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Arambam K, Krishnani KK, Singh RD, Verma AK, Banerjee K, Chanu TI, Kumar N. Medicinal and aromatic plants assisted bioremediation of ammonical and bacterial contaminants in aquaponics water. WATER ENVIRONMENT RESEARCH : A RESEARCH PUBLICATION OF THE WATER ENVIRONMENT FEDERATION 2025; 97:e70017. [PMID: 39916314 DOI: 10.1002/wer.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 01/06/2025] [Accepted: 01/10/2025] [Indexed: 05/08/2025]
Abstract
An experiment was conducted under laboratory conditions to examine the effect of sixteen medicinal and aromatic plants (MAPs), namely Aloe barbadensis, Cymbopogen citratus, Bacopa monnieri, Senna sigueana, Plantado ovata, Asparagus racemosses, Phylanthus emblica, Vitex negundo, Cammiphora wightii, Cymbopogon martini, Andrographis paniculate, Ocimum tenuiflorum, Gymnema sylvestre, Centella asiatica, Adhatoda vasica, and Cyamopsis tetragonoloba in the removal of total ammonia-N (TAN) from aquaponics water. The different dried and grounded MAPs were added @ 100 mgl-1 into individual conical flasks containing 100 ml aquaponics water (spiked with 5 mgl-1 ammonia) and placed in a shaker. The effectiveness of different MAPs in removing TAN was evaluated at 24 hrs intervals until one of the MAPs achieved a removal rate of over 80%. The study also investigated their potential activity against fish bacterial pathogens viz. Edwardsiella tarda, Escherichia coli, Vibrio parahaemolyticus, Aeromonas hydrophila, and Staphylococcus aureus using the agar well diffusion method. The study indicates a negligible removal of TAN in the first twelve hours for all the MAPs. TAN concentration significantly reduced from 24 hrs for amla-treated water followed by satavari-treated water. Within 96 hrs., amla, satavari, and jalbrahmi removed 88.13 ± 0.81%, 79.52 ± 2.27%, and 77.22 ± 0.70 of TAN respectively. Other MAPs showed little effectiveness in removing ammonia, while cluster beans and ardushi increased the ammonia level in the water. Additionally, the methanol extract of amla exhibited strong antibacterial activities against all tested pathogens especially, against E. tarda. This study suggests the potential application of a MAP-based One-Health approach for mitigating abiotic and biotic stresses in aquaculture. PRACTITIONER POINTS: Evaluated 16 different medicinal and aromatic plants (MAPs) for their ammonia removal activity from aquaponics water. Amla treated water showed the highest ammonia removal followed by Satavaari and Jalbrahmi. Cluster beans and Ardushi treated water resulted in increasing ammonia levels due to their high nitrogen contents. Methanolic extract of amla showed bactericidal activity against fish pathogens Edwardsiella tarda, E. coli, Vibrio parahaemolyticus, A. hydrophila, and S. aureus. Potential applications in developing aquaponics production system of fish with medicinal plants through nutrient cycling and water recycling.
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Affiliation(s)
- Kalpana Arambam
- ICAR-Central Institute of Fisheries Education, Mumbai, India
| | | | | | | | | | | | - Neeraj Kumar
- ICAR-National Institute of Abiotic Stress Management, Malegaon (Kh), India
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Kołodziejska R, Tafelska-Kaczmarek A, Pawluk M, Sergot K, Pisarska L, Woźniak A, Pawluk H. Ashwagandha-Induced Programmed Cell Death in the Treatment of Breast Cancer. Curr Issues Mol Biol 2024; 46:7668-7685. [PMID: 39057095 PMCID: PMC11275341 DOI: 10.3390/cimb46070454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
The aim of this review is to provide experimental evidence for the programmed-death activity of Ashwagandha (Withania somnifera) in the anti-cancer therapy of breast cancer. The literature search was conducted using online electronic databases (Google Scholar, PubMed, Scopus). Collection schedule data for the review article covered the years 2004-2024. Ashwagandha active substances, especially Withaferin A (WA), are the most promising anti-cancer compounds. WS exerts its effect on breast cancer cells by inducing programmed cell death, especially apoptosis, at the molecular level. Ashwagandha has been found to possess a potential for treating breast cancer, especially estrogen receptor/progesterone receptor (ER/PR)-positive and triple-negative breast cancer.
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Affiliation(s)
- Renata Kołodziejska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Agnieszka Tafelska-Kaczmarek
- Department of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Toruń, Poland;
| | - Mateusz Pawluk
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Krzysztof Sergot
- Laboratory of Laser Molecular Spectroscopy, Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology, Wroblewskiego 15, 93-590 Lodz, Poland;
| | - Lucyna Pisarska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Alina Woźniak
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Hanna Pawluk
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
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Sharma D, Singh N, Srivastava S. Skin Cancer: An Insight on its Association with Aging, Pathogenesis and Treatment Strategies. Curr Drug Res Rev 2024; 16:134-144. [PMID: 37366353 DOI: 10.2174/2589977515666230627154048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023]
Abstract
Skin cancer is one of the deadly diseases of the skin characterized by pain and uncontrolled growth of cells. The pathogenesis of skin cancer involves the uncontrolled division of abnormal cells in the part of the body affected by an accumulation of genome variation over the course of a lifetime. The incidence of skin cancer has been increasing all over the world and has been reported more in old-aged persons. Furthermore, aging plays a vital role in promoting malignancy. Cancer necessitates lifelong administration of drugs to maintain the quality of life. The major challenge of treatment is the side effects associated with these drugs. Novel and targeted approaches are now formulated to explore as an alternative measure to treat cancer. The current review summarizes the pathogenesis of cancer and its treatment strategies. These approaches are discussed with regard to the drugs, mechanism of action, causative factors, distribution of cancer, mortality rate, and treatment strategies.
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Affiliation(s)
- Divya Sharma
- Department of Pharmacy, School of Medical and Allied Science, Galgotias University, Yamuna Expressway, Gautam Buddha Nagar, Greater Noida, Uttar Pradesh, 201306, India
- PDM Faculty of Engineering & Technology, Bahadurgarh, Haryana, 124507, India
| | - Nikhil Singh
- Department of Pharmacy, School of Medical and Allied Science, Galgotias University, Yamuna Expressway, Gautam Buddha Nagar, Greater Noida, Uttar Pradesh, 201306, India
| | - Shikha Srivastava
- Department of Pharmacy, School of Medical and Allied Science, Galgotias University, Yamuna Expressway, Gautam Buddha Nagar, Greater Noida, Uttar Pradesh, 201306, India
- Institute of Pharmacy, Shri Ramswaroop Memorial University, Barabanki, Uttar Pradesh, 225003, India
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D'Cruz M, Andrade C. Potential clinical applications of Ashwagandha ( Withania somnifera) in medicine and neuropsychiatry. Expert Rev Clin Pharmacol 2022; 15:1067-1080. [PMID: 36062480 DOI: 10.1080/17512433.2022.2121699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Ashwagandha (ASW) is the extract of the plant Withania somnifera. It is widely used in complementary, alternative, and integrative medicine (CAIM) but is little discussed in mainstream modern medical literature. AREAS COVERED We performed a review of potential pharmacotherapeutic properties of ASW. Studies were sourced from relevant online and offline databases. In animal models, ASW displays antioxidant activity. It has GABAergic and other neurotransmitter modulatory effects. It reduces apoptosis and promotes synaptic plasticity. It improves cognition and reverses induced cognitive deficits. It attenuates indices of stress. In human subjects, ASW enhances adaptogenesis in healthy adults. It modestly benefits generalized anxiety disorder and obsessive-compulsive disorder, and symptom severity in schizophrenia, substance use disorders, and attention deficit hyperactivity disorder. It improves sleep quality. EXPERT OPINION ASW may confer modest benefit in certain neuropsychiatric conditions. Its benefits may arise from induction of neuroplasticity, antioxidant and anti-inflammatory effects, and modulation of GABA and glutamate, as well as other neurotransmitters. The antioxidant and anti-inflammatory actions may also benefit neurodegenerative states. Reports of clinical benefit with ASW must be interpreted with caution, given the paucity of randomized clinical trials (RCTs). Greater methodological rigor is necessary before clinical recommendations on ASW can be confidently made.
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Affiliation(s)
- Migita D'Cruz
- Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Chittaranjan Andrade
- Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences, Bangalore, India
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Sharifi-Rad J, Quispe C, Ayatollahi SA, Kobarfard F, Staniak M, Stępień A, Czopek K, Sen S, Acharya K, Matthews KR, Sener B, Devkota HP, Kırkın C, Özçelik B, Victoriano M, Martorell M, Rasul Suleria HA, Alshehri MM, Chandran D, Kumar M, Cruz-Martins N, Cho WC. Chemical Composition, Biological Activity, and Health-Promoting Effects of Withania somnifera for Pharma-Food Industry Applications. J FOOD QUALITY 2021; 2021:1-14. [DOI: 10.1155/2021/8985179] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2023] Open
Abstract
The Withania genus comes from the Solanaceae family and includes around 23 species, spread over some areas of the Mediterranean, Asia, and East Africa. Widely used in traditional medicine for thousands of years, these plants are rich in secondary metabolites, with special emphasis on steroidal lactones, named withanolides which are used as ingredients in numerous formulations for a plethora of diseases, such as asthma, diabetes, arthritis, impotence, amnesia, hypertension, anxiety, stress, cancer, neurodegenerative, and cardiovascular diseases, and many others. Among them, Withania somnifera (L.) Dunal is the most widely addressed species from a pharmacological and agroindustrial point of view. In this sense, this review provides an overview of the folk uses, phytochemical composition, and biological activity, such as antioxidant, antimicrobial, anti-inflammatory, and cytotoxic activity of W. somnifera, although more recently other species have also been increasingly investigated. In addition, their health-promoting effects, i.e., antistress, anxiolytic, adaptogenic, antirheumatoid arthritis, chemoprotective, and cardiorespiratory-enhancing abilities, along with safety and adverse effects are also discussed.
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Affiliation(s)
- Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Cristina Quispe
- Facultad de Ciencias de la Salud, Universidad Arturo Prat, Avda. Arturo Prat 2120, Iquique 1110939, Chile
| | - Seyed Abdulmajid Ayatollahi
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Pharmacognosy and Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farzad Kobarfard
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mariola Staniak
- Institute of Soil Science and Plant Cultivation–State Research Institute, Czartoryskich 8, Puławy 24-100, Poland
| | - Anna Stępień
- Institute of Soil Science and Plant Cultivation–State Research Institute, Czartoryskich 8, Puławy 24-100, Poland
| | - Katarzyna Czopek
- Institute of Soil Science and Plant Cultivation–State Research Institute, Czartoryskich 8, Puławy 24-100, Poland
| | - Surjit Sen
- Molecular and Applied Mycology and Plant Pathology Laboratory, Department of Botany, University of Calcutta, Kolkata 700019, India
- Department of Botany, Fakir Chand College, Diamond Harbour, West Bengal 743331, India
| | - Krishnendu Acharya
- Molecular and Applied Mycology and Plant Pathology Laboratory, Department of Botany, University of Calcutta, Kolkata 700019, India
| | - Karl R. Matthews
- Department of Food Science, Rutgers University, New Brunswick, New Jersey, USA
| | - Bilge Sener
- Gazi University, Faculty of Pharmacy, Department of Pharmacognosy, Ankara 06330, Turkey
| | - Hari Prasad Devkota
- Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
| | - Celale Kırkın
- Department Food Engineering, Faculty of Chemical and Metallurgical Engineering, Istanbul Technical University, Maslak, Istanbul 34469, Turkey
| | - Beraat Özçelik
- Department Food Engineering, Faculty of Chemical and Metallurgical Engineering, Istanbul Technical University, Maslak, Istanbul 34469, Turkey
- Bioactive Research & Innovation Food Manufacturing Industry Trade Ltd. Co., Maslak, Istanbul 34469, Turkey
| | - Montserrat Victoriano
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepción, Concepción 4070386, Chile
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepción, Concepción 4070386, Chile
- Centre for Healthy Living, University of Concepción, Concepción 4070386, Chile
| | | | - Mohammed M. Alshehri
- Pharmaceutical Care Department, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
| | - Deepak Chandran
- Department of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore 642109, India
| | - Manoj Kumar
- Chemical and Biochemical Processing Division, ICAR–Central Institute for Research on Cotton Technology, Mumbai 400019, India
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
- Institute of Research and Advanced Training in Health Sciences and Technologies (CESPU), Rua Central de Gandra, 1317, Gandra 4585-116, Portugal
- TOXRUN–Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
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Ethnobotanical investigation of significant seasonal medicinal weeds of Toba Tek Singh District, Punjab, Pakistan. HERBA POLONICA 2021. [DOI: 10.2478/hepo-2021-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Summary
Introduction: Medicinal plants are found throughout the world but most are considered weeds. They are – directly or indirectly – the major source of medicines in pharmaceutical and herbal industries. Formulations used to prepare medicines or the method of use for these plants are mainly based on folk or traditional knowledge. This folk knowledge is not documented in many areas and needs to be explored.
