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Sailo BL, Garhwal A, Mishra A, Hegde M, Vishwa R, Girisa S, Abbas M, Alqahtani MS, Abdulhammed A, Sethi G, Kempson I, Kunnumakkara AB. Potential of capsaicin as a combinatorial agent to overcome chemoresistance and to improve outcomes of cancer therapy. Biochem Pharmacol 2025; 236:116828. [PMID: 40023449 DOI: 10.1016/j.bcp.2025.116828] [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: 11/22/2024] [Revised: 02/10/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025]
Abstract
Capsaicin (CAPS), a bioactive alkaloid derived from chili peppers, has garnered significant interest for its potential role as a combinatorial and chemosensitizing agent in cancer therapy. Numerous preclinical studies have demonstrated that CAPS enhanced the efficacy of various anticancer agents by promoting apoptosis, modulating autophagy and inhibiting angiogenesis, tumor growth, and metastasis. Additionally, CAPS modulated critical regulators of chemoresistance, such as P-glycoprotein (P-gp), extracellular signal-regulated kinase (ERK), nuclear factor-kappa B (NF-κB) pathway, and signal transducer and activator of transcription 3 (STAT3) pathway, thereby contributing to the reversal of multidrug resistance (MDR). Moreover, when administered in combination with chemotherapeutic agents, CAPS has been shown to improve treatment efficacy at lower drug concentrations. Given its multitargeted mechanism of action, CAPS represents a promising adjunct to conventional cancer therapies. However, due to its lipophilic nature, the development of optimized formulation strategies is essential to enhance its bioavailability and ensure consistent therapeutic outcomes. In conclusion, CAPS holds significant potential as a combinatorial and chemosensitizing agent, helping to overcome chemoresistance and enhance treatment outcomes across various malignancies. These promising findings warrant further preclinical and clinical investigations.
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Affiliation(s)
- Bethsebie Lalduhsaki Sailo
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Anushka Garhwal
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Anamika Mishra
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, 61421 Abha, Saudi Arabia
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, 61421 Abha, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Ayman Abdulhammed
- Department of Biochemistry and Hormone, King Fahad Central Hospital, Gizan 82666, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117699, Singapore.
| | - Ivan Kempson
- Future Industries Institute, University of South Australia, Mawson Lakes, South Australia 5095, Australia.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India.
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Dar MI, Gulya A, Abass S, Dev K, Parveen R, Ahmad S, Qureshi MI. Hallmarks of diabetes mellitus and insights into the therapeutic potential of synergy-based combinations of phytochemicals in reducing oxidative stress-induced diabetic complications. Nat Prod Res 2025; 39:2929-2943. [PMID: 39290074 DOI: 10.1080/14786419.2024.2402461] [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: 02/21/2024] [Revised: 08/03/2024] [Accepted: 09/05/2024] [Indexed: 09/19/2024]
Abstract
Diabetes mellitus (DM) is a serious health issue and is still one of the major causes of mortality around the globe. Natural products have progressively integrated into modern, advanced medical practices. Phytoconstituents from some medicinal plants have demonstrated therapeutic activity in treating different metabolic disorders and have been used to treat DM and its severe complications. The present review provides details of the major anti-diabetic targets identified in the literature and also provides comprehensive information regarding the therapeutic role of a synergy-based combination of phytoconstituents that functions by controlling specific molecular pathways synchronously by inhibiting certain key regulators involved in the development and progression of DM. The review also implicated the role of oxidative stress in diabetic complications and presented scientific validations of phytochemicals and their synergy-based combination using in vitro and or in vivo approaches.
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Affiliation(s)
- Mohammad Irfan Dar
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
- School of Pharmaceutical Education and Research, Centre of Excellence in Unani Medicine (Pharmacognosy & Pharmacology), and Bioactive Natural Product Laboratory, New Delhi, India
| | - Anu Gulya
- All India Institute of Medical Science, New Delhi, India
| | - Sageer Abass
- School of Pharmaceutical Education and Research, Centre of Excellence in Unani Medicine (Pharmacognosy & Pharmacology), and Bioactive Natural Product Laboratory, New Delhi, India
- School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Kapil Dev
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Rabea Parveen
- School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Sayeed Ahmad
- School of Pharmaceutical Education and Research, Centre of Excellence in Unani Medicine (Pharmacognosy & Pharmacology), and Bioactive Natural Product Laboratory, New Delhi, India
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Madrigal-Santillán E, Portillo-Reyes J, Morales-González JA, Garcia-Melo LF, Serra-Pérez E, Vidović K, Sánchez-Gutiérrez M, Álvarez-González I, Madrigal-Bujaidar E. Evaluation of the Antigenotoxic Potential of Two Types of Chayote ( Sechium edule) Juices. PLANTS (BASEL, SWITZERLAND) 2024; 13:2132. [PMID: 39124250 PMCID: PMC11314257 DOI: 10.3390/plants13152132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/17/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024]
Abstract
Sechium edule (Jacq.) Swartz is a perennial herbaceous climbing plant with tendrils and tuberous roots belonging to the Cucurbitaceae family. Its fruits ("chayote"), stems, roots, and leaves are edible and are commonly ingested by humans. It has shown medicinal properties attributed to its bioactive compounds (vitamins, phenolic acids, flavonoids, carotenoids, triterpenoids, polyphenolic compounds, phytosterols, and cucurbitacins), which together have been associated with the control and prevention of chronic and infectious diseases, highlighting its antibacterial, anti-cardiovascular/antihypertensive, antiepileptic, anti-inflammatory, hepatoprotective, antiproliferative, and antioxidant activities. The objective of the study was to determine the antigenotoxic potential of two types of fresh chayote juice (filtered (FChJ) and unfiltered (UFChJ)) against DNA damage produced by benzo[a]pyrene (B[a]P) using an in vivo mouse peripheral blood micronucleus assay (MN). The juices were consumed freely for 2 weeks. A negative control, a control group of each juice, a positive batch [B[a]P], and two combined batches (B[a]P plus FChJ or UFChJ) were included. Blood smears were stained and observed under a microscope to quantify the number of micronucleated normochromic erythrocytes (MNNEs). The results indicate: (a) B[a]P increased the frequency of MNNEs and reduced the rate of PEs; and (b) no juice produced toxic effects or induced MN. On the contrary, both juices were genoprotective. However, the most significant effect was presented by UFChJ at the end of the experiment (70%). It is suggested that UFChJ has a greater amount of fiber and/or phytochemicals that favor the therapeutic effect. Possibly, the genoprotection is also related to its antioxidant capacity.
