional systems of medicine [30]. Furthermore, in initiation of pharmacologic interventions early, terms of the social context of South Asia, the region is resulting in a slower progression from CKD to ESRD. known for a rich heritage of traditional systems of Early diagnosis of the disease may reduce the risks for medicine that have been practiced for centuries [5]. cardiovascular events as well as the associated More than 70% of the South Asian population relies comorbidities and mortality [15]. on these nonallopathic systems of medicine that are However, pharmacologic management strategies in based on knowledge generated from centuries of CKD are constrained by several limitations. First, no experience, observation, and investigation. Traditional medication is available to cure CKD, and the available systems of medicine served as the mainstay of treatment pharmacologic approaches mainly comprise measures in most of the South Asian countries before colonization to control the signs and symptoms and reduce the by West [5, 6]. Traditional medicines comprise a variety complications of disease [9, 22]. Second, although the of therapeutic approaches, including food habits and the management of hypertension would be beneficial in use of herbs, metals, minerals, and precious stones. The delaying the decline in renal function for patients with approaches may vary among the different countries CKD, the therapeutic use of antihypertensive within the region [6, 31, 32]. medications, such as angiotensin-converting enzyme Several CAM systems of have been used in South inhibitors and angiotensin II receptor blockers, has been Asia. For example, Bangladesh, India, Nepal, and Sri undermined because of their serious adverse effects, Lanka mainly practice Ayurveda, Siddha, and Unani including neutropenia, proteinuria, angioneurotic medicine, whereas Maldivians practice their own edema, and hyperkalemia [14, 23, 24]. unique system known as Dhivehi beys [5, 6]. As the Management of ESRD is possible only with renal oldest system of medicine, originating in 1500–2000 replacement therapy [23, 25, 26]. Dialysis and kidney BC [5, 31] Ayurveda is not simply a system of transplantation are two main components of renal medicine—rather it is the science of life [6, 31, 32]. Its replacement therapy; however, their application may be objective is not just treating the diseased person, but limited because these approaches to management are also for the person to achieve physical, mental, social, highly sophisticated and expensive [23]. and spiritual well-being [6, 31, 32]. Ayurveda is based Although the use of pharmaceutical agents has been on the individualized treatment approaches that promote beneficial to some extent, the comorbidities and healing mechanisms and self-repair processes in the mortality associated with CKD have increased within body [5]. Thus, Ayurveda is effective in the the past few years. Patients with CKD are more likely management of common diseases as well as many to develop other systemic diseases, such as chronic diseases [6]. The Siddha system of medicine has atherosclerosis and cardiovascular disease, which are a a striking similarity to Ayurveda, but is specialized with frequent cause of mortality [23, 25, 27]. Based on these regard to iatrochemistry with the use of herbomineral factors of disease progression and the unavailability of products [6]. Moreover, this system uses extensive extensive management options and renal replacement astrology and incantations during treatments [32]. The therapy facilities, the annual mortality rate for CKD Unani system of medicine has its origins in Greece. patients is high in South Asian countries compared with Different modes of treatments including regimental other countries globally. Therefore, prevention of therapy, diet modification, pharmacotherapy, and TMR | September 2020 | vol. 5 | no. 5 | 392 Submit a manuscript: https://www.tmrjournals.com/tmr

REVIEW doi: 10.12032/TMR20200603189 surgery are practiced in Unani [5, 31]. However, substances work to prevent renal damage by reducing medicinal plants play a key role in all of these traditional lipid peroxidation and increasing endogenous systems of medicine [6]. antioxidants [9, 19, 38, 39]. Therefore, supplementation with medicinal plant-derived antioxidants is of utmost Nephroprotective role of natural products importance in curtailing the free radical pathologies Herbs are the most common forms of CAM used by present in CKD [14]. However, the literature provides CKD patients [30, 33]. The traditional treatment evidence for the capacity of natural whole products approaches based on medicinal plants focus the cause as rather than single antioxidants or their combinations in well as the outcomes of kidney diseases to forestall the preventing or managing kidney diseases [19]. need for hemodialysis and to reduce the adverse Another important mechanism of nephroprotection is consequences of dialysis treatments [1, 2, 3, 4]. In the anti-inflammatory effects of medicinal plants. The addition, herbs are beneficial to relieve some of the compounds such as curcumin and resveratrol found in associated symptoms of CKD comorbidities, including medicinal plants have shown promising effects in cutaneous pruritus, fatigue, depression, muscle cramps, nephroprotection by modulating inflammation and uremic bruising. [29, 30, 33]. These herbs may processes [30]. Moreover, other pharmacologic decrease the frequency of dialysis treatment as well. characteristics, such as diuresis, immunomodulation, Therefore, over the past decade there has been a reduction in proteinuria, and stimulation of renal repair remarkable increase in the use of medicinal plant- mechanisms, may contribute to slowing the progression derived herbal medicines by patients who undergo from kidney-related disease conditions to later-stage hemodialysis [33]. The diuretic properties of these disease [1, 36]. herbal medicines are not only useful for patients on Polyphenols in medicinal plants play an important hemodialysis, but also for pre-dialysis patients by role in nephroprotection by acting as antioxidant, anti- stimulating their declining kidney function and thus inflammatory, and diuretic agents [1, 36]. The delaying the need for dialysis [34]. enormous value of these phytoconstituents mandates Since herbal medicines have been used for thousands investigating the bioactivities of medicinal plants for the of years, their use is popular among general public. discovery of nephroprotective therapeutic agents. In this Moreover, medicinal plants used in the traditional context, medicinal plants used in the management of systems of medicine have been beneficial in the kidney-related diseases in traditional systems of discovery of number of modern allopathic medicines. medicine have drawn increasingly more research Examples include aspirin, atropine, ephedrine, digoxin, attention. morphine, quinine, reserpine, and tubocurarine, all of Although a large number of medicinal plants are used which have been developed based on the observations in the therapy for kidney diseases in the indigenous and of indigenous medicine [35]. It is estimated that nearly traditional systems of medicine, most have not been one-third of all newly approved compounds in modern scientifically scrutinized for their therapeutic effects as pharmacology are derived from medicinal plants [36]. well as for their safety. Therefore, it is important to Therefore, the World Health Organization has also validate the use of these plants through phytochemical recommended promoting herbal medicine in order to analysis and investigation of their relevant fulfill the requirements for disease management unmet pharmacologic activities [35]. In view of that goal, by modern allopathic medicine [5]. The literature many research studies have been conducted in the fields supports a number of medicinal plants used in these of pharmacognosy, chemistry, pharmacology, and traditional systems of medicine that show promising clinical therapeutics, on native medicinal plants through effects in renal failure [2, 37]. the approach of reverse pharmacology, facilitated by traditional knowledge [1, 3, 31, 40, 41, 42, 43, 44]. Nephroprotection by suppression of oxidative stress Table 1 summarizes an overview of such and chronic inflammation ethnomedicinal plants of South Asian origin, with Several mechanisms are suggested for the potential for the treatment of kidney diseases. nephroprotective activity of medicinal plants. Among them the most common mechanism is through the Nephroprotective activity of medicinal plant antioxidant defense system [19, 37]. Antioxidants are extracts on animal models the molecules that combat the oxidative stress A number of medicinal plants with nephroprotective developed from an imbalance between the rate of activity have been effective in the treatment of kidney production and removal of produced oxidants. diseases as shown in animal models [36, 41, 72, 69, 88]. Oxidative stress is the causative factor for a wide variety These plants have been useful in the management of of diseases, including CKD [19]. A key advantage to glomerulonephritis, different forms of nephropathies, medicinal plants is that they are rich sources of glomerulosclerosis, nephrotic syndrome, lupus, and antioxidants, mainly present in the form of phenolic tubulointerstitial nephritis, as well as in the treatment of compounds (flavonoids, phenolic acids, tocopherols, kidney stones [36]. tocotrienols), ascorbic acid, and carotenoids. These Different mechanisms of nephrotoxicity are used for

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 393

doi: 10.12032/TMR20200603189 REVIEW

Table 1 Overview of South Asian medicinal plants used in therapy for kidney diseases Botanical name Family Local name Part used Chemical constituents References Carotene, folic acid, thiamine, riboflavin, tocopherol, palmitic Abelmoschus Fruit, seed, acid, tannins, mucilages, 1. Malvaceae Bhendi [3, 45] esculentus L. root flavonoids, leuco-anthocyanins, reducing compounds, sterols, terpenes. Glucoside, alkaloid, flavonoids, Abrus 2. Leguminosae Gunja Root, leaves phenols, saponins, tannins, [3, 46] precatorius L. carbohydrate, terpenoids Acacia arabica 3. Leguminosae Babul Leaves Tannin, flavonoid [3, 47, 48] (Willd) Acacia catechu Flavonoid, tannin, phenol, saponins, 4. Mimosaceae Khair Bark [3, 49] L. carbohydrates, alkaloids, glycosides Acacia sinuate 5. Mimosaceae Cikakai Bark, pods Saponin, flavonoid, tannin [3] (Lour) Merrill Flavonoids, tannins, Acer phenylpropanoids, 6. Aceraceae Striped maple Bark [1, 40] pensylvanicum diarylheptanoids, terpenoids, benzoic acid derivatives Achilla Alkaloid, essential oil, flavonoid, 7. Compositae Gandana Whole plant [3, 50, 51] millefolium L. tannins, saponins Adiantum Flavonoids, terpenoids, tannin, 8. Lunulatum Polypodiaceae Hansraj Leaves volatile oil, steroid, anthocyanin, [3, 52] Burm alkaloids, anthraquinones Alangium Alkaloids, akoline lamarkine, 9. salvifolium Alanglaceae Ankol Bark [3, 53] steroids, saponin, flavonoids Wang Essential oil, orgnic sulfide, 10. Allium cepa L. Alliaceae Onion Bark flavonoid, phenolic acid, tannins, [3, 54, 55] alkaloids Amaranthus Alkanes, quinoline,sterols, terpene, 11. Amaranthaceae Katelichaulai Root [3, 56] spinosus L. alkaloids, glycosides Andropogon Leaves, 12. Graminae Kalavala Essential oil [3] muricatus Retz. flower Anogeissus Tannins, calcium, gum, qurecetin, 13. Combretaceae Dhavara Bark, root [3, 57] latifolia (Roxb) phenolic compounds Alkaloid, amino acids, camphor, Anona Leaves, 14. Annonaceae Custard apple anonaine, flavonoids, coumarins, [3, 58] squamosa L. seed terpenoids Arachis Vitamin E, flavonoid, tannins, 15. Fabaceae Mung-phali Seed [3, 59] hypogaea L. alkaloid, fat, oils, lignins, saponins Arctium lappa Flavonoid, hexasaccharide, tannin, 16. Compositae Great burdock Root [3, 60] L. volatile oil, lignans Asclepias 17. Asclepiadaceae Mohari Root Asclepiadin, glucol [3] syriaca L. Asparagus 18. racemosus Liliaceae Shatavari Root Oil, saponin [3, 31] Willd Atropa 19. Solanaceae Belladona Root Alkaloid, tannin, starch [3, 61] belladona L. Alkaloid, flavonoid, steroid, Azadirachta glycosides, amino acid, reducing 20. Meliaceae Nimb Leaves [3, 62] indica L. sugar, azardin, resin, tannin, saponins, phenols, fixed oils,

