Article

Growth inhibition of human tumor cell lines by withanolides from Withania somnifera leaves

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Abstract

Ayurvedic medicines prepared in India consist of Withania somnifera roots as one of the main ingredients. It is consumed as a dietary supplement around the world. The leaves of W. somnifera were used in the treatment of tumors and inflammation in several Asian countries. We have isolated twelve withanolides such as withaferin A (1), sitoindoside IX (2), 4-(1-hydroxy-2, 2-dimethylcyclpropanone)-2, 3-dihydrowithaferin A (3), 2, 3-dihydrowithaferin A (4), 24, 25-dihydro-27-desoxywithaferin A (5), physagulin D (1-->6)-beta-D-glucopyranosyl- (1-->4)-beta-D-glucopyranoside (6), 27-O-beta-D-glucopyranosylphysagulin D (7), physagulin D (8), withanoside IV (9), and 27-O-beta-D-glucopyranosylviscosalactone B (10), 4, 16-dihydroxy-5beta, 6beta-epoxyphysagulin D (11), viscosalactone B (12) from the leaves of this species. Compounds 1-12 and diacetylwithaferin A (13) were tested for their antiproliferative activity on NCI-H460 (Lung), HCT-116 (Colon), SF-268 (Central Nervous System; CNS and MCF-7 (Breast) human tumor cell lines. The inhibitory concentration to afford 50% cell viability (IC50) for these compounds was determined by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Withaferin A and its derivatives exhibited inhibitory concentrations (50%) ranging from 0.24 +/- 0.01 to 11.6 +/- 1.9 microg/mL. Viscosalactone B (12) showed the 50% inhibition at concentrations ranging from 0.32 +/- 0.05 to 0.47 +/- 0.15 microg/mL whereas its 27-O-glucoside derivative (10) exhibited IC50 between 7.9 +/- 2.9 and 17.3 +/- 3.9 microg/ml. However, Physagulin D type withanolides showed either weak or no activity at 30 microg/mL. Therefore, incorporation of withanolides in the diet may prevent or decrease the growth of tumors in human.

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... Withanolides belong to a group of naturally occurring C-28 steroid lactones [6]. These compounds are generally highly oxygenated, and these functionalities have led to many structural modifications [7][8][9][10]. The current classification of withanolides constitutes 22 types based on their structural differences. ...
... µM. Withanolides with 5β,6β-epoxy (10) and 5α-Cl,6β-OH (13,14) moieties were the most potent against all the tested cancer cell lines. These compounds also showed a substantial inhibitory effect on nitric oxide (NO) production. ...
... This is in direct contrast to the bioactivities of other previously reported withanolides, where the presence of a glucose group reduces the cytotoxicity up to >10-fold. For example, the reported IC50 values for WA and its glycoside form against MCF-7 cells are 0.6 and 7.9 μM, respectively [10]. ...
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Natural products are a major source of biologically active compounds that make promising lead molecules for developing efficacious drug-like molecules. Natural withanolides are found in many flora and fauna, including plants, algae, and corals, that traditionally have shown multiple health benefits and are known for their anti-cancer, anti-inflammatory, anti-bacterial, anti-leishmaniasis, and many other medicinal properties. Structures of these withanolides possess a few reactive sites that can be exploited to design and synthesize more potent and safe analogs. In this review, we discuss the literature evidence related to the medicinal implications, particularly anticancer properties of natural withanolides and their synthetic analogs, and provide perspectives on the translational potential of these promising compounds.
... The biological activities of W. somnifera are anxiolytic, antidepressant, antifungal (Bhattacharya et al., 2000b), antimicrobial (Girish et al., 2006), antimalarial (Dikasso et al., 2006), apoptotic (Senthil et al., 2007), chondroprotective (Sumantran et al., 2007), cardioprotective (Hamza et al., 2008), immunomodulator (Davis and Kuttan, 2000), and neuroprotective (Sankar et al., 2007), promote inhibition of COX-2 enzyme (Jayaprakasam et al., 2003), and promote learning and memory in Alzheimer's disease (AD) (Bhattacharya et al., 1995). Numerous studies indicated that Ashwagandha possesses antioxidant, antitumor, antistress, anti-inflammatory, immunomodulatory, hematopoietic, antiaging, anxiolytic, antidepressive, and rejuvenating properties, and that it also influences various neurotransmitter receptors in the central nervous system (CNS) (Pattipati et al., 2003). ...
... Treat Alzheimer's disease (AD) and associated problems Isolated rabbit jejunum Choudhary et al. (2005) Leaves (Atta-ur- Rahman et al., 1991;Choudary et al., 1996;Bandyopadhyay et al., 2007) Antimicrobial activities Balb/C mice Owais et al. (2005) Withaferin A Leaves (Jayaprakasam et al., 2003) Stimulating tumor cell apoptosis MCF-7 breast cancer cells Zhang et al. (2011Zhang et al. ( , 2012 Leaves (Jayaprakasam et al., 2003) Causes G2 and M phase cell cycle arrest ...
... Treat Alzheimer's disease (AD) and associated problems Isolated rabbit jejunum Choudhary et al. (2005) Leaves (Atta-ur- Rahman et al., 1991;Choudary et al., 1996;Bandyopadhyay et al., 2007) Antimicrobial activities Balb/C mice Owais et al. (2005) Withaferin A Leaves (Jayaprakasam et al., 2003) Stimulating tumor cell apoptosis MCF-7 breast cancer cells Zhang et al. (2011Zhang et al. ( , 2012 Leaves (Jayaprakasam et al., 2003) Causes G2 and M phase cell cycle arrest ...
Chapter
Withania somnifera, commonly known as Ashwagandha (winter cherry), is an important medicinal plant that has been used in Ayurvedic and indigenous medicine for more than 3000 years. Some herbalists refer to Ashwagandha as Indian ginseng. The plant extract has many bioactive compounds that exert antioxidant, antiinflammatory, and immunomodulatory activities. The plant extract and its bioactive compounds are used in the prevention and treatment of many diseases, such as arthritis, impotence, amnesia, anxiety, cancer, neurodegenerative and cardiovascular diseases, and others. This chapter describes multiple health benefits of Ashwagandha in humans and animals.
... In-vitro studies proved anti-carcinogenic activity of withanolides by suppressing TNF (Tumour necrosis factor), NF-κB (Nuclear factor -kappa B) levels and ultimately potentiating the apoptosis signaling pathway in the cell lines used such as DU-145, PC-3, HCT-15, A-549 and IMR-32 (Ichikawa et al., 2006: Yadav et al.2010 [19,41] . Ashwagandha has also shown to reduce the size of tumours (Prakash et al.2002: Jayaprakasam et al., 2003 [33,20] . The most outstanding research was performed by checking the anti-carcinogenic effect of Ashwagandha in adult male mice, in which lung tumours were induced by urethane (Singh et al.1986) [42] . ...
... In-vitro studies proved anti-carcinogenic activity of withanolides by suppressing TNF (Tumour necrosis factor), NF-κB (Nuclear factor -kappa B) levels and ultimately potentiating the apoptosis signaling pathway in the cell lines used such as DU-145, PC-3, HCT-15, A-549 and IMR-32 (Ichikawa et al., 2006: Yadav et al.2010 [19,41] . Ashwagandha has also shown to reduce the size of tumours (Prakash et al.2002: Jayaprakasam et al., 2003 [33,20] . The most outstanding research was performed by checking the anti-carcinogenic effect of Ashwagandha in adult male mice, in which lung tumours were induced by urethane (Singh et al.1986) [42] . ...
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Nanoparticles synthesis using biological materials is a recent trend in modern nanotechnology and nanoscience. The hairy root of Withania somnifera was used as biogenic materials and their extract was employed for synthesizing the silver nanoparticles (AgNPs). Several parts of the shrub "Ashwagandha" (Withania somnifera) of family Solanaceae, contains bioactive steroidal lactones, saponins and alkaloids. Characterization of the synthesized silver nanoparticles were done through UVS (UV-Visible spectroscopy), XRD (X-ray diffraction), SEM (Scanning electron microscope), TEM (Transmission electron microscope), DLS (Dynamic light scattering analysis), and FTIR (Fourier Transform Infrared Spectroscopy). The silver nanoparticles are created by reducing the silver metal ions in a rapid and eco-friendly way, which can be seen as the peak when the synthesized AgNPs were subjected to UV-vis spectroscopy. The synthesized silver nanoparticle's crystalline nature was further confirmed by carrying out the XRD analysis. The shape and size of the biosynthesized silver nanoparticles was investigated by TEM and SEM images. The probable functional groups that are part of the silver nanoparticle synthesis were identified through the FT-IR analysis. The solution phase technique, DLS reveals the particle size distribution of biosynthesized AgNPs. However, the synthesised silver nanoparticles using Ashwagandha hairy root extract demonstrated cytotoxic behaviour in the human bone cancer cell line using MG-63 by MTT assay. As a whole, this eco-friendly technique of biological silver nanoparticles synthesis renders the synthesis rates faster or comparable to that of the chemical methods and can be used in various biomedical applications.
... Mirjalili et al. (2009) isolated a new dimeric thiowithanolide (withanolide containing sulfur molecule), known as ashwagandhanolide (Table 3) from the roots of W. somnifera. Jayaprakasam et al. (2003) isolated twelve withanolides (Table 3) i. e. [1 (Withaferin-A), 2 (Sitoindoside IX), 3 (4-(1-Hydroxy-2, 2-dimethylcyclpropanone)-2, 3-dihydrowithaferin-A), 4 (2,3-Dihydrowithaferin-A), 5 (24, 25-Dihydro-27-desoxywithaferin-A), 6 (Physagulin-D (1 → 6)-β-D-glucopyranosyl-(1 → 4)-β-D-glucopyranoside), 7 (27-O-β-D-glucopyrano-sylphysagulin-D), 8 (Physagulin-D), 9 (Withanoside IV), 10 (27-O-β-D-glucopyranosylviscosalactone-B), 11 (4, 16-Dihydroxy-5β, 6β-epoxyphysagulin-D) and 12 (Viscosalactone-B)] from the leaves of W. somnifera. ...
... Thus, numerous studies focusing on anticancerous role of W. somnifera have been reviewed. Jayaprakasam et al. (2003) isolated thirteen withanolides (Table 3) and evaluated them against various tumor cell lines viz. NCI-H460 (lung), HCT-116 (colon), SF-268 (central nervous system) and MCF-7 (breast cancer) and observed WA as most potent anticarcinogenic agent followed by diacetylwithaferin-A. Subbaraju et al. (2006) evaluated the anticancer potential of ashwagandhanolides against viz. ...
Article
Ethnopharmacological relevance. Withania somnifera, commonly known as Ashwagandha, is an important medicinal herb belonging to family Solanaceae. It is widely used in folkloric and Ayurvedic medicines since antiquity. Traditionally, the plant is highly practiced throughout the globe as immunomodulator, anti-inflammatory, anti-stress, anti-parkinson, anti-alzheimer, cardio protective, neural and physical health enhancer, neurodefensive, anti-diabetic, aphrodisiac, memory boosting etc. The plant is also effective in combating various cancer and related problems of colon, mammary, lung, prostate, skin, blood, liver and kidney. Aim of this review. The present review represents the critical assessment of the literature available on the anticancerous role of W. somnifera. The present study throws light on its diverse chemical compounds and the possible mechanisms of action involved. This review also suggests further research strategies to harness the therapeutic potential of this plant. Materials and methods. The present review is the outcome of a systematic search of scientific literature about ‘Withania somnifera and its role in cancer prevention’. The scientific databases viz. Google Scholar, Science Direct, Pubmed and Web of Science were searched from 2001 to 2019. Textbooks, magazines and newspapers were also consulted. This review summarizes all the published literature about its therapeutic potential for the treatment of different types of cancers. Results. W. somnifera has been widely used in traditional and ayurvedic medicines for treatment of numerous problems related to health and vitality. The plant is a reservoir of diverse phytoconstituents like alkaloids, steroids, flavonoids, phenolics, nitrogen containing compounds and trace elements. Withanolides are the major alkaloids which renders its anticancer potential due to its highly oxygenated nature. The plant is highly effective in combating various types of cancers viz. colon, mammary, lung, prostate, skin, blood, liver and kidney. Previous studies depict that this plant is more effective against breast cancer followed by colon, lung, prostate and blood cancer. Furthermore, from different clinical studies it has been observed that the active constituents of the plant like withaferin-A, withanolide-D have least toxic effects. Conclusion. The present review confirms the various medicinal values of W. somnifera without any significant side effects. Withaferin-A (WA) and Withanolides are its most promising anticancer compounds that play a major role in apoptosis induction. Keeping in mind the anticancerous potential of this plant, it is suggested that this plant may further be investigated and more clinical studies can be performed.