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Affiliation(s)
- Eduardo Madrigal-Santillán
- Unidad Casco de Santo Tomas, Instituto Politécnico Nacional, Escuela Superior de Medicina, Ciudad de Mexico 11340, Mexico; (J.P.-R.); (J.A.M.-G.)
| | - Jacqueline Portillo-Reyes
- Unidad Casco de Santo Tomas, Instituto Politécnico Nacional, Escuela Superior de Medicina, Ciudad de Mexico 11340, Mexico; (J.P.-R.); (J.A.M.-G.)
| | - José A. Morales-González
- Unidad Casco de Santo Tomas, Instituto Politécnico Nacional, Escuela Superior de Medicina, Ciudad de Mexico 11340, Mexico; (J.P.-R.); (J.A.M.-G.)
| | - Luis F. Garcia-Melo
- Laboratorio de Nanotecnología e Ingeniería Molecular, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de Mexico 09340, Mexico;
| | - Estrella Serra-Pérez
- Chemical Engineering and Materials Department, Faculty of Chemistry, Complutense University, 28040 Madrid, Spain;
| | - Kristijan Vidović
- National Institute of Chemistry, Department of Analytical Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia;
| | - Manuel Sánchez-Gutiérrez
- Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca de Soto 42080, Mexico;
| | - Isela Álvarez-González
- Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional A. López Mateos, Ciudad de Mexico 07738, Mexico; (I.Á.-G.); (E.M.-B.)
| | - Eduardo Madrigal-Bujaidar
- Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional A. López Mateos, Ciudad de Mexico 07738, Mexico; (I.Á.-G.); (E.M.-B.)
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Rodrigues Esperandim T, Barcelos Ribeiro A, Silva Squarisi I, Teixeira Marcos de Souza L, Olimpio de Souza T, Oliveira Acésio N, Ferreira Conceição Santos M, Kenupp Bastos J, Ricardo Ambrósio S, Crispim Tavares D. Toxicological and chemoprevention studies of Brazilian brown propolis from Araucaria sp. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2023; 86:791-802. [PMID: 37592437 DOI: 10.1080/15287394.2023.2243976] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/19/2023]
Abstract
Brazilian brown propolis (BBP) is a natural product derived predominantly from the south region of Brazil, where Araucaria forests are dominant. Despite its potential as a source of bioactive compounds with leishmanicidal, anti-inflammatory, nociceptive, and antimicrobial properties, BBP has not been comprehensively studied compared to green propolis. Therefore, this study aimed to determine the safety and chemopreventive potential of BBP. The cytotoxicity attributed to BBP was assessed using two different assays, while the Salmonella/microsome assay was employed to evaluate mutagenicity. The acute toxicity attributed to BBP was determined using a zebrafish model, while the chemopreventive potential was investigated utilizing Chinese hamster lung (V79) cell lines. Data demonstrated that BBP exerted cytotoxic effects at concentrations greater than or equal to 10 µg/ml and did not exhibit mutagenicity in Salmonella typhimurium strains TA98 and TA100. However, at the highest concentration tested (4000 µg/plate), BBP induced a significant increase in revertant colonies in S. typhimurium TA102 strain. The LC50 equivalent to 8.83 mg/L was obtained in the acute toxicity evaluation in zebrafish. BBP also showed antigenotoxic effect by significantly reducing chromosomal damage induced by the mutagen doxorubicin in V79 cell cultures at a concentration of 2.5 μg/ml. Compared to Brazilian green and red propolis, BBP exhibited greater toxicity. On the other hand, at lower concentrations, BBP displayed chemopreventive potential, which may be associated with the antioxidant capacity of the extract. These findings contribute to a better understanding of the biological properties and potential applications of BBP in treating various diseases.