Objectives: This study was aimed to enlist the seasonal weed species with traditional medicinal usage in Toba Tek Singh District, Punjab, Pakistan.
Methods: Field surveys were arranged in winter and summer 2019–2020 to enlist the important medicinal weeds and traditional knowledge of the local community. Data collected were as follows: local name of weed, medicinal use, method and part used.
Results: Numerous wild perennial, biennial and annual plants were identified, 30 of them were ethnomedicinally important in the local community. They were grouped in 16 families. It was found that whole weed is used in many prescriptions (37%). Achyranthes aspera L. (Amaranthaceae) was the most common weed used in treating fevers, respiratory problems and asthma. Cichorium intybus L. (Asteraceae) was used in summer drinks to reduce thirst, improve digestion and liver function. Chenopodium album L. (Amaranthaceae) was used with 0.71 UV and 0.147 RFC values. Medicago polymorpha L. (Fabaceae) was used to treat kidney, intestinal and bladder infections. Its UV was 0.65 and RFC was 0.121. Tribulus terrestris L. (Zygophyllaceae) was used in impotency treatment, and in the removal of kidney stones and urinary tract infections treatment. It has 0.63 UV and 0.21 RFC values. This weed also showed the highest Fidelity Level (FL) (77%), as compared to other weeds.
Conclusion: It was concluded that there are many significant medicinal weeds in the Toba Tek Singh District, Punjab, Pakistan that are used in traditional medicines in treating various disorders. These plants also showed herbal or pharmacological importance that can be used to develop medicine at commercial scale.
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Chugh N, Koul A. Altered presence of extra cellular matrix components in murine skin cancer: Modulation by Azadirachta indica leaf extract. J Tradit Complement Med 2021; 11:197-208. [PMID: 34012866 PMCID: PMC8116721 DOI: 10.1016/j.jtcme.2020.03.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 02/13/2020] [Accepted: 03/20/2020] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND AND AIM Although, the anticancer potential of Aqueous Azadirachta indica leaf extract (AAILE) has been robustly established against cutaneous squamous cell carcinoma (SCC) in mice, however, its ability in modulating tumor associated extra cellular matrix (ECM) is largely unknown. Therefore, the present study was conceived to explore changes in ECM during murine skin cancer and its chemoprevention by AAILE. EXPERIMENTAL PROCEDURE Skin tumors were induced using a two-stage model of carcinogenesis employing topical application of 7,12-Dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoyl phorbol-13-acetate (TPA) as carcinogen and promoter respectively. AAILE was administered orally to the animals. Male Laca mice were divided into four groups: control, AAILE, DMBA/TPA and AAILE + DMBA/TPA. RESULTS The tumors obtained in DMBA/TPA and AAILE + DMBA/TPA groups were histologically identified as SCC. Tumor induction in these groups was accompanied by raised serum carcinoembryonic antigen (CEA) levels when compared to control counterparts. Assessment of hydroxyproline levels and histochemical staining with sirius red and trichrome stain revealed an increase in collagen in tumors of DMBA/TPA group. An increase in glycosaminoglycans (GAGs) levels was also observed in DMBA/TPA group as made evident by biochemical studies and histochemical staining using mucicarmine and alcian blue-periodic acid schiff's stain. Administration of AAILE to DMBA/TPA treated animals caused a decrease in collagen and GAG levels along with a decrease in serum CEA levels. CONCLUSION Skin tumors exhibited altered presence of ECM components which is indicative of a modified ECM. AAILE administration antagonised tumor associated ECM alterations which may be contributing to its chemopreventive activity as reported previously.
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Affiliation(s)
- N.A. Chugh
- Department of Biophysics, Basic Medical Sciences Block, Panjab University, South Campus, Sector 25, Chandigarh, 160014, India
| | - A. Koul
- Department of Biophysics, Basic Medical Sciences Block, Panjab University, South Campus, Sector 25, Chandigarh, 160014, India
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Singh N, Yadav SS, Rao AS, Nandal A, Kumar S, Ganaie SA, Narasihman B. Review on anticancerous therapeutic potential of Withania somnifera (L.) Dunal. JOURNAL OF ETHNOPHARMACOLOGY 2021; 270:113704. [PMID: 33359918 DOI: 10.1016/j.jep.2020.113704] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 09/23/2020] [Accepted: 12/15/2020] [Indexed: 06/12/2023]
Abstract
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 types of cancer and other 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.
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Affiliation(s)
- Neetu Singh
- Department of Botany, Maharshi Dayanand University, Rohtak, Haryana, 124 001, India
| | - S S Yadav
- Department of Botany, Maharshi Dayanand University, Rohtak, Haryana, 124 001, India.
| | - Amrender Singh Rao
- Department of Botany, Maharshi Dayanand University, Rohtak, Haryana, 124 001, India
| | - Abhishek Nandal
- Department of Botany, Maharshi Dayanand University, Rohtak, Haryana, 124 001, India
| | - Sanjiv Kumar
- Department of Pharmaceutical Sciences, Ch. Bansi Lal University, Bhiwani, Haryana, India
| | - S A Ganaie
- Department of Botany, Maharshi Dayanand University, Rohtak, Haryana, 124 001, India
| | - B Narasihman
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, 124 001, India
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Withaferin A-A Promising Phytochemical Compound with Multiple Results in Dermatological Diseases. Molecules 2021; 26:molecules26092407. [PMID: 33919088 PMCID: PMC8122412 DOI: 10.3390/molecules26092407] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/10/2021] [Accepted: 04/20/2021] [Indexed: 12/16/2022] Open
Abstract
Withaferin A (WFA) was identified as the most active phytocompound of the plant Withania somnifera (WS) and as having multiple therapeutic/ameliorating properties (anticancer, antiangiogenic, anti-invasive, anti-inflammatory, proapoptotic, etc.) in case of various diseases. In drug chemistry, WFA in silico approaches have identified favorite biological targets, stimulating and accelerating research to evaluate its pharmacological activity—numerous anticancer effects manifested in various organs (breast, pancreas, skin, colon, etc.), antivirals, anti-infective, etc., which are not yet sufficiently explored. This paper is a synthesis of the most relevant specialized papers in the field that are focused on the use of WFA in dermatological diseases, describing its mechanism of action while providing, at the same time, details about the results of its testing in in vitro/in vivo studies.
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Ni Z, Lin X, Wen Q, Kintoko, Zhang S, Huang J, Xu X, Huang R. WITHDRAWN: Effect of 2-dodecyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione, isolated from Averrhoa carambola L. (Oxalidaceae) roots, on advanced glycation end-product-mediated renal injury in type 2 diabetic KKAy mice. Toxicol Lett 2021; 339:88-96. [PMID: 33423876 DOI: 10.1016/j.toxlet.2020.11.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published in [Toxicology Letters, 339C (2021) 88–96], https://doi.org/10.1016/j.toxlet.2020.11.022. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal
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Affiliation(s)
- Zheng Ni
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Xing Lin
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Qingwei Wen
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Kintoko
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Shijun Zhang
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Jianchun Huang
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Xiaohui Xu
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
| | - Renbin Huang
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China.
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Ishtiaq M, Maqbool M, Ajaib M, Ahmed M, Hussain I, Khanam H, Mushtaq W, Hussain T, Azam S, Hayat Bhatti K, Ghani A. Ethnomedicinal and folklore inventory of wild plants used by rural communities of valley Samahni, District Bhimber Azad Jammu and Kashmir, Pakistan. PLoS One 2021; 16:e0243151. [PMID: 33439877 PMCID: PMC7806180 DOI: 10.1371/journal.pone.0243151] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 11/16/2020] [Indexed: 12/28/2022] Open
Abstract
The current study describes ethnobotanical (EB) and traditional ethnomedicinal (TEMs) uses of medicinal plants (MPs) of Tehsil Samahni area of Azad Jammu and Kashmir, Pakistan. Indigenous inhabitants of the area mostly reside in remote mountainous areas and depend on wild plants for life necessities and treatment of different diseases. This paper presents first quantitative ethnobotanical study describing the popularity level of MPs in indigenous communities by using relative popularity level (RPL) and rank order of priority (ROP) indices. The data of TEMs and EB uses were collected from 200 interviewees consisting of traditional herbal practioners (110) and farmers (90) from study area using structured and semi-structured interview methodology during year 2019. It was found that illiterate peasants have more knowledge and practice of TEMs than other people. A total of 150 plant species belonging to 58 families with botanical and local names, parts used, mode of recipes preparation, administration mechanism and TEMs uses were documented in systematic manner. It was explored that highest number (7.69%) of plants of Moraceae were used in TEMs and followed by species of Asteraceae (6.29%). The ethnobotanical data was analyzed by using quantitative ethnobotanical tools viz: informant consensus factor (ICF), fidelity level (FL), relative frequency of citation (RFC), use value index (UVI), relative importance of plants (RIP), relative populatiry level (RPL) and rank order of popularity (ROP). The leaf ranked first (36.49%) and fruit 2nd (12.07%) being used in TEMs while prevalent use-form was decoction (29.28%), followed by tea (23.05%) and preferably taken as oral (46.66%). ICF analysis proved that diabetes, hypertension, rabies, snake sting and joint pains were the most prevalent occurring infirmities. The highest RFC (0.95) was found for Acacia modesta, followed by Boerhavia procumbens (RFC:0.87) and Berberis lycium (RFC:0.85). The relative importance of MPs was calculated by using UVI and Moringa oleifera showed highest (1.38), followed by Zanthoxylum armatum (1.25) and Withania somnifera (1.24) use-values. High UVI of plants depicts that these species are predominantly used in local health care system. The plants Phyllanthus emblica, Morus macruora, Justicia adhatoda and Melia azedarach depicted high values (1.00) of FL and RPL proving that these taxa are commonly used in indigenous medicines by local inhabitants and have better potential for drug discovery by ethnopharmacological analysis. Out of total, 26 species had more than 50% ROP index and Phyllanthus emblica and Flacourtia indica (ROP = 100) followed by Morus macruora (ROP: 97) were used to cure 'hypertension and hyperlipidemia' and 'cough, chest infection', respectively. It was found that 30% of total species were previously reported as medicinal while 70% plants were first time reported to be used in TEMs and authenticated by using of quantitative ethnobotanical tools. Ethnopharmacological potential of indigenous plants was confirmed by RIP and RPL indices which had been used to cure one or more body systems and were promulgated in the local herbal medicine system. The research provides clues to screen these plant species by using latest phytochemical and pharmacological analysis for novel drug discovery. This study will also be useful for conservation of bioculture traditional knowledge of indigenous communities and the most important is to conserve medicinal plants of the study area for future generations.