TMR | September 2020 | vol. 5 | no. 5 | 394 Submit a manuscript: https://www.tmrjournals.com/tmr

REVIEW doi: 10.12032/TMR20200603189

Table 1 Overview of South Asian medicinal plants used in therapy for kidney diseases (continued) Botanical name Family Local name Part used Chemical constituents References 21. Bacopa monnieri L. Scrophulariacea Brahmmi Leaves Essential oil, alkaloid [3, 31] Saponins, amino acid, Balanites carbohydrate, alkaloid, 22. Balanitaceae Hingol Root, fruit [3, 63] roxburghii L. flavonoids, tannins, phenolic compounds Alkaloids, graminae, cardiac glycoside, phorbol esters, Baliospermum 23. Euphorbiaceae Danti Leaves, root terpenoid, tannin, saponins, [3, 64] montanum Willd hydrocarbon, sitoserol, D- glucoside Flavonoid, phenols, steroids, Bambusa 24. Graminae Bamboo Leaves tannins, quinones, cholin, [3, 65] arundinacea Von betain, nuclease, urease Cholin, betain, nuclease, 25. Bambusa nutans L. Arundinacea Bamboo Leaves [3] urease Alkaloid, phenolic compounds, tannins, Barleria prionitis 26. Aceanthaceae Kate-Koranti Leaves, flowers saponins, essential oil, [3, 66] Linn. flavonoid glycoside, β- sitosterol Alkaloid, saponnins, iodine, fiuorine, carotenoids, 27. Basella alba L. Basellaceae Indian spinach Leaves [3, 67] flavonoid, diterpenes, phenols, tannin Alkaloid, glycoside, Benincasa hispida flavonoids, phenolic 28. Cucurbitaceae White gourd Fruit, seed [3, 68] (Thunb) Cogn compounds, glucoge, mannitol, β-sitosterol, protene Tannins, β–sitosterol, D- 29. Bombax ceiba L. Bombacaceae Salmali Fruit [3] glucoside Boswellia serrata Tanins, pentosans, lignin, 30. Burseraceae Dhupali, Salai Gum [3, 31] roxb holocellulose, β–sitosterol Essentinl, amino acid, Brassica oleracea 31. Brasscaceae Cabbage Leaves alkaloid, tannins, flavonoids, [3, 69] L. glycosides, terpenes Butea monosperma Glucoside, butine, proteolytic 32. Fabaceae Palash leaves [3, 31] Lam lipolytic enzyme, flavonoid Amino acid, galactoside, 33. Cajanus cajan L. Fabaceae Millsp, Tuvar Leaves, seed tannins, saponins, alkaloids, [3, 70] flavonoids, phenols 34. Carica papaya L. Caricaceae Papaya Fruit Alkaloid, papain enzymes [3, 4, 41] Alkaloid, sitosterol, 35. Cassia absus L. Caesalpiniaceae Ran Kulith Leaves, seed [3, 71] glucoside, flavonoid 36. Cassia fistula L. Caesalpiniaceae Bahava Leaves, pods Glycoside, tannin, flavonoid [3, 31] Chelidonium jajus 37. Papaveraceae Celandine Flowers Alkaloids, flavonoids [3] L. Teraxeron, glucoside, 38. Clitoria terneata L. Papilionaceae Aparajita Root [42] oligosaccharide Saccharose, sorbitol alcohol, Leaves, seed, ketones, alkaloid, tannins, 39. Cocos nucitera L. Arecaceae Coconut [3, 72] fruit saponins, steroid, glycosides, terpenoids Commiphora mukul 40. Burseraceae Guggal Gum Guggulsterone, flavonoid [3] Engl 41. Cornus canadensis Cornaceae Bunchberry Whole plant Antioxidant phenolics [1]

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 395

doi: 10.12032/TMR20200603189 REVIEW

Table 1 Overview of South Asian medicinal plants used in therapy for kidney diseases (continued) Botanical name Family Local name Part used Chemical constituents References Alkaloid, tannin, coumarins, Cordia dichotoma 42. Boraginaceae Bhoker Fruit flavonoids, saponins, terpenes, [3, 73] Forst sterols Linalool, linalyl acetate, thymol, Crataeva Religoea β-caryphyllene, α-pinene borneol, 43. Capparidaceae Varun Bark, leaves [3] Buch, Ham limonene, Β-pheliandrene, citranellol Saponins, curculigo, Curculigo 44. Amaryllidaceae Kalimusli Root phenolicglycoside, alkaloids, [3, 74] orchioides Gaertn steroids β-ionone, 2-propionic4- Cynodon dactylon 45. Gramineae Durva Root hydroxybenzoic, tannins, [3, 75] Pers saponins, phenols, flavonoids Essential oil, cyperene, cyperol, starch, β-sitosterol, phenolic 46. Cyperus rotundus Cyperaceae Nagermotha Root [3, 76] compounds, steroids, flavonoids, glycosides Alkaloid, scopolamine, Leaves, hyposcymine, atropin, vitamin C, 47. Datura metal L. Solanaceae Datura [3, 77] flowers saponins, flavonoids, phenols, alkaloids, glycosides, steroids Oil, carotol, essential oil, 48. Daucus carota L. Umbelliferae Carrot Root [3, 78] flavones, phenolic compounds Demostachya 49. Compositae Kush Root Alkaloid, terpenoid [3, 79] bipinnata L. Desmodium 50. Fabaceae Salpan Root Alkaloids [3, 31] gangeticum L. Glycosides, flavonoids, saponin, Digitalis Purpurea 51. Scrophulariacea Hrutpatri Leaves volatile oil, fatty matter, starch, [3, 80] L. gum, sugars Urease, lectin, carbohydrate, 52. Dolichos biflorus L. Leguminosae Kulith Seed [3, 81] glycosides, tannins, saponin Elettaria Palmitic acid, phenols, starch, 53. cardamomum Zingiberaceae Chhoti elaichi Seed tannins, terpinoids, flavonoids, [3, 82] Maton. proteins, sterols Methyl chavicol, limonene, Foeniculum vulgare Seed, essential oil, terpinoids, 54. Apiaceae Saunf [3, 83] Mill flowers flavonoids, sterols, tannins, reducing sugars Volatile oil, sugar, glycosides, Gmeliana arborea tannins, alkaloids, flavonoids, 55. Verbenaceae Jivanti Fruit, leaves [3, 84] (Roxb) sterols, steroid, phenolic compounds Betaine, choline, salicylic acid, Gossypium 56. Malvaceae Cotton Leaves tannins, reducing sugars, steroid, [3, 85] arboreum L. l flavonoids, terpenoid Gymnema sylvestrer Leaves, 57. Asclepiadaceae Gudmar Saponine, I-V, gymnemic acid [3, 31] (Retz) R. Br whole plant Haldina cordifolia Oleoresin, essential oil, cellulose, 58. Rubiaceae Haldu Bark, fruit [3, 86] (Roxb) β-sitosterol, alkaloids, flavonoids Albumin, globulin, glutelin, 59. Helianthus annus L. Compositae Sunflower Seed, root [3] βsitosterol Organic acid, anthocyanin Hibiscus sabdariffa 60. Malvaceae China rose Leaves vitamin, saponins, steroids, [3, 87] L. flavonoids, tannins. TMR | September 2020 | vol. 5 | no. 5 | 396 Submit a manuscript: https://www.tmrjournals.com/tmr

REVIEW doi: 10.12032/TMR20200603189

Table 1 Overview of South Asian medicinal plants used in therapy for kidney diseases (continued) Botanical name Family Local name Part used Chemical constituents References Holarrhena 61. Apocynaceae Kala-Kuda Bark, seed Alkaloids, tannin, triterpene [3, 31] antidysentrica L. Volatile oil, polyphenolic, 62. Humulus lupulus L. Cannabidaceae Hop Fruit [3] tannin, aspargin Fatty oil, alkaloid, saponins, Hygrophila auriculata 63. Acanthaceae Neermali Root, leaves steroids, tannins, flavonoids, [3, 88] K.Schum. Triterpenoids Alkaloid, salicylic acid, Jasmium 64. Oleaceae Chameli Leaves essencial oil, ascorbic acid, [3] grandiflorum L. glycoside β-glucosides, p-coumaric 65. Larix laricina Pinaceae Tamarack Gum [1] acid, α-glucoside 2-hydroxy- 1,4naphthquinoneFlavonoid, Seed, root, 66. Lawsonia inermis L. Lythraceae Mehandi βsitosterol, alkaloid, saponins, [3, 89] leaves steroids, tannins, flavonoids, glycoside Leptadenia reticulata 67. Asclepiadaceae Jivanti Root Stigma sterol, tocopherol [3, 31] W. & A Linum usitatissimum Fixed oil, protene wax, resin, 68. Linaceae Aalsi Seed, root [3] L. sugar glycoside Flavonoid, phenolic acid, 69. Mangiifera indica L. Anacardiaceae Mango plant Leaves Vitamin A, B, C, D, alkaloid, [3, 90] tannins Essential oil, carvones, flavonoids, saponin, 70. Menta arvensis L. Labiatae Podina Leaves [3, 91] alkaloids, tannins, terpenoids, cardiac glycosides Palmitic, stearic, oleic, 71. Mesua ferrea L. Guttiferae Nagkesarah Seed [3] linoleic Essential oil, fatty oil, Leaves, flavonoids, saponin, 72. Michelia champaca L. Magnoliaceae Champa [3, 92] whole plant alkaloids, tannins, sterol, carbohydrate, amino acid Alkaloids, mimosine, terpenoids, flavonoids, 73. Mimosa pudica L. Leguminosae Lajalu Leaves, root [3, 93] glycosides, quinines, phenols, tannins, saponins, coumarin Glycoside, saponin, alkaloids, Momordica dioica Jangali 74. Cucurbitaceae Root steroids, triterpenoids, [3, 94] Roxb ex willd karelaa flavonoids, triterpenes Calcium, phosphorus, iron, 75. Mucana pruriens L. Leguminosae Khaj-kuiri Root, seed [3, 31] sulfur, alkaloids Calcium, glucoside, alkaloids, 76. Mucuna adans L. Leguminosae Khaj-kuiri Root, seed [3] β-sitosterol Albumin, globulin, glutelin, 77. Musa paradiciaea L Scistaminaceae Banana Seed [3, 95] proteoses Alkaloids, nuciferine, protene Seed, sugar, vitamin, cardiac Nelumbium nucifera 78. Nelumbonaceae Lotus leaves, fruit, glycosides, flavonoids, [3, 96] gaertn rhizome saponin, tannin, phlobatanins, phenolic compounds Glycoside, digitoxigenin, 79. Nerium indicum Mill Apocynaceae Kaner Leaves, root tannins, terpenoids, alkaloids, [3, 97] flavonoids, carbohydrates