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Affiliation(s)
| | - Arthur Barcelos Ribeiro
- University of Franca, Av. Dr. Armando Salles Oliveira, 201, 14.404-600 Franca, São Paulo, Brazil
| | - Iara Silva Squarisi
- University of Franca, Av. Dr. Armando Salles Oliveira, 201, 14.404-600 Franca, São Paulo, Brazil
| | | | - Thiago Olimpio de Souza
- University of Franca, Av. Dr. Armando Salles Oliveira, 201, 14.404-600 Franca, São Paulo, Brazil
| | - Nathália Oliveira Acésio
- University of Franca, Av. Dr. Armando Salles Oliveira, 201, 14.404-600 Franca, São Paulo, Brazil
| | | | - Jairo Kenupp Bastos
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Sérgio Ricardo Ambrósio
- University of Franca, Av. Dr. Armando Salles Oliveira, 201, 14.404-600 Franca, São Paulo, Brazil
| | - Denise Crispim Tavares
- University of Franca, Av. Dr. Armando Salles Oliveira, 201, 14.404-600 Franca, São Paulo, Brazil
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Utage B, Patole M, Nagvenkar P, Gacche R. Prosopis juliflora (Sw.) DC.induces apoptotic-like programmed cell death in Leishmania donovani via over production of oxidative stress, mitochondrial dysfunction and ATP depletion. J Tradit Complement Med 2023; 13:611-622. [PMID: 38020554 PMCID: PMC10658441 DOI: 10.1016/j.jtcme.2023.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 05/03/2023] [Accepted: 06/29/2023] [Indexed: 12/01/2023] Open
Abstract
Background Leishmaniasis is endemic in more than 60 countries with a large number of mortality cases. The current chemotherapy approaches employed for managing the leishmaniasis is associated with severe side effects. Therefore there is a need to develop effective, safe, and cost affordable antileishmanial drug candidates. Purpose of the study This study was designed to evaluate the in vitro antileishmanial activity of a Prosopis juliflora leaves extract (PJLME) towards the Leishmania donovani parasites. Material and methods PJLME was evaluated for its cytotoxicity against the L. donovani parasites and the mouse macrophage cells. Further, various in vitro experiments like ROS assay, mitochondrial membrane potential assay, annexin v assay, cell cycle assay, and caspase 3/7 assay were performed to understand the mechanism of cell death. Phytochemical profiling of P. juliflorawas performed by utilizing HPTLC and GC-MS analysis. Results PJLME demonstrated antileishmanial activity at a remarkably lower concentration of IC50 6.5 μg/mL. Of note, interestingly PJLME IC50 concentration has not demonstrated cytotoxicity against the mouse macrophage cell line. Performed experiments confirmed ROS inducing potential of PJLME which adversely affected the mitochondrial membrane potential and caused loss of mitochondrial membrane potential and thereby ATP levels. PJLME also arrested the cell cycle and induced apoptotic-like cell death in PJLME treated L. donovani promastigotes. Conclusion The results clearly established the significance of Prosopis juliflora as an effective and safe natural resource for managing visceral leishmaniasis. The findings can be used as a baseline reference for developing novel leads/formulations for effective management of visceral leishmaniasis.
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Affiliation(s)
| | - Milind Patole
- National Centre for Cell Science, NCCS Complex, Pune, 411007, MS, India
| | - Punam Nagvenkar
- National Centre for Cell Science, NCCS Complex, Pune, 411007, MS, India
| | - Rajesh Gacche
- Department of Biotechnology, Savitribai Phule Pune University, Pune, 411007, MS, India
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Liu J, Velu P, Vijayalakshmi A, Zareian M, Xi H. Betanin inhibits PI3K/AKT/mTOR/S6 signaling pathway, cell growth and death in osteosarcoma MG-63 cells. ENVIRONMENTAL TOXICOLOGY 2023; 38:2173-2181. [PMID: 37401526 DOI: 10.1002/tox.23854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 05/10/2023] [Accepted: 05/28/2023] [Indexed: 07/05/2023]
Abstract
It is possible to develop new chemopreventive compounds so that cancer cells can be targeted in an exclusive manner. Bioactive natural compounds have demonstrated to be efficient chemotherapeutic agents, safe and cost-effective. Majority of anti-cancer medications are derived from natural sources, particularly of plant origins. Betanin (betanidin-5-O-β-glucoside) is the most common betacyanin with antioxidant, anti inflammatory and anticancer properties. The present study therefore investigated the effect of betanin onosteosarcoma MG-63 cells. The mechanistic pathway of inflammatory responses, cell proliferation and apoptosis were investigated. The MG-63 cells were treated with betanin for 24 h. Betanin actions on the appearance of cell arrangements, morphological changes, ROS induced Δψm , cell migration, cell adhesion and proliferative mechanistic marker expression of PI3K/AKT/mTOR/S6were analyzed. Betanin inhibited MG-63 cells at IC50 concentrations between 9.08 and 54.49 μM and induced apoptosis by triggering the ROS mechanism. Betanin inhibited proliferation and migration of MG-63 cells and induced DNA fragmentation. Betanin also modified the key mediator expression levels of PI3K/AKT/mTOR/S6 signaling pathways. Betanin can potentially be utilized in bone carcinoma therapeutics to inhibit, reverse or delay osteosarcoma.
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Affiliation(s)
- Jichao Liu
- Department of Hand and Foot Micro Burn Plastic Surgery, 3201 Hospital, Hanzhong, China
| | - Periyannan Velu
- Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram, India
| | - Annamalai Vijayalakshmi
- PG and Research Department of Biochemistry, Rabiammal Ahamed Maideen College for Women, Tiruvarur, India
| | - Mohsen Zareian
- Department of Life Sciences, Chalmers University of Technology, Göteborg, Sweden
| | - Haitao Xi
- Department of Orthopeadic Surgery Area 2, Xi'an NO.3 Hospital, Xi'an, China
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Ismail NZ, Md Saad S, Adebayo IA, Md Toha Z, Abas R, Mohamad Zain NN, Arsad H. The antiproliferative and apoptotic potential of Clinacanthus nutans against human breast cancer cells through targeted apoptosis pathway. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:81685-81702. [PMID: 35737268 DOI: 10.1007/s11356-022-20858-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 05/12/2022] [Indexed: 06/15/2023]
Abstract
Clinacanthus nutans dichloromethane fraction (CN-Dcm) extract has previously been proven to suppress breast cancer (MCF7) cell proliferation. Despite this, the extrinsic and intrinsic apoptosis mechanisms involved in C. nutans extract-treated MCF7 cells are still unknown. This study was intended to subfractionate CN-Dcm extract using column chromatography and analyse the treated MCF7 cells using the CellTiter 96® AQueous One Solution Cell Proliferation (MTS) assay, Annexin V/propidium iodide (PI) assay, western blot, and reverse transcription-qualitative polymerase chain reaction (RT-qPCR). Out of nine subfraction extracts (SF1 to SF9), SF2 extract strongly inhibited MCF7 cells with the lowest IC50 value (23.51 ± 1.00 µg/mL) and substantially induced apoptosis in the MCF7 cells. In treated MCF7 cells, SF2 extract significantly upregulated the expression of P53, BAX, BID, caspase-8, caspase-9, and caspase-3, while downregulating the expression of BCL2. The presence of potential bioactive chemical compounds in the SF2 extract was identified using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Thus, the SF2 extract has the potential to induce apoptosis in MCF7 cells through intrinsic and extrinsic pathways.