... The extract showed remarkable DMSO (Dimethyl sulfoxide) inhibitory activity, induced to produce cytotoxicity and decreased the TNF-G production in chicken Lymphocyte. [50] Withaferin A from the leaves, are known to posses anti-cancer properties [42] by inhibition of the cell growth of various human cancer cell lines, including lung cancer (NCI-H460). It also showed anti-proliferative activity against head and neck squamous carcinoma, by reduced cell viability in cell lines in-vitro. ...
... The results indicate that, at least part of chronic stress-induced pathology may be due to oxidative stress, which is mitigated by WSG, lending support to the clinical use of the plant as an antistress adaptogen. [53,42] Cardiovascular Activity Phytosterol precursors to the cardiac glycosides biosynthetic pathway (important compounds in the treatment of cardiac insufficiency in humans)is basically deduced from studies using radiolabelled precursors. [58] The newly isolated withanolide from W. coagulans fruits with a chemical structure similar to the aglycones of the cardiac glycosides was examined for its cardiovascular effects. ...
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... In previously many reports revealed that it is used in treating various forms of cancer, the antitumor and radiosensitizing effects of WithaferinA (WFA) have been studied. This withaferin-A from roots are reported to have an antiproliferative activity (Jayaprakasam et al., 2003) and possess an inhibitory effect on the cyclooxygenase-2 (COX-2) enzyme (Jayaprakasam and Nair 2003). However, despite the observation of diverse medicinal activities attributed to this plant, very few biochemical studies have been investigated the molecular mechanisms of the effect of root extract of Withaferin-A (WFA) on hepatocellular carcinoma in experimental rats. ...
... In previously many reports revealed that it is used in treating various forms of cancer, the antitumor and radiosensitizing effects of WithaferinA (WFA) have been studied. This withaferin-A from roots are reported to have an antiproliferative activity (Jayaprakasam et al., 2003) and possess an inhibitory effect on the cyclooxygenase-2 (COX-2) enzyme (Jayaprakasam and Nair 2003). However, despite the observation of diverse medicinal activities attributed to this plant, very few biochemical studies have been investigated the molecular mechanisms of the effect of root extract of Withaferin-A (WFA) on hepatocellular carcinoma in experimental rats. ...
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The purpose of this study was to investigate the Amelioration of Withaferin-A on the alterations of carbohydrate metabolic enzymes on N-Nitrosodiethylamine induced hepatocellular carcinoma in Wistar rats. Hepatocellular carcinoma (HCC) belongs to the group of epithelial cancers and represents with a frequency of about 85 % the most common primary liver cancer. The estimated incidence may be located between 500.000-1.000.000 new cases per year and is characterized by a wide geographic variation; it ranges from less than 10 cases / 100.000 in the USA and Western Europe to 50-150 cases / 100.000 in parts of Africa and Asia. The most prominent etiological factors associated with hepatocellular carcinoma are chronic hepatitis B and C viral infections, chronic ethanol abuse and intake of aflatoxin B1-contaminated food. Hepatocellular carcinoma was induced in rats by N-Nitrosodiethylamine at the dosage of 0.01% of DEN was dissolved in drinking water and administered to experimental animals daily for 15 weeks after conformation of hepatocellular carcinoma treated with Withaferin-A for 21 days. The levels of carbohydrate enzymes were significantly decreased were markedly increased in Withaferin-A treated animals when compared with cancer bearing animals. Moreover, the levels of carbohydrate metabolic enzymes a good indicators of restoring the liver architecture, were also reversed in liver damage subjects after treatment with the herbal compounds preparation. So, from the obtained results it is concluded that a Withaferin-A is capable of restoring the liver architecture and can also increase the carbohydrate metabolic activities in hepatocellular carcinoma rats.
... [17] Imperatorin Hespiridine In vitro studies revealed that Viscosalactone B and 27-O-glucoside derivative may prevent or decrease the growth of tumors in human. [19] 3. Polysaccharides: PSK (Krestin) is protein-bound polysaccharide K isolated from Coriolus versicolor; it has a molecular weight of approximately 100 kDa and a protein content of 18-38%. [20] Tsutsumi et al. have found that PSK effectively reduced the mortality induced associated with dextran sodium sulphate induced colitis and inhibited the development of CRC, suggesting that it shows dual antagonism against both inflammation and CRC. ...
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ABSTRACT DMH (Dimethyl Hydrazine) is widely used as a carcinogen to induce colon cancer in animal models. Exploration of DMH-induced colon carcinogenesis in rodent models provides the knowledge to perceive the biochemical, molecular and histological mechanisms of different stages of colon carcinogenesis. The procarcinogen DMH, after a series of metabolic reactions, finally reaches the colon, there produces the ultimate carcinogen and reactive oxygen species (ROS), which further alkylate the DNA and initiate the development of colon carcinogenesis. 5-Fluorouracil (5-FU) is widely used in the treatment of cancer. Over the past 20 years, increased understanding of the mechanism of action of 5-FU has led to the development of strategies that increase its anticancer activity. Rodent model for colon cancer is one of the best ways to understand the underlying mechanism of colon carcinogenesis and its progression, as well as the comprehensive treatment approaches. Although several anticancer drugs are already in the market, they are found to be expensive and thus not affordable by the major population. Therefore, there remains a great need for affordable and reliable anticancer drugs particularly of plant origin.
... Ashwagandha has long been used as Rasayana, especially for children, in the treatment of malnutrition (50)(51) . It has also been reported to have immunomodulatory (52)(53) , anti-aging (54) , anti-stress (55) , and cardiovascular protection properties (56) . It has also been shown to be effective against hypothyroidism (57) , anxiety, and depression (58) . ...
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Ashwagandha scientifically known as Withania somnifera described in Ayurveda as a powerful rejuvenating herbal medicine. Their roots are thick and whitish brown, the leaves are somewhat oval in shape, hairless, and small. Withania somnifera is pharmacology as an adaptogen, antibiotic, abortion, aphrodisiac, astringent, anti-inflammatory, obtrusive, diuretic, narcotic, sedative, tonic, etc. Ashwagandha has been found to provide strong antioxidant protection. It stimulates the activation of immune system cells such as lymphocytes and phagocytic cells. Withania somnifera (L.) Dunal has been used to treat all kinds of illnesses and human illnesses. Withania somnifera is an important medicinal plant that has been used in Ayurvedic and indigenous medicine for over 3000 years.
... Withania somnifera (L.) Dunal (the family of Solanaceae), commonly known as 'Ashwagandha' or 'Indian ginseng', is a perennial shrub widely distributed across India, Sri Lanka, South Africa, and the Mediterranean region [1]. This plant is used in Indian Ayurveda as a traditional medicine for various inflammatory diseases, such as diabetes and nervous and reproductive system disorders [2]. ...
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Withania somnifera (Solanaceae), well-known as ‘Indian ginseng’ or ‘Ashwagandha’, is a medicinal plant that is used in Ayurvedic practice to promote good health and longevity. As part of an ongoing investigation for bioactive natural products with novel structures, we performed a phytochemical examination of the roots of W. somnifera employed with liquid chromatography–mass spectrometry (LC/MS)-based analysis. The chemical analysis of the methanol extract of W. somnifera roots using repeated column chromatography and high-performance liquid chromatography under the guidance of an LC/MS-based analysis resulted in a new withanolide, withasomniferol D (1). The structure of the newly isolated compound was elucidated by spectroscopic methods, including one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) and high-resolution (HR) electrospray ionization (ESI) mass spectroscopy, and its absolute configuration was established by electronic circular dichroism (ECD) calculations. The anti-adipogenic activities of withasomniferol D (1) were evaluated using 3T3-L1 preadipocytes with Oil Red O staining and quantitative real-time polymerase chain reaction (qPCR). We found that withasomniferol D (1) inhibited adipogenesis and suppressed the enlargement of lipid droplets compared to the control. Additionally, the mRNA expression levels of adipocyte markers Fabp4 and Adipsin decreased noticeably following treatment with 25 μM of withasomniferol D (1). Taken together, these findings provide experimental evidence that withasomniferol D (1), isolated from W. somnifera, exhibits anti-adipogenic activity, supporting the potential application of this compound in the treatment of obesity and related metabolic diseases.
... Withania somnifera (Solanaceae), widely recognized as Indian ginseng and ashwagandha, is widely distributed in the dry regions of India, Sri Lanka, South Africa, and the Mediterranean [1,2]. Indian ginseng has been used as a functional food for promoting health and longevity via activation of the immune system against diseases, revitalizing the organ systems in weakened conditions, and curbing the process of aging [2,3]. ...
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Background Withania somnifera (Solanaceae), generally known as Indian ginseng, is a medicinal plant that is used in Ayurvedic practice for promoting health and longevity. This study aims to identify the bioactive metabolites from Indian ginseng and elucidate their structures. Methods Withanolides were purified by chromatographic techniques, including HPLC coupled with LC/MS. Chemical structures of isolated withanolides were clarified by analyzing the spectroscopic data from 1D and 2D NMR, and HR-ESIMS experiment. Absolute configurations of the withanolides were established by the application of NMR chemical shifts and ECD calculations. Anti-adipogenic activities of isolates were evaluated using 3T3-L1 preadipocytes with Oil Red O staining and quantitative real-time PCR (qPCR). Results Phytochemical examination of the roots of Indian ginseng afforded to the isolation of six withanolides (1-6), including three novel withanolides, withasilolides G–I (1–3). All the six compounds inhibited adipogenesis and suppressed the enlargement of lipid droplets, compared to those of the control. Additionally, the mRNA expression levels of Fabp4 and Adipsin, the adipocyte markers decreased noticeably following treatment with 25 μM of 1–6. The active compounds (1–6) also promoted lipid metabolism by upregulating the expression of the lipolytic genes HSL and ATGL and downregulating the expression of the lipogenic gene SREBP1. Conclusion The results of our experimental studies suggest that the withasilolides identified herein have anti-adipogenic potential and can be considered for the development of therapeutic strategies against adipogenesis in obesity. Our study also provides a mechanistic rationale for using Indian ginseng as a potential therapeutic agent against obesity and related metabolic diseases.
... It is a small, perennial shrub, mainly cultivated in drier regions of India and is also found in China, Yemen, and Nepal. The roots and leaves of this plant have been traditionally used to cure and prevent several diseases (Jayaprakasam et al. 2003). ...
... Larger trials are needed to validate these findings, establish an optimal dose, and determine long-term safety.In addition, microarray analysis revealed that Ashwagandha repressed proinflammatory gene expression, including interleukin-6 (IL-6), IL-1β, IL-8, heat shock protein 70, and STAT2, and induced p38/MAPK-kinase expression in a prostate cancer cell line (Aalinkeel et al., 2010). The root extracts were shown to exert cytotoxic effects in lung, colon, central nervous system, and breast cancer cell lines (Jayaprakasam et al., 2003). Active constituent of Ashwagandha demonstrated anticancer effects in leukemia cells (Malik et al., 2007)as well as in estrogen receptor-positive and estrogen receptor-negative breast cancer cells, via inducing apoptosis and decreasing tumor size . ...
... components were identified as Withaferin A, which activated mitochondrial apoptotic pathways, and induced the dysfunction of mitochondrial in human leukemia HL-60 cell lines [6]. Also, the extracts of W. somnifera displayed a potent anticancer profile on breast, pancreatic, prostate, renal, and fibrosarcoma cell lines [7][8][9][10][11]. W. Somnifera extract is considered one of the authoritative nutritional supplements through its containment of alkaloids components, and despite the classification of the plant extract as a toxic substance, it was found that it has an effective activity in combating the growth of the diverse of cancer cells according to the type of solvent used in the process of extracting the components of the plant from roots, leaves, stems, and fruits [12]. ...