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Affiliation(s)
- Muhammad Ishtiaq
- Department of Botany, Mirpur University of Science and Technology (MUST), Mirpur, Azad Jammu & Kashmir, Pakistan
| | - Mehwish Maqbool
- Department of Botany, Mirpur University of Science and Technology (MUST), Mirpur, Azad Jammu & Kashmir, Pakistan
| | - Muhammad Ajaib
- Department of Botany, Mirpur University of Science and Technology (MUST), Mirpur, Azad Jammu & Kashmir, Pakistan
| | - Maqsood Ahmed
- Department of Botany, Mirpur University of Science and Technology (MUST), Mirpur, Azad Jammu & Kashmir, Pakistan
| | - Iqbal Hussain
- Department of Botany, Government College University Faisalabad, Faisalabad, Pakistan
| | - Humaira Khanam
- Department of Botany, Mirpur University of Science and Technology (MUST), Mirpur, Azad Jammu & Kashmir, Pakistan
| | - Waheeda Mushtaq
- Department of Botany, Mirpur University of Science and Technology (MUST), Mirpur, Azad Jammu & Kashmir, Pakistan
| | - Tanveer Hussain
- Department of Botany, Mirpur University of Science and Technology (MUST), Mirpur, Azad Jammu & Kashmir, Pakistan
| | - Shehzad Azam
- Department of Botany, Mirpur University of Science and Technology (MUST), Mirpur, Azad Jammu & Kashmir, Pakistan
| | | | - Abdul Ghani
- Department of Botany, University of Sargodha, Sargodha, Pakistan
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Mehta V, Chander H, Munshi A. Mechanisms of Anti-Tumor Activity of Withania somnifera (Ashwagandha). Nutr Cancer 2020; 73:914-926. [PMID: 33949906 DOI: 10.1080/01635581.2020.1778746] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Increasing herbal formulations have been used to treat several diseases including cancer. W. somnifera (Ashwagandha) is one such plant the extracts of which have been tested against a number of ailments including cancer, which remains as one of the most dreadful diseases on the globe. The ever-increasing number of cancer related mortality demands the development of novel chemopreventive agents with minimum side effects. Different compounds isolated from various parts of the plant like root, stem, and leaves have been reported to display significant anti-cancerous and immunomodulating properties and thus can be used alone or in combination with other chemotherapeutic drugs for cancer treatment. Through this review, we highlight the importance of W. somnifera in countering the potential oncogenic signaling mediators that are modulated by active constituents of W. somnifera in a variety of cancer types. Further, we hope that active constituents of W. somnifera will be tested in clinical trials so that they can be used as an important adjuvant in the near future for the effective treatment of cancer.
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Affiliation(s)
- Vikrant Mehta
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India
| | - Harish Chander
- National Institute of Biologicals, Noida, Uttar Pradesh, India
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India
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Saggam A, Tillu G, Dixit S, Chavan-Gautam P, Borse S, Joshi K, Patwardhan B. Withania somnifera (L.) Dunal: A potential therapeutic adjuvant in cancer. JOURNAL OF ETHNOPHARMACOLOGY 2020; 255:112759. [PMID: 32173425 DOI: 10.1016/j.jep.2020.112759] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 02/05/2020] [Accepted: 03/08/2020] [Indexed: 05/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Withania somnifera (L.) Dunal (WS) is one of the moststudied Rasayana botanicals used in Ayurveda practice for its immunomodulatory, anti-aging, adaptogenic, and rejuvenating effects. The botanical is being used for various clinical indications, including cancer. Several studies exploring molecular mechanisms of WS suggest its possible role in improving clinical outcomes in cancer management. Therefore, research on WS may offer new insights in rational development of therapeutic adjuvants for cancer. AIM OF THIS REVIEW The review aims at providing a detailed analysis of in silico, in vitro, in vivo, and clinical studies related to WS and cancer. It suggests possible role of WS in regulating molecular mechanisms associated with carcinogenesis. The review discusses potential of WS in cancer management in terms of cancer prevention, anti-cancer activity, and enhancing efficacy of cancer therapeutics. MATERIAL AND METHODS The present narrative review offers a critical analysis of published literature on WS studies in cancer. The reported studies were analysed in the context of pathophysiology of cancer, commonly referred as 'cancer hallmarks'. The review attempts to bridge Ayurveda knowledge with biological insights into molecular mechanisms of cancer. RESULTS Critical analysisof the published literature suggests an anti-cancer potential of WS with a key role in cancer prevention. The possible mechanisms for these effects are associated with the modulation of apoptotic, proliferative, and metastatic markers in cancer. WS can attenuate inflammatory responses and enzymes involved in invasion and metastatic progression of cancer.The properties of WS are likely to be mediated through withanolides, which may activate tumor suppressor proteins to restrict proliferation of cancer cells. Withanolides also regulate the genomic instability, and energy metabolism of cancer cells. The reported studies indicate the need for deeper understanding of molecular mechanisms of WS in inhibiting angiogenesis and promoting immunosurveillance. Additionally, WS can augment efficacy and safety of cancer therapeutics. CONCLUSION The experimentally-supported evidence of immunomodulatory, anti-cancer, adaptogenic, and regenerative attributes of WS suggest its therapeutic adjuvant potential in cancer management. The adjuvant properties of withanolides can modulate multidrug resistance and reverse chemotherapy-induced myelosuppression. These mechanisms need to be further explored in systematically designed translational and clinical studies that will pave the way for integration of WS as a therapeutic adjuvant in cancer management.
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Affiliation(s)
- Akash Saggam
- AYUSH Center of Excellence, Center for Complementary and Integrative Health, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Pune, India
| | - Girish Tillu
- AYUSH Center of Excellence, Center for Complementary and Integrative Health, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Pune, India
| | | | - Preeti Chavan-Gautam
- AYUSH Center of Excellence, Center for Complementary and Integrative Health, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Pune, India
| | - Swapnil Borse
- AYUSH Center of Excellence, Center for Complementary and Integrative Health, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Pune, India
| | - Kalpana Joshi
- Department of Biotechnology, Sinhgad College of Engineering, Pune, India
| | - Bhushan Patwardhan
- AYUSH Center of Excellence, Center for Complementary and Integrative Health, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Pune, India.
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14
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Kim SH, Singh KB, Hahm ER, Lokeshwar BL, Singh SV. Withania somnifera root extract inhibits fatty acid synthesis in prostate cancer cells. J Tradit Complement Med 2020; 10:188-197. [PMID: 32670813 PMCID: PMC7340880 DOI: 10.1016/j.jtcme.2020.02.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 02/04/2020] [Accepted: 02/05/2020] [Indexed: 01/07/2023] Open
Abstract
Prior research argues for a role of increased de novo fatty acid synthesis in pathogenesis of prostate adenocarcinoma, which remains a leading cause of cancer-associated mortality in American men. A safe and effective inhibitor of fatty acid synthesis is still a clinically unmet need. Herein, we investigated the effect of ethanol extract of Withania somnifera root (WRE) standardized for one of its components (withaferin A) on fatty acid synthesis using LNCaP and 22Rv1 human prostate cancer cells. Withania somnifera is a medicinal plant used in the Ayurvedic medicine practiced in India. Western blotting and confocal microscopy revealed a statistically significant decrease in protein levels of key fatty acid metabolism enzymes including ATP citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and carnitine palmitoyltransferase 1A (CPT1A) in WRE-treated cells compared with solvent control. The mRNA levels of ACLY, ACC1, FASN, and CPT1A were also lower in WRE-treated cells in comparison with control. Consequently, WRE treatment resulted in a significant decrease in intracellular levels of acetyl-CoA, total free fatty acids, and neutral lipid droplets in both LNCaP and 22Rv1 cells. WRE exhibited greater potency for fatty acid synthesis inhibition at equimolar concentration than cerulenin and etomoxir. Exposure to WRE results in downregulation of c-Myc and p-Akt(S473) proteins in 22Rv1 cell line. However, overexpression of only c-Myc conferred protection against clonogenic cell survival and lipogenesis inhibition by WRE. In conclusion, these results indicate that WRE is a novel inhibitor of fatty acid synthesis in human prostate cancer cells.
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Key Words
- ACC1, acetyl-CoA carboxylase 1
- ACLY, ATP citrate lyase
- ANOVA, one-way analysis of variance
- ATP citrate lyase
- Acetyl-CoA carboxylase 1
- CPT1A, carnitine palmitoyltransferase 1A
- CTCF, corrected total cell fluorescence
- Cer, cerulenin
- Chemoprevention
- Eto, etomoxir
- FASN, fatty acid synthase
- Fatty acid synthase
- GAPDH, glyceraldehyde 3-phosphate dehydrogenase
- Prostate cancer
- Vec, pcDNA3 empty vector transfected cells
- WRE, Withania somnifera root extract
- caAkt, constitutively active Akt
- qRT-PCR, quantitative reverse transcription-polymerase chain reaction
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Affiliation(s)
- Su-Hyeong Kim
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Krishna B. Singh
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Eun-Ryeong Hahm
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | | | - Shivendra V. Singh
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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15
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Mandlik Ingawale DS, Namdeo AG. Pharmacological evaluation of Ashwagandha highlighting its healthcare claims, safety, and toxicity aspects. J Diet Suppl 2020; 18:183-226. [PMID: 32242751 DOI: 10.1080/19390211.2020.1741484] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Withania somnifera, commonly known as "Ashwagandha" or "Indian ginseng" is an essential therapeutic plant of Indian subcontinent regions. It is regularly used, alone or in combination with other plants for the treatment of various illnesses in Indian Systems of Medicine over the period of 3,000 years. Ashwagandha (W. somnifera) belongs to the genus Withania and family Solanaceae. It comprises a broad spectrum of phytochemicals having wide range of biological effects. W. somnifera has demonstrated various biological actions such as anti-cancer, anti-inflammatory, anti-diabetic, anti-microbial, anti-arthritic, anti-stress/adaptogenic, neuro-protective, cardio-protective, hepato-protective, immunomodulatory properties. Furthermore, W. somnifera has revealed the capability to decrease reactive oxygen species and inflammation, modulation of mitochondrial function, apoptosis regulation and improve endothelial function. Withaferin-A is an important phytoconstituents of W. somnifera belonging to the category of withanolides been used in the traditional system of medicine for the treatment of various disorders. In this review, we have summarized the active phytoconstituents, pharmacologic activities (preclinical and clinical), mechanisms of action, potential beneficial applications, marketed formulations and safety and toxicity profile of W. somnifera.
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Affiliation(s)
- Deepa S Mandlik Ingawale
- Department of Pharmacology, Bharati Vidyapeeth Deemed to be University, Poona College of Pharmacy, Erandwane, Pune, India
| | - Ajay G Namdeo
- Department of Pharmacology, Bharati Vidyapeeth Deemed to be University, Poona College of Pharmacy, Erandwane, Pune, India
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16
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Avila-Carrasco L, Majano P, Sánchez-Toméro JA, Selgas R, López-Cabrera M, Aguilera A, González Mateo G. Natural Plants Compounds as Modulators of Epithelial-to-Mesenchymal Transition. Front Pharmacol 2019; 10:715. [PMID: 31417401 PMCID: PMC6682706 DOI: 10.3389/fphar.2019.00715] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 06/05/2019] [Indexed: 12/13/2022] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is a self-regulated physiological process required for tissue repair that, in non-controled conditions may lead to fibrosis, angiogenesis, loss of normal organ function or cancer. Although several molecular pathways involved in EMT regulation have been described, this process does not have any specific treatment. This article introduces a systematic review of effective natural plant compounds and their extract that modulates the pathological EMT or its deleterious effects, through acting on different cellular signal transduction pathways both in vivo and in vitro. Thereby, cryptotanshinone, resveratrol, oxymatrine, ligustrazine, osthole, codonolactone, betanin, tannic acid, gentiopicroside, curcumin, genistein, paeoniflorin, gambogic acid and Cinnamomum cassia extracts inhibit EMT acting on transforming growth factor-β (TGF-β)/Smads signaling pathways. Gedunin, carnosol, celastrol, black rice anthocyanins, Duchesnea indica, cordycepin and Celastrus orbiculatus extract downregulate vimectin, fibronectin and N-cadherin. Sulforaphane, luteolin, celastrol, curcumin, arctigenin inhibit β-catenin signaling pathways. Salvianolic acid-A and plumbagin block oxidative stress, while honokiol, gallic acid, piperlongumine, brusatol and paeoniflorin inhibit EMT transcription factors such as SNAIL, TWIST and ZEB. Plectranthoic acid, resveratrol, genistein, baicalin, polyphyllin I, cairicoside E, luteolin, berberine, nimbolide, curcumin, withaferin-A, jatrophone, ginsenoside-Rb1, honokiol, parthenolide, phoyunnanin-E, epicatechin-3-gallate, gigantol, eupatolide, baicalin and baicalein and nitidine chloride inhibit EMT acting on other signaling pathways (SIRT1, p38 MAPK, NFAT1, SMAD, IL-6, STAT3, AQP5, notch 1, PI3K/Akt, Wnt/β-catenin, NF-κB, FAK/AKT, Hh). Despite the huge amount of preclinical data regarding EMT modulation by the natural compounds of plant, clinical translation is poor. Additionally, this review highlights some relevant examples of clinical trials using natural plant compounds to modulate EMT and its deleterious effects. Overall, this opens up new therapeutic alternatives in cancer, inflammatory and fibrosing diseases through the control of EMT process.