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 397

doi: 10.12032/TMR20200603189 REVIEW

Table 1 Overview of South Asian medicinal plants used in therapy for kidney diseases (continued) Botanical name Family Local name Part used Chemical constituents References Oil, manitol, tannin, βsitosterol, Nyctanthus tannins, terpenoids, saponins, 80. Oleaceae Parijat Leaves [3, 98] arbortristis L. steroids, carbohydrates, cardiac glycosides, alkaloids, proteins Leaves, Essential oil, methylcinnamate, 81. Ocimum basillicum L. Labiatae Sweet basil [3] root, seed eugenol, alkaloid, Flavonoid Essential oil, eugenol, βsitosterol, flavonoids, 82. Ocimum canum L. Labiatae Sathra Seed [3, 99] carbohydrates, phytosterols, tannins Leaves, Eugenol, methol, ether, 83. Ocimum Sanctum L. Labiatae Tulasi [3, 31] root carvacol Whole Volatile oil, loroglosin, 84. Orchis latifolia L. Orchidaceae Salam [3] plant glucoside Alkaloid, oriline, protene, fat, 85. Orza sativa L. Gramineae Chawal Seed carbohydrate, flavonoid, [3, 100] terpenoids, tannins, phytosterols Dimethoxy, isoflavone, Ougeinia oojeinensis homoferreiri, saponin, 86. Fabaceae Dandan Bark [3, 101] (Roxb) Hochr alkaloids, tannins, glycosides, carbohydrate, flavonoid Essential oil, alkaloids, foetida, Leaves, iridoid glycosides, sitosterol, 87. Paederia foetida L. Rubiaceae Hirenwel [3, 102] root stigmasterol, carbohydrates, protein, amino acid Essential oil, methyl ether, Pandanus 88. Pandanaceae Ketek Leaves phenyl ethyl alcohol, alkaloid, [3, 103] odoratissimus L. flavonoid 89. Phaseolus mungo L. Leguminoseae Green gram Seed Oil [3] Alkaloid, flavonoids, phyllanthin, hypophyiianthin, 90. Phyllanthus niruri L. Euphorbiaceae Bhui awala Seed terpenoids, cardiac glycoside, [3, 104] saponins, tannins, cyanogenic glycosides Alkaloid, flavonoid-quercetin, Phyllanthus urinaria Valaitisaunf, 91. Euphorbiaceae Seed astragalin, carboxylic acids, [3, 105] L Muhuri tannins, coumarins, lignans Phyllanthus Tannic acid, steroid, tannin, 92. Euphorbiaceae Jarmala Leaves [3, 106] reticulates Pair quinone, phenol 93. Pimpinella anisum L. Umbelliferae Rajanigandh Leaves Volatile oil, flavonoid, sterol [3] Diterpenes, strobol, strobal, 94. Pinus strobus Pinaceae White pine Bark, twig manoyl oxide, cis- and trans- [1, 43] abienols Piperin, piredin alkaloid, 95. Piper nigrum L. Pipereceae Blak piper Seed [3, 31] chavicine essential, oil Saccharum 96. Poaceae Suger cane Seed, root Phenol, glycolic acid [3] officinarum L. Santalbic acid,palmitic acid, 97. Santalum album L. Santalaeae Safed chandan Weed [3] olic acid Tannin, atechol, sterol, Leaves, 98. Saraca indica L. Leguminosae Ashok tree glycocide, steroid, saponin, [3, 107] seed, bark tannin, phenolic compounds Purple pitcher Quercetin, taxifolin compounds, 99. Sarracenia purpurea Sarraceniaceae Root [1, 44] plant betulinic acid, ursolic acid

TMR | September 2020 | vol. 5 | no. 5 | 398 Submit a manuscript: https://www.tmrjournals.com/tmr

REVIEW doi: 10.12032/TMR20200603189

Table 1 Overview of South Asian medicinal plants used in therapy for kidney diseases (continued) Botanical name Family Local name Part used Chemical constituents References Securinega Alkaloids, freetriterpens, 100. Euphorbiaceae Hartto Leaves [3] leucopyrus Muell-Arg steroids, tannin Alkaloid, enzymes, steroidal glycoside, sesquiterpenoids, hydroxycoumarins, phenolic 101. Solanum indicum L. Solanaceae Dorli Whole plant [3, 108] compounds, coumarins, alkaloids, saponin, fatty acid, polysaccharide, triterpenes Solanum surattense Gluco alkaloid, solasodine, 102. Solanaceae Katali Kattay Fruit, flower [3] burn solasonine Solanum xantocarpum Carpesterol, glucoside, 103. Solanaceae Kateringani Root [3, 31, 42] schrad & Wendell alkaloid, solanocarpine Solena amplexicaulis Gomathi 104. Umbelliferae Root Alkaloid, glycoside, steroid [3] Lam Tawgaula Calcium, phosphate, silica 105. Tectona grandis L. Verbenaceae Teak Whole plant [3, 41, 42] ammonium Tephrosia purpurpa 106. Fabaceae Sarphomka Leaves Tephrosin, rotenone [3, 42] L. Terminalia chebula Palmitic, stearic, oleic, 107. Combrataceae Hirda Seed [3, 31] Retz linoleic, astrigent, tannic acid Flavonoids, amines, steroids, phenols, phytosterols, 108. Urtica dioica L. Urticaceae Guelder rose Root [3, 109] saponins, tannins, amino acids Amino acid, linoleic, Vernonia 109. Asteraceae Kalijira Fruit myristic, oleic, palmitic, [3, 110] antheimintica Willid sterols, alkaloid, flavanoids Thiamine, niacin, biotin, 110. Vitis vinifera L. Vitaceae Wine grape Fruit tocoferol, coumarins, [3, 111] flavanoids Zingiber officinale 111. Scitaminaceae Ginger Rhizome Essential oil, volatile oil [3, 42] (Rose) Alkaloid, zizipine, flavonoids, 112. Zizyphus xylopyrus L. Rhamnaceae Kath ber Leaves [3, 112] saponins, tannins the scientific investigation of nephroprotective activity the cellular surface changing the area available for ion of the medicinal plants in animal models. Several transportation. These changes may result in different nephrotoxic agents, including therapeutic accumulation of intracellular calcium and loss of drugs, diagnostic agents, and chemicals, have been used enzymes and nucleotides. An increase in calcium in the to induce nephrotoxicity in animal models. The most renal cortex and mitochondria may lead to features of common among them is the use of various cellular necrosis and renal failure [114]. Further, antineoplastic agents including the following: cisplatin, intracellular metabolism of these toxic drugs lead to the cyclophosphamide, streptozotocin, carmustine, formation of reactive metabolites, such as free radicals, lomustine, semustine, mitomycin, mithramycin, and which are toxic for cells. The superoxide ions formed doxorubicin. Moreover, aminoglycosides, such as during oxidation of hydroxyl radicals in turn leads to gentamycin, amikacin, kanamycin, and streptomycin, lipid peroxidation. This effect may result in oxidative and antimicrobial agents, such as tetracycline, deterioration of polyunsaturated lipids of membranes, acyclovir, pentamidine, sulfadiazine, trimethoprim, and causing modification of the structure and function. rifampicin are widely used as nephrotoxic agents. Moreover, these nephrotoxins may reduce the Furthermore, the literature supports the use of heavy concentration of antioxidants, superoxide dismutase, metals such as Hg, As, Pb, and Bi as nephrotoxic agents glutathione, catalase, vitamin E, and ascorbic acid, all [113, 114]. of which are protective against free radical injury. In These toxins may directly affect the membrane addition, these toxins might induce changes in the permeability of renal tubular cells, thereby causing integrity of renal tubular cells, thereby causing several potential injury. Further, they involve in remodeling of lethal changes such as development of abnormally

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 399 doi: 10.12032/TMR20200603189 REVIEW enlarged lysosomes and myeloid bodies, loss of brush were investigated in several studies [120, 121, 125, 131, border membrane, and vacuolization and dilation of the 132, 136, 139]. Assessment of histopathology in endoplasmic reticulum. Free radical-induced renal hematoxylin and eosin-stained kidney sections for the damage has been demonstrated in several in vivo and in features of glomerular congestion, tubular casts, vitro studies that have shown the development of peritubular congestion, epithelial desquamation, blood glomerular dysfunction and proteinuria because of vessel congestion, and presence of inflammatory cells altered glomerular permselectivity by chemical infusion have also been conducted for the evaluation of the of reactive oxygen species [114]. nephroprotective effects of these medicinal plants in Table 2 details the nephroprotective medicinal plants selected animal models [114, 115, 116]. for which the protective activity was investigated in In addition to these medicinal plants, the animal models. The nephroprotective activity was nephroprotective activity of a polyherbal mixture evaluated using changes in renal function parameters as composed of Bauhinia racemosa (Caesalpiniaceae; follows: serum creatinine, blood urea, serum protein, stem bark), Dolichos biflorus (Fabaceae; seed), serum albumin, urine creatinine, urinary protein, Sphaeranthus indicus (Asteraceae; flower), Tectona albumin, uric acid, and urinary osmolality [113, 118, grandis (Verbenaceae; saag seed), Tephrosia purpurea 121, 124, 129, 143]. Furthermore, plasma (Fabaceae; leaves) and Tribulus terrestris concentrations of malondialdehyde, superoxide (Zygophyllaceae; fruit) have been investigated for dismutase, reduced glutathione, and total antioxidants nephroprotective effect by Chopda et al. [8].