Article
Withania somnifera L. is a medicinal herb related to Solanaceae family, known as ashwagandha. The aqueous extract of W. somnifera was utilized for the green synthesis of zinc nanoparticles to investigated their antioxidant and anticancer potentials. The synthesized zinc nanoparticle solution of W. somnifera extract was characterized by phytochemical analysis, Transmission Electron Microscope (TEM), and zeta potential. The results revealed reduced values of the phytochemical constitutes, large surface area, and high stability of the nanoparticles. The antioxidant activity of the extracted W. somnifera and its zinc nanoparticles was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH•) assay, in which the original extract has the more antioxidant capacity with IC50= 0.701 mg/mL, along with potent results for both samples relative to ascorbic acid. The extracted W. somnifera, its zinc nanoparticles, and zinc sulfate solution were in vitro assessed as anticancer agents on well-known six human tumor, and a normal cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The results demonstrated that the synthesized zinc nanoparticles of the W. somnifera extract shown the most potent cytotoxicity with IC50= 19.17 µg/mL on HeLa cell line. The synthesized nano-zinc solution of the W. somnifera aqueous extract performed to be proficient as a potent anticancer characteristic than the plant extract with developed biological potency.
... The leaves of Withania somnifera have also been shown to inhibit the growth of human cancer cell lines equivalent to that produced by adriamycin. The leaf extract produced anti-cancer activity on NCI-H460 (lung), HCT-116 (colon), SF-268(central nervous system) and MCF-7(breast) human tumor cell lines [15] . These are some indicative observations of the protective effect of Withania somnifera is a cancer-causing agent. ...
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Cancer is one of the most death-causing diseases and the number of cases rising around the world. So, there is a developing demand to get a durable cure to treat this awful disease. Currently, conventional techniques such as chemotherapy are not suitable for their destructive post-treatment outcomes, and sometimes it is not a budget-friendly option to every person. Various medicinal plant acquired metabolites have become the core of interest due to their fewer side effects and variable application in averting cancer. Bangladesh is an agricultural country, and a remarkable variety of medicinal plants is available here with significant anticancer properties. Numerous natural products and their analogs have been recognized as potent anticancer agents. This review has been plotted to explore diverse medicinal plants of Bangladesh with anticancer activity and their effectual compounds to treat cancer. Based on the results of the various articles indexed in Google Scholar, PubMed, Scopus etc. a number of plants have been reported to be used in the treatment and prevention of different kinds of cancer disorders. The plants include Phyllanthus emblica, Terminalia chebula, Withania somnifera, Azadirachta indica, Zingiber officinale, Allium sativum, Cinnamomum Verum, Nigella sativa, Catharanthus roseus, Cannabis sativa, Camellia sinensis, Hibiscus rosa-Sinensis, Solanum Lycopersicum, etc. Different anticancer metabolites found in these plants has potential to treat different cancer. Phytochemical investigations have scrutinized the therapeutic effects of medicinal plants constructive on numerous cancers and their possible mechanisms of action and clinical effects.
... WS also helps patients to recover from the adverse effects of chemotherapy.The anticancer effect of Withania has been studiedextensively (Devi et al., 1992;Devi, 1996;Davis and Kuttan, 2000;Prakash et al., 2002;Senthilnathan et al., 2006;Winters, 2006;Widodo et al., 2007;Wadhwa et al., 2013), and it wasfound that it is the most effective agent in preventingcancer through its ability to reduce the tumor size.Treatment of root extract of W. somnifera on induced skincancer in mice exhibited significant decrease in the incidenceand average number of skin lesions compared tocontrol group (Prakash et al., 2002). Withaferin A showedtumorinhibitory activity against cells derived from humancarcinoma of the nasopharynx (Jayaprakasam et al., 2003) and it also inhibited the growth of roots of Allium cepa by arresting the cell division at metaphase (Palyi et al., 1969). In another study, W. somnifera was evaluatedfor its antitumor effect in urethaneinduced lungadenomas in adult male albino mice. ...
... In fact, most withanolides inhibit various hallmarks of cancer and A study identified inhibitory concentration in µg/ml of a mixture of withanolide-A for 50% reduction of lung, CNS, breast and colon cancer cells as 0.24 ± 0.01 to 11.6 ± 1.9 respectively for withaferin A and its derivatives, and 0.32 ± 0.05 to 0.47 ± 0.15 for visosalactone B and 7.9 ± 2.9 to 17.3 ± 3.9 for 27-O-glucoside derivative. No inhibition was seen in Physagulin D (45). ...
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Cancer is a leading cause of mortality worldwide, the conventional chemotherapeutic drugs have been known for their toxicity and numerous side effects. A new approach to treat cancer involves phytochemical drugs. In the present review, anti-cancer activity of a class of steroidal lactones called withanolides obtained from Withania somnifera (L.) Dunal is discussed. The commonly studied bioactive compounds namely withaferin-A, withanoside IV, withanoside VI and withanolide-A among others obtained from methanolic and chloroform extract of the leaves and various alcoholic, aqueous and chloroform extract of roots have shown inhibition to various human cancer cell lines including skin, breast, colon, prostate, liver, ovary, cervical and lung. Prominent mechanisms of action include induction of apoptosis by NOS upregulation, ROS production and NBS2 or COX-2 inhibition; cytotoxicity by humoral and cell mediated immune response, activation of p53 and pRB and inhibition of various viral oncoproteins; cell cycle arrest by Cdc2 facilitated mitotic catastrophe, cyclin-D1 down-regulation and inhibition of transcription factors. Cancers are also controlled by inhibition of angiogenesis and metastasis of the tumor cells. In addition to anti-tumorogenic properties, W. somnifera also holds properties that make it a potential adjuvant in integrated cancer therapeutics and in enhancing the effectiveness of ongoing radiation therapy.
... Trivedi et al. (2017) identified a total of 43 withanolides in the hydroalchoholic extract of Ashwagandha root using LC/MS, GC/MS and NMR, including withaferin A, withanolide A, withanoside IV and VI, withanolide D, dihydrowithanolide D and withanolide sulfoxide [8]. Of these, withaferin A and withanolide A possess therapeutic properties for the treatment of cancer and neurodegenerative diseases, such as Parkinson's and Alzheimer's [9][10][11]. ...
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Ashwagandha (Withania somnifera) is considered a potent adaptogen and anti-stress agent that could have some potential to improve physical performance. This preferred reporting items for systematic reviews and meta-analyses (PRISMA)-based comprehensive systematic review and Bayesian meta-analysis aimed to evaluate clinical trials up to 2020 from PubMed, ScienceDirect, and Google Scholar databases regarding the effect of Ashwagandha supplementation on physical performance in healthy individuals. Besides implementing estimation statistics analysis, we developed Bayesian hierarchical models for a pre-specified subgroup meta-analysis on strength/power, cardi-orespiratory fitness and fatigue/recovery variables. A total of 13 studies met the requirements of this systematic review, although only 12 were included in the quantitative analysis. A low-to-moderate overall risk of bias of the trials included in this study was detected. All Bayesian hierarchical models converged to a target distribution (Ȓ = 1) for both meta-analytic effect size (μ) and between-study standard deviation (τ). The meta-analytic approaches of the included studies revealed that Ashwagandha supplementation was more efficacious than placebo for improving variables related to physical performance in healthy men and female. In fact, the Bayesian models showed that future interventions might be at least in some way beneficial on the analyzed outcomes considering the 95% credible intervals for the meta-analytic effect size. Several practical applications and future directions are discussed, although more comparable studies are needed in exercise training, and athletic populations are needed to derive a more stable estimate of the true underlying effect.
... Withanolides isolated from W. somnifera inhibited the growth of cancerous cells in the central nervous system, lungs, breasts, and colon cell lines. It was investigated that withaferin A significantly reduced the growth of breast and colon cancer cell lines more effectively than famous anticancer drug doxorubicin (85). Blocking of NFκβ activation sites may involve the inducible or constitutive mechanisms of suppression which resulted in the elevation of apoptosis, inhibition of invasion, and osteoclastogenesis. ...
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Withania somnifera L. is a multipurpose medicinal plant of family Solanaceae occurring abundantly in sub-tropical regions of the world. The folk healers used the plant to treat several diseases such as fever, cancer, asthma, diabetes, ulcer, hepatitis, eyesores, arthritis, heart problems, and hemorrhoids. The plant is famous for the anti-cancerous activity, low back pain treatment, and muscle strengthening, which may be attributed to the withanolide alkaloids. W. somnifera is also rich in numerous valued secondary metabolites such as steroids, alkaloids, flavonoids, phenolics, saponins, and glycosides. A wide range of preclinical trials such as cardioprotective, anticancer, antioxidant, antibacterial, antifungal, anti-inflammatory, hepatoprotective, anti-depressant, and hypoglycemic have been attributed to various parts of the plant. Different parts of the plant have also been evaluated for the clinical trials such as male infertility, obsessive-compulsive disorder, antianxiety, bone and muscle strengthening potential, hypolipidemic, and antidiabetic. This review focuses on folk medicinal uses, phytochemistry, pharmacological, and nutrapharmaceutical potential of the versatile plant.
... In fact, most withanolides inhibit various hallmarks of cancer and A study identified inhibitory concentration in µg/ml of a mixture of withanolide-A for 50% reduction of lung, CNS, breast and colon cancer cells as 0.24 ± 0.01 to 11.6 ± 1.9 respectively for withaferin A and its derivatives, and 0.32 ± 0.05 to 0.47 ± 0.15 for visosalactone B and 7.9 ± 2.9 to 17.3 ± 3.9 for 27-O-glucoside derivative. No inhibition was seen in Physagulin D (45). ...
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Cancer is a leading cause of mortality worldwide, the conventional chemotherapeutic drugs have been known for their toxicity and numerous side effects. A new approach to treat cancer involves phytochemical drugs. In the present review, anti-cancer activity of a class of steroidal lactones called withanolides obtained from Withania somnifera (L.) Dunal is discussed. The commonly studied bioactive compounds namely withaferin-A, withanoside IV, withanoside VI and withanolide-A among others obtained from methanolic and chloroform extract of the leaves and various alcoholic, aqueous and chloroform extract of roots have shown inhibition to various human cancer cell lines including skin, breast, colon, prostate, liver, ovary, cervical and lung. Prominent mechanisms of action include induction of apoptosis by NOS upregulation, ROS production and NBS2 or COX-2 inhibition; cytotoxicity by humoral and cell mediated immune response, activation of p53 and pRB and inhibition of various viral oncoproteins; cell cycle arrest by Cdc2 facilitated mitotic catastrophe, cyclin-D1 down-regulation and inhibition of transcription factors. Cancers are also controlled by inhibition of angiogenesis and metastasis of the tumor cells. In addition to anti-tumorogenic properties, W. somnifera also holds properties that make it a potential adjuvant in integrated cancer therapeutics and in enhancing the effectiveness of ongoing radiation therapy.
... [42] In one study, the herb was evaluated for its anti-tumor effect in urethane-induced lung tumors in adult male mice. [43] Following administration of Ashwagandha over a period of seven months, the histological appearance of the lungs of animals which received the herb was similar to those observed in the lungs of control animals. ...
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Attitude, behavior, concentration, dedication and enthusiasm are very much necessary for the continuation and successful completion of any task. Owing to day by day decline of these qualities, masses are in search of a safe agent which can help them in leading happy lives through accomplishment of their works smoothly. Ashwagandha is very much capable of meeting this demand of the people. It is classified as a Rasayana (rejuvenation-medicine) and accepted to increase longevity and vitality. The drug is reported with anti-inflammatory, anti-arthritic, caridioprotective, anti-stress, tranquillizer-like sedative activity, hypoglycemic, thyroprotective activity and proved to be an effective remedy in the malignant growth of different organs. Although many articles have been published on this wonderful drug, the holistic approach has not been addressed till date. This article is for serving that very purpose. The review includes various activities of Ashwagandha in experimental models along with clinical evaluation of the drug in various dosage forms. Thorough review of various books, scientific research journals, theses, articles etc. available on Ashwagandha along with internet was performed to bring about the article in present form. The classical literatures in Ayurveda, Unani & Allopathy on this natural gift were studied at fundamental level, interpreted and analyzed logically and are presented in this detail research article.