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Affiliation(s)
- Lorena Avila-Carrasco
- Therapeutic and Pharmacology Department, Health and Human Science Research, Academic Unit of Human Medicine and Health Sciences, Autonomous University of Zacatecas, Zacatecas, Mexico
| | - Pedro Majano
- Molecular Biology Unit, Research Institute of University Hospital La Princesa (IP), Madrid, Spain
| | - José Antonio Sánchez-Toméro
- Department and Nephrology, Research Institute of University Hospital La Princesa (IP), Madrid, Spain.,Renal research network REDINREN, Madrid, Spain
| | - Rafael Selgas
- Research Institute of La Paz (IdiPAZ), University Hospital La Paz, Madrid, Spain.,Renal research network REDINREN, Madrid, Spain
| | - Manuel López-Cabrera
- Renal research network REDINREN, Madrid, Spain.,Molecular Biology Research Centre Severo Ochoa, Spanish Council for Scientific Research (CSIC), Madrid, Spain
| | - Abelardo Aguilera
- Molecular Biology Unit, Research Institute of University Hospital La Princesa (IP), Madrid, Spain.,Renal research network REDINREN, Madrid, Spain
| | - Guadalupe González Mateo
- Research Institute of La Paz (IdiPAZ), University Hospital La Paz, Madrid, Spain.,Renal research network REDINREN, Madrid, Spain.,Molecular Biology Research Centre Severo Ochoa, Spanish Council for Scientific Research (CSIC), Madrid, Spain
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17
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Issa ME, Wijeratne EMK, Gunatilaka AAL, Cuendet M. Withanolide D Exhibits Similar Cytostatic Effect in Drug-Resistant and Drug-Sensitive Multiple Myeloma Cells. Front Pharmacol 2017; 8:610. [PMID: 28943850 PMCID: PMC5596074 DOI: 10.3389/fphar.2017.00610] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 08/22/2017] [Indexed: 11/13/2022] Open
Abstract
In spite of recent therapeutic advances, multiple myeloma (MM) remains a malignancy with very low curability. This has been partly attributed to the existence of a drug-resistant subpopulation known as cancer stem cells (CSCs). MM-CSCs are equipped with the necessary tools that render them highly resistant to virtually all conventional therapies. In this study, the growth inhibitory effects of withanolide D (WND), a steroidal lactone isolated from Withania somnifera, on drug-sensitive tumoral plasma cells and drug-resistant MM cells have been investigated. In MTT/XTT assays, WND exhibited similar cytostatic effects between drug-resistant and drug-sensitive cell lines in the nM range. WND also induced cell death and apoptosis in MM-CSCs and RPMI 8226 cells, as examined by the calcein/ethidium homodimer and annexin V/propidium iodide stainings, respectively. To determine whether P-glycoprotein (P-gp) efflux affected the cytostatic activity of WND, P-gp was inhibited with verapamil and results indicated that the WND cytostatic effect in MM-CSCs was independent of P-gp efflux. Furthermore, WND did not increase the accumulation of the fluorescent P-gp substrate rhodamine 123 in MM-CSCs, suggesting that WND may not inhibit P-gp at the tested relevant doses. Therefore, the WND-induced cytostatic effect may be independent of P-gp efflux. These findings warrant further investigation of WND in MM-CSC animal models.
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Affiliation(s)
- Mark E Issa
- School of Pharmaceutical Sciences, University of Geneva, University of LausanneGeneva, Switzerland
| | - E M K Wijeratne
- Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, The University of Arizona, TucsonAZ, United States
| | - A A L Gunatilaka
- Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, The University of Arizona, TucsonAZ, United States
| | - Muriel Cuendet
- School of Pharmaceutical Sciences, University of Geneva, University of LausanneGeneva, Switzerland
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18
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Yadav DK, Kumar S, Saloni, Singh H, Kim MH, Sharma P, Misra S, Khan F. Molecular docking, QSAR and ADMET studies of withanolide analogs against breast cancer. DRUG DESIGN DEVELOPMENT AND THERAPY 2017; 11:1859-1870. [PMID: 28694686 PMCID: PMC5491705 DOI: 10.2147/dddt.s130601] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Withanolides are a group of pharmacologically active compounds present in most prodigal amounts in roots and leaves of Withania somnifera (Indian ginseng), one of the most important medicinal plants of Indian traditional practice of medicine. Withanolides are steroidal lactones (highly oxygenated C-28 phytochemicals) and have been reported to exhibit immunomodulatory, anticancer and other activities. In the present study, a quantitative structure activity relationship (QSAR) model was developed by a forward stepwise multiple linear regression method to predict the activity of withanolide analogs against human breast cancer. The most effective QSAR model for anticancer activity against the SK-Br-3 cell showed the best correlation with activity (r2=0.93 and rCV2 =0.90). Similarly, cross-validation regression coefficient (rCV2=0.85) of the best QSAR model against the MCF7/BUS cells showed a high correlation (r2=0.91). In particular, compounds CID_73621, CID_435144, CID_301751 and CID_3372729 have a marked antiproliferative activity against the MCF7/BUS cells, while 2,3-dihydrowithaferin A-3-beta-O-sulfate, withanolide 5, withanolide A, withaferin A, CID_10413139, CID_11294368, CID_53477765, CID_135887, CID_301751 and CID_3372729 have a high activity against the Sk-Br-3 cells compared to standard drugs 5-fluorouracil (5-FU) and camptothecin. Molecular docking was performed to study the binding conformations and different bonding behaviors, in order to reveal the plausible mechanism of action behind higher accumulation of active withanolide analogs with β-tubulin. The results of the present study may help in the designing of lead compound with improved activity.
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Affiliation(s)
- Dharmendra K Yadav
- Department of Pharmacy, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea
| | - Surendra Kumar
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Babu Banarasi Das Northern India Institute of Technology, Lucknow
| | - Saloni
- Department of Pharmacy, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea
| | - Harpreet Singh
- Department of Bioinformatics, Indian Council of Medical Research, New Delhi
| | - Mi-Hyun Kim
- Department of Pharmacy, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur
| | - Sanjeev Misra
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur
| | - Feroz Khan
- Metabolic & Structural Biology Department, CSIR-Central Institute of Medicinal & Aromatic Plant, Lucknow, India
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Umair M, Altaf M, Abbasi AM. An ethnobotanical survey of indigenous medicinal plants in Hafizabad district, Punjab-Pakistan. PLoS One 2017; 12:e0177912. [PMID: 28574986 PMCID: PMC5456064 DOI: 10.1371/journal.pone.0177912] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 05/05/2017] [Indexed: 12/20/2022] Open
Abstract
Present paper offers considerable information on traditional uses of medicinal plants by the inhabitants of Hafizabad district, Punjab-Pakistan. This is the first quantitative ethnobotanical study from the area comprising popularity level of medicinal plant species intendedby using relative popularity level (RPL) and rank order priority (ROP) indices.Ethnobotanical data were collected by interviewing 166 local informants and 35 traditional health practioners (THPs) from different localities of Hafizabad district. Demographic features of informants; life form, part used, methods of preparation, modes of application and ethnomedicinal uses were documented. Ethnobotanical data were analyzed using quantitative tools, i.e. Relative frequency citation (RFC), use value (UV), informant consensus factor (ICF) fidelity level (FL), RPL and ROP indices. A total of 85 species belonging to 71 genera and 34 families were documented along with ethnomedicinal uses. Solanum surattense, Withania somnifera, Cyperus rotundus, Solanum nigrum and Melia azedarach were the most utilized medicinal plant species with highest used value. The reported ailments were classified into 11 disease categories based on ICF values and highest number of plant species was reported to treat dermatological and gastrointestinal disorders. Withania somnifera and Ranunculus sceleratus with maximum FL (100%), were used against gastrointestinal and urinary disorders, respectively. The RPL and ROP values were calculated to recognize the folk medicinal plant wealth; six out of 32 plant species (19%) were found popular, based on citation by more than half of the maximum number of informant viz. 26. Consequently, the ROP value for these species was more than 75. The comparative assessment with reported literature revealed 15% resemblance and 6% variation to previous data;however79% uses of the reported species were recorded for the first time. The diversity of medicinal plant species and associated traditional knowledge is significant in primary health care system. Medicinal plant species with high RPL values should be screened for comprehensive phytochemical and pharmacological studies. This could be useful in novel drug discovery and to validate the ethomendicinal knowledge.
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Affiliation(s)
- Muhammad Umair
- School of Agriculture and Biology and Research Center for Low-Carbon Agriculture Shanghai Jiao Tong University, Shanghai, China
| | - Muhammad Altaf
- Department of Zoology, Women University of Azad Jammu and Kahmir, Bagh, Pakistan
| | - Arshad Mehmood Abbasi
- Department of Environment Sciences, COMSATS Institute of Information Technology, Abbottabad, Pakistan
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Natural Withanolides in the Treatment of Chronic Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 928:329-373. [PMID: 27671823 PMCID: PMC7121644 DOI: 10.1007/978-3-319-41334-1_14] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Withanolides, and in particular extracts from Withania somnifera, have been used for over 3,000 years in traditional Ayurvedic and Unani Indian medical systems as well as within several other Asian countries. Traditionally, the extracts were ascribed a wide range of pharmacologic properties with corresponding medical uses, including adaptogenic, diuretic, anti-inflammatory, sedative/anxiolytic, cytotoxic, antitussive, and immunomodulatory. Since the discovery of the archetype withaferin A in 1965, approximately 900 of these naturally occurring, polyoxygenated steroidal lactones with 28-carbon ergostane skeletons have been discovered across 24 diverse structural types. Subsequently, extensive pharmacologic research has identified multiple mechanisms of action across key inflammatory pathways. In this chapter we identify and describe the major withanolides with anti-inflammatory properties, illustrate their role within essential and supportive inflammatory pathways (including NF-κB, JAK/STAT, AP-1, PPARγ, Hsp90 Nrf2, and HIF-1), and then discuss the clinical application of these withanolides in inflammation-mediated chronic diseases (including arthritis, autoimmune, cancer, neurodegenerative, and neurobehavioral). These naturally derived compounds exhibit remarkable biologic activity across these complex disease processes, while showing minimal adverse effects. As novel compounds and analogs continue to be discovered, characterized, and clinically evaluated, the interest in withanolides as a novel therapeutic only continues to grow.
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Yaseen Malik M, Taneja I, Raju KSR, Rahaman Gayen J, Singh SP, Sangwand NS, Wahajuddin M. RP-HPLC Separation of Isomeric Withanolides: Method Development, Validation and Application to In situ Rat Permeability Determination. J Chromatogr Sci 2017; 55:729-735. [DOI: 10.1093/chromsci/bmx027] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Indexed: 11/14/2022]
Affiliation(s)
- Mohd Yaseen Malik
- Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Isha Taneja
- Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific & Innovative Research, New Delhi 110020, India
| | - Kanumuri Siva Rama Raju
- Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific & Innovative Research, New Delhi 110020, India
| | - Jiaur Rahaman Gayen
- Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific & Innovative Research, New Delhi 110020, India
| | - Sheelendra Pratap Singh
- Pesticide Toxicology Laboratory, Regulatory Toxicology and Nanotherapeutics & Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research, Lucknow 226001, India
| | - Neelam S. Sangwand
- Division of Metabolic and Structural Biology, CSIR-Central Institute of Medicinal and Aromatic Plants, Luckow, India
| | - Muhammad Wahajuddin
- Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific & Innovative Research, New Delhi 110020, India
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Sati J, Mohanty BP, Garg ML, Koul A. Pro-Oxidant Role of Silibinin in DMBA/TPA Induced Skin Cancer: 1H NMR Metabolomic and Biochemical Study. PLoS One 2016; 11:e0158955. [PMID: 27414401 PMCID: PMC4944989 DOI: 10.1371/journal.pone.0158955] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 06/23/2016] [Indexed: 01/08/2023] Open
Abstract
Silibinin, a major bioactive flavonolignan in Silybum marianum, has received considerable attention in view of its anticarcinogenic activity. The present study examines its anticancer potential against 7, 12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) induced skin cancer. Male LACA mice were randomly segregated into 4 groups: Control, DMBA/TPA, Silibinin and Silibinin+DMBA/TPA. Tumors in DMBA/TPA and Silibinin+DMBA/TPA groups were histologically graded as squamous cell carcinoma. In the Silibinin+DMBA/TPA group, significant reduction in tumor incidence (23%), tumor volume (64.4%), and tumor burden (84.8%) was observed when compared to the DMBA/TPA group. The underlying protective mechanism of Silibinin action was studied at pre-initiation (2 weeks), post-initiation (10 weeks) and promotion (22 weeks) stages of the skin carcinogenesis. The antioxidant nature of Silibinin was evident at the end of 2 weeks of its treatment. However, towards the end of 10 and 22 weeks, elevated lipid peroxidation (LPO) levels indicate the pro-oxidative nature of Silibinin in the cancerous tissue. TUNEL assay revealed enhanced apoptosis in the Silibinin+DMBA/TPA group with respect to the DMBA/TPA group. Therefore, it may be suggested that raised LPO could be responsible for triggering apoptosis in the Silibinin+DMBA/TPA group. 1H Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the metabolic profile of the skin /skin tumors. Dimethylamine (DMA), glycerophosphocholine (GPC), glucose, lactic acid, taurine and guanine were identified as the major contributors for separation between the groups from the Principal Component Analysis (PCA) of the metabolite data. Enhanced DMA levels with no alteration in GPC, glucose and lactate levels reflect altered choline metabolism with no marked Warburg effect in skin tumors. However, elevated guanine levels with potent suppression of taurine and glucose levels in the Silibinin+DMBA/TPA group are suggestive of the pro-oxidative nature of Silibinin in regressing tumors. Thus, supporting the theory of augmented LPO levels resulting in increased apoptosis in the skin tumors treated with Silibinin.