Table 2 South Asian medicinal plants investigated for nephroprotective activity in animal models Botanical Chemical Reported Family Local name Part used Screening method References name constituents bioactivities Cisplatin (ethanol Asparagines, Abutilon Whole 1. Malvaceae Atibalaa extract- mucilage, tannin, Antioxidants [113, 73, 3] indicum plant pretreatment) alkaloids Diuretic, spermicidal, anti- Deprived of water allergic, for eighteen hours cardiovascular, Achyranthes Whole for investigation of Alkaloids, saponin, 2. Amaranthaceae Apamarga nephroprotective, [119, 3] aspera Linn plant diuretic acivity tannin oil antiparasitic, (methanolic hypoglyceamic, extract) analgesic, and antipyretic Antidiabetes, Monoterpene, antiproliferative, Acetaminophen Acorus Bach, Aerial sesquiterpene, immunosuppressive 3. Araceae (ethanol extract- [120] calamus L. Ugragandha part phenylpropanoid, , antidiarrhoeal, pretreatment) flavonoid, quinone hypolipidemic, antioxidant Aegeline, aegelinine, rutin, lupeol, sterol, Cardiotonic effect, tannins, flavanoids, antifungal, quercetin β- Aegle Gentamicin analgesic and sitostersol, β-D- [41, 113, 4. marmelos Rutacae Bael Leaves (aqueous extract- antioxidant glucoside, 121] Linn pretreatment) activities, cellular marmesinine, anti-inflammatory phlobatannins, activity umbelliferone, volatile oils Isoquercetin, 5 methylmellein, Antioxidant and 2hydroxy -3-O-β free radical Aerva Cisplatin (aqueous primeveroside scavenging [113, 122, 5. javanica Amaranthaceae Pasanabheda Roots extract- naphthalene-1, properties, 123] Juss. posttreatment) 4dione, apigenin anthelmintic, 7oglucoronide, diuretic, demulcent kaempferol TMR | September 2020 | vol. 5 | no. 5 | 400 Submit a manuscript: https://www.tmrjournals.com/tmr

REVIEW doi: 10.12032/TMR20200603189

Table 2 South Asian medicinal plants investigated for nephroprotective activity in animal models (continued) Botanical Part Screening Reported Family Local name Chemical constituents References name used method bioactivities Cisplatin (ethanol flavonoides, glycoside, Diuretic, hepato 6. extract- botulin, β-sitostersol, protective, Aerva Pasanabheda Whole posttreatment) amyrin, campesterol, antidiabetic, [41, 113, lanata L. Amaranthaceae , Chaya, plant Gentamicin kaempferol,propionic antimicrobial, 114] Juss Gorakhganja (ethanol acid, aervoside, anthelmintic and

extract- aervolanine demulcent activity pretreatment) Gentamicin Antioxidant and free (aqueous radical scavenging 7. extract- activity, anti- pretreatment) inflammatory, antiviral, antitumor, moisturizing, anti- Anthraquinones, tannin, aging effect, Aloe [42, 113, Xanthorrhoeaceae Aloe vera Leaves saponin, flavonoids, antiseptic, enhance barbadensis Cisplatin 124] terpenoids immune system, (aqueous 8. hypoglycemic, extract- cytotoxic, antiulcer pretreatment) and antidiabetic effects, antibacterial effect, antioxidant, cardiovascular effect Antimicrobial, antifungal, anti- inflammatory, analgesic, Glycerol Flavonoids, terpinoids, Azima Wel dehi, antioxidant, antiulcer, 9. Salvadoraceae Root (ethanol alkaloids, tannins, [10, 125] tetracantha Katuniyanda anticancer, anti-snake extract) saponins, glucosinolates venom, diuretic and hepatoprotective activity, vasodilatory activity Antitumour, antimicrobial, anti- Gentamicin Flavonoids, tannins, inflammatory, Bauhinia (ethanol and steroids, saponins, Koboleela, antioxidant, 10. Variegata Caesalpiniaceae Root aqueous triterpenes, quercetin, [10, 41, 127] Kovidara hepatoprotective, Linn. extracts-post rutin, apigenin, apigenin antihyperlipidemic, treatment) 7-O-glucoside immunomodulatory activities. Flavanoids, alkaloids, Acetaminophe triterpenoids, proteins, Diuretic, anti- Boerhaavia n (aqueous carbohydrates, [31, 41, 113, 11. Nyctaginaceae Punarnava Roots inflammatory, diffusa extract- glycosides, lipids, 114, 123] antiarthritic pretreatment) lignins, glycoprotiens, steroids, lignins, CCL4 (ethanolic and Antiviral, anticancer, Bridelia Stem Glycosides, steroids, 12. Euphorbiaceae Kajja aqueous hypotensive [11, 128] retusa bark tannins, terpenoids extracts-post properties treatment)

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 401 doi: 10.12032/TMR20200603189 REVIEW

Table 2 South Asian medicinal plants investigated for nephroprotective activity in animal models (continued) Botanical Part Chemical Reported Family Local name Screening method References name used constituents bioactivities Antimalarial, Flavone, aglycones, antifilarial, Acetaminophen triterpinoids, antiparasitic, Cardiosper (methanol and glycosides, antipyretic, anti- mum Whole 13. Sapindaceae Kanphuti petroleum ether carbohydrates, fatty inflammatory, [114, 129] halicacabum plant extracts- acids, volatile ester antianxiety, Linn. pretreatment) sterol, saponins, antiulcer activity, flavonoids, tannin antihyperglycemic activity Cisplatin (ethanol 14. extract-post Tannins, Di-(2 ethyl) Antioxidant and Ranawara, treatment) Cassia hexyl phthalate, free radical [10, 41, 42, Fabaceae Avartaki, Roots Gentamicin auriculata alkaloids, resins, Ca2+ scavenging 114] Adaari (ethanol extract- and phosphorous property both pre and post treatment) Gentamicin Diuretic, anti- 15. Fruits (aqueous extract- inflammatory, post treatment) antioxidant, cardio- Kaemferol-3-O-a-D- protective, glucoside, quercitin3- hepatoprotective, O-a-D-glucoside, Crataeva lithonotriptic, anti- [113, 114, Capparidaceae Varuna flavanoids, nurvala Cisplatin (ethanol rheumatic, anti- 130] Stem glucosinolates, 16. extract- periodic, bark steroids, lupeol, pretreatment) contraceptive, tannins antiprotozoal, rubifacient, vesicant Glycosides, carbohydrates, Indigofera Nephroprotective, Whole Paracetamol flavonoids, tannins & [113, 134, 17. barberi Fabaceae Thummajalari hepatoprotective plant (ethanol extract) phenols, steroids, 135] Linn. activity triterpenoids, tannins, phenols. tannin, saponin, gluanol acetate, βsitosterol, leucopelargonidin-3- O -β-D- glucopyranoside, Antitumor activity, Cisplatin (methyl leucopelargonidin-3- anthelmintic Ficus alcohol extract- [113, 114, 18. Moraceae Pepal Bark O-α-L- activity, religiosa both pre and post 132] rhamnopyranoside, antimicrobial treatment) lupeol, ceryl activity behenate, lupeol acetate, α-amyrin acetate, leucoanthocyanidin, leucoanthocyanin Flavanoids, Gentamicin bilobalide, gingkolide Ginkgo Maidenhair Whole (aqueous extract- 19. Ginkgoceae A, gingkolide B, Antioxidant effect [41, 114] biloba tree plant concurrent gingkolide C, administration) biflanoide TMR | September 2020 | vol. 5 | no. 5 | 402 Submit a manuscript: https://www.tmrjournals.com/tmr

REVIEW doi: 10.12032/TMR20200603189

Table 2 South Asian medicinal plants investigated for nephroprotective activity in animal models (continued) Botanical Reported Family Local name Part used Screening method Chemical constituents References name bioactivities Anticancer, chemopreventive, immunomodulatory activity, wound healing activity, 2-hydroxy 4-methoxy antiulcer activity, benzaldehyde, fatty antioxidant and free Gentamicin acids, saponin, tannins, Hemidesm radical scavenging (aqueous extract- resinal fractions, resin 20. us indicus Asclepiadaceae Anantmool Root activity, [1, 116, 133] concurrent acids, sterols, β- Linn. hepatoprotective administration) sitosterol, stigmasterol, activity, anti- sarsapic acid, lupeol, inflammatory vanillin, rutin effect, diuretic, antihypergycemic effect, antimicrobial activity Antioxidant, Eruca HgCl2 (ethanolic Glucosinolate, 21. Brassicaceae Arugula Seed astringent, diuretic, [113, 131] sativa extract-pretreated) flavanoids, caratenoids digestive Antioxidant and Cyclophosphamide Carbohydrates, free radical (methanol and Murraya Curry leaf flavonoids, tannins, scavenging activity, 22. Rutaceae Leaves aqueous extracts- [136] koenigii plan alkaloids, glycosides, hypoglycemic, anti- concurrent protein, steroid cancer, administration) hepatoprotectve Sodium fluoride Hypotensive, Moringa Carotene, nicotic acid, (aqueous extract- anticancer, 23. oleifera Moringaceae Malunggay Seed ascorbic acid, amino [3] concurrent antibacterial M. acid administration) activities Diuretic, antihypertensive, antidiabetic, anticancer and Alanine, L-spinasterol, immunomodulatory arabic acid, arginine, , analgesic, aminoacid, aspargine, antimicrobial, aspartic acid, carvone, anthelmintics, Nigella Gentamicin [41, 114, 24. Ranunculaceae Black seed Seed cystine, cholesterol, analgesics and anti- sativa (oil-post treatment) 137] glutamic acid, linoleic inflammatory, acid, melanthin, spasmolytic, myristic acid, oleic acid, bronchodilator, tannins gastroprotective, hepatoprotective, renal protective, and antioxidant properties. Anti-inflammatory, Flavonoids, antibacterial, Orthosiph Gentamicin polyphenols, diuretic, [41, 115, Cat’s 25. on Lamiaceae Leaves (methanol extract- carbohydrates, steroids, hypoglycemic 117, 138, whiskers stamineus post treatment) tannins, glycosides, activity, 139] terpins, saponins antihypertensive activities