... Ashwagandha, the commonly found Herbal ingredient in Indian system of medicine, is also known as Indian Ginseng, and was scientifically called the Withania somnifera, from the Solanaceae family. Since the extracts of Withania somnifera suggested to modulate various biological responses, it is extensively used in indigenous preparations for its properties like anti-ageing, aphrodisiac, cardiotonic, thyro-regulatory, antiperoxidative, anti-inflammatory, antitumor, anti-stress, anti-oxidant, immuno-modulatory, hemopoietic, and rejuvenating 1,2,3 . In kerala, Ashwagandha is used as a major herbal ingredient in many traditional medicinal formulations. ...
Article
Withania somnifera is an annual evergreen shrub from the Solanaceae family, commonly known as Indian ginseng or Ashwagandha. The plant is mainly found in Asia and Africa regions. In the traditional Indian medicinal system ayurveda, Withania somnifera is used as a rejuvenator and sold in many countries as a dietary supplement. Withanolides are the major phytochemical constituent group found in the Withania somnifera, among which withaferin A and withanone, are considered to be major withanolides, which believed to be involved in majority of biological activity of Withania somnifera. Various studies including both in vitro and in vivo have reported regarding the anticancer potential of Withania somnifera. Along with the anticancer activity of W.somnifera, the anticancer efficacy of one of its major ingredients Withaferin A is also studied previously. This study aimed to analyse the anticancer potential of another major Withanolide present in W. Somnifera, Withanone. The study used Molecular Docking method to find the molecular binding affinity of Withanone towards various cancer proteins. The four major cancer proteins were B-cell lymphoma- extra large (Bcl-xL), Cellular FLICE (c-FLIP), Glutathione Reductase (GR) and Glutathione S- Transferases (GST). The protein structure obtained from the protein data bank and the structure of the molecule obtained from pubchem were modified and prepared for Docking studies with the help of MGL Tools. The protein ligand interaction study was conducted using the software, Autodock vina. The already known anticancer standard, 5-FluoroUracil is used as standard for comparison. Output obtained from the study is visualised using molecular visualiser tool, Pymol. Like the Withaferin A, Withanone also exhibited promising anticancer activity while studied using molecular docking methods.
... However, the most potent bioactive compound isolated from Withania somnifera roots is the highly oxygenated lactone Withaferin A (WA). Indeed, studies show that most beneficial health effects of Withania somnifera, ranging from anti-inflammatory to anti-cancer effects, can be attributed to WA [31][32][33][34]. These effects are mostly accomplished via the covalent binding of WA with target proteins, resulting in a loss of activity of the latter [29]. ...
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Chronic inflammatory diseases are considered to be one of the biggest threats to human health. Most prescribed pharmaceutical drugs aiming to treat these diseases are characterized by side-effects and negatively affect therapy adherence. Finding alternative treatment strategies to tackle chronic inflammation has therefore been gaining interest over the last few decades. In this context, Withaferin A (WA), a natural bioactive compound isolated from Withania somnifera, has been identified as a promising anti-cancer and anti-inflammatory compound. Although the majority of studies focus on the molecular mechanisms of WA in cancer models, recent evidence demonstrates that WA also holds promise as a new phytotherapeutic agent against chronic inflammatory diseases. By targeting crucial inflammatory pathways, including nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2 related factor 2 (Nrf2) signaling, WA suppresses the inflammatory disease state in several in vitro and preclinical in vivo models of diabetes, obesity, neurodegenerative disorders, cystic fibrosis and osteoarthritis. This review provides a concise overview of the molecular mechanisms by which WA orchestrates its anti-inflammatory effects to restore immune homeostasis.
... The main bioactive compounds present in W. somnifera are withanolides, which are steroidal lactones with an ergostane backbone (Ganzera et al. 2003;Kulkarni and Dhir 2008). Withaferin A (1) and withanolide A (2) have been repeatedly stated as the most potent and abundant withanolides (Ganzera et al. 2003;Jayaprakasam et al. 2003;Kulkarni and Dhir 2008). ...
Article
Withania somnifera (L.) Dunal, Solanaceae, is a shrub known to have anti-cancer, anti-hypertensive, anti-inflammatory, and immunostimulatory properties. The main bioactive compounds present in this plant are steroidal lactones or withanolides. The anti-melanoma efficacy of W. somnifera extracts and bioactive compounds and any selectivity for melanoma A375 cells versus keratinocytes HaCaT was investigated. Withaferin A and withanolide A were selected as marker compounds. Three crude extracts were prepared using water, and 80% and 50% ethanol as solvents. Cytotoxicity and apoptosis assays were carried out on A375 and HaCaT cells to determine the effects of the marker compounds and crude W. somnifera extracts. Further investigations were carried out to determine the influence of crude extract encapsulation in solid lipid nanoparticles and the presence of an extracellular matrix (Matrigel). Both withaferin A and withanolide A presented with cytotoxic and apoptotic properties that were relatively selective for A375 cells, as indicated by the IC50 values of withaferin A (26.25 μg/ml), withanolide A (80.61 μg/ml), and their combination (13.87 μg/ml). Results obtained revealed that the pure compounds were selective for melanoma cells and more active than the crude extracts in both 2D and 3D environments.
... PH-HM-10 compound (Pegaharmine E) was analyzed for its anticancer activity against six selected human cancer cell lines using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays [36]. The results of the study suggest the already reported trend of a strong correlation between dosage and the inhibition of cancer cell growth [37]. The absorbance level was affected by the concentration of the compound, hence it validated the relationship between concentration and absorbance [38]. ...
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Conventional cancer treatments normally involve chemotherapy or a combination of radio- and chemotherapy. However, the adverse effects of synthetic medicines encouraged the exploration of novel therapeutic medications of a bio-friendly nature. In an effort to explore anticancer compounds from natural resources, crude extract of Peganum harmala (seeds) was fractionated on the basis of polarity, and the fractions were further tested for anticancer activity. Brine shrimp lethality assays and potato disc antitumor assays were used to test each fraction for cytotoxic and antitumor potential. The ethyl acetate fraction was found to be most potent, with LC50 and IC50 values of 34.25 µg/mL and 38.58 µg/mL, respectively. Further activity-guided fractionation led to the isolation of the bioactive compound PH-HM-10 which was identified and characterized by Mass Spectroscopy (MS), Infrared Spectroscopy (IR), Proton Nuclear Magnetic Resonance Spectroscopy (1HNMR), Carbon Nuclear Magnetic Resonance Spectroscopy (13CNMR) and Heteronuclear Single Quantum Correlation (HSQC). Anticancer aspects in the isolated compound were determined against six human cancer cell lines with a maximum anticancer effect (IC50 = 36.99 µg/mL) against the tested human myeloid leukemia (HL-60) cell line, followed by the human lung adenocarcinoma epithelial cell line (A549) and the breast cancer cell line (MCF-7) with an IC50 of 63.5 µg/mL and 85.9 µg/mL, respectively). The findings of the current study suggest that the isolated compound (Pegaharmine E) is significantly active against the tested cancer cell lines and can be further investigated to develop future novel anticancer chemotherapeutic agents.
... It possesses anti-stress characteristics (Bhattacharya and Muruganandam, 2003), immunomodulatory, cytotoxic, antibacterial, antifungal, and immunosuppressive properties (Al-Hindawi et al., 1992;Meena et al., 2019). The leaves of this plant are used to treat tumors, tubercular glands and as an anti-inflammatory due to their antibacterial, antifungal, and anticancer properties (Chopra, 1994;Devi et al., 1993;Jayaprakasam et al., 2003;Meena et al., 2019). ...
Article
The vital herb ashwagandha was farmed for commercial purposes in India. This study aimed to estimate the nature and amount of genetic variation in the 20 attributes in the 29 genotypes of ashwagandha in order to understand the correlations and character contributions to dry root weight/plant and alkaloid content with the selection of potential parents for ashwagandha crop improvement. Twenty-nine ashwagandha genotypes were assessed using a range of genetic metrics, including analysis of variance (ANOVA), genetic variability components , correlation, principal component analysis (PCA), and Mahalanobis D 2. The ANOVA confirms a large amount of variability in the genotypes/varieties under study. Out of twenty the four traits, namely fresh leaf weight per plant (X 8), dry leaf weight per plant (X 9), seed yield per plant (X 13), and dry root weight per plant (X 16)-indicates the presence of additive gene action in the current study were highly heritable and had a high genetic advance mean value. Starch estimation, main root length, and root diameter were found to be positively and significantly correlated with dry root production per plant and total alkaloid content. The principle component analysis (PCA) results showed that the first four PCA accounted for the bulk (79.56%) of the differences. All genotypes are divided into four clusters based on the distances between and within clusters. Based on the findings mentioned above, it is recommended that genotypes from clusters IV (Poshita, CIMAP-Chetak), cluster II (AKAS-10, AKAS-11, NMITLI-101, and NMITLI-118), and cluster I (AKAS-02, IC-286632, and CIMAP Pratap) be chosen for a different hybridization program. Based on the multidisciplinary investigation, some of the genotypes with desired qualities have been found. They can be employed in upcoming breeding programs to increase alkaloid content and dry root yield.
... W. somnifera's roots and leaves are used in the Indian traditional system of medicine, Ayurveda and the plant's therapeutic virtues have led to it being sold all over the world. It's also one among the GRAS (generally recognized as safe) herbs that has a variety of medicinal applications (Jayaprakasam et al., 2003). W. somnifera extract is commonly used to control a wide range of biological reactions. ...
Chapter
Natural products have been used to prevent and to treat various diseases from thousands of years. Cancer chemoprevention with natural phytochemical compounds is an emerging strategy to preventor cure cancer with affordable conditions. Several unfavourable side effects might arise with chemotherapy. Certain bioactive components from the plants have been used for their anticancer activities. These include curcumin, andrographolide, asiaticoside, phyllanthin, withaferin A, gingerol etc. In cancer therapy, using plant-derived compounds may help to reduce negative side effects. However, a myriad of many plant products exist that have shown very promising anti-cancer properties in vitro, but have yet to be evaluated for human’s use. Further study is required to determine the efficacy of these phytochemicals in treating cancers. In recent years, the various plants derived chemical compounds that have shown as anticancer agents and will outline their potential mechanism of action.
... The leaf extract of Withania somnifera (L.) Dunal showed anti-proliferative activity in vitro. In their study, Jayaprakasam and the team speculated withanolides are responsible for the anti-cancer property of Withania somnifera (L.) Dunal (Jayaprakasam et al. 2003). ...
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Breast cancer (BC) is the most prevalent neoplasm among women. Genetic and environmental factors lead to BC development and on this basis, several preventive – screening and therapeutic interventions have been developed. Hormones, both in the form of endogenous hormonal signaling or hormonal contraceptives, play an important role in BC pathogenesis and progression. On top of these, breast microbiota includes both species with an immunomodulatory activity enhancing the host’s response against cancer cells and species producing proinflammatory cytokines associated with BC development. Identification of novel multitargeted therapeutic agents with poly-pharmacological potential is a dire need to combat advanced and metastatic BC. A growing body of research has emphasized the potential of natural compounds derived from medicinal plants and microbial species as complementary BC treatment regimens, including dietary supplements and probiotics. In particular, extracts from plants such as Artemisia monosperma Delile, Origanum dayi Post, Urtica membranacea Poir. ex Savigny, Krameria lappacea (Dombey) Burdet & B.B. Simpson and metabolites extracted from microbes such as Deinococcus radiodurans and Streptomycetes strains as well as probiotics like Bacillus coagulans and Lactobacillus brevis MK05 have exhibited antitumor effects in the form of antiproliferative and cytotoxic activity, increase in tumors’ chemosensitivity, antioxidant activity and modulation of BC – associated molecular pathways. Further, bioactive compounds like 3,3’-diindolylmethane, epigallocatechin gallate, genistein, rutin, resveratrol, lycopene, sulforaphane, silibinin, rosmarinic acid, and shikonin are of special interest for the researchers and clinicians because these natural agents have multimodal action and act via multiple ways in managing the BC and most of these agents are regularly available in our food and fruit diets. Evidence from clinical trials suggests that such products had major potential in enhancing the effectiveness of conventional antitumor agents and decreasing their side effects. We here provide a comprehensive review of the therapeutic effects and mechanistic underpinnings of medicinal plants and microbial metabolites in BC management. The future perspectives on the translation of these findings to the personalized treatment of BC are provided and discussed.