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Affiliation(s)
- Jasmine Sati
- Department of Biophysics, Basic Medical Sciences Block, Panjab University, Chandigarh, 160014, India
| | - Biraja Prasad Mohanty
- Department of Biophysics, Basic Medical Sciences Block, Panjab University, Chandigarh, 160014, India
| | - Mohan Lal Garg
- Department of Biophysics, Basic Medical Sciences Block, Panjab University, Chandigarh, 160014, India
| | - Ashwani Koul
- Department of Biophysics, Basic Medical Sciences Block, Panjab University, Chandigarh, 160014, India
- * E-mail:
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Srivastava AN, Ahmad R, Khan MA. Evaluation and Comparison of the In Vitro Cytotoxic Activity of Withania somnifera Methanolic and Ethanolic Extracts against MDA-MB-231 and Vero Cell Lines. Sci Pharm 2015; 84:41-59. [PMID: 27110497 PMCID: PMC4839554 DOI: 10.3797/scipharm.1507-13] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 09/26/2015] [Indexed: 01/01/2023] Open
Abstract
Withania somnifera Dunal (WS), commonly known as Ashwagandha in India, belongs to the family Solanaceae. It is extensively used in most of the Indian herbal pharmaceuticals and nutraceuticals. In the current study, the in vitro cytotoxic activity of methanolic, ethanolic, and aqueous extracts of WS stems was evaluated using cytometry and the MTT assay against the MDA-MB-231 human breast cancer cell line. Methanolic and ethanolic extracts of WS showed potent anticancer activity on the MDA-MB-231 human breast cancer cell line, whereas the aqueous extract did not exhibit any significant activity at 100 µg/ml. The percentage viability of the cell lines was determined by using the Trypan blue dye exclusion method. Cell viability was reduced to 21% and 0% at 50 and 100 µg/ml of the methanolic extract, respectively, as compared to 19% and 0% at 50 and 100 µg/ml for the ethanolic extract and 37% at 100 µg/ml in sterile Milli-Q water after 48 hours of treatment. Methanolic and ethanolic extracts of WS were shown to possess IC50 values of 30 and 37 µg/ml, respectively, by the MTT assay and cytometer-based analysis, with the methanolic extract being more active than the other two. On the other hand, methanolic and ethanolic extracts of WS did not exhibit any significant in vitro activity against the normal epithelial cell line Vero at 50 µg/ml. HPLC was carried out for the analysis of its phytochemical profile and demonstrated the presence of the active component Withaferin A in both extracts. The methanolic and ethanolic extracts of Withania should be studied further for the isolation and characterization of the active components to lead optimization studies.
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Affiliation(s)
- A N Srivastava
- Dept. of Pathology, Era's Lucknow Medical College & Hospital, Sarfarazganj, Hardoi Road, Lucknow-226003, India
| | - Rumana Ahmad
- Dept. of Pathology, Era's Lucknow Medical College & Hospital, Sarfarazganj, Hardoi Road, Lucknow-226003, India
| | - Mohsin Ali Khan
- Chairman Research, Era's Lucknow Medical College & Hospital, Sarfarazganj, Hardoi Road, Lucknow-226003, India
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Lee HE, Shin JA, Jeong JH, Jeon JG, Lee MH, Cho SD. Anticancer activity of Ashwagandha against human head and neck cancer cell lines. J Oral Pathol Med 2015; 45:193-201. [PMID: 26332363 DOI: 10.1111/jop.12353] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/27/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND The aim of this study was to determine the apoptotic activity of methanol extract of Ashwagandha (MEAG) and in human head and neck squamous cell carcinoma (HNSCC) cells and to investigate the underlying mechanisms. METHODS We investigated the effects of MEAG on programmed cell death in HNSCC cells using a Live/Dead assay, detection of nuclear morphologic changes, Mitotracker, siRNA knockdown, and RT-PCR. RESULTS Treatment with MEAG showed dose-dependent growth-inhibitory activity that attribute to caspase-dependent apoptosis. Loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase 9 suggested that MEAG leads to activation of mitochondria-mediated apoptosis. MEAG selectively upregulated the expression of Bim protein at the transcriptional level and induced the translocation of Bim into the mitochondria. Knockdown of Bim by siRNA partially blocked MEAG-mediated apoptosis. MEAG also caused an increase in truncated Bid (t-Bid), cleaved caspase-8, and death receptor 5 (DR5). Interestingly, withaferin A (WA), a bioactive component of MEAG, clearly induced apoptosis accompanied by upregulation of Bim, t-Bid, caspase-8, and DR5 similar to the effects of MEAG. CONCLUSIONS These suggest that MEAG and WA may be potential natural materials for the treatment of HNSCC.
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Affiliation(s)
- Haeng-Eun Lee
- Department of Oral Pathology, School of Dentistry and Institute of Biodegradable Material, Institute of Oral Bioscience, Brain Korea 21 Project, Chonbuk National University, Jeon-ju, Korea
| | - Ji-Ae Shin
- Department of Oral Pathology, School of Dentistry and Institute of Biodegradable Material, Institute of Oral Bioscience, Brain Korea 21 Project, Chonbuk National University, Jeon-ju, Korea
| | - Joseph H Jeong
- Department of Dermatology and Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jae-Gyu Jeon
- Department of Preventive Dentistry, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju, Korea
| | - Min-Ho Lee
- Department of Dental Biomaterials and Institute of Biodegradable Material, Institute of Oral Bioscience and BK21 Plus Project, School of Dentistry, Chonbuk National University, Jeonju, Korea
| | - Sung-Dae Cho
- Department of Oral Pathology, School of Dentistry and Institute of Biodegradable Material, Institute of Oral Bioscience, Brain Korea 21 Project, Chonbuk National University, Jeon-ju, Korea
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Kumar V, Dey A, Hadimani MB, Marcovic T, Emerald M. Chemistry and pharmacology of withania somnifera: An update. ACTA ACUST UNITED AC 2015. [DOI: 10.5667/tang.2014.0030] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Nature curing cancer - review on structural modification studies with natural active compounds having anti-tumor efficiency. ACTA ACUST UNITED AC 2015. [PMID: 28626698 PMCID: PMC5466266 DOI: 10.1016/j.btre.2015.01.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Cancer treatment has raised many drugs and radiation therapies whose side-effects are visible. Ongoing research throughout the world for effective treatment mainly concentrates on methods either in the form of drugs or therapies against this lethal disease. However returning to ayurvedic roots enlightens the fact that nature has many efficient components with anti-cancerous, anti-proliferating and anti-angiogenesis effects. Evidences confirm the participation of plants extracts in synthesizing many medicines against already existing and even emerging diseases. Structure activity relationship (SAR) studies and structural modifications are helping in observing the basis of compounds characteristics to exhibit inhibitor's nature against carcinogenic agents by modifying parent compounds for creating an improved and potent compound. Many components are under clinical trials but most of them still need attention. In this review an attempt has been made to focus on the natural components gifted by nature and even included in our diet with their structures and sources that could be supportive in designing drug either by computational methods or by experimental methods.
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Pandit S, Song KY, Jeon JG. Withania somnifera attenuates acid production, acid tolerance and extra-cellular polysaccharide formation of Streptococcus mutans biofilms. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2014; 42:157-71. [PMID: 24467542 DOI: 10.1142/s0192415x14500116] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Withania somnifera (Ashwagandha) is a plant of the Solanaceae family. It has been widely used as a remedy for a variety of ailments in India and Nepal. The plant has also been used as a controlling agent for dental diseases. The aim of the present study was to evaluate the activity of the methanol extract of W. somnifera against the physiological ability of cariogenic biofilms and to identify the components of the extract. To determine the activity of the extract, assays for sucrose-dependent bacterial adherence, glycolytic acid production, acid tolerance, and extracellular polysaccharide formation were performed using Streptococcus mutans biofilms. The viability change of S. mutans biofilms cells was also determined. A phytochemical analysis of the extract was performed using TLC and LC/MS/MS. The extract showed inhibitory effects on sucrose-dependent bacterial adherence (≥ 100 μg/ml), glycolytic acid production (≥ 300 μg/ml), acid tolerance (≥ 300 μg/ml), and extracellular polysaccharide formation (≥ 300 μg/ml) of S. mutans biofilms. However, the extract did not alter the viability of S. mutans biofilms cells in all concentrations tested. Based on the phytochemical analysis, the activity of the extract may be related to the presence of alkaloids, anthrones, coumarines, anthraquinones, terpenoids, flavonoids, and steroid lactones (withanolide A, withaferin A, withanolide B, withanoside IV, and 12-deoxy withastramonolide). These data indicate that W. somnifera may be a potential agent for restraining the physiological ability of cariogenic biofilms.
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Affiliation(s)
- Santosh Pandit
- Department of Preventive Dentistry, Chonbuk National University, Jeonju 561-756, Republic of Korea
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Kim SH, Singh SV. Mammary cancer chemoprevention by withaferin A is accompanied by in vivo suppression of self-renewal of cancer stem cells. Cancer Prev Res (Phila) 2014; 7:738-47. [PMID: 24824039 DOI: 10.1158/1940-6207.capr-13-0445] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Current dogma favors elimination of therapy-resistant cancer stem cells for chemoprevention of breast cancer. We showed recently that mammary cancer development in a transgenic mouse model (mouse mammary tumor virus-neu; MMTV-neu) was inhibited significantly upon treatment with withaferin A (WA), a steroidal lactone derived from a medicinal plant. Herein, we demonstrate that the mammary cancer prevention by WA is accompanied by in vivo suppression of breast cancer stem cells (bCSC). In vitro mammosphere formation was dose-dependently inhibited by WA treatment in MCF-7 and SUM159 human breast cancer cells. Other markers of bCSC, including aldehyde dehydrogenase 1 (ALDH1) activity and CD44(high)/CD24(low)/epithelial-specific antigen-positive (ESA+) fraction, were also decreased significantly in the presence of plasma achievable doses of WA. However, WA exposure resulted in cell line-specific changes in Oct4, SOX-2, and Nanog mRNA expression. WA administration to MMTV-neu mice (0.1 mg/mouse, 3 times/week for 28 weeks) resulted in inhibition of mammosphere number and ALDH1 activity in vivo. Mechanistic studies revealed that although urokinase-type plasminogen activator receptor overexpression conferred partial protection against bCSC inhibition by WA, Notch4 was largely dispensable for this response. WA treatment also resulted in sustained (MCF-7) or transient (SUM159) downregulation of Bmi-1 (B-cell-specific Moloney murine leukemia virus insertion region-1) protein. Ectopic expression of Bmi-1 conferred partial but significant protection against ALDH1 activity inhibition by WA. Interestingly, WA treatment caused induction of Kruppel-like factor 4 (KLF4) and its knockdown augmented bCSC inhibition by WA. In conclusion, this study shows in vivo effectiveness of WA against bCSC.