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 403 doi: 10.12032/TMR20200603189 REVIEW

Table 2 South Asian medicinal plants investigated for nephroprotective activity in animal models (continued) Botanical Part Screening Reported Family Local name Chemical constituents References name used method bioactivities b-glucouronidase Monoterpene inhibitory activity, glycosides, Streptozotozin lipoxygenase monoterpene (alcohol and inhibiting activity, Paeonia emodi galactosides, triterpene, 26. Paeoniaceae Ood-saleeb Root hydroalcohol hydroxyl radical [117] Royle 1,5-dihydroxy-3- extracts-post scavenging activity, methyl-anthraquinone, treatment) neuroprotection, ethylgallate, methyl anticonvulsant grevillate activity Cisplatin Flavanoids, flavones, Diuretic, analgesic Pedalium (ethanol alkaloids, titerpenoids, and antipyretic [41, 140, 27. Pedaliaceae Gokhru Fruit murex Linn extract-post carbohydrates, activities, 141] treatment) glycosides, saponins antioxidant activity Cisplatin Flavonoids, pongamol, Magul Pongamia (ethanol protien, alkaloids, [4, 41, 114, 28. Papilionaceae karanda, Flower Antioxidant pinnata extract-post tannins, sugar, resin, 126] Indian beach treated) fatty oil Salvianolic acid –G, Cisplatin rosmarinic acid, Whole (methanol [4, 41, 114, 29. Salviae radix Lamiaceae Red sage lithospermic acid, Antioxidant plant extract-post 142] isoferulic acid, treatment) tanshinone I, IIA, IIB Laxative, emollient and demulcent, Streptozotocin protect the liver Tocopherols, induced from oxidative phytosterols, Sesamum diabetic rats- damage, 30. Pedaliaceae Sesame Seed resveratrol, flavonoids, [1, 143, 144] indicum Linn. ethanol antibacterial, anti- lignans sesamin, and extract-post fungal, antiviral sesamolin. treated and anti- inflammatory, analgesic activity Alloxan induced Antiulcer, Tectona diabetes Calcium, phosphate, antimicrobial, 31. Verbenaceae Teak Bark [145] grandis Linn. (ethanol silica ammonium wound healing, extract-post anticancer activity treatment) Gentamicin Saponine, diosgenine, Tribulus (aqueous 32. Zygophyllaceae Gokshura Fruits gitogenine, flaonoids, Diuretic [46, 50, 117] terrestris extract-post alkaloid treatment) Gentamicin Alkaloids, withaminon, (aqueous wasamin, sugars, Withania Antioxidant 33. Solanaceae Ashwagandha Root extract- glycosides, aminoacids, [1, 41, 116] somnifera activity concurrent essential oils, withaniol, administration) phytosterol, oils

Gentamicin was administered to induce renal toxicity. tubular necrosis, increased urinary space, loss of Coadministration of the polyherbal mixture at three epithelial lining, and inconspicuous nucleoli in the selected doses resulted in reverting changes in nephrotoxic control group. However, the highest dose biochemical parameters. The protective effect was of the polyherbal mixture resulted in restoration of the found increased with the increased dose of the mixture. changes induced by gentamicin in the animal model. Assessment of histopathology revealed the features of Further, the polyherbal preparation has shown relatively TMR | September 2020 | vol. 5 | no. 5 | 404 Submit a manuscript: https://www.tmrjournals.com/tmr

REVIEW doi: 10.12032/TMR20200603189 high antioxidant activity in the kidney tissues [8]. been given to the use of phytochemicals as a protective Moreover, the protective role of the aged garlic strategy against nephrotoxicity [146]. A major turning extract (AGE), which works as an antioxidant, has been point was the demonstration of nephroprotective investigated on gentamicin induced nephrotoxicity in potential for phenolic compounds, including flavonoids male Wistar rats. Pretreatment with the AGE at a dose [146]. Table 3 depicts such phytoconstituents/ of 1.2 mL/kg every 12 hours ameliorated the changes in compounds isolated from South Asian medicinal plants biochemical parameters and histopathology induced by with proven nephroprotective effects against gentamicin, suggesting the use of AGE for the nephrotoxicity tested in animal models. prevention of gentamicin induced nephrotoxicity [114]. Similar studies have been used for evaluation of the In vitro assessment of nephroprotective activity nephroprotective effect of compounds isolated from Based on the ethical concerns and the “3R” principle: medicinal plants, and increasingly more attention has reduction, replacement, and refinement, more attention

Table 3 Nephroprotective secondary metabolites from South Asian medicinal plants against nephrotoxicity in animal models Secondary Chemical name (IUPAC Animal Plant source Chemical structure References metabolite name) model

S Cisplatin induced C Benzyl (Isothiocyanatomethyl) Cruciferous 1 nephrotoxici N [147] isothiocyanate benzene vegetables ty in Swiss Albino mice

Bis [(2S, 3R, 4S, 5S, 6R) 3, 4, 5 trihydroxy-6

({[(2R,3R,4S,5S,6R) 3,4,5- OH

OH HO

trihydroxy6 O Cisplatin OH (hydroxymethyl) O OH Crocin induced O CH3 CH3 O

tetrahydro-2H-pyran- Crocus HO O 2 (carotenoid nephrotoxici O OH [148, 149] OH O O CH3 CH3 2yl]oxy} methyl) sativus L. HO pigment) ty in Wistar O

tetrahydro-2Hpyran-2-yl] HO albino rats O OH (2E, 4E, 6E, 8E, 10E, 12E, HO OH 14E) 2, 6, 11, 15- tetramethyl2, 4, 6, 8, 10, 12, 14hexadeca heptaenedioate

Adriamycin O OH (1E, 6E)-1, 7-Bis induced (4hydroxy- Curcuma 3 Curcumin nephrotoxici [148, 150] 3methoxyphenyl)-1, longa HO OH ty in Wistar O O H3C 6heptadiene-3, 5-dione CH3 rats O OH

NaF- 3, 4, 5-trihydroxybenzoic Peltiphyllum 4 Gallic acid intoxicated [151] acid peltatum Wistar rats HO OH

OH Low-dose

Naringenin 5, 7-dihydroxy-2-(4- streptozotoc HO O 5 (bioactive hydroxyphenyl) chroman-4- Citrus fruits in induced [152] flavonoid) one damage in mice OH O

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 405 doi: 10.12032/TMR20200603189 REVIEW

Table 3 Nephroprotective secondary metabolites from South Asian medicinal plants against nephrotoxicity in animal models (continued) Secondary Chemical name Plant Animal model Chemical structure References metabolite (IUPAC name) source

Cassia OH

auriculata OH 2-(3, 4- Gentamicin Quercetin , Phoenix dihydroxyphenyl) 3, induced HO O 6 (polyphenolic dactylifer [148, 153] 5, 7-trihydroxy- nephrotoxicity in ﬂavonoid) a L., 4Hchromen-4-one Wistar albino rats OH Ramulus mori OH O

5-[(E)-2- Cisplatin induced Resveratrol Grapes HO (4hydroxyphenyl) nephrotoxicity in 7 (polyphenolic and [147, 148] ethenyl] benzene-1, Swiss Albino phytoalexin) berries 3diol mice

Cisplatin and 2-Isopropyl- gentamicin Nigella 8 Thymoquinone 5methylbenzo-1, 4- induced [137, 148] sativa quinone nephrotoxicity in rats

O has been recently directed toward in vitro cell-based of research studies are being conducted on medicinal studies for the discovery of new therapeutic candidates. plants native to the South Asian region, in combination Accordingly, a number of studies have been conducted with modern technology for the discovery of on the therapeutic efficacy of medicinal plants in kidney nephroprotective agents. The discoveries will be diseases using different cell lines such as human renal beneficial in the near future in the clinical arsenal of proximal tubule cells HK-2, pig kidney epithelial cells medicine, especially for patients with limited access to LLC-PK1, and human embryonic kidney cells use expensive Western systems of medicine. Further, HEK293, in different nephrotoxicity models [154]. The these findings will be advantageous for developing nephroprotective effect was assessed by the nutraceuticals with high nephroprotective effects in the measurement of cell viability through 3-(4, 5- management of CKD. dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) bioassay in most of the studies [146]. References Scoparia dulcis Linn. (Scrophulariaceae) is one such South Asian medicinal plant for which nephroprotective 1. Chand MG, Chand T. A Critical review on activity was determined by MTT assay in HEK 293 commonly used herbal drugs in CKD. J Med Plants against gentamycin-induced nephrotoxicity [155]. Stud 2015, 3: 44–47. However, sparse evidence is available for the in vitro 2. Srivastava AK, Kaushik D, Shrivastava AK, et al. assessment of nephroprotective medicinal plants of Nephroprotective ethno-medicinal action of South Asian origin. selected Indian medicinal plants. Int J Pharm Sci Drug Res 2017, 8: 11–24. Conclusion 3. Talele BD, Mahajan RT, Chopda MZ, et al. Nephroprotective plants: a review. Int J Pharm Medicinal plants used in traditional systems of medicine Pharm Sci 2012, 4: 8–16. have become valuable sources of knowledge for modern 4. Gaikwad K, Dagle P, Choughule P, et al. A review medicine. This plant-based knowledge serves as a on some nephroprotective medicinal plants. Int J powerful search engine as well as a facilitator for the Pharml Sci Res 2012, 3: 2451–2454. discovery of novel drugs. Accordingly, a large number 5. Gogtay NJ, Bhatt HA, Dalvi SS, et al. The use and

TMR | September 2020 | vol. 5 | no. 5 | 406 Submit a manuscript: https://www.tmrjournals.com/tmr