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Affiliation(s)
- Noor Zafirah Ismail
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200, Penang, Kepala Batas, Malaysia
| | - Salwani Md Saad
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200, Penang, Kepala Batas, Malaysia
| | - Ismail Abiola Adebayo
- Department of Clinical Biology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda
- Analystical Biochemistry Research Centre, Universiti Sains Malaysia, Penang, Malaysia
- Microbiology and Immunology Department, School of Biomedical Sciences, Kampala International University, Western Campus, P.O. Box 71, Ishaka-Bushenyi, Uganda
| | - Zaleha Md Toha
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200, Penang, Kepala Batas, Malaysia
| | - Rafedah Abas
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200, Penang, Kepala Batas, Malaysia
| | - Nur Nadhirah Mohamad Zain
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200, Penang, Kepala Batas, Malaysia
| | - Hasni Arsad
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200, Penang, Kepala Batas, Malaysia.
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Ghazzawy HS, Gouda MM, Awad NS, Al-Harbi NA, Alqahtani MM, Abdel-Salam MM, Abdein MA, Al-Sobeai SM, Hamad AA, Alsberi HM, Gabr GA, Hikal DM. Potential bioactivity of Phoenix dactylifera fruits, leaves, and seeds against prostate and pancreatic cancer cells. Front Nutr 2022; 9:998929. [PMID: 36386915 PMCID: PMC9650284 DOI: 10.3389/fnut.2022.998929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 09/12/2022] [Indexed: 01/28/2023] Open
Abstract
The use of functional foods' phytochemicals in the chemoprevention of different cancer diseases has become one of the hot scientific areas in the clinical nutrition field. For instance, the Khalas palm cultivar (KPC; Phoenix dactylifera) is one of the natural sustainable resources that have high bioactivity and functionality. This study aimed to investigate the antiproliferative activity and mode of action of KPC's different parts on prostate (Pc3) and pancreatic (panc1) cancer cells at a molecular level. In the methods, KPC's leaves, seeds, and fruits' chemical composition and phytochemical analysis were analyzed. Also, the cytotoxic effects of each extract were assessed against pc3 and panc1 cell lines. Besides, induction of apoptosis, cell cycle analysis, and gene expression of both Cap3 and Cap9 were studied. The obtained results indicated that KPC leaves extract exhibited the highest significant (P < 0.01) anti-proliferation activity against the utilized cancer cell lines compared to fruits and seeds extracts. Also, there were significant (P < 0.05) differences in the phenolic contents, flavonoid of compounds, and antioxidant power of the leaves when compared to the seeds and fruits. Additionally, the highest cytotoxic effect (lowest IC50) was recorded with leave extract than seeds and fruits. Meanwhile, the seeds extract induced (P < 0.05) the apoptosis and arrested cells in the G2/M phase as well as up-regulated the gene expression of the apoptotic-related genes (Casp3 and Casp9) compared to the control group. In conclusion, this study showed that the presence of bioactive components in the KPC different parts extracts have the significant ability to induce the apoptotic pathway that could down-regulate the proliferation of prostate (pc3) and pancreatic (panc1) cancer cells. The pathway mechanism of action was induced by the phytol molecule presented in its leaves extract.