... The preclinical in-vitro and in-vivo pharmacological activities of the said aerial parts been studied with positive outcomes. To elaborate further, the leaf extracts of Withania somnifera plant have preclinically demonstrated several pharmacological activities like, anti-cancer [12][13][14][15][16] , anti-neuroinflammatory 17,18 , anxiolytic and sleep inducing 18,19 , cardioprotective 20 , antidiabetic 21,22 , anti-microbial 23,24 , and anti-osteoporotic 25 . Moreover, in certain studies, the extracts prepared from the leaves have found to possess a superior activity when compared to the roots of Withania somnifera. ...
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Withania somnifera (L.) Dunal (Ashwagandha) is widely used in Ayurveda, Unani and Siddha systems of medicines due to its therapeutic application in numerous ailments. Traditionally, the medications prepared from the plant employ only its roots and based on the currently available scientific literature, their efficacy and safety is well established. Apart from the roots, the aerial parts also contain bioactive components and correspondingly certain marketed preparations also employ the leaves of the plant. Accordingly, Ministry of Ayush, Government of India has lately issued an advisory emphasizing the need for extensive efficacy and safety profiling of leaf-based products. Consequently, we have conducted the present GLP-driven study, in which the non-clinical safety of a hydromethanolic extract of the whole plant of Withania somnifera (WSWPE) has been assessed according to OECD guideline 407. In this study Sprague Dawley rats of either sex were orally administered with WSWPE for 28-consecutive days at the doses of 100, 300 and 1000 mg/kg/day. The study also included a satellite group of animals that received WSWPE for 28-days followed by a 14-days recovery period. Withania somnifera Whole Plant Extract was found to be safe up to the dose level of 1000 mg/kg/day as no toxicologically relevant findings could be detected.
... Its leaves are used for treating cancers and tubercular glands in Ayurvedic and Unani systems. W. somnifera have anxiolytic-antidepressant properties [22], antifungal [23]) antimalarial [24] apoptotic [25]. There are many studies reporting the physicochemical and pharmacological importance of W. somnifera [26]. ...
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Green synthesis of metal nanoparticles is of great importance in the modern health care system. In this study, zinc nanoparticles (ZnONPs) were synthesized using leaf and root extracts of Withania somnifera using four different solvents. ZnONPs were characterized by UV-vis spec�trophotometer with a range between 350–400 nm. Scanning electron microscope revealed spherical morphology with an overall size of 70–90 nm and XRD pattern confirmed the crystalline structure. The total flavonoids, phenolic, and alkaloid contents were significantly greater in the crude extracts as compared to ZnONPs. The highest scavenging activity was observed in ZnONPs from n-hexane and ethyl-acetate extracts of roots with IC50 values of 27.36 µg/mL and 39.44 µg/mL, respectively. ZnONPs from methanol and aqueous extracts showed significant antibacterial activity against Es�cherichia coli, Staphylococcus aureus, and Bacillus subtilis while none of the extracts were found to have significant antifungal activity. Maximum cytotoxic activity was observed in ZnONPs synthe�sized from aqueous and n-hexane root extracts with LC50 values of 9.36 µg/mL and 18.84 µg/mL, respectively. The highest antidiabetic potential was exhibited by ZnONPs from n-hexane leaf ex�tracts, i.e., 47.67 ± 0.25%. Maximum protein kinase inhibitory potential was observed in ZnONPs of ethyl-acetate extract of roots with a bald zone of 12 mm. These results indicated that Withania somnifera-based ZnONPs showed significant biological activities compared to crude extracts. These findings can further be utilized for in-vivo analysis of nano-directed drug delivery systems.
... Its leaves are used for treating cancers and tubercular glands in Ayurvedic and Unani systems. W. somnifera have anxiolytic-antidepressant properties [22], antifungal [23]) antimalarial [24] apoptotic [25]. There are many studies reporting the physicochemical and pharmacological importance of W. somnifera [26]. ...
Article
Citation: Kiani, B.H.; Haq, I.-u.-; Alhodaib, A.; Basheer, S.; Fatima, H.; Naz, I.; Ur-Rehman, T. Comparative Evaluation of Biomedical Applications of Zinc Nanoparticles Synthesized by Using Withania somnifera Plant Extracts. Plants 2022, 11, 1525. https://doi.
... Withania somnifera (Ashwagandha) is one of the most versatile plants used in traditional Indian medicine system (Ayurveda). It is highly reputed as 'Indian ginseng' and is a member of plants generally regarded as safe (GRAS) (Jayaprakasam et al., 2003), which is cultivated in India for their medicinal purposes. The roots and leaves of Ashwagandha contain various alkaloids, viz., withanolides and withaferins (Atta et al., 1991). ...
Article
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Transformation of Withania somnifera was carried out by using three Agrobacterium rhizogenes strains (ATCC 15834, R1000 and K599) for hairy root induction. Induction of hairy root was carried out in leaf, petiole and internodal explants. Hairy root induction was successful only in ATCC 15834 and R1000. The highest frequency of hairy root was obtained in petiole explants (64%) infected with R1000 and it resulted in five distinct morpho-types (callus (fragile), callus (hard), callus + hairy roots, hairy roots and callusing roots). The frequency of R1000 transformation was increased up to 93.2% by the addition of acetosyringone during various steps of infection. Molecular identification through PCR analysis of rolC confirmed the presence of Ri T-DNA. The half strength Murashige and Skoog (MS) liquid medium was found to be the best medium that supports the high root biomass accumulation than the other tested medium types (MS full strength, Gamborg B5 medium (B5) full strength and B5 half strength). High performance liquid chromatography (HPLC) analysis of hairy roots revealed the accumulation of withaferin-A (72.3 mg/g dw). This study reports the influence of Agrobacterium strains, explant types and acetosyringone in the hairy root induction of W. somnifera.
... Major Withanolides found in this species, such as withanolide A and withaferin A, have been shown to exhibit distinct anti-carcinogenic, anti-Parkinson's, and anti-Alzheimer's properties [100,101]. Gynecological diseases, bronchitis, arthritis, rheumatism, and drug addiction, such as opiate addiction, are also treated with Withania somnifera [95,102]. ...
Article
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Medicinal plants are an inevitable source of pharmaceutical drugs and most of the world population depends on these plants for health benefits. The increasing global demand for bioactive compounds from medicinal plants has posed a great threat to their existence due to overexploitation. Adventitious root and hairy root culture systems are an alternative approach to the conventional method for mass production of valuable compounds from medicinal plants owing to their rapid growth, biosynthetic and genetic stability. The main purpose of this review is to investigate the recent scientific research published worldwide on the application of adventitious and hairy root cultures to produce valuable compounds from medicinal plants. Furthermore, a comparison of adventitious root vs. hairy root cultures to produce valuable compounds has also been discussed. Various aspects such as medium composition, carbon source, pH, amount of macronutrients, optimization strategy, scale-up cultures, and use of biotic abiotic and nano-elicitors at various concentrations are the topic of discussion in this review. Several studies on adventitious and hairy root cultures of Polygonum multiflorum¸ Withania somnifera¸ Echinacea purpurea and Ajuga bracteosa have been discussed in detail which highlights the importance of elicitation strategies and bioreactor system, presenting commercial applications.
Article
Novel withangulatin A (WA) derivatives were synthesized and evaluated for antiproliferative activity against four human cancer cell lines (U2OS, MDA-MB-231, HepG2, and A549). Among these derivatives, 10 exhibited the most potent antiproliferative activity, with an IC50 value of 74.0 nM against the human breast cancer cell line MDA-MB-231 and potency that was 70-fold that of WA (IC50 = 5.22 µM). Moreover, 10 caused G2-phase cell cycle arrest in a concentration-dependent manner and induced the apoptosis of MDA-MB-231 cells by increasing intracellular reactive oxygen species (ROS). Compound 10 showed a high selectivity index (SI = 267.03) for breast cancer MDA-MB-231 cells. These results suggest that 10 is a promising anticancer agent.
Article
Ethnopharmacological relevance Ashwagandha has been used as an ayurvedic medicine in the form of 'Rasayana' (as a tonic) even before 3000 BC in India. As per Ayurveda, it has long been used traditionally for the treatment of inflammation, weakness, impotence, pulmonary tuberculosis. This plant is also beneficial in lumbago and leucorrhea in the female. In the recent past, Withania has shown its anti-cancerous activity in various experimental models. In addition, Withania also possesses many other properties such as anti-oxidant, anti-stress, adaptogenic, and regenerative which will eventually be beneficial and safe in treating cancer patients. Aim of the study This review aims to provide experimental evidence along with a deeper insight into molecular mechanisms of Ashwagandha (Withania somnifera (L.) Dunal) through which it acts as a chemotherapeutic agent against different types of breast cancer. Materials and methods Literature searches with the help of electronic online databases (Elsevier, Google Scholar, Scopus, Springer Link, ScienceDirect, ResearchGate, PubMed) were carried out. The timeline for collection of data for the review article was from 2000 to 2019. The plant name was validated from The Plant List (2013). Version 1.1. Published on http://www.theplantlist.org/(accessed 21st March, 2020). Results Various forms of Withania somnifera were used and several in vitro, in vivo, and clinical studies were reported by researchers. They found ashwagandha to exhibit anti-apoptotic, anti-metastatic, anti-invasive and anti-inflammatory properties and gave the evidence that ashwagandha has a capability for averting and treating breast cancer. Conclusion Various in vitro and in vivo studies suggested Ashwagandha may possess a potential for treating breast cancer, especially ER/PR positive breast cancer and triple-negative breast cancer. A clinical trial has also been conducted in the past that suggested its potential in refining quality of life in breast cancer patients. Studies directed towards molecular pathways have helped in unravelling the key mechanisms of ashwagandha. Future research should be directed towards translational studies involving breast cancer patients. These will reinforce the ancient power of our Ayurvedic medicine.
Article
Cancer and infectious diseases are among the leading causes of death in the world. Despite the diverse array of treatments available, challenges posed by resistance, side effects, high costs, and inaccessibility persist. In the Solanaceae plant family, few studies with Vassobia breviflora species relating to biological activity are known, but promising results have emerged. The phytochemicals present in the ethyl acetate fraction were obtained using ESI-MS-QTOF, and the antioxidants assays 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2’-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radical capture (ABTS), plasma ferric reduction capacity (FRAP), and total antioxidant capacity (TAC). Cytotoxic activity was evaluated by MTT, Neutral Red, and lactate dehydrogenase (LDH) released. The production of reactive oxygen species, nitric oxide, and purinergic enzymes was also investigated. Antibacterial activity was measured through minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and antibiofilm activity, in addition to genotoxicity in plasmid DNA. Five major masses were identified D-glucopyranose II, allyl disulfide, γ-lactones, pharbilignoside, and one mass was not identified. V. breviflora exhibited relevant antioxidant and cytotoxic activity against the HeLa cell line and enhanced expression effect in modulation of purinergic signaling. Antibacterial activities in the assays in 7 ATCC strains and 8 multidrug-resistant clinical isolates were found. V. breviflora blocked biofilm formation in producing bacteria at the highest concentrations tested. However, there was no plasmid DNA cleavage at the concentrations tested. Data demonstrated that V. breviflora exhibited an antioxidant effect through several methods and proved to be a promising therapeutic alternative for use against tumor cells via purinergic signaling and multidrug-resistant microorganisms, presenting an anti-biofilm effect.