REVIEW doi: 10.12032/TMR20200603189 safety of non-allopathic Indian medicines. Drug injury prevention. J Renal Injury Prev 2013, 2: 63– Saf 2002, 25: 1005–1019. 65. 6. World Health Organization [Internet]. Traditional 20. Oluyombo R, Ayodele OE, Akinwusi PO, et al. medicine in Asia [cited 11 March 2020]. Available Awareness, knowledge and perception of chronic from: http://origin.searo.who.int/entity/medicines/ kidney disease in a rural community of South-West documents/traditional_medicines_in_asia.pdf. Nigeria. Nigerian J Clin Pract 2016, 19: 161–169. 7. Sheehan HE, Hussain SJ. Unani tibb: history, 21. Wijetunge S, Ratnatunga NVI, Abeysekera TDJ, et theory, and contemporary practice in south Asia. al. Endemic chronic kidney disease of unknown Ann Am Acad Political Soc Sci 2002, 583: 122– etiology in Sri Lanka: correlation of pathology 135. with clinical stages. Indian J Nephrol 2015, 25: 8. Chopda MZ, Talele D, Mahajan NG, et al. 274–280. Nephroprotective study of polyherbal formulation 22. Das S, Vasudeva N, Sharma S. Kidney disorders in drug induced nephrotoxic rats. Int J Appl Res and management through herbs: a review. J 2017, 3: 243–246. Phytochem 2019, 8: 21–27. 9. Ahmad QZ, Jahan N, Ahmad G. An appraisal of 23. Cerbo AD, Iannitti T, Guidetti G, et al. A nephroprotection and the scope of natural products nutraceutical diet based on Lespedeza spp., in combating renal disorders. J Nephrol Ther 2014, Vaccinium macrocarpon and Taraxacum ofﬁcinale 4: 4–10. improves spontaneous feline chronic kidney 10. Jayaweera DMA. Medicinal plants (indigenous disease. Physiol Rep 2018, 6: e13737. and exotic) used in Ceylon. Monog Collect 1980, 24. Ash S, Campbell KL, Bogard J, et al. Nutrition 3:110–111. prescription to achieve positive outcomes in 11. Institute of Ayurveda and Alternative Medicine chronic kidney disease: a systematic review. [Internet]. Ayurvedic medicinal plants of Sri Nutrients 2014, 6: 416–451. Lanka [cited 11 March 2020]. Available from: 25. Levin A, Stevens PE, Bilous RW, et al. Kidney http://www.instituteofayurveda.org/plants/plants_ disease: improving global outcomes (KDIGO) search.php. CKD work group. KDIGO 2012 clinical practice 12. Ene-iordache B, Perico N, Bikbov B, et al. Chronic guideline for the evaluation and management of kidney disease and cardiovascular risk in six chronic kidney disease. Kidney Int Supp 2013, 3: regions of the world (ISN-KDDC): a cross- 1–150. sectional study. Lancet Glob Health 2016, 4: 307– 26. Nikolaidou B, Katsiki N, Lazaridis A, et al. The 319. effects of nutraceuticals in patients with or without 13. Pugsley D, Norris KC, Garcia-garcia G, et al. chronic kidney disease: classification matters. Global approaches for understanding the Open Hypertens J 2013, 5: 35. disproportionate burden of chronic kidney disease. 27. Riccio E, Nuzzi AD, Pisani A. Nutritional Ethnic Dis 2009, 19: S1-1–S1-2. treatment in chronic kidney disease: the concept of 14. Gomes M, Mastroianni G. Chronic kidney disease: nephroprotection. Clin Exp Nephrol 2015, 19: importance of early diagnosis, immediate referral 161–167. and structured interdisciplinary approach to 28. Medscape [Internet]. 2018. Chronic kidney disease improve outcomes in patients not yet on dialysis. treatment and management [cited 11 March 2020]. Braz J Nephrol 2011, 33: 74–87. Available from: 15. Rukhaimi M Al, Sahow A Al, Boobes Y, et al. https://emedicine.medscape.com/article/238798. Adaptation and implementation of the “kidney 29. Akyol AD, Yildirim Y, Toker E, et al. The use of disease: improving global outcomes (KDIGO)” complementary and alternative medicine among guidelines for evaluation and management of chronic renal failure patients. J Clin Nurs 2011, 20: mineral and bone disorders in chronic kidney 1035–1043. disease for practice in the middle east countries. 30. Shamsuddin N, Gnanasan S, Karuppanan M, et al. Saudi J Kid Di Transpl 2014, 25: 133–148. Complementary and alternative medicine (CAM) 16. Mishra SR, Adhikari S, Sigdel MR, et al. Chronic in chronic kidney disease (CKD): more evidence kidney disease in south Asia. Lancet Glob Health needed. Altern Integr Med 2016, 5:4–5. 2016, 4: e523. 31. Ravishankar B, Shukla VJ. Indian systems of 17. Jha V. Current status of chronic kidney disease medicine: a brief profile. Afr J Tradit Complement care in Southeast Asia. Semi Nephrol 2009, 29: Altern Med 2007, 4: 319–337. 487–496. 32. Chaudhary A, Singh N. Contribution of World 18. Abraham G, Varughese S, Thandavan T, et al. Health Organization in the global acceptance of Chronic kidney disease hot spots in developing Ayurveda. J Ayurveda Int Med 2011, 2: 179–186. countries in South Asia. Clin Kidney J 2016, 9: 33. Zyoud SH, Al-jabi SW, Sweileh WM, et al. Use of 135–141. complementary and alternative medicines in 19. Rafieian-kopaei M. Medicinal plants for renal haemodialysis patients: a cross-sectional study

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 407 doi: 10.12032/TMR20200603189 REVIEW from Palestine. BMC Complement Altern Med phytochemical analysis and in vitro antibacterial 2016, 16: 204. activity of Acacia catechu willd bark against 34. Combest W, Newton M, Combest A, et al. Effects Streptococcus mitis, Streptococcus sanguis and of herbal supplements on the kidney. Urol Nurs Lactobacillus acidophilus. Int J Phytomedicine 2005, 25: 381–387. 2011, 3: 579–584. 35. Rahmatullah M, Jahan R, Khatun MA, et al. A 50. Georgieva L, Gadjalova A, Mihaylova D, et al. pharmacological evaluation of medicinal plants Achillea millefolium L.—phytochemical profile used by folk medicinal practitioners. Am Eurasian and in vitro antioxidant activity. Int Food Res J J Sustain Agric 2010, 4: 170–195. 2015, 22: 1347–1352. 36. Ghayur MN, Janssen LJ. Nephroprotective drugs 51. Souza TM, Rangel VLBI, Pietro RCLRr, et al. from traditionally used Aboriginal medicinal Phytochemical screening of Achillea millefolium plants. Kidney Int 2010, 77: 470–471. harvested at Araraquara—SP. Braz J Med Plants 37. Swathi N, Sreedevi A, Bharathi K. Evaluation of 2006, 8: 151–154. nephroprotective activity of fruits of Ficus hispida 52. Mengane SK. Phytochemical analysis of Adiantum on cisplatin-induced nephrotoxicity. Pharmacogn J lunulatum. Int J Curr Microbiol Appl Sci 2016, 5: 2011, 3: 62–68. 351–356. 38. Vaidya ADB, Devasagayam TPA. Current status 53. Venkateshwarlu R, Raju AB, Yerragunta VG. of herbal drugs in India: An overview. J Cli Phytochemistry and pharmacology of Alangium Biochem Nutr 2007, 41: 1–11. salvifolium: a review. J Pharm Res 2011, 4: 1423– 39. Ali SS, Kasoju N, Luthra A, et al. Indian medicinal 1425. herbs as sources of antioxidants. Food Res Int 54. Dalhat MH, Adefolake FA, Musa M. Nutritional 2008, 41: 1–15. composition and phytochemical analysis of 40. Bi W, Gao Y, Shen J, et al. Traditional uses, aqueous extract of Allium cepa (onion) and Allium phytochemistry, and pharmacology of the genus sativum (garlic). Asian Food Sci J 2018, 3: 1–9. Acer (maple): a review. J Ethnopharmacol 2016, 55. Ogbonna OJ, Udia PM, Abe PN, et al. 189: 31–60. Phytochemical and proximate analysis, mineral 41. Jose S, Sreedevi A. A review on medicinal plants and vitamin compositions of Allium Cepa bulb possessing nephroprotector activity. Int J Pharm extract. Adv Biomed pharma 2016, 3: 181–186. 2015, 4: 191–196. 56. Jhade D, Ahirwar D, Jain R, et al. Pharmacognostic 42. Swati P, Rajashekhar I. Role of pants as standardization, physico-and phytochemical nephroprotective agents—a review. Int J Ther evaluation of Amaranthus spinosus Linn. root. J Appl 2015, 26: 6–14. Young Pharm 2011, 3: 221–225. 43. Zinkel DF, Evans BB, Service F. Terpenoids of 57. Dubey R, Shaikh S, Dhande S, et al. Anogeissus Pinus strobus cortex tissue. Phytochemistry 1972, latifolia-an overview. Res J Pharmacogn 11: 3387–3389. Phytochem 2012, 4: 287–290. 44. Muhammad A, Haddad PS, Durst T, et al. 58. Biba VS, Lakshmi S, Dhanya GS, et al. Phytochemical constituents of Sarracenia Phytochemical analysis of Annona squamosa seed purpurea L. (pitcher plant). Phytochemistry 2013, extracts. Int Res J Pharm Appl Sci 2013, 3: 29–31. 94: 238–242. 59. Marka R, Talari S, Penchala S, et al. Preliminary 45. Reine GBS, Houndékon BP, Marcelline G, et al. phytochemical analysis of leaf, stem, root and seed Phytochemical composition and antioxydant extracts of Arachis hypogaea L. Int J Pharm Sci capacity of Abelmoschus esculentus L. fresh Rev Res 2013, 20: 134–139. immature fruits. Am J Food Sci Food Sci Technol 60. Al-Snafi AE. The pharmacological importance and 2018, 6: 223–227. chemical constituents of Arctium lappa. A review. 46. Hussain AZ, Kumaresan S. Phytochemical and Int J Pharm Res Scholars 2014, 3: 663–670. antimicrobial evaluation of Abrus precatorius L. 61. Asha Rani NS, Prasad MP. Comparison studies on Asian Pac J Cancer Prev 2014, 4: 10–14. callus induction of fresh and reused explants of 47. Roqaiya M, Begum W, Jahufe R. Acacia arabica Atropa belladonna. Asian J Plant Sci Res 2014, 4: (Babool)-a review on ethnobotanical and Unani 50–53. traditional uses as well as phytochemical and 62. Ramadass N, Subramanian N. Study of pharmacological properties. Int J Pharm phytochemical screening of neem (Azadirachta Phytopharmacol Res 2015, 4: 315–321. indica). Int J Zoo Stud 2018, 3: 209–212. 48. Farzana MUZN, Tharique IAL, Sultana A. A 63. Singh V, Patel JR, Tyagi LK, et al. Antimicrobial review of ethnomedicine, phytochemical and activity and phytochemical analysis of stem bark pharmacological activities of Acacia nilotica of Balanites roxburghii Planch. Acad J Plant Sci (Linn) willd. J Pharmacogn Phytochem 2014, 3: 2009, 2: 109–112. 84–90. 64. Bijekar SR, Gayatri MC, Rajanna L. 49. Lakshmi T, Aravind Kumar S. Preliminary Phytochemical profile of Baliospermum TMR | September 2020 | vol. 5 | no. 5 | 408 Submit a manuscript: https://www.tmrjournals.com/tmr