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Affiliation(s)
- Su-Hyeong Kim
- Authors' Affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Shivendra V Singh
- Authors' Affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Hahm ER, Singh SV. Autophagy fails to alter withaferin A-mediated lethality in human breast cancer cells. Curr Cancer Drug Targets 2014; 13:640-50. [PMID: 23607597 DOI: 10.2174/15680096113139990039] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Revised: 03/16/2012] [Accepted: 03/16/2012] [Indexed: 01/12/2023]
Abstract
We have shown previously that withaferin A (WA), which is a highly promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits viability of cultured breast cancer cells in association with reactive oxygen species (ROS)-dependent apoptosis induction. Because ROS production is implicated in induction of autophagy, which is an evolutionary conserved process for bulk degradation of cellular components including organelles (e.g., mitochondria) and considered a valid cancer chemotherapeutic target, we questioned whether WA treatment resulted in autophagy induction. Indeed exposure of MDA-MB-231 and MCF-7 human breast cancer cells as well as a spontaneously immortalized and non-tumorigenic normal human mammary epithelial cell line (MCF-10A) to pharmacologic concentration of WA resulted in autophagy as evidenced by transmission electron microscopy, processing of microtubuleassociated protein 1 light chain 3 isoform B, and/or acridine orange staining. Inhibition of MDA-MB-231 xenograft growth in vivo by WA administration was also associated with a significant increase in level of LC3 protein in the tumor. However, WA-mediated inhibition of MDA-MB-231 and MCF-7 cell viability was not compromised either by pharmacological suppression of autophagy using 3-methyl adenine or genetic repression of autophagy by RNA interference of Atg5, a critical component of the autophagic machinery. Finally, Beclin1 was dispensable for WA-mediated autophagy as well as inhibition of MDA-MB-231 cell viability. Based on these observations we conclude that autophagy induction fails to have any meaningful impact on WA-mediated lethality in breast cancer cells, which may be a therapeutic advantage because autophagy serves to protect against apoptosis by several anticancer agents.
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Affiliation(s)
- Eun-Ryeong Hahm
- 2.32A Hillman Cancer Center Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA 15213, USA
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Antony ML, Lee J, Hahm ER, Kim SH, Marcus AI, Kumari V, Ji X, Yang Z, Vowell CL, Wipf P, Uechi GT, Yates NA, Romero G, Sarkar SN, Singh SV. Growth arrest by the antitumor steroidal lactone withaferin A in human breast cancer cells is associated with down-regulation and covalent binding at cysteine 303 of β-tubulin. J Biol Chem 2013; 289:1852-65. [PMID: 24297176 DOI: 10.1074/jbc.m113.496844] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Withaferin A (WA), a C5,C6-epoxy steroidal lactone derived from a medicinal plant (Withania somnifera), inhibits growth of human breast cancer cells in vitro and in vivo and prevents mammary cancer development in a transgenic mouse model. However, the mechanisms underlying the anticancer effect of WA are not fully understood. Herein, we report that tubulin is a novel target of WA-mediated growth arrest in human breast cancer cells. The G2 and mitotic arrest resulting from WA exposure in MCF-7, SUM159, and SK-BR-3 cells was associated with a marked decrease in protein levels of β-tubulin. These effects were not observed with the naturally occurring C6,C7-epoxy analogs of WA (withanone and withanolide A). A non-tumorigenic normal mammary epithelial cell line (MCF-10A) was markedly more resistant to mitotic arrest by WA compared with breast cancer cells. Vehicle-treated control cells exhibited a normal bipolar spindle with chromosomes aligned along the metaphase plate. In contrast, WA treatment led to a severe disruption of normal spindle morphology. NMR analyses revealed that the A-ring enone in WA, but not in withanone or withanolide A, was highly reactive with cysteamine and rapidly succumbed to irreversible nucleophilic addition. Mass spectrometry demonstrated direct covalent binding of WA to Cys(303) of β-tubulin in MCF-7 cells. Molecular docking indicated that the WA-binding pocket is located on the surface of β-tubulin and characterized by a hydrophobic floor, a hydrophobic wall, and a charge-balanced hydrophilic entrance. These results provide novel insights into the mechanism of growth arrest by WA in breast cancer cells.
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Affiliation(s)
- Marie L Antony
- From the Departments of Pharmacology and Chemical Biology and
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Lee J, Hahm ER, Marcus AI, Singh SV. Withaferin A inhibits experimental epithelial-mesenchymal transition in MCF-10A cells and suppresses vimentin protein level in vivo in breast tumors. Mol Carcinog 2013; 54:417-29. [PMID: 24293234 DOI: 10.1002/mc.22110] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 10/23/2013] [Accepted: 10/25/2013] [Indexed: 11/10/2022]
Abstract
We have shown previously that withaferin A (WA), a bioactive component of the medicinal plant Withania somnifera, inhibits growth of cultured and xenografted human breast cancer cells and prevents breast cancer development and pulmonary metastasis incidence in a transgenic mouse model. The present study was undertaken to determine if the anticancer effect of WA involved inhibition of epithelial-mesenchymal transition (EMT). Experimental EMT induced by exposure of MCF-10A cells to tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β) was partially reversed by treatment with WA but not by its structural analogs withanone or withanolide A. Combined TNF-α and TGF-β treatments conferred partial protection against MCF-10A cell migration inhibition by WA. Inhibition of TNF-α and TGF-β-induced MCF-10A cell migration by WA exposure was modestly attenuated by knockdown of E-cadherin protein. MCF-7 and MDA-MB-231 cells exposed to WA exhibited sustained (MCF-7) or transient (MDA-MB-231) induction of E-cadherin protein. On the other hand, the level of vimentin protein was increased markedly after 24 h treatment of MDA-MB-231 cells with WA. WA-induced apoptosis was not affected by vimentin protein knockdown in MDA-MB-231 cells. Protein level of vimentin was significantly lower in the MDA-MB-231 xenografts as well as in MMTV-neu tumors from WA-treated mice compared with controls. The major conclusions of the present study are that (a) WA treatment inhibits experimental EMT in MCF-10A cells, and (b) mammary cancer growth inhibition by WA administration is associated with suppression of vimentin protein expression in vivo.
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Affiliation(s)
- Joomin Lee
- Department of Pharmacology & Chemical Biology, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Sinha P, Ostrand-Rosenberg S. Myeloid-derived suppressor cell function is reduced by Withaferin A, a potent and abundant component of Withania somnifera root extract. Cancer Immunol Immunother 2013; 62:1663-73. [PMID: 23982485 PMCID: PMC11028968 DOI: 10.1007/s00262-013-1470-2] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 08/16/2013] [Indexed: 12/12/2022]
Abstract
Myeloid cells play a crucial role in tumor progression. The most common tumor-infiltrating myeloid cells are myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAMs). These cells promote tumor growth by their inherent immune suppressive activity which is enhanced by their cross-talk. The root extract of the plant Withania somnifera (Ashwagandha) (WRE) has been reported to reduce tumor growth. HPLC analysis identified Withaferin A (WA) as the most abundant constituent of WRE and led us to determine whether the anti-tumor effects of WRE and WA involve modulating MDSC and TAM activity. A prominent effect of MDSC is their production of IL-10 which increases upon cross-talk with macrophages, thus polarizing immunity to a pro-tumor type 2 phenotype. In vitro treatment with WA decreased MDSC production of IL-10 and prevented additional MDSC production of IL-10 generated by MDSC-macrophage cross-talk. Macrophage secretion of IL-6 and TNFα, cytokines that increase MDSC accumulation and function, was also reduced by in vitro treatment with WA. Much of the T-cell suppressive activity of MDSC is due to MDSC production of reactive oxygen species (ROS), and WA significantly reduced MDSC production of ROS through a STAT3-dependent mechanism. In vivo treatment of tumor-bearing mice with WA decreased tumor weight, reduced the quantity of granulocytic MDSC, and reduced the ability of MDSC to suppress antigen-driven activation of CD4+ and CD8+ T cells. Thus, adjunctive treatment with WA reduced myeloid cell-mediated immune suppression, polarized immunity toward a tumor-rejecting type 1 phenotype, and may facilitate the development of anti-tumor immunity.
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Affiliation(s)
- Pratima Sinha
- Department of Biological Sciences, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD, 21250, USA,
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Water extract of Ashwagandha leaves has anticancer activity: identification of an active component and its mechanism of action. PLoS One 2013; 8:e77189. [PMID: 24130852 PMCID: PMC3795014 DOI: 10.1371/journal.pone.0077189] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Accepted: 09/03/2013] [Indexed: 12/13/2022] Open
Abstract
Background Cancer is a leading cause of death accounting for 15-20% of global mortality. Although advancements in diagnostic and therapeutic technologies have improved cancer survival statistics, 75% of the world population live in underdeveloped regions and have poor access to the advanced medical remedies. Natural therapies hence become an alternative choice of treatment. Ashwagandha, a tropical herb used in Indian Ayurvedic medicine, has a long history of its health promoting and therapeutic effects. In the present study, we have investigated an anticancer activity in the water extract of Ashwagandha leaves (ASH-WEX). Methodology/Principal Findings Anticancer activity in the water extract of Ashwagandha leaves (ASH-WEX) was detected by invitro and invivo assays. Bioactivity-based size fractionation and NMR analysis were performed to identify the active anticancer component(s). Mechanism of anticancer activity in the extract and its purified component was investigated by biochemical assays. We report that the ASH-WEX is cytotoxic to cancer cells selectively, and causes tumor suppression invivo. Its active anticancer component was identified as triethylene glycol (TEG). Molecular analysis revealed activation of tumor suppressor proteins p53 and pRB by ASH-WEX and TEG in cancer cells. In contrast to the hypophosphorylation of pRB, decrease in cyclin B1 and increase in cyclin D1 in ASH-WEX and TEG-treated cancer cells (undergoing growth arrest), normal cells showed increase in pRB phosphorylation and cyclin B1, and decrease in cyclin D1 (signifying their cell cycle progression). We also found that the MMP-3 and MMP-9 that regulate metastasis were down regulated in ASH-WEX and TEG-treated cancer cells; normal cells remained unaffected. Conclusion We provide the first molecular evidence that the ASH-WEX and TEG have selective cancer cell growth arrest activity and hence may offer natural and economic resources for anticancer medicine.
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Vyas AR, Singh SV. Molecular targets and mechanisms of cancer prevention and treatment by withaferin a, a naturally occurring steroidal lactone. AAPS JOURNAL 2013; 16:1-10. [PMID: 24046237 DOI: 10.1208/s12248-013-9531-1] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 08/21/2013] [Indexed: 02/07/2023]
Abstract
The plants used in Ayurvedic medicine, which has been practiced in India for thousands of years for the treatment of a variety of disorders, are rich in chemicals potentially useful for prevention and treatment of cancer. Withania somnifera (commonly known as Ashwagandha in Ayurvedic medicine) is one such medicinal plant whose anticancer value was realized over four decades ago after isolation of a crystalline steroidal compound (withaferin A) from the leaves of this shrub. The root and leaf extracts of W. somnifera are shown to confer protection against chemically-induced cancers in experimental rodents, and retard tumor xenograft growth in athymic mice. Anticancer effect of W. somnifera is generally attributable to steroidal lactones collectively referred to as withanolides. Withaferin A (WA) appears most active against cancer among structurally divergent withanolides isolated from the root or leaf of W. somnifera. Cancer-protective role for WA has now been established using chemically-induced and oncogene-driven rodent cancer models. This review summarizes the key in vivo preclinical studies demonstrating anticancer effects of WA. Molecular targets and mechanisms likely contributing to the anticancer effects of WA are also discussed. Finally, challenges in clinical development of WA for the prevention and treatment of cancer are highlighted.