Chapter
A strong, healthy immune system is the basis of good health. Immunity is the balanced state of having adequate biological defense to fight against infection, disease, or unwanted biological invasion while having tolerance to avoid allergy and autoimmune diseases. Immune responses occur due to effective interaction between innate (natural and nonspecific) and acquired (adaptive and specific) components of the immune system. The interaction of phagocyte and microorganism in the immunological system is a protective pathway but when unreasonably or improperly organized can damage the body and contribute to the development of several long-term inflammatory conditions like allergies, autoimmune disease, rheumatic arthritis, carcinoma, and many more. Over the past years, remarkable changes have occurred in the immune system due to exposure to chemicals, drugs, or environmental pollutants. Numerous factors perform a major part in alterations of the immunological system such as age, sex, stress, genetic variability, alcohol/drug abuse, lifestyle, malnutrition, and environmental pollution. In clinical practice, immunomodulators can be classified into three main categories such as immunostimulants, immunosuppressants, and immunoadjuvants. Majority of the immunomodulators and immunosuppressive agents used in medicinal practice are toxic and have detrimental adverse effects on the host body. Hence, there is a rising need for the usage of herbal drugs that leads to modulation of immunological system which will prevent the infections rather than to treat the immunological disorders. Phytoconstituents such as alkaloids, glycosides, flavonoids, lactones, tannins, saponins, phenolic compounds, polysaccharides, and diterpenoids of herbal origin have been confirmed for their immunostimulating characteristics. Therefore, the exploration of herbs derived potent and safe immunomodulator drugs is gaining more attention. Hence, the current book chapter will focus attention on summary of extensively scrutinized phyto-immunomodulator plants such as Boerhaavia diffusa, Withania somnifera, Allium sativum, Azadirachta indica, Acacia catechu, Curcuma longa, Ficus benghalensis, Tinospora cordifolia, Murraya koenigii and Ocimum sanctum. These plant-derived immunomodulators drugs have displayed their action by acting on cellular and humoral immune system in variety of animal models, and we need to explore their role in clinical trials also.
Article
Withania somnifera (L.) Dunal is a well-known and important medicinal plant widely used in several indigenous systems of medicine for the treatment of various ailments, viz. asthma, bronchitis, inflammatory diseases, ulcer and stomach problems. Steroidal lactones have been reported as the major phytoconstituents of this species. Different pharmacological experiments in a number of in vitro and in vivo models have convincingly demonstrated the ability of W. somnifera to exhibit anti-inflammatory, anti-oxidative, antimicrobial, anti-anxiety, aphrodisiac, immunomodulation, anti- diabetic, anti-ulcer, anticancer, central nervous system depressant and hepatoprotective activities, lending support to the rationale behind several of its traditional uses. The species is also used to treat some neurological disorders like Parkinson’s and Alzheimer’s. The phytochemicals such as withaferin A, withanolide A and withanolide D isolated from this plant are potential bioactive molecules. Due to the remarkable biological activity of W. somnifera and its constituents, it will be appropriate to develop them as a medicine and make them more potent by chemical modifications and biotransformation. This review has covered botany, chemistry and pharmacology of the plant besides its traditional and folkloric uses.
Article
Ethnopharmacological relevance Datura metel L. has been used as an anesthetic in clinic for more than 1800 years in China, and the main efficacy of D. metel L. flower is relieving asthma and cough, relieving spasm and relieving pain. From 1978 to 1980, Datura metel L. was used as an anesthetic agent and occasionally cured psoriasis patients during anesthesia clinically, and our group confirmed that the effective portion is total withanolides (YWS). Moreover, the new drug “Datura metel L. capsule” composed of YWS has since been approved and used for the treatment of more than 3,000 psoriasis patients, with efficacy and cure rates greater than 90% and 65%. However, the immunological mechanism has not been elucidated. Aim of the study Nowadays, although total withanolides from Datura metel L. have a better clinical efficacy in the treatment of psoriasis, there is a lack of overall understanding of the mechanism of their treatment, especially about some immune cells and proteins closely related to psoriasis and their relationship in executive function and biological significance. This study focused on investigating the mechanism of psoriasis treatment by YWS and determined the biochemical processes in the treatment of psoriasis based on Treg/Th17 axis cell-mediated bidirectional immunoregulatory functions, which provides an important scientific basis for understanding the mechanism underlying the treatment of psoriasis by YWS. Materials and methods The effects of YWS on the lesion pathology of IMQ-induced psoriasis mice and the underlying molecular mechanism were assessed directly using HE staining, the PASI score and the animal body mass. We also investigated the effects of YWS on the Treg/Th17 axis and their critical functions in psoriasis pathogenesis via molecular biological methods. Finally, we performed differential proteomics analysis on skin in IMQ-induced psoriasis mice to clarify the effect of YWS by incorporates mass spectrometry-bioinformatics and annotated the functions and pathways associated with the differential proteins through GO enrichment, KEGG pathway analysis and PPI networks analysis, respectively. Results YWS regulated the imbalance of the Treg/Th17 axis. And proteomic analysis showed that YWS up-regulated 46 and down-regulated 37 proteins. According to the bioinformatics analysis, the improvement of Treg/Th17 imbalance may be the key immunological mechanism of YWS in the treatment of psoriasis by up-regulating the butyrate metabolism pathway, down-regulating leukocyte migration, inhibiting the phagocytic function of natural killer cells, suppressing osteoclast differentiation and interfering with chemokine activity, and the critical proteins involved are Lyn, HMGCS2, ABAT, ITGβ2, PRKCβ, MMP9, NCF1, JUNβ, and Hck. Conclusion This research clarified that the improvement of the imbalance of the Treg/Th17 axis may be the key immunological mechanism of YWS in the treatment of psoriasis through metabolic pathways and influencing key proteins. The results not only expand the therapeutic targets and approaches for the treatment of psoriasis, which is a challenging and complex disease, but also deepens the understanding of the mechanism of YWS in the treatment of psoriasis and other important conditions to open up a new way of thinking for research on YWS in the treatment of psoriasis.
Chapter
Inflammation is a biological function that is caused after a mechanical tissue disorder or from the reactions by the occurrence of a physical, chemical, or biological mediator in the body. It is also an essential act provided by the immune system during infection and tissue injury to preserve normal tissue homeostasis. Numerous health problems are associated with prolonged inflammation, which effects nearly all minor to major diseases. Current antiinflammatory drugs are expensive and have a high risk of side effects. Hence, the natural product-based formulations have received extensive recognition by medical experts and the public to treat inflammation, and this has provided extensive value for pharmaceutical discoveries over the last century. This chapter provides an update on inflammation and its associated diseases, molecular targets, inflammatory mediators, and the function of natural products. Accordingly, the current studies in identifying new molecules from natural products can lead to future antiinflammatory pharmaceutical and nutraceutical discoveries.
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In this study, various parts of cucurbitacin-rich plant Citrullus colocynthis extracts were assayed the biological activities like antimicrobial, cytotoxicity in Allium sativum root tips, MTT assay with MDA-MD-231cancer cells, and DNA cleavage. Antimicrobial activity, high concentration of root extract was found to be more effective on both gram-positive and gram-negative bacteria, almost similar results to low concentration of standard cucurbitacin E, whereas other extracts showed a moderate effect. Cytotoxicity was observed in Allium sativum root tips with all extracts in both durations (4 hrs and 24 hrs) with increasing duration of treatment. More chromosomal aberrations in mitotic cell division were observed with root and fruit pulp extracts. At higher concentrations, root extract showed positive results in MTT assay, whereas no effect of other extracts was observed. Most effective DNA cleavage was recorded with root extracts in both concentrations. The cumulative biological effect was observed by root extract while comparing with other extracts.
Article
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Phytochemical studies on the aerial parts of Withania somnifera L. Dunal. (Solanaceae) led to the isolation of a chlorinated steroidal lactone (27-acetoxy-4b,6a-dihydroxy-5b-chloro-1-oxowitha-2,24-dienolide), a diepoxy withanolide (5b,6b,14a,15a-diepoxy-4b,27-dihydroxy-1-oxowitha-2,24-dienolide), and withaf-erin A. Their structures were elucidated by using spectroscopic techniques. All three compounds exhibited a growth inhibition and cytotoxic activity against human lung cancer cell line (NCI-H460), with withaferin A being the most potent (GI 50 = 0.18 lg/mL and LC 50 = 0.45 lg/mL) among three compounds tested.
Book
Inflammation and Natural Products brings together research in the area of the natural products and their anti-inflammatory action in medical, nutraceutical and food products, addressing specific chronic inflammatory diseases like cancer and the mechanistic aspects of the mode of action of some key natural products. Inflammation is a complicated process, driven by infection or injury or genetic changes, which results in triggering signalling cascades, activation of transcription factors, gene expression, increased levels of inflammatory enzymes, and release of various oxidants and pro-inflammatory molecules in inflammatory cells. Excessive oxidants and inflammatory mediators have a harmful effect on normal tissue, including toxicity, loss of barrier function, abnormal cell proliferation, inhibiting normal function of tissues and organs and finally leading to systemic disorders. The emerging development of natural product formulations utilizing the unique anti-inflammatory compounds such as polyphenols, polysaccharides, terpenes, fatty acids, proteins and several other bioactive components has shown notable successes. Inflammation and Natural Products: Recent Development and Current Status provides a comprehensive resource, ranging from detailed explanation on inflammation to molecular docking strategies for naturally occurring compounds with anti-inflammatory activity. It is useful for graduate students, academic and professionals in the fields of pharmaceutical and medical sciences and specialists from natural product-related industries.
Chapter
In the era of COVID pandemic, it is highly desirable to improve body’s immune responses. Many of the diseases including COVID impact the immune system and make it defenseless. There is a growing interest of herbal medicine around the world owing to effective pharmacological actions attributed by its unique phytocompounds. Majority of the immunomodulatory drugs including both immunosuppressor and immuno-stimulators are synthetic organic compounds having side effects. Therefore, there is a growing interest to use plant-based products to regulate immune responses. The present chapter deals with the recognition of members of the family Solanaceae for their use as potential immunomodulators. There are quite a few reports of active phytocompounds isolated from different solanaceous plants that have a myriad of medicinal properties. Various phytochemicals such as phenolic compounds, flavonoids, alkaloids, terpenes, lactones, and glycosides have been shown to have various therapeutic effects on human body owing to their ability to influence body’s immune system. The present chapter will give a comprehensive overview of plant-based therapeutics of solanaceous plants including withanolides isolated from Withania somnifera and Physalis sps, capsaicinoids isolated from Capsicum, and lycopene from tomato. Solanaceae is one of the superfamily having huge repertoire of plants belonging to major food crops utilized throughout the world (tomato, potato, capsicum etc.) as well as in medicine category. Besides several members of the Solanaceae family such as Physalis sps, Atropa sps, Datura stramonium, and Solanum xanthocarpum have potential phytomolecules belonging to alkaloids, terpenoids, and steroid category, which are recognized as medicines. This chapter will also give a critical overview of the possibilities, facts, and prospects of the use of members of Solanaceae family as potential future immunomodulatory drugs.KeywordsSolanaceaeAtropa spsHyoscyamus spsPhysalis sps Withania somnifera CapsicumWithanolidesCapsaicinoids
Chapter
It is essential to be aware of the advances in the nutritional aspects of cancer for oncology practitioners. Unlike the popular myth, the term “Cachexia” more effectively defines the present status in oncology patients rather than “cancer-related malnutrition” (CRM). The consensus guidelines recommend the usage of management algorithm, staging of the CRM involving screening for the nutritional risk and also devising a management strategy consistent with a phenotype and the staging. There should be an inclusion of preventive measures for the CRM in the management algorithm like pharmacological and non-pharmacological interventions aiming both anabolic and the anti-catabolic measures as well as repeated checking of the status of Nutrition. At present, the multimodal mechanism is the optimum method to battle catabolic resulting in CRM. This method should be simultaneously given with anticancer treatments and involve pharmaconutrients, nutritional intervention and the multiple target drug treatments and physical activity. This article provides the practitioners with an awareness of the recent development in the area of nutritional care and as well as defined guidelines to regulate cancer therapy during treatment. This book chapter thus gives insightful guidelines pointing on crucial aspects of Nutrition for cancer treatment.