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Affiliation(s)
- Hesham S. Ghazzawy
- Date Palm Research Center of Excellence, King Faisal University, Al Ahsa, Saudi Arabia
- Central Laboratory for Date Palm Research and Development, Agriculture Research Center, Giza, Egypt
| | - Mostafa M. Gouda
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, Zhejiang, China
- Department of Nutrition and Food Science, National Research Centre, Giza, Egypt
| | - Nabil S. Awad
- Department of Genetics, Faculty of Agriculture and Natural Resources, Aswan University, Aswan, Egypt
- College of Biotechnology, Misr University for Science and Technology, Giza, Egypt
| | - Nadi Awad Al-Harbi
- Biology Department, University College of Tayma, University of Tabuk, Saudi Arabia
| | - Mesfer M. Alqahtani
- Department of Biological Sciences, Faculty of Science and Humanities, Shaqra University, Ad-Dawadimi, Saudi Arabia
| | - Maha M. Abdel-Salam
- Department of Pomology, Faculty of Agriculture, Assiut University, Assiut, Egypt
| | - Mohamed A. Abdein
- Department of Biology, Faculty of Arts and Science, Northern Border University, Rafha, Saudi Arabia
| | - Sanad M. Al-Sobeai
- Sajir College of Arts and Science, Shaqra University, Sharqa, Saudi Arabia
| | - Asmaa A. Hamad
- Department of Biology, Faculty of Science, Taif University, Taif, Saudi Arabia
- Department of Botany and Microbiology, Faculty of Science, Cairo University, Giza, Egypt
| | - Hassan M. Alsberi
- Department of Biology, Faculty of Science, Taif University, Taif, Saudi Arabia
- Department of Basic Medical Science and Histopathology, National Organization for Drug Control and Research, Giza, Egypt
| | - Gamal A. Gabr
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
- Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center, Giza, Egypt
| | - Dalia M. Hikal
- Nutrition and Food Science, Department of Home Economics, Faculty of Specific Education, Sohag University, Sohag, Egypt
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Rondina DBL, de Lima LVA, da Silva MF, Zanetti TA, Felicidade I, Marques LA, Coatti GC, Mantovani MS. Differential mRNA expression in the induction of DNA damage, G 2/M arrest, and cell death by zerumbone in HepG2/C3A cells. Toxicol In Vitro 2022; 85:105474. [PMID: 36122806 DOI: 10.1016/j.tiv.2022.105474] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/29/2022] [Accepted: 09/12/2022] [Indexed: 11/18/2022]
Abstract
Zerumbone (ZER) is a phytochemical with antioxidant and antiproliferative properties. This study evaluated the cytoxicity of ZER combined with chemotherapeutic agents and the expression of mRNA genes related to cell cycle, cell death, xenobiotic metabolism, DNA damage, and endoplasmic reticulum (ER) stress in HepG2/C3A cells. ZER was cytotoxic (IC50, 44.31 μM). ZER-induced apoptosis was related to BBC3 and ERN1 upregulation (ER stress), and its antiproliferative effects were attributable to MYC, IGF1, and NF-kB mRNA inhibition. ZER-induced G2/M arrest and DNA damage was associated with mRNA expression of cell cycle (CDKN1A) and DNA damage (GADD45A) genes. Increased CYP1A2 and CYP2C19 mRNA expression suggested ZER metabolization, and reduced CYP1A1 and CYP2D6 expression indicated a longer time of action of ZER in the cell, enhancing its pharmacological effect. ZER downregulated TP53, PARP1, BIRC5 (apoptosis), and MAP1LC3A (autophagy). In apoptosis assay, the data of the association treatments with ZER suggested antagonism. In cytotoxicity assay, the data of the association treatments with ZER suggested synergism action to cisplatin and antagonism action to doxorubicin and 5-fluorouracil. Thus, ZER has potential for application in chemotherapy as it modulates mRNA targets; however, it may not have the desired efficiency when combined with other chemotherapeutic agents.
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Affiliation(s)
- Débora Berbel Lirio Rondina
- Departamento de Biologia Geral, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
| | - Luan Vitor Alves de Lima
- Departamento de Biologia Geral, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
| | - Matheus Felipe da Silva
- Departamento de Biologia Geral, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
| | - Thalita Alves Zanetti
- Departamento de Biologia Geral, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
| | - Ingrid Felicidade
- Departamento de Biologia Geral, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
| | - Lilian Areal Marques
- Departamento de Biologia Geral, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
| | - Giuliana Castello Coatti
- Departamento de Biologia Geral, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil
| | - Mario Sergio Mantovani
- Departamento de Biologia Geral, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
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10
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Al-Qadhi G, Ali Mohammed MM, Al-Ak'hali M, Al-Moraissi EA. Khat (Catha Edulis Forsk) induced apoptosis and cytotoxicity in cultured cells: A scoping review. Heliyon 2021; 7:e08466. [PMID: 34926848 PMCID: PMC8646973 DOI: 10.1016/j.heliyon.2021.e08466] [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: 07/01/2021] [Revised: 08/05/2021] [Accepted: 11/19/2021] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Khat (Catha edulis Forsk) leaves are chewed by people in certain regions of East Africa and the Middle East for their stimulating amphetamine-like effects. The purpose of this scoping review is to systematically map the current in vitro publications that investigated the toxicological potential effects of khat on cultured human or animal cells in terms of cellular viability and activity. METHODS A comprehensive electronic database search was undertaken up to December 2020 without starting date or language restrictions in accordance with the PRISMA extension for scoping review guideline and methodological quality evaluation based on the guidelines for reporting pre-clinical in vitro studies on dental materials. All in vitro studies that investigated the effect of khat plant extract (Catha Edulis) on the cultured human or animal cells were included. RESULTS The initial search yielded 599 articles and 16 articles were finally selected to be included. The treatment of cells with khat produced different degrees of cellular changes, including decreased cellular survival, induction of apoptosis, increased ROS production, alteration of cell phenotype, and of arrest cell cycle. In this contest, khat-exposed cells expressed higher levels of pro-apoptotic protein Bax and lower levels of anti-apoptotic Bcl-2, up-regulated p38, p53, p16, and p21 proteins, as well as premature expression of differentiation markers. CONCLUSION Based on the current scoping review, khat induced apoptosis and cytotoxicity in cultured human cells, including oral cells.