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Affiliation(s)
- Avani R Vyas
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Zheng N, Lin X, Wen Q, Kintoko, Zhang S, Huang J, Xu X, Huang R. Effect of 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione, isolated from Averrhoa carambola L. (Oxalidaceae) roots, on advanced glycation end-product-mediated renal injury in type 2 diabetic KKAy mice. Toxicol Lett 2013; 219:77-84. [PMID: 23500658 DOI: 10.1016/j.toxlet.2013.03.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Revised: 02/27/2013] [Accepted: 03/02/2013] [Indexed: 11/18/2022]
Abstract
The roots of Averrhoa carambola L. (Oxalidaceae) have a long history of medical use in traditional Chinese medicine for treating diabetes and diabetic nephropathy. 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) was isolated from the tuberous roots of A. carambola L. The purpose of this study was to investigate the beneficial effect of DMDD on the advanced glycation end-product-mediated renal injury in type 2 diabetic KKAy mice with regard to prove its efficacy by local traditional practitioners in the treatment of kidney frailties in diabetics. KKAy mice were orally administrated DMDD (12.5, 25, 50mg/kg body weight/d) or aminoguanidine (200mg/kg body weight/d) for 8 weeks. Hyperglycemia, renal AGE formation, and the expression of related proteins, such as the AGE receptor, nuclear factor-κB, transforming growth factor-β1, and N(ε)-(carboxymethyl)lysine, were markedly decreased by DMDD. Diabetes-dependent alterations in proteinuria, serum creatinine, creatinine clearance, and serum urea-N and glomerular mesangial matrix expansion were attenuated after treatment with DMDD for 8 weeks. The activities of superoxide dismutase and glutathione peroxidase, which are reduced in the kidneys of KKAy mice, were enhanced by DMDD. These findings suggest that DMDD may inhibit the progression of diabetic nephropathy and may be a therapeutic agent for regulating several pharmacological targets to treat or prevent of diabetic nephropathy.
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MESH Headings
- Administration, Oral
- Animals
- Antioxidants/metabolism
- Blotting, Western
- Cyclohexenes/administration & dosage
- Cyclohexenes/isolation & purification
- Cyclohexenes/therapeutic use
- Cyclohexenes/toxicity
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Diabetic Nephropathies/etiology
- Diabetic Nephropathies/metabolism
- Diabetic Nephropathies/prevention & control
- Drugs, Chinese Herbal/administration & dosage
- Drugs, Chinese Herbal/isolation & purification
- Drugs, Chinese Herbal/therapeutic use
- Drugs, Chinese Herbal/toxicity
- Embryophyta/chemistry
- Glycation End Products, Advanced/antagonists & inhibitors
- Glycation End Products, Advanced/metabolism
- Guanidines/administration & dosage
- Guanidines/pharmacology
- Lethal Dose 50
- Lipid Peroxidation/drug effects
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred Strains
- Plant Roots/chemistry
- Toxicity Tests, Acute
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Affiliation(s)
- Ni Zheng
- Department of Pharmacology, Guangxi Medical University, Nanning 530021, PR China
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Bamhania K, Khatakar S, Punia A, Yadav OP. Genetic Variability Analysis Using ISSR Markers inWithania SomniferaL. Dunal Genotypes from Different Regions. ACTA ACUST UNITED AC 2013. [DOI: 10.1080/10496475.2012.734770] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Srivastava J, Vankar PS. Principal phenolic phytochemicals and antioxidant property in Eucalyptus bark. ACTA ACUST UNITED AC 2012. [DOI: 10.1108/00346651211277663] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Withaferin A causes activation of Notch2 and Notch4 in human breast cancer cells. Breast Cancer Res Treat 2012; 136:45-56. [PMID: 22965833 DOI: 10.1007/s10549-012-2239-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Accepted: 08/28/2012] [Indexed: 10/27/2022]
Abstract
Ayurvedic medicine plants continue to draw attention for the discovery of novel anticancer agents. Withaferin A (WA) is one such small-molecule constituent of the ayurvedic medicine plant Withania somnifera with efficacy against cultured and xenografted human breast cancer cells. However, the mechanism underlying anticancer effect of WA is not fully understood. This study was undertaken to determine the role of Notch signaling in anticancer effects of WA using human breast cancer cells as a model. Notably, Notch signaling is often hyperactive in human breast cancers. Exposure of MDA-MB-231 and MCF-7 human breast cancer cells to pharmacological concentrations of WA resulted in cleavage (activation) of Notch2 as well as Notch4, which was accompanied by transcriptional activation of Notch as evidenced by RBP-Jk, HES-1A/B, and HEY-1 luciferase reporter assays. On the other hand, WA treatment caused a decrease in levels of both transmembrane and cleaved Notch1. The WA-mediated activation of Notch was associated with induction of γ-secretase complex components presenilin1 and/or nicastrin. Inhibition of MDA-MB-231 and MDA-MB-468 cell migration resulting from WA exposure was significantly augmented by knockdown of Notch2 as well as Notch4 protein. Activation of Notch2 was not observed in cells treated with withanone or withanolide A, which are structural analogs of WA. The results of this study indicate that WA treatment activates Notch2 and Notch4, which impede inhibitory effect of WA on breast cancer cell migration.
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Hahm ER, Singh SV. Withaferin A-induced apoptosis in human breast cancer cells is associated with suppression of inhibitor of apoptosis family protein expression. Cancer Lett 2012; 334:101-8. [PMID: 22935676 DOI: 10.1016/j.canlet.2012.08.026] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Revised: 08/20/2012] [Accepted: 08/21/2012] [Indexed: 01/04/2023]
Abstract
The present study provides novel insight into the mechanism of apoptosis induction by withaferin A (WA), which is a bioactive constituent of an Ayurvedic medicine plant (Withania somnifera). Exposure of MDA-MB-231 and MCF-7 human breast cancer cells to WA resulted in suppression of XIAP, cIAP-2, and Survivin protein levels. The WA-induced apoptosis was significantly attenuated by ectopic expression of XIAP, Survivin, and cIAP-2 in both cells. However, the WA-mediated inhibition of MDA-MB-231 xenograft growth in vivo was associated with suppression of Survivin protein level only. These results indicate important contribution of Survivin suppression in WA-induced apoptosis.
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Affiliation(s)
- Eun-Ryeong Hahm
- Department of Pharmacology & Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Shivendra V Singh
- Department of Pharmacology & Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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Devkar S, Badhe Y, Jagtap S, Hegde M. Quantification of major bioactive withanolides inWithania somnifera(Ashwagandha) roots by HPTLC for rapid validation of Ayurvedic products. JPC-J PLANAR CHROMAT 2012. [DOI: 10.1556/jpc.25.2012.4.2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Kumar M, Samarth R, Kumar M, Selvan SR, Saharan B, Kumar A. Protective effect of Adhatoda vascia Nees against radiation-induced damage at cellular, biochemical and chromosomal levels in Swiss albino mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 4:343-50. [PMID: 17965765 PMCID: PMC1978234 DOI: 10.1093/ecam/nel098] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2006] [Accepted: 10/30/2006] [Indexed: 11/21/2022]
Abstract
Extract of Adhatoda vasica (L) Nees leaves has been used for treatment of various diseases and disorders in Ayurved and Unani medicine. Modulatory effect of ethanolic extract of A. vasica (L) Nees against radiation-induced changes in terms of histological alterations in testis, reduced glutathione (GSH), lipid peroxidation (LPO), acid and alkaline phosphatases levels, and chromosomal alterations in Swiss albino mice was studied at various post-irradiation intervals between 1 and 30 days. Mice exposed to 8 Gy radiation showed radiation-induced sickness including marked changes in histology of testis and chromosomal aberrations in bone marrow cells with 100% mortality within 22 days. When ethanolic leaf extract of A. vasica was given orally at a dose of 800 mg kg−1 body weight per mouse for 15 consecutive days and then exposed to radiation, death of Adhatoda-pretreated irradiated mice was reduced to 70% at 30 days. The radiation dose reduction factor was 1.43. There was significantly lesser degree of damage to testis tissue architecture and various cell populations including spermatogonia, spermatids and Leydig cells. Correspondingly, a significant decrease in the LPO and an increase in the GSH levels were observed in testis and liver of Adhatoda-pretreated irradiated mice. Similarly, a significant decrease in level of acid phosphatase and increase in level of alkaline phosphatase were observed. Adhatoda pretreatment significantly prevented radiation-induced chromosomal damage in bone marrow cells. The study suggests that Adhatoda plant extract has significant radioprotective effects on testis that warrants further mechanistic studies aimed at identifying the role of major ingredients in the extract.
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Affiliation(s)
- Meenal Kumar
- Laboratory of Radiation and Cancer Biology, Department of Zoology, University of Rajasthan Jaipur 302004, India.
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Rahman S, Ansari RA, Rehman H, Parvez S, Raisuddin S. Nordihydroguaiaretic Acid from Creosote Bush (Larrea tridentata) Mitigates 12-O-Tetradecanoylphorbol-13-Acetate-Induced Inflammatory and Oxidative Stress Responses of Tumor Promotion Cascade in Mouse Skin. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 2011:734785. [PMID: 19861506 PMCID: PMC3138708 DOI: 10.1093/ecam/nep076] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2009] [Accepted: 06/02/2009] [Indexed: 01/01/2023]
Abstract
Nordihydroguaiaretic acid (NDGA) is a phenolic antioxidant found in the leaves and twigs of the evergreen desert shrub, Larrea tridentata (Sesse and Moc. ex DC) Coville (creosote bush). It has a long history of traditional medicinal use by the Native Americans and Mexicans. The modulatory effects of topically applied NDGA was studied on acute inflammatory and oxidative stress responses in mouse skin induced by stage I tumor promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA). Double TPA treatment adversely altered many of the marker responses of stage I skin tumor promotion cascade. Pretreatment of NDGA in TPA-treated mice mitigated cutaneous lipid peroxidation and inhibited production of hydrogen peroxide. NDGA treatment also restored reduced glutathione level and activities of antioxidant enzymes. Elevated activities of myeloperoxidase, xanthine oxidase and skin edema formation in TPA-treated mice were also lowered by NDGA indicating a restrained inflammatory response. Furthermore, results of histological study demonstrated inhibitory effect of NDGA on cellular inflammatory responses. This study provides a direct evidence of antioxidative and anti-inflammatory properties of NDGA against TPA-induced cutaneous inflammation and oxidative stress corroborating its chemopreventive potential against skin cancer.
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Affiliation(s)
- Shakilur Rahman
- Department of Medical Elementology and Toxicology, Hamdard University, New Delhi 110062, India
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Cabrini DA, Moresco HH, Imazu P, da Silva CD, Pietrovski EF, Mendes DAGB, da Silveira Prudente A, Pizzolatti MG, Brighente IMC, Otuki MF. Analysis of the Potential Topical Anti-Inflammatory Activity of Averrhoa carambola L. in Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 2011:908059. [PMID: 21785638 PMCID: PMC3137785 DOI: 10.1093/ecam/neq026] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2009] [Accepted: 03/08/2010] [Indexed: 12/29/2022]
Abstract
Inflammatory skin disorders, such as psoriasis and atopic dermatitis, are very common in the population; however, the treatments currently available are not well tolerated and are often ineffective. Averrhoa carambola L. (Oxalidaceae) is an Asian tree that has been used in traditional folk medicine in the treatment of several skin disorders. The present study evaluates the topical anti-inflammatory effects of the crude ethanolic extract of A. carambola leaves, its hexane, ethyl acetate, and butanol fractions and two isolated flavonoids on skin inflammation. Anti-inflammatory activity was measured using a croton oil-induced ear edema model of inflammation in mice. Topically applied ethanolic extract reduced edema in a dose-dependent manner, resulting in a maximum inhibition of 73 ± 3% and an ID50 value of 0.05 (range: 0.02–0.13) mg/ear. Myeloperoxidase (MPO) activity was also inhibited by the extract, resulting in a maximum inhibition of 60 ± 6% (0.6 mg/ear). All of the fractions tested caused inhibition of edema formation and of MPO activity. Treatment with the ethyl acetate fraction was the most effective, resulting in inhibition levels of 75 ± 5 and 54 ± 8% for edema formation and MPO activity, respectively. However, treatment of mice with isolated compounds [apigenin-6-C-β-l-fucopyranoside and apigenin-6-C-(2″-O-α-l-rhamnopyranosyl)-β-l-fucopyranoside] did not yield successful results. Apigenin-6-C-(2″-O-α-l-rhamnopyranosyl)-β-l-fucopyranoside caused only a mild reduction in edema formation (28 ± 11%). Taken together, these preliminary results support the popular use of A. carambola as an anti-inflammatory agent and open up new possibilities for its use in skin disorders.