Article
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Chemotherapy is one of the prime treatment options for cancer. However, the key issues with traditional chemotherapy are recurrence of cancer, development of resistance to chemotherapeutic agents, affordability, late-stage detection, serious health consequences, and inaccessibility. Hence, there is an urgent need to find innovative and cost-effective therapies that can target multiple gene products with minimal adverse reactions. Natural phytochemicals originating from plants constitute a significant proportion of the possible therapeutic agents. In this article, we reviewed the advances and the potential of Withania somnifera (WS) as an anticancer and immunomodulatory molecule. Several preclinical studies have shown the potential of WS to prevent or slow the progression of cancer originating from various organs such as the liver, cervix, breast, brain, colon, skin, lung, and prostate. WS extracts act via various pathways and provide optimum effectiveness against drug resistance in cancer. However, stability, bioavailability, and target specificity are major obstacles in combination therapy and have limited their application. The novel nanotechnology approaches enable solubility, stability, absorption, protection from premature degradation in the body, and increased circulation time and invariably results in a high differential uptake efficiency in the phytochemical’s target cells. The present review primarily emphasizes the insights of WS source, chemistry, and the molecular pathways involved in tumor regression, as well as developments achieved in the delivery of WS for cancer therapy using nanotechnology. This review substantiates WS as a potential immunomodulatory, anticancer, and chemopreventive agent and highlights its potential use in cancer treatment.
Article
Ashwagandha is a medicinal plant used in traditional Asian medicines as an adaptogen to promote both physical and mental health. Withanolides are the major bioactive phytochemicals in Ashwagandha; they are a group of naturally occurring C28-steroidal lactones with an ergostane-based skeleton. Despite the broad use of Ashwagandha, data on the pharmacokinetic and toxicological properties of withanolides remain scarce. Here, 75 withanolides in Ashwagandha were identified in journal publications, databases, and monographs. In silico quantitative structure-activity relationship (QSAR) models were used to evaluate the physicochemical and pharmacokinetic properties as well as the acute toxicity of withanolides. Withanolides had high molecular weight and pKa, low aqueous solubility, and high lipophilicity. QSAR models also predicted high effective human jejunal permeability and plasma protein binding, tissue partitioning, extensive metabolism, hepatic uptake, and renal excretion for certain withanolides. In addition, two thirds of the withanolides evaluated had predicted median lethal dose (LD50) under 100 mg/kg after oral administration in rats. These in silico results could be used to guide further testing and confirmed by in vitro and in vivo studies.
Conference Paper
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CDKs are pivotal mediators essential for the cellular cycle progression. CDKs have relatively constant levels, and their activity is regulated by cyclins, proteins whose concentrations fluctuate during each cell cycle. Consequently, more CDK family members were found that occupy crucial functions in a variety of processes. Moreover, CKS2 is a member of the CDK family, which has been implicated in several malignancies as an oncogene. Additionally, CKS2 is engaged in many biological processes, including the cell cycle transition. CKS2 may act synergistically to promote embryonic development and somatic cell division. Current CDK2 drugs, however, also suppress CDK1, posing a toxicity risk. Investigators demonstrated that the potential conformational maps of cyclin-free CDK1 and CDK2 exhibit slight but substantial differences. The CDK1 unique characteristics may be used to distinguish it from other CDKs in prospective cancer treatment design. Computational-based in silico docking investigations were performed to uncover promising CDK1/Cks2 (6GU7) inhibitors utilizing the Maestro tool. Curcumin, quercetin, withanolide, and genistein were selected against the protein CDK1/Cks2 for protein-ligand XP docking. The physicochemical, lipophilicity, water-solubility, pharmacokinetics, drug-likeness, medicinal chemistry, and toxicological properties were analyzed using SwissADME and pkCSM of the selected ligands. Curcumin exerted an excellent docking score complexed with 6GU7 compared to other ligands. The revealed hit may be a potent inhibitor of 6GU7. However, it will require to be assessed extensively in vivo and in vitro experimental models.
Article
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Diabetes mellitus is a metabolic disorder which characterised by deficiency of insulin secretion. About 150 million people suffering from diabetes worldwide. India leads the way with its largest number of diabetic subject in any given country. It has been estimated the number of diabetes patient in India is expected to increase 57.2 million by the year 2025. Diabetes mellitus is a crucial metabolic disease that lead to several complication nephropathy, and retinopathy, kidney failure and cardiovascular disease many other metabolic abnormalities occur notably an increase in ketone bodies in the where is several lack of insulin blood. Diabetes is still not completely curable by the present anti diabetic agents. In the last few years there has been an exponential growth in the field of herbal medicine. And these drugs are gaining popularity both in developing and developed countries because of natural origin and less side effect. This review focus on the herbal drug and plant used in the treatment of diabetes. In this review spotlight is on the herbal treatment over diabetes. The profile presented include information about the scientific and family name plant part and active constituent which are responsible for Anti diabetic activity. The importance of the herbal plant used in treatment of diabetes.
Article
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CDKs are pivotal mediators essential for the cellular cycle progression. CDKs have relatively constant levels, and their activity is regulated by cyclins, proteins whose concentrations fluctuate during each cell cycle. Consequently, more CDK family members were found that occupy crucial functions in a variety of processes. Moreover, CKS2 is a member of the CDK family, which has been implicated in several malignancies as an oncogene. Additionally, CKS2 is engaged in many biological processes, including the cell cycle transition. CKS2 may act synergistically to promote embryonic development and somatic cell division. Current CDK2 drugs, however, also suppress CDK1, posing a toxicity risk. Investigators demonstrated that the potential conformational maps of cyclin-free CDK1 and CDK2 exhibit slight but substantial differences. The CDK1 unique characteristics may be used to distinguish it from other CDKs in prospective cancer treatment design. Computational-based in silico docking investigations were performed to uncover promising CDK1/Cks2 (6GU7) inhibitors utilizing the Maestro tool. Curcumin, quercetin, withanolide, and genistein were selected against the protein CDK1/Cks2 for protein–ligand XP docking. The physicochemical, lipophilicity, water-solubility, pharmacokinetics, drug-likeness, medicinal chemistry, and toxicological properties were analyzed using SwissADME and pkCSM of the selected ligands. Curcumin exerted an excellent docking score complexed with 6GU7 compared to other ligands. The revealed hit may be a potent inhibitor of 6GU7. However, it will require to be assessed extensively in vivo and in vitro experimental models.
Article
Background : Ayurveda is a highly recognized, well-documented, and well-accepted traditional medicine system. This system utilizes many natural products in various forms for therapeutic purposes. Thousands of plants mentioned in the Ayurvedic system are useful in disease mitigation and health preservation. One potential plant of the Ayurvedic system is “Ashwagandha” [Withania somnifera (L.) Dunal], commonly regarded as Indian Ginseng. It possesses various therapeutic activities, such as neuroprotective, hypoglycemic, hepatoprotective, antiarthritic, and anticancer effects. Purpose : Here we present a comprehensive insight on the anticancer effects of W. somnifera and mechanistic attributes of its bioactive phytocompounds. This review also provides an updated information on the clinical studies pertaining to cancer, safety evaluation and opportunities for chemical modifications of withanolides, a group of specialized phytochemicals of W. somnifera. Methods : The present study was performed in accordance with the guidelines of the Preferred Reporting Items for Systemic Reviews and Meta-Analysis. Various scientific databases, such as PubMed, Science Direct, Scopus, Google Scholar, were explored for related studies published up to May 2021. Results : An updated review on the anticancer potential and mechanisms of action of the major bioactive components of W. somnifera, including withanolides, withaferin A and withanone, is presented. Comprehensive information on clinical attributes of W. somnifera and its active components are presented with the structure-activity relationship (SAR) and toxicity evaluation. Conclusion : The outcome of the work clearly indicates that W. somnifera has a significant potential for cancer therapy. The SAR revealed that various withanolides in general and withaferin A in particular have binding energies against various proteins and tremendous potential to serve as the lead for new chemical entities. Nevertheless, additional studies, particularly well-designed clinical trials are required before therapeutic application of withanolides for cancer treatment.
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The inhibitory action of tea (Camellia sinensis) and tea components against cancer formation has been demonstrated in different animal models involving different organ sites in many laboratories. The possible preventive activity of tea against cancer in humans, however, is not clear. A critical question is whether the information obtained from animal studies is applicable to humans because of possible species differences or the difference in the quantity of tea used in animal studies and that consumed by humans. This article will discuss the results from animal studies and possible cancer inhibitory mechanisms that might be applicable to human cancer prevention. To provide a basis for more quantitative analyses of the effect of tea on carcinogenesis, the levels of tea polyphenols in blood, urine and tissue samples have been analyzed, and the pharmacokinetic properties of tea polyphenols studied. Studies with cell lines have demonstrated that tea polyphenols affect signal transduction pathways, inhibit cell proliferation and induce apoptosis, but the effective concentrations are usually much higher than those observed in blood and tissues. More mechanistic studies in these areas will help us to understand the inhibitory action of tea against carcinogenesis and provide background for evaluating the effects of tea consumption on human carcinogenesis.
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Epidemiological studies consistently indicate that consumption of fruits and vegetables lowers cancer risk in humans and suggest that certain dietary constituents may be effective in preventing colon cancer. Plant-derived phenolic compounds manifest many beneficial effects and can potentially inhibit several stages of carcinogenesis in vivo. In this study, we investigated the efficacy of several plant-derived phenolics, including caffeic acid phenethyl ester (CAPE), curcumin, quercetin and rutin, for the prevention of tumors in C57BL/6J-Min/+ (Min/+) mice. These animals bear a germline mutation in the Apc gene and spontaneously develop numerous intestinal adenomas by 15 weeks of age. At a dietary level of 0.15%, CAPE decreased tumor formation in Min/+ mice by 63%. Curcumin induced a similar tumor inhibition. Quercetin and rutin, however, both failed to alter tumor formation at dietary levels of 2%. Examination of intestinal tissue from the treated animals showed that tumor prevention by CAPE and curcumin was associated with increased enterocyte apoptosis and proliferation. CAPE and curcumin also decreased expression of the oncoprotein beta-catenin in the enterocytes of the Min/+ mouse, an observation previously associated with an antitumor effect. These data place the plant phenolics CAPE and curcumin among a growing list of anti-inflammatory agents that suppress Apc-associated intestinal carcinogenesis.
Article
Epidemiological studies consistently indicate that consump- enzymes and reduce the expression of ornithine decarboxylase tion of fruits and vegetables lowers cancer risk in humans (8–10). Finally, plant phenolics both inhibit cell proliferation and suggest that certain dietary constituents may be effect- and induce cell death or differentiation in tumor cells, sugive in preventing colon cancer. Plant-derived phenolic gesting that they may antagonize all phases of carcinogenesis compounds manifest many beneficial effects and can poten- (7,11–13). tially inhibit several stages of carcinogenesis in vivo. In this Caffeic acid phenethyl ester (CAPE) and curcumin (Figure study, we investigated the efficacy of several plant-derived 1) characterize plant phenolics that are structurally related to phenolics, including caffeic acid phenethyl ester (CAPE), 3,4-dihydroxycinnamic acid (6). CAPE may be obtained from curcumin, quercetin and rutin, for the prevention of tumors propolis, a substance produced by the bark of conifer trees in C57BL/6J-Min/ (Min/) mice. These animals bear a and carried by honeybees to their hives (14). Curcumin is the germline mutation in the Apc gene and spontaneously yellow pigment of tumeric and mustard that is widely used develop numerous intestinal adenomas by 15 weeks of age. for flavoring and coloring in foods. Both CAPE and curcumin At a dietary level of 0.15%, CAPE decreased tumor are effective in vitro inhibitors of the growth of transformed formation in Min/ mice by 63%. Curcumin induced a cells (15–20) and in vivo inhibitors of tumor initiation and similar tumor inhibition. Quercetin and rutin, however, promotion in different carcinogen-induced rodent models both failed to alter tumor formation at dietary levels of (14,21–26). 2%. Examination of intestinal tissue from the treated Flavonoids constitute another promising class of dietary animals showed that tumor prevention by CAPE and antioxidants that are ubiquitously found in fruits, vegetables curcumin was associated with increased enterocyte and tea. Like the cinnamates, these phytochemicals exhibit apoptosis and proliferation. CAPE and curcumin also anti-inflammatory activity and inhibit tumor cell growth in decreased expression of the oncoprotein β-catenin in the culture and animal bioassays. Quercetin is the most common enterocytes of the Min/ mouse, an observation previously biologically active flavonoid. The glycosidic derivatives of the associated with an antitumor effect. These data place the flavonoids are preferentially absorbed in humans (6). Rutin is plant phenolics CAPE and curcumin among a growing list the glycoside form of quercetin and is hydrolyzed to quercetin of anti-inflammatory agents that suppress Apc-associated by colonic microflora, possibly enhancing its bioavailability intestinal carcinogenesis. in the colon (27). Quercetin and rutin inhibit neoplasia in carcinogen-induced skin and colon cancer models (25,26,28– 30).