REVIEW doi: 10.12032/TMR20200603189 montanum (Wild.) Muell. Arg. Int J Innov Sci Res Phytochemical studies on Desmostachya bipinnata 2014, 12: 37–42. rootstock. Int J pharm bio sci 2015, 6: 305–310. 65. Thamizharasan S, Umamaheswari S, Rajeswari 80. Al-Snafi AE. Phytochemical constituents and Hari, et al. Quantitative phytochemical analysis of medicinal properties of Digitalis lanata and Bambusa arundinacea seeds. Int J Pharmacogn Digitalis purpurea—a review. Indo Ame J Pharm Phytochem Res 2015, 7: 980–983. Sci 2017, 4: 225–234. 66. Kapoor A, Shukla S, Kaur R, et al. Preliminary 81. Alok S, Jain SK, Verma A, et al. Pharmacognostic phytochemical screening and antioxidant activity and phytochemical evaluation of Dolichos biflorus of whole plant of Barleria prionitis Linn. Int J Adv Linn. Asian Pac J Trop Dis 2014, 4: 97–101. Pharm Biol Chem 2014, 3: 410–419. 82. Rajan A, Rajan AR, Philip D. Elettaria 67. Tongco JVV, Añis AD, Tamayo JP. Nutritional cardamomum seed mediated rapid synthesis of analysis, phytochemical screening, and total gold nanoparticles and its biological activities. phenolic content of Basella alba leaves from the Open Nano 2017, 2: 1–8. Philippines. Int J Pharmacogn Phytochem Resh 83. Ahmed ZM, Eltayeb IM, Hamad AEH. 2015, 7: 1031–1033. Phytochemical screening and contractile activity 68. Rana S, Suttee A. Phytochemical investigation and of Foeniculum vulgare seeds on rat intestinal and evaluation of free radical scavenging potential of uterine muscles. J Pharm Phytochem 2017, 6: 346– Benincasa hispida peel extracts. Int J Curr Pharml 350. Res 2012, 3: 43–46. 84. Nayak BS, Rath AK, Pattnaik SC. Traditional use, 69. Ahmed MF, A. Rao S, Ahemad SR, et al. toxicity study and phytochemical screening of Phytochemical studies and antioxidant activities of Gmelina arborea roxb fruits. Int J Phytopharm Res Brassica oleracea L. var. capitata. Int J Pharm 2015; 6: 78–81. Pharm Sci 2012, 4: 374–378. 85. Kazeem MI, Abimbola SG, Ashafa AOT. 70. Sahu M, Verma D, Harris KK. Phytochemical Inhibitory potential of Gossypium arboreum leaf analysis of the leaf, stem and seed extracts of extracts on diabetes key enzymes, α-amylase and Cajanus cajan L (dicotyledoneae: Fabaceae). α-glucosidase. Bangladesh J Pharmacol 2013, 8: World J Pharm Pharmaceut Sci 2014, 3: 694–733. 149–155. 71. Nancy P, Ashlesha V. Pharmacognostic and 86. Dash PP, Mishra A, Chaturvedi D, et al. Search for phytochemical studies of Cassia absus seed an herbal medicine: anti-inflammatory activity of extracts. Int J Pharm Pharm Sci 2016, 8: 325–332. methanolic extract of Haldina cordifolia. J Pharm 72. Joshua OO, Elijah P, Nkechi EJ. Phytochemical Phytochem 2015, 3: 79–82. analyses of Cocos nucifera L. Arch Pharm Sci Res 87. Adamu H, Ngwu RO. Phytochemical screening 2009, 1: 87–96. and antibacterial activities of Hibiscus sabdariffa 73. Jamkhande PG, Barde SR, Patwekar SL, et al. L. leaf extracts. Nige J Chem Res 2015, 20: 46–52. Plant profile, phytochemistry and pharmacology of 88. Hussain MS, Fareed S, Ali M. Hygrophila Cordia dichotoma (Indian cherry): a review. Asian auriculata (K. Schum) Heine: ethnobotany, Pac J Trop Biomed 2013, 3: 1009–1012. phytochemistry and pharmacology. Asian J Tradit 74. Agrahari AK, Panda SK, Meher A, et al. Med 2010, 5:122–131. Phytochemical screening of Curculigo orchioides 89. Rao NB, SitaKumari O, Rajesh Goud G. Gaertn. root tubers. J Chem Pharm Res 2010, 2: Phytochemical analysis and antimicrobial activity 107–111. of Lawsonia inermis (Henna). J Plant Sci Res 75. Deore SR, Namdeo AG. Pharmacognostic 2016, 3: 158. investigation of Cynodon dactylon Pers roots. 90. Rakholiya K, Kaneria M, Chanda S. Pharmacogn J 2014, 6: 1–6. Physicochemical and phytochemical analysis of 76. Sivapalan SR, Jeyadevan P. Physio–chemical and different parts of Indian Kesar mango—a unique phyto-chemical study of rhizome of Cyperus variety from Saurashtra region of Gujarat. Pharm J rotundus Linn. Int J Pharm Pharm Technol 2012, 2016, 8: 502–506. 1: 42–46. 91. Patil DB, Palshikar N, Patil SB, et al. 77. Muthusamy A, Punitha M, Beslin LG. Phytochemical investigation and antimicrobial Phytochemical screening of Datura metel Linn and activity of Mentha arvensis L. [Pudina]. World J its antimicrobial activity on selected human Pharm Res 2015, 4: 1829–1834. pathogens. Int J Bioassays 2014, 3: 3474–3478. 92. Ganesh I, Suhas P, Yash G, et al. Phytochemical 78. Chatatikun M, Chiabchalard A. Phytochemical screening and investigation of antibacterial and screening and free radical scavenging activities of anticancer potential of Michelia champaca L. orange baby carrot and carrot (Daucus carota flowers. International Conference on Plant Linn.) root crude extracts. J Chem Pharm Res Research and Resource Management and 25th 2013, 5: 97–102. APSI Silver Jubilee Scientist Meet 2016, 345–353. 79. Shakila R, Arul Antony S, Gopakumar K. 93. Ranjan RK, Kumar MS, Seethalakshmi I, et al.

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 409 doi: 10.12032/TMR20200603189 REVIEW Phytochemical analysis of leaves and roots of Phytochem Res 2012, 4: 109–111. Mimosa pudica collected from Kalingavaram, 107. Nataraj HR, Hiremath SK. Pharmacognostic and Tamil Nadu. J Che Pharm Res 2013, 5: 53–55. phytochemical analysis of different market 94. Bawara B, Dixit M, Chauhan NS, et al. Phyto- samples of Ashoka (Saraca indica Linn). Anc Sci pharmacology of Momordica dioica Roxb. ex. Life 2009, 29: 7–11. Willd: a review. Int J Phytomed 2010, 2: 1–9. 108. Sharma V, Hem K, Seth A, et al. Solanum indicum 95. Imam MZ, Akter S. Musa paradisiaca L. and Linn.: an ethnopharmacological, phytochemical Musa sapientum L.: a phytochemical and and pharmacological review. Curr Res J Pharm All pharmacological review. J Appl Pharml Sci 2011, Sci 2017, 1: 1–9. 1: 14–20. 109. Joshi BC, Mukhija M, Kalia AN. 96. Ullah H, Khan R, Shah GM, et al. Ethnomedicinal, Pharmacognostical review of Urtica dioica L. Int J phytochemical and nutritional analysis of Green Pharm 2014, 201–209. Nelumbium nucifera Gaertn rhizome. MOJ Food 110. Manva MN, Desai TR. Vernonia anthelmintica Process Technol 2018, 6: 122–127. Willd.: an overview on phytopharmacological 97. Chetwani K, Agnihotri RK, Chaturvedi P. properties. Invent Rapid Ethnopharmacol 2012, 4: Aqueous, acetone and ethanolic extract of Nerium 1–4. indicum L. as potential antibacterial agent against 111. Saad KJ. Phytochemical investigation of fruits and Pseudomonosa aeruginosa. Int J Appl Environ Sci seeds of grape (Vitis vinifera L.) grown in Iraq. Int 2017, 12: 1721–1732. J Pharm Sci Rev Res 2017, 42: 65–66. 98. Paikara D, Singh S, Pandey B. Phytochemical 112. Sharma VK, Tiwari M, Chauhan NS, et al. analysis of leave extract of Nyctanthes arbortristis. Phytochemical investigation on the ethanolic IOSR J Environ Sci Toxicol Food Technol 2015, extract on the leaves of Zizyphus xylopyrus (Retz.) 1: 39–42. Willd. In J Agron Plant Pro 2012, 3: 26–37. 99. Rai S, Ghosh H, Basheer M. Phytochemical 113. Chatterjee P, Chakraborty B, Nandy S. Review on characterization and antioxidative property of nephroprotective activity study by different plant Ocimum canum: effect of ethanolic extract of extract. Adv J Pharm Life Sci Res 2014, 2: 24–40. leaves and seeds on basic immunologic and 114. Vaya RK, Sharma A, Singhvi IJ, et al. metabolic status of male rats. J Immunobiology Nephroprotective Plants: a review. Bio Sci 2016, 1: 1–7. Technol 2017, 8: 801–812. 100. Mannan MA, Sarker TC, Rahman MM, et al. 115. Padhye MR, Jogdand SD, Bhattacharjee J. Screening of phytochemical compounds and Evaluation and comparison of nephroprotective antioxidant properties in local and HYV of effect of Hemidesmus indicus Linn. and Withania Bangladeshi rice (Oryza sativa L.). Int J Biosci somnifera Linn. on gentamicin induced 2013, 3: 151–160. nephrotoxicity in Albino rats. Int J Basic Clin 101. Gunasekaran R, Usha M, Arunachalam G. Pharm 2018, 7:691–695. Pharmacognostical and phytochemical evaluation 116. Kannappan N, Madhukar A, Sindhura PU, et al. of Ougeinia oojeinensis (Roxb) Hochr. bark. Int J Evaluation of nephroprotective activity of Pharm Sci Res 2011, 2: 706–712. Orthosiphon stamineus benth extract using rat 102. Khushbu C, Anar P, Mayuree P, et al. Paederia model. Int J Pharm Tech Res 2010, 2: 209–215. foetida Linn. as a potential medicinal plant: a 117. Sarshar S, Brandt S, Asadi Karam MR, et al. review. J Pharm Res 2010, 3: 3135–3137. Aqueous extract from Orthosiphon stamineus 103. Kumar D, Kumar S, Kumar S, et al. Antimicrobial leaves prevents bladder and kidney infection in and preliminary phytochemical screening of crude mice. Phytomedicine 2017, 15: 1–9. leaf extract of Pandanus odoratissimus L. 118. Lakshmi MS, Reddy UT, Kumar ACK, et al. Pharmacologyonline 2010, 2: 600–610. Protective effect of Abutilon indicum L. 104. Danladi S, Idris MA, Umar II. Review on (Malvaceae) against cisplatin induced pharmacological activities and phytochemical nephrotoxicity in rats. Inn J Life Sci 2013, 1: 35– constituents of Phyllanthus niruri (Amarus). J 39. Phytopharmacol 2018, 7: 341–348. 119. Srivastav S, Singh P, Jha KK, et al. Diuretic 105. Guankui Du, Xiao M, Yu S, et al. Phyllanthus activity of whole plant extract of Achyranthes urinaria: a potential phytopharmacological source aspera Linn. Inn J Life Sci 2011, 1: 97–102. of natural medicine. Int J Clin Exp Med 2018, 11: 120. Palani S, Raja S, Praveen Kumar R, et al. 6509–6520. Therapeutic efficacy of Acorus calamus on 106. Gopinath SM, Rakesh CK, Murthy TPN, et al. acetaminophen induced nephrotoxicity and Preliminary phytochemical evaluation of leaf oxidative stress in male albino rats. Acta Pharm Sci extracts of Gymnema sylvestre, Phyllanthus 2010, 52: 89–100. amarus, Phyllanthus reticulatus of Siddarabetta, 121. Kore KJ, Shete RV, Jadhav PJ. RP-HPLC method Tumkur district, Karnataka. Int J Pharm of simultaneous nephroprotective role of A. TMR | September 2020 | vol. 5 | no. 5 | 410 Submit a manuscript: https://www.tmrjournals.com/tmr