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Affiliation(s)
- Gamilah Al-Qadhi
- Department of Basic Dental Sciences, Faculty of Dentistry, University of Science and Technology, Yemen
| | - Marwan Mansoor Ali Mohammed
- Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, United Arab Emirates
| | - Mohammed Al-Ak'hali
- Department of Preventive Dental Sciences, College of Dentistry, Jazan University, Jazan, Saudi Arabia
- Department of Periodontology, Faculty of Dentistry, Sana'a University, Sana'a, Yemen
| | - Essam Ahmed Al-Moraissi
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Thamar University, Yemen
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Chota A, George BP, Abrahamse H. Interactions of multidomain pro-apoptotic and anti-apoptotic proteins in cancer cell death. Oncotarget 2021; 12:1615-1626. [PMID: 34381566 PMCID: PMC8351602 DOI: 10.18632/oncotarget.28031] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 07/13/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer is a global public health concern that is characterized by the uncontrolled growth of tumor cells. It is regarded as the subsequent cause of death after cardiovascular disease. The most common types of cancer include breast, colorectal, lung, and prostate. The risk factors attributed to the development of common types of cancer are tobacco smoking, excessive alcohol consumption, dietary factors, ultraviolet radiation (UV), and lack of physical activities. Two major cellular apoptotic pathways targeted in cancer therapies are intrinsic and extrinsic. These two pathways are regulated by different types of proteins, the multidomain pro-apoptotic proteins (Bak, Bax, and Bok), BH3-only pro-apoptotic proteins (Bid, Bim, Bad, Noxa, and Puma), and the anti-apoptotic proteins (Mcl-1, Bfl-1, Bcl-XL, Bcl-2, Bcl-w, and Bcl-B). Other significant molecules/factors that are known to execute cellular apoptotic pathways include bioactive compounds, and reactive oxygen species (ROS). Proteolytic caspases are known to play a vital role in the initiation of apoptotic activities in cancerous cells. Based on their functions, they are categorized into initiators and executioners. Nanotechnology has produced novel outcomes in modern medicine. The green synthesis of nanoparticles has demonstrated prospective improvements in cancer therapies in combination with the existing therapies including photodynamic therapy. This review aims at highlighting the association between pro-apoptotic and anti-apoptotic proteins, and their significance in cancer therapy.
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Affiliation(s)
- Alexander Chota
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Doornfontein 2028, South Africa
| | - Blassan P. George
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Doornfontein 2028, South Africa
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Doornfontein 2028, South Africa
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12
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Spyridopoulou K, Aravidou T, Lampri E, Effraimidou E, Pappa A, Chlichlia K. Antitumor Potential of Lippia citriodora Essential Oil in Breast Tumor-Bearing Mice. Antioxidants (Basel) 2021; 10:875. [PMID: 34070804 PMCID: PMC8228289 DOI: 10.3390/antiox10060875] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Lippia citriodora is a flowering plant cultivated for its lemon-scented leaves and used in folk medicine for the preparation of tea for the alleviation of symptoms of gastrointestinal disorders, cold, and asthma. The oil extracted from the plant leaves was shown to possess antioxidant potential and to exert antiproliferative activity against breast cancer. The aim of this study was to further investigate potential antitumor effects of L. citriodora oil (LCO) on breast cancer. The in vitro antiproliferative activity of LCO was examined against murine DA3 breast cancer cells by the sulforhodamine B assay. We further explored the LCO's pro-apoptotic potential with the Annexin-PI method. The LCO's anti-migratory effect was assessed by the wound-healing assay. LCO was found to inhibit the growth of DA3 cells in vitro, attenuate their migration, and induce apoptosis. Finally, oral administration of LCO for 14 days in mice inhibited by 55% the size of developing tumors in the DA3 murine tumor model. Noteworthy, in the tumor tissue of LCO-treated mice the apoptotic marker cleaved caspase-3 was elevated, while a reduced protein expression of survivin was observed. These results indicate that LCO, as a source of bioactive compounds, has a very interesting nutraceutical potential.
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Affiliation(s)
- Katerina Spyridopoulou
- Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus-Dragana, 68100 Alexandroupolis, Greece; (K.S.); (T.A.); (E.L.); (A.P.)
| | - Tamara Aravidou
- Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus-Dragana, 68100 Alexandroupolis, Greece; (K.S.); (T.A.); (E.L.); (A.P.)
| | - Evangeli Lampri
- Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus-Dragana, 68100 Alexandroupolis, Greece; (K.S.); (T.A.); (E.L.); (A.P.)
| | - Eleni Effraimidou
- Department of Medicine, Democritus University of Thrace, University Campus-Dragana, 68100 Alexandroupolis, Greece;
| | - Aglaia Pappa
- Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus-Dragana, 68100 Alexandroupolis, Greece; (K.S.); (T.A.); (E.L.); (A.P.)
| | - Katerina Chlichlia
- Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus-Dragana, 68100 Alexandroupolis, Greece; (K.S.); (T.A.); (E.L.); (A.P.)
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13
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Mannucci C, Casciaro M, Sorbara EE, Calapai F, Di Salvo E, Pioggia G, Navarra M, Calapai G, Gangemi S. Nutraceuticals against Oxidative Stress in Autoimmune Disorders. Antioxidants (Basel) 2021; 10:261. [PMID: 33567628 PMCID: PMC7914737 DOI: 10.3390/antiox10020261] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/29/2021] [Accepted: 02/04/2021] [Indexed: 02/06/2023] Open
Abstract
Antioxidant mechanisms are constituted of enzymes, endogenous, and non-enzymatic, exogenous, which have the role of counterbalancing oxidative stress. Intake of these compounds occurs in the diet. Vegetables, plants, and fruits contain a wide range of alkaloids, polyphenols, and terpenoids which are called "phytochemicals". Most of these substances are responsible for the positive properties of fruits and vegetables, which are an essential part of a healthy life with roles in ameliorating chronic illnesses and favoring longevity. Nutraceuticals are substances contained in a food or fragment of it influencing health with positive effects on health helping in precenting or treating disorders. We conducted a review illustrating the principal applications of nutraceuticals in autoimmune disorders. Literature reported several studies about exogenous dietary antioxidant supplementation in diverse autoimmune diseases such as rheumatoid arthritis, lupus, diabetes, and multiple sclerosis. In these pathologies, promising results were obtained in some cases. Positive outcomes were generally associated with a reduction of oxidative stress parameters and a boost to antioxidant systems, and sometimes with anti-inflammatory effects. The administration of exogenous substances through food derivates or dietary supplements following scientific standardization was demonstrated to be effective. Further bias-free and extended studies should be conducted that include ever-increasing oxidative stress biomarkers.