Article
This chapter focuses on withanolides that mainly occur in the Solanaceous plants. The withanolides are a group of naturally occurring steroids built on an ergostane skeleton, in which C-22 and C-26 are appropriately oxidized to form a δ-lactone ring. Withanolides generally contain 28 carbon atoms with polyoxygenated functionalities. A common feature of all known withanolides, including the related modified ergostane derivatives, is oxidation at C-1, C-22, and C-26. Over 90% of withanolides contain a 1-oxo-group. C-26 is oxidized in most instances to the carboxylic acid level, thus, allowing the formation of a 26, 22 lactone. Hydroxylation is a common feature in withanolides. Withanolide glycosides isolated so far are listed with their physical constants in the chapter. Mass spectrometry is a useful tool in diagnosing the characteristics of a withanolide. The molecular ion in electron impact is either weakly present or totally absent in some cases. Also, there are several investigations on the microbiological transformations of withanolides.
Article
Four novel withanolide glycosides and a withanolide have been isolated from the leaves of Withania somnifera. The structures of the novel compounds were elucidated as physagulin D (1→6)-β-d-glucopyranosyl-(1→4)-β-d-glucopyranoside (1), 27-O-β-d-glucopyranosyl physagulin D (2), 27-O-β-d-glucopyranosyl viscosalactone B (3), 4,16-dihydroxy-5β, 6β-epoxyphysagulin D (4), and 4-(1-hydroxy-2,2-dimethylcyclo-propanone)-2,3-dihydrowithaferin A (5) on the basis of 1D-, 2D NMR and MS spectral data. In addition, seven known withanolides withaferin A (6), 2,3-dihydrowithaferin A (7), viscosalactone B (8), 27-desoxy-24,25-dihydrowithaferin A (9), sitoindoside IX (10), physagulin D (11), and withanoside IV (12) were isolated. These withanolides were assayed to determine their ability to inhibit cycloxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes and lipid peroxidation. The withanolides tested, except compound 9, showed selective COX-2 enzyme inhibition ranging from 9 to 40% at 100μg/ml. Compounds 4, 10 and 11 also inhibited lipid peroxidation by 40, 44 and 55%, respectively. The inhibition of COX-2 enzyme by withanolides is reported here for the first time.
Article
An ethyl acetate-soluble extract of the leaves and stems of Physalis philadelphica has been investigated, leading to the isolation of three new withanolides, philadelphicalactones A (1) and B (2), and ixocarpalactone B (3), four known withanolides, ixocarpalactone A (4), withaphysacarpin (5), 18-hydroxywithanolide D (6), and withanone (7), one new ceramide, (2S,3S,4R,9E)-1,3,4-trihydroxy-2-[(2′R)-2′-hydroxytetracosanoylamino]-9-octadecene (8), two known ceramides, (2S,3S,4R)-2-[(2′R)-2′-hydroxytetracosanoylamino]-1,3,4-octadecanetriol (9), and (2S,3S,4R)-2-tetracosanoylamino-1,3,4-octadecanetriol (10), as well as the known chlorophyllide a (11). The structures of the new compounds were elucidated based on spectroscopic and chemical methods. Single-crystal X-ray diffraction analysis was used to confirm the relative stereochemistry of compounds 1 and 4. The absolute stereochemistry of compounds 1–4 and 8 was established by Mosher ester methodology and chemical transformation. All isolates were evaluated for their potential cancer chemopreventive properties utilizing in vitro assays to determine quinone reductase induction and inhibition of murine epidermal JB6 cell transformation.
Article
The fruits of Physalis philadelphica, known commonly as tomatillos, are an ingredient of the condiment ''salsa verde''. As part of an ongoing project to discover natural product cancer chemopreventive agents, an ethyl acetate-soluble extract of the commercially available fresh fruits of P. philadelphica was found to induce quinone reductase activity in cultured Hepa 1c1c7 murine hepatoma cells. Bioassay-directed fractionation of an EtOAc extract of the fruits, aided by LC/MS, led to the isolation of a series of structurally related withanolides. One novel substance, 2,3-dihydro-3-methoxywithaphysacarpin (1), and two known compounds, withaphysacarpin (2) and 24,25-dihydrowithanolide D (3), were isolated, with the structure of 1 characterized spectroscopically. All three withanolides significantly induced quinone reductase activity in Hepa 1c1c7, TAPclBP(r)c1, and BP(r)cl murine hepatoma cells, suggesting that these compounds are monofunctional inducers, specifically elevating phase II enzymes responsible for detoxification, while not influencing phase I enzymes that may activate carcinogens.
Article
Study of antitumor and radiosensitizing properties of W. somnifera (Ashwagandha), a well known medicinal plant, have yielded encouraging results. The alcoholic extract of the dried roots of the plant as well as the active component withaferin A isolated from the extract showed significant antitumor and radiosensitizing effects in experimental tumors in vivo, without any noticeable systemic toxicity. Withaferin A gave a sensitizer enhancement ratio of 1.5 for in vitro cell killing of V79 Chinese hamster cells at a non toxic concentration of approximately 2 microM. The mechanism of action of this compound is not known. The studies so far indicate that W. somnifera could prove to be a good natural source of a potent and relatively safe radiosensitizer/chemotherapeutic agent. Further studies are needed to explore the clinical potential of this plant for cancer therapy.
Article
Milled Piper methysticum roots were extracted sequentially with hot water and methanol. Cyclooxygenase (COX) enzyme inhibitory assay directed purification of the methanol extract yielded bornyl esters of 3,4-methylenedioxy cinnamic acid (1) and cinnamic acid (2), pinostrobin (3), flavokawain B (4), and 5,7-dimethoxyflavanone (5). The structures of compounds 1-5 were accomplished by spectral experiments. The aqueous extract contained previously reported kava lactones, as confirmed by TLC analysis. Compounds 3 and 5 were isolated for the first time from kava kava roots. Compound 4 showed the highest COX-I inhibitory activity at 100 microg/mL. All the compounds tested gave good COX-I and moderate COX-II enzyme inhibitory activities at 100 microg/mL. This is the first report of COX-I and -II inhibitory activities for compounds 1-5.
Article
Limonoids have been shown to inhibit the growth of estrogen receptor-negative and -positive human breast cancer cells in culture. The primary objective of this study was to test the antiproliferative activity of limonoids (obacunone 17 beta-D-glucopyranoside, nomilinic acid 17 beta-D-glucopyranoside, limonin, nomilin, and a limonoid glucoside mixture), found in high concentrations in mandarin (Citrus reticulata Blanco), against a series of human cancer cell lines. The human cancer cell lines included leukemia (HL-60), ovary (SKOV-3), cervix (HeLa), stomach (NCI-SNU-1), liver (Hep G2), and breast (MCF-7). The growth-inhibitory effects of the four limonoids and the limonoid glucoside mixture against MCF-7 cells were significant, and the antiproliferative activity of the different citrus limonoids was also dose and time dependent. No significant effects were observed on growth of the other cancer cell lines treated with the four individual limonoids at 100 micrograms/ml. At 100 micrograms/ml, the limonoid glucoside mixture demonstrated a partial inhibitory effect on SKOV-3 cancer cells. With use of flow cytometry, it was found that all the limonoid samples could induce apoptosis in MCF-7 cells at relatively high concentrations (100 micrograms/ml). Considering the high concentration needed to induce apoptosis, it is unlikely that this is the primary mechanism of action for the cytotoxic effects seen with limonoids in this study. Further work is needed in this area to establish the mechanism of action of citrus limonoids on human breast cancer cells.
Article
The chemopreventive effect of Withania somnifera hydroalcoholic root extract (WSRE) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin cancer was investigated in Swiss albino mice. The skin lesions were induced by the twice-weekly topical application of DMBA (100 nmol/ 100 microliters acetone) for 8 wk on the shaved back of mice. WSRE was administered at the maximal tolerated dose of 400 mg/kg p.o. three times per week on alternate days 1 wk before DMBA and continued for 24 wk thereafter. The results of the study revealed a significant decrease in incidence and average number of skin lesions in mice compared with DMBA alone at the end of Week 24. Biochemical parameters were assessed in the lesions of WSRE-treated and untreated control mice. A significant impairment was noticed in the levels of reduced glutathione, malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase in skin lesions of DMBA-treated control mice compared with vehicle-treated mice. These parameters were returned to near normal by administration of WSRE to DMBA-treated mice. The above findings were supported by histopathological studies. From the present study, it can be inferred that WRSE possesses potential chemopreventive activity in this experimental model of cancer. The chemopreventive activity may be linked to the antioxidant/free radical-scavenging constituents of the extract. The anti-inflammatory and immunomodulatory properties of WSRE are also likely to contribute to its chemopreventive action.
Article
Bioassay-guided purification of an extract of Cucurbita andreana fruits yielded cucurbitacins B (1), D (2), E (3), and I (4). These cucurbitacins were evaluated for their inhibitory effects on the growth of human colon (HCT-116), breast (MCF-7), lung (NCI-H460), and central nervous system (CNS) (SF-268) cancer cell lines, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes and on lipid peroxidation. Inhibitory activities of cucurbitacins B (1), D (2), E (3) and I (4), respectively, were for colon 81.5, 80.4, 77, and 65% at 0.4 microM, breast 87, 78, 66.5, and 12% at 0.4 microM, lung 96, 43, 37 and 2% at 0.1 microM and CNS 92, 25, 24 and 4% at 0.05 microM. Adriamycin (doxorubicin) was used as a positive control, which showed 64, 47, 45 and 71% inhibition of HCT-116 (colon), MCF-7 (breast), NCI-H460 (lung) and SF-268 (CNS) cell lines, respectively, at 0.3 x 10(-5) M. Compounds 1, 2, 3, and 4 inhibited the COX-2 enzyme by 32, 29, 35, and 27%, respectively, at 100 microg/ml. However these compounds did not inhibit the COX-1 enzyme at this concentration. Ibuprofen, naproxen and vioxx, commercial antiinflammatory drugs, were tested as controls for the inhibition of COX-1 and COX-2 enzymes at concentrations of 2.1, 2.5 and 1.67 microg/ml, respectively. Ibuprofen and naproxen exhibited 59 and 95% COX-1, and 53 and 79% COX-2 inhibitory activities, respectively. Vioxx showed specific COX-2 inhibition by 71%. Also, cucurbitacins 1 and 4 inhibited lipid peroxidation by 59 and 23%, respectively, at 100 microg/ml.
Tea in chemoprevention of cancer: epidemiologic and experimental studies
  • Kathiyar
Kathiyar, S.K., Mukthar, H., 1996. Tea in chemoprevention of cancer: epidemiologic and experimental studies. Int. J. Onc. 8 (2), 221 -238.
Major medicinal plants of India. Central Institute of Medicinal and Aromatic Plants
  • R S Thakur
  • H S Puri
  • A Husain
Thakur, R.S., Puri, H.S., Husain, A., 1989. Major medicinal plants of India. Central Institute of Medicinal and Aromatic Plants, Lucknow, India, 531.