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Affiliation(s)
- Daniela Almeida Cabrini
- Laboratory of Inflammation, Department of Pharmacology, Universidade Federal do Paraná, Curitiba, PR, Brazil
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Varma A, Padh H, Shrivastava N. Andrographolide: a new plant-derived antineoplastic entity on horizon. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 2011:815390. [PMID: 19752167 PMCID: PMC3139959 DOI: 10.1093/ecam/nep135] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Accepted: 08/05/2009] [Indexed: 12/25/2022]
Abstract
Plant-derived natural products occupy an important position in the area of cancer chemotherapy. Molecules such as vincristine, vinblastine, paclitaxel, camptothecin derivatives, epipodophyllotoxin, and so forth, are invaluable contributions of nature to modern medicine. However, the quest to find out novel therapeutic compounds for cancer treatment and management is a never-ending venture; and diverse plant species are persistently being studied for identification of prospective anticancer agents. In this regard, Andrographis paniculata Nees, a well-known plant of Indian and Chinese traditional system of medicines, has drawn attention of researchers in recent times. Andrographolide, the principal bioactive chemical constituent of the plant has shown credible anticancer potential in various investigations around the globe. In vitro studies demonstrate the capability of the compound of inducing cell-cycle arrest and apoptosis in a variety of cancer cells at different concentrations. Andrographolide also shows potent immunomodulatory and anti-angiogenic activities in tumorous tissues. Synthetic analogues of the compound have also been created and analyzed, which have also shown similar activities. Although it is too early to predict its future in cancer chemotherapy, the prologue strongly recommends further research on this molecule to assess its potential as a prospective anticancer agent.
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Affiliation(s)
- Astha Varma
- B. V. Patel Pharmaceutical Education & Research Development (PERD) Centre, Sarkhej-Gandhinagar Highway, Thaltej, Ahmedabad 380054, Gujarat, India
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Bhattacharjee N, Pathak S, Khuda-Bukhsh AR. Amelioration of carcinogen-induced toxicity in mice by administration of a potentized homeopathic drug, natrum sulphuricum 200. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2009; 6:65-75. [PMID: 18955221 PMCID: PMC2644277 DOI: 10.1093/ecam/nem067] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2006] [Accepted: 05/08/2007] [Indexed: 12/22/2022]
Abstract
To examine if a potentized homeopathic drug, Natrum Sulphuricum 200 (Nat Sulph-200) has protective potentials against hepatocarcinogenesis, liver tumors were induced in mice through chronic feeding of P-dimethylaminoazobenzene (p-DAB; initiator of hepatocarcinogenesis) and phenobarbital (PB; promoter). Mice were divided into five sub-groups: fed normal low protein diet (Gr. I, normal control); fed normal low protein plus alcohol-200 (vehicle of the homeopathic remedy) (Gr. II); fed diet mixed with 0.06% p-DAB plus 0.05% PB (Gr. III); fed diet and carcinogens like Gr.III, plus alcohol 200 (positive control for drug fed mice) (Gr. IV) and fed diet and carcinogens like Gr. III, plus Natrum Sulphuiricum-200 (Gr. V; drug fed). Mice were sacrificed at day 7, 15, 30, 60, 90 and day 120 for study of cytogenetical endpoints like chromosome aberrations (CA), micronuclei (MN), mitotic index (MI) and sperm head anomaly (SHA) and biochemical toxicity parameters like aspartate amino transferase (AST), alanine amino transferase (ALT), acid (AcP) and alkaline (AlkP) phosphatases, lipid peroxidation (LPO) and reduced glutathione (GSH) content. Less number of liver tumors were observed in Gr. V (drug fed) mice. Administration of Nat Sulph 200 reduced genomic damage, activities of AcP, AlkP, AST, ALT, LPO and increased GSH content. Therefore, independent replication of the study by others is encouraged.
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Jahangir T, Sultana S. Perillyl Alcohol Protects Against Fe-NTA-Induced Nephrotoxicity and Early Tumor Promotional Events in Rat Experimental Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2007; 4:439-45. [PMID: 18227911 PMCID: PMC2176137 DOI: 10.1093/ecam/nel104] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2006] [Accepted: 11/20/2006] [Indexed: 01/12/2023]
Abstract
Plants have been widely used as protective agents against a wide variety of processes and compounds that damage tissues via free radical mechanisms. Perillyl alcohol (PA) is a naturally occurring monoterpene found in the essential oils of numerous species of plants including mints, cherries and celery seeds. This monocyclic monoterpene has shown antioxidant and therapeutic activity in various studies against various xenobiotics. In this study, we have analyzed the effects of PA against single intraperitoneal dose of ferric nitrilotriacetate (Fe-NTA) (9 mg iron per kg body weight)-induced nephrotoxicity and early tumor promotional events. The pretreatment of Fe-NTA-treated rats with 0.5% per kg body weight dose and 1% per kg body weight dose of PA for seven consecutive days significantly reversed the Fe-NTA-induced malondialdehyde formation, xanthine oxidase activity (P < 0.001), ornithine decarboxylase activity (P < 0.001) and (3)[H]thymidine incorporation in renal DNA (P < 0.001) with simultaneous significant depletion in serum toxicity markers blood urea nitrogen and creatinine (P < 0.001). Significant restoration at both the doses was recorded in depleted renal glutathione content, and its dependent enzymes with prophylactic treatment of PA. Present results suggest that PA potentially attenuates against Fe-NTA-induced oxidative damage and tumor promotional events that preclude its development as a future drug to avert the free radical-induced toxicity.
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Affiliation(s)
- Tamanna Jahangir
- Section of Chemoprevention and Nutrition Toxicology, Department of Medical Elementology and Toxicology Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, India
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Essa MM, Subramanian P. Hibiscus sabdariffa affects ammonium chloride-induced hyperammonemic rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2007; 4:321-5. [PMID: 17965762 PMCID: PMC1978237 DOI: 10.1093/ecam/nel087] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2005] [Accepted: 10/12/2006] [Indexed: 12/12/2022]
Abstract
Hibiscus sabdariffa (HS) is an edible medicinal plant, indigenous to India, China and Thailand and is used in Ayurveda and traditional medicine. Alcoholic extract of HS leaves (HSEt) was studied for its anti-hyperammonemic and antioxidant effects in brain tissues of ammonium chloride-induced hyperammonemic rats. Oral administration of HSEt (250 mg kg(-1) body weight) significantly normalizes the levels of ammonia, urea, uric acid, creatinine and non-protein nitrogen in the blood. HSEt significantly reduced brain levels of lipid peroxidation products such as thiobarbituric acid and reactive substances (TBARS) and hydroperoxides (HP). However, the administered extract significantly increased the levels of antioxidants such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH) in brain tissues of hyperammonemic rats. This investigation demonstrates significant anti-hyperammonemic and antioxidant activity of HS.
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Affiliation(s)
- M Mohamed Essa
- Department of Biochemistry, Faculty of Science, Annamalai University Annamalainagar 608 002, Tamil Nadu, India
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Ichikawa H, Takada Y, Shishodia S, Jayaprakasam B, Nair MG, Aggarwal BB. Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-kappaB (NF-kappaB) activation and NF-kappaB-regulated gene expression. Mol Cancer Ther 2006; 5:1434-45. [PMID: 16818501 DOI: 10.1158/1535-7163.mct-06-0096] [Citation(s) in RCA: 130] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The plant Withania somnifera Dunal (Ashwagandha), also known as Indian ginseng, is widely used in the Ayurvedic system of medicine to treat tumors, inflammation, arthritis, asthma, and hypertension. Chemical investigation of the roots and leaves of this plant has yielded bioactive withanolides. Earlier studies showed that withanolides inhibit cyclooxygenase enzymes, lipid peroxidation, and proliferation of tumor cells. Because several genes that regulate cellular proliferation, carcinogenesis, metastasis, and inflammation are regulated by activation of nuclear factor-kappaB (NF-kappaB), we hypothesized that the activity of withanolides is mediated through modulation of NF-kappaB activation. For this report, we investigated the effect of the withanolide on NF-kappaB and NF-kappaB-regulated gene expression activated by various carcinogens. We found that withanolides suppressed NF-kappaB activation induced by a variety of inflammatory and carcinogenic agents, including tumor necrosis factor (TNF), interleukin-1beta, doxorubicin, and cigarette smoke condensate. Suppression was not cell type specific, as both inducible and constitutive NF-kappaB activation was blocked by withanolides. The suppression occurred through the inhibition of inhibitory subunit of IkappaB alpha kinase activation, IkappaB alpha phosphorylation, IkappaB alpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. NF-kappaB-dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR-associated death domain, TNFR-associated factor 2, and IkappaB alpha kinase was also suppressed. Consequently, withanolide suppressed the expression of TNF-induced NF-kappaB-regulated antiapoptotic (inhibitor of apoptosis protein 1, Bfl-1/A1, and FADD-like interleukin-1beta-converting enzyme-inhibitory protein) and metastatic (cyclooxygenase-2 and intercellular adhesion molecule-1) gene products, enhanced the apoptosis induced by TNF and chemotherapeutic agents, and suppressed cellular TNF-induced invasion and receptor activator of NF-kappaB ligand-induced osteoclastogenesis. Overall, our results indicate that withanolides inhibit activation of NF-kappaB and NF-kappaB-regulated gene expression, which may explain the ability of withanolides to enhance apoptosis and inhibit invasion and osteoclastogenesis.
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Affiliation(s)
- Haruyo Ichikawa
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
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Vojdani A, Erde J. Regulatory T cells, a potent immunoregulatory target for CAM researchers: modulating tumor immunity, autoimmunity and alloreactive immunity (III). EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2006; 3:309-16. [PMID: 16951715 PMCID: PMC1513145 DOI: 10.1093/ecam/nel047] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2006] [Accepted: 06/12/2006] [Indexed: 12/11/2022]
Abstract
Regulatory T (T(reg)) cells are the major arbiter of immune responses, mediating actions through the suppression of inflammatory and destructive immune reactions. Inappropriate T(reg) cell frequency or functionality potentiates the pathogenesis of myriad diseases with ranging magnitudes of severity. Lack of suppressive capability hinders restraint on immune responses involved in autoimmunity and alloreactivity, while excessive suppressive capacity effectively blocks processes necessary for tumor destruction. Although the etiology of dysfunctional T(reg) cell populations is under debate, the ramifications, and their mechanisms, are increasingly brought to light in the medical community. Methods that compensate for aberrant immune regulation may not address the underlying complications; however, they hold promise for the alleviation of debilitating immune system-related disorders. The dominant immunoregulatory nature of T(reg) cells, coupled with recent mechanistic knowledge of natural immunomodulatory compounds, highlights the importance of T(reg) cells to practitioners and researchers of complementary and alternative medicine (CAM).
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Affiliation(s)
- Aristo Vojdani
- Immunosciences Lab., Inc., 8693 Wilshire Boulevard, Suite 200, Beverly Hills, CA 90211, USA.
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Bani S, Gautam M, Sheikh FA, Khan B, Satti NK, Suri KA, Qazi GN, Patwardhan B. Selective Th1 up-regulating activity of Withania somnifera aqueous extract in an experimental system using flow cytometry. JOURNAL OF ETHNOPHARMACOLOGY 2006; 107:107-15. [PMID: 16603328 DOI: 10.1016/j.jep.2006.02.016] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2005] [Revised: 02/04/2006] [Accepted: 02/23/2006] [Indexed: 05/07/2023]
Abstract
Withania somnifera (Ashwagandha) is reported to be immunoprotective and immunoadjuvant. We studied its roots aqueous extract on T helper (Th) immunity using flow cytometry. This extract was standardized with six withanolides as marker compounds using HPLC. Once daily dose ranging from 25 to 400 mg/kg/p.o. was used to study effect on Th1: IFN-gamma, IL-2 and Th2: IL-4 cytokine modulation. We also studied effect on CD4 and CD8 in normal and immunesuppressed mice. The results indicate that extract at 100 mg/kg resulted significant selective up-regulation of Th1 response. Treatment with extract showed significant increase in CD4 and CD8 counts as compared to control and cyclopsorin A, with a faster recovery of CD4+ T cells in immunesuppressed animals. Under immunesuppressed conditions, potentiation of cellular and humoral immune responses of extract was comparable to levamisole. This study indicates the selective Th1 up-regulating effect of extract and suggests its use for selective Th1/Th2 modulation.
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Affiliation(s)
- Sarang Bani
- Department of Pharmacology, Regional Research Laboratory, Jammu Tawi, India.
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