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Affiliation(s)
- Carmen Mannucci
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (C.M.); (E.E.S.); (G.C.)
| | - Marco Casciaro
- Department of Clinical and Experimental Medicine, Unit and School of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy;
| | - Emanuela Elisa Sorbara
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (C.M.); (E.E.S.); (G.C.)
| | - Fabrizio Calapai
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (F.C.); (M.N.)
| | - Eleonora Di Salvo
- Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy;
| | - Giovanni Pioggia
- Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), 98164 Messina, Italy;
| | - Michele Navarra
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; (F.C.); (M.N.)
| | - Gioacchino Calapai
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (C.M.); (E.E.S.); (G.C.)
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, Unit and School of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy;
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Saida L, Tulasi CDSLN, Narasu ML. Evaluation of chemo-preventive efficacy of Ficus religiosa latex extract by flow cytometry analysis and gene expression studies performed by RT-PCR in various cell lines. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2021. [DOI: 10.1186/s43094-021-00182-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Abstract
Background
An extract of Ficus religiosa latex has been previously found to possess potent pharmacological activity with high antioxidant content phytochemical. The present research was conducted to investigate the chemo-preventive efficacy of latex extract on human breast adenocarcinoma MDA MB 231, human neroblastoma IMR 32, and human colorectal HCT 116 cell lines.
Results
The results showed that the latex crude extract induced cytotoxicity in all the selected cell lines with IC50 value 4.8 ± 1.13 μg/ml against the IMR 32 cell line. The cell cycle analysis results indicated the arrest and accumulation of cells at G1 phase in case of MDA MB 231 cells and HCT 116 cells whereas in the case of IMR 32 cells the arrest was in G2/M phase. The clear bands of fragments observed in DNA ladder experiments showed that apoptosis is induced by extracts in the cell lines. This could be correlated with the gene level expression studies on selected pro-apoptotic (p53 and caspase-3) and anti-apoptotic (Bcl-2, AKT) genes, which got upregulated and downregulated, respectively.
Conclusion
Based on the experimental evidence, Ficus religiosa contains phytochemicals with potent antitumor activities.
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Islam MS, Rahi MS, Jahangir CA, Jerin I, Hasan MM, Hoque KMF, Reza MA. Deciphering the molecular pathways of apoptosis using purified fractions from leaf extract of Basella alba through studying the regulation of apoptosis related genes. Mol Biol Rep 2021; 48:85-96. [PMID: 33454909 DOI: 10.1007/s11033-021-06136-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 01/02/2021] [Indexed: 11/26/2022]
Abstract
Apoptosis plays a pivotal role in the exclusion of abnormal cells without any ruin of surrounding healthy cells. Generally, it occurs through an orderly and autonomously process which is controlled by proper function of various genes. Therefore, the current experiments detect the expression level/pattern of those genes to confirm the involvement of extrinsic and intrinsic pathway using Basella alba leaf (BAL). Several fractions after gel filtration chromatography of BAL extract have been pooled to evaluates its apoptosis induction potentiality on Ehrlich's Ascites Carcinoma (EAC) cells through conducting a number of bio-assays such as cell growth inhibition assay, fluorescence and optical microscopy, DNA fragmentation assay and gene expression analysis etc. The pooled fractions of BAL showed 12-56% inhibitory effect on EAC cell line at the concentration range of 25-400 μg/ml that was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. They also exhibited excellent cell growth inhibition at in vivo and in vitro condition when treated with 10, 20 and 40 mg/kg day. After administration of six consequent days, significant morphological features of apoptosis were observed in EAC cells under both fluorescence and optical microscope which was further supported by DNA fragmentation assay. The polymerase chain reaction amplification of bax, bcl-2 (B-cell lymphoma 2), p53, tumor necrosis factor-α, Fas, NF-kβ (Nuclear factor-Kappa-B), PARP-1 (Poly (ADP-ribose) polymerase), Cyt-c cas-8, cas-9 and cas-3 revealed that the experimental sample able to induce apoptosis in both extrinsic and intrinsic pathways through altering the gene expression. The current findings suggest that sample from BAL occupy wonderful competence to induce cell apoptosis and become an ideal resource for cancer treatment.
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Affiliation(s)
- Md Shihabul Islam
- Molecular Biology and Protein Science Laboratory, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Md Sifat Rahi
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh
| | - Chowdhury Arif Jahangir
- Cancer Biology and Therapeutics Laboratory, School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - Israt Jerin
- Molecular Biology and Protein Science Laboratory, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Md Mahmudul Hasan
- Molecular Biology and Protein Science Laboratory, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Kazi Md Faisal Hoque
- Molecular Biology and Protein Science Laboratory, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Md Abu Reza
- Molecular Biology and Protein Science Laboratory, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, 6205, Bangladesh.