REVIEW doi: 10.12032/TMR20200603189 marmelos extract. Int J Res Pharm Chem 2011, 1: vivo antioxidant studies of whole plant of 70 % 617–623. ethanolic extracts of Indigofera barberi Gah 122. Movaliya V, Khamar D, Setty MM. mbles. Int J Innov Pharm Sci Res 2014, 5: 378– Nephroprotective activity of aqueous extracts of 388. Aerva javanica roots in cisplatin induced renal 135. Srinivasan N, Sathyanarayana D. toxicity in rats. Pharmacologyonline 2011, 1: 68– Pharmacognostical investigation of Indigofera 74. barberi Gamble (Fabaceae)—a threatened 123. Asif M. A review on various medicinal plants with medicinal herb. Hygeia J Drugs Med 2014, 6: 45– for nephroprotective activity. Int J Rec Adv Bio 56. Nanotechnol 2018, 1: 1–29. 136. Mahipal P, Pawar RS. Nephroprotective effect of 124. Chatterjee P, Mukherjee A, Nandy S. Protective Murraya koenigii on cyclophosphamide induced effects of the aqueous leaf extract of Aloe nephrotoxicity in rats. Asian Pac J Trop Med 2017, barbadensis on gentamicin and cisplatin-induced 10: 808–812. nephrotoxic rats. Asian Pac J Trop Bio 2012, 137. Ahmad A, Husain A, Mujeeb M, et al. Review on S1754–S1763. therapeutic potential of Nigella sativa: a miracle 125. Rao V, Arunachalam R, Eerike M, et al. herb. Asian Pac J Trop Biomed 2013, 3: 337–352. Nephroprotective effect of ethanolic extract of 138. Ramesh K, Manohar S, Rajeshkumar S. Azima tetracantha root in glycerol induced acute Nephroprotective activity of ethanolic extract of renal failure in Wistar albino rats. J Tradit Orthosiphon stamineus leaves on ethylene glycol Complement Med 2016, 6: 347–354. induced urolithiasis in Albino rats. Int J Pharm 126. Sharma RK, Rajani GP, Sharma V, et al. Effect of Tech Res 2014, 6: 403–408. ethanolic and aqueous extracts of Bauhinia 139. Kishore L, Kaur N, Singh R. Nephroprotective variegata Linn. on gentamicin-induced effect of Paeonia emodi via inhibition of advanced nephrotoxicity in rats. Indian J Pharm Educ Res glycation end products and oxidative stress in 2011, 45: 192–198. streptozotocin-nicotinamide induced diabetic 127. Cordeiro MC, Kaliwal BB. Hepatoprotective and nephropathy. J Food Drug Anal 2016, 25: 576– nephroprotective activity of bark extract of 588. Bridelia retusa Spreng in CCL4 treated female 140. Jayanthy A, Deepak M, Remashree AB. mice. Int J Mol Bio 2011, 2: 22–30. Pharmacognostic characterization and comparison 128. Tatiya A, Saluja A, Kalaskar M, et al. of fruits of Tribulus terrestris L. and Pedalium Phytochemical characterization and anti- murex L. Int J Herb Med 2013, 1: 29–34. inflammatory activity of Bridelia retusa bark 141. Shelke TT, Kothai R, Adkar PP, et al. Spreng. in acute and chronic inflammatory Nephroprotective activity of ethanolic extract of conditions: a possible mechanism of action. Eur J dried fruits of Pedalium murex Linn. Cell Tissue Pharm Med Res 2017, 4: 686–696. Res 2009, 9: 1687–1690. 129. Parameshappa B, Basha SA, Sen S, et al. 142. Cheon J, Man W, Ho C, et al. Salviae radix extract Acetaminophen-induced nephrotoxicity in rats: prevents cisplatin-induced acute renal failure. protective role of Cardiospermum halicacabum. Nephron 2001, 88: 241–246. Pharml Bio 2012, 50: 247–253. 143. Bhuvaneswari P, Krishnakumari S. 130. Shelkea TT, Bhaskarb VH, Adkara PP, et al. Nephroprotective effects of ethanolic extract of Nephroprotective activity of ethanolic extract of Sesamum indicum seeds (Linn.) in streptozotocin stem barks of Crataeva nurvula Buch Hum. Int J induced diabetic male albino rats. Int J Green Pharm Sci Res 2011, 2: 2712–2717. Pharma 2012, 6: 330–335. 131. Alam MS, Kaur G, Jabbar Z, et al. Eruca sativa 144. Anilakumar KR, Pal A, Khanum F, et al. seeds possess antioxidant activity and exert a Nutritional, medicinal and industrial uses of protective effect on mercuric chloride induced Sesame (Sesamum indicum L.) seeds-an overview. renal toxicity. Food Chem Toxicol 2007, 45: 910– Agr Consp Sci 2010, 75: 159–168. 920. 145. Ghaisas MM, Navghare VV, Takawale AR, et al. 132. Yadav YC, Srivastava DN, Saini V, et al. Antidiabetic and nephroprotective effect of Experimental studies of Ficus religiosa (L) latex Tectona grandis Linn. in alloxan induced diabetes. for preventive and curative effect against cisplatin Ars Pharm 2010, 51: 195–206. induced nephrotoxicity in Wistar rats. J Chem 146. Kpemissi M, Eklu-Gadegbeku K, Veerapur VP et Pharm Res 2011, 3: 621–627. al. Antioxidant and nephroprotection activities of 133. Banerjee A, Ganguly S. Medicinal importance of Combretum micranthum: a phytochemical, in-vitro Hemidesmus indicus: a review on its utilities from and ex-vivo studies. Heliyon 2019, 5: e01365. ancient ayurveda to 20th century. Adv Biores 147. Ibrahim A, Al-Hizab FA, Abushouk AI et al. 2014, 5: 208–213. Nephroprotective effects of benzyl isothiocyanate 134. Reddy JSV, Rao DG. Evaluation of in vitro & in and resveratrol against cisplatin-induced oxidative

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 411 doi: 10.12032/TMR20200603189 REVIEW stress and inﬂammation. Front Pharmacol 2018, 9: 1268. 148. Sundararajan R, Bharampuram A, Koduru R. A review on phytoconstituents for nephroprotective activity. Pharmacophore 2014, 5: 160–182. 149. Naghizadeh B, Mansouri SMT, Mashhadian, NV. Crocin attenuates cisplatin-induced renal oxidative stress in rats. Food Chem Toxicol 2010, 48: 2650– 2655. 150. Venkatesan N, Punithavathi D, Arumugam V. Curcumin prevents adriamycin nephrotoxicity in rats. Br J Pharmacol 2000, 129: 231–234. 151. Nabavi SM, Habtemariam S, Nabavi SF et al. Protective effect of gallic acid isolated from Peltiphyllum peltatum against sodium ﬂuoride- induced oxidative stress in rat’s kidney. Mol Cell Biochem 2013, 372:233–239. 152. Rajappa R, Magesh SB, Sarvajayakesavulu S, et al. Nephroprotective effect of Naringenin against multiple low dose streptozotocin (MLDSTZ) induced renal damage in mice. Biomed Pharmacol J 2017, 10: 583–593. 153. Abdel-Raheem IT, Abdel-Ghany AA, Mohamed GA. Protective effect of quercetin against gentamicin-induced nephrotoxicity in rats. Biol Pharm Bull 2009, 32: 61–67. 154. Ma Z, Cao X, Guo X, et al. Establishment and validation of an in vitro screening method for traditional Chinese medicine-induced nephrotoxicity. Evid Based Complement Alternat Med 2018, 2018: 1–15. 155. Kumari V, Narayanan PK. An exploratory study to evaluate the nephro-protective effect of Scopariadulcis. Linn. ethanol extracts in gentamycin induced toxicity in HEK 293 cells. Int J Pharm Sci Rev Res 2017, 45: 11–13.

TMR | September 2020 | vol. 5 | no. 5 | 412 Submit a manuscript: https://www.tmrjournals.com/tmr