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Menegazzi M, Masiello P, Novelli M. Anti-Tumor Activity of Hypericum perforatum L. and Hyperforin through Modulation of Inflammatory Signaling, ROS Generation and Proton Dynamics. Antioxidants (Basel) 2020; 10:antiox10010018. [PMID: 33379141 PMCID: PMC7824709 DOI: 10.3390/antiox10010018] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/17/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
In this paper we review the mechanisms of the antitumor effects of Hypericum perforatum L. (St. John's wort, SJW) and its main active component hyperforin (HPF). SJW extract is commonly employed as antidepressant due to its ability to inhibit monoamine neurotransmitters re-uptake. Moreover, further biological properties make this vegetal extract very suitable for both prevention and treatment of several diseases, including cancer. Regular use of SJW reduces colorectal cancer risk in humans and prevents genotoxic effects of carcinogens in animal models. In established cancer, SJW and HPF can still exert therapeutic effects by their ability to downregulate inflammatory mediators and inhibit pro-survival kinases, angiogenic factors and extracellular matrix proteases, thereby counteracting tumor growth and spread. Remarkably, the mechanisms of action of SJW and HPF include their ability to decrease ROS production and restore pH imbalance in tumor cells. The SJW component HPF, due to its high lipophilicity and mild acidity, accumulates in membranes and acts as a protonophore that hinders inner mitochondrial membrane hyperpolarization, inhibiting mitochondrial ROS generation and consequently tumor cell proliferation. At the plasma membrane level, HPF prevents cytosol alkalization and extracellular acidification by allowing protons to re-enter the cells. These effects can revert or at least attenuate cancer cell phenotype, contributing to hamper proliferation, neo-angiogenesis and metastatic dissemination. Furthermore, several studies report that in tumor cells SJW and HPF, mainly at high concentrations, induce the mitochondrial apoptosis pathway, likely by collapsing the mitochondrial membrane potential. Based on these mechanisms, we highlight the SJW/HPF remarkable potentiality in cancer prevention and treatment.
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Affiliation(s)
- Marta Menegazzi
- Department of Neuroscience, Biomedicine and Movement Sciences, Biochemistry Section, School of Medicine, University of Verona, Strada Le Grazie 8, I-37134 Verona, Italy
- Correspondence: ; Tel.: +39-045-802-7168
| | - Pellegrino Masiello
- Department of Translational Research and New Technologies in Medicine and Surgery, School of Medicine, University of Pisa, Via Roma 55, I-56126 Pisa, Italy; (P.M.); (M.N.)
| | - Michela Novelli
- Department of Translational Research and New Technologies in Medicine and Surgery, School of Medicine, University of Pisa, Via Roma 55, I-56126 Pisa, Italy; (P.M.); (M.N.)
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Agrawal SK, Agrawal M, Sharma PR, Ahmad K, Shawl AS, Arora S, Saxena AK. Anagallis arvensis Induces Apoptosis in HL-60 Cells Through ROS-Mediated Mitochondrial Pathway. Nutr Cancer 2020; 73:2720-2731. [PMID: 33305590 DOI: 10.1080/01635581.2020.1856893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The present study was taken up to evaluate the apoptosis inducing ability of alcoholic extract of whole plant of Anagallis arvensis (AAE) in HL-60 cells. We observed time and concentration dependent decrease in cell viability after treatment with AAE. Fluorescent staining and scanning electron micrographs of treated HL-60 cells demonstrated chromatin condensation, nuclear fragmentation and formation of apoptotic blebs. There was a marked increase in hypodiploid population of cells as observed by cell cycle analysis. Annexin V-FITC/PI also depicted the presence of apoptotic cells. Anti-apoptotic protein Bcl-2 was observed to be decreased by 62% at 20 µg/ml concentration and a significant increase in ROS production up to 6.9-fold was observed in time dependent manner. In addition, alteration in mitochondrial membrane potential was observed, which was followed by cytochrome c release to cytoplasm. Activated levels of mitochondrial downstream pathway protein namely Caspase-3 and 9, were detected in treated HL-60 cells by colorimetric analysis. DNA ladder formation, a biochemical hallmark of apoptosis was also observed in treated HL-60 cells. The results of the present study support the apoptotic potential of AAE and probability of its promising role in development as effective anticancer agent against leukemia cells.
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Affiliation(s)
- Satyam Kumar Agrawal
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
| | - Madhunika Agrawal
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
| | - Parduman Raj Sharma
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
| | - Khursheed Ahmad
- CSIR-Indian Institute of Integrative Medicine-Branch, Sanat Nagar, Srinagar, India
| | - Abdul Sami Shawl
- CSIR-Indian Institute of Integrative Medicine-Branch, Sanat Nagar, Srinagar, India
| | - Saroj Arora
- Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar, India
| | - Ajit Kumar Saxena
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
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Emerging role of phytochemicals in targeting predictive, prognostic, and diagnostic biomarkers of lung cancer. Food Chem Toxicol 2020; 144:111592. [PMID: 32702507 DOI: 10.1016/j.fct.2020.111592] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/03/2020] [Accepted: 07/07/2020] [Indexed: 02/07/2023]
Abstract
Lung-cancer is the foremost cause of cancer in humans worldwide, of which 80-85% cases are composed of non-small cell lung carcinoma. All treatment decisions depend on the pattern of biomarkers selection to enhance the response to the targeted therapies. Although advanced treatments are available for lung-cancer, the disease treatment remains not adequate. There are several synthetic chemotherapeutic agents available for the treatment of lung cancer. However, due to their toxic effect, survival rate is still 15-18%. Besides, medicinal plants are a huge reservoir of natural products that provide protective effects against lung cancer. Likewise, successful studies of potential phytochemicals in targeting lung-cancer biomarkers have created a novel paradigm for the discovery of potent drugs against lung-cancer. Hence, to defeat severe toxicity and resistance towards the synthetic drugs, detailed studies are required regarding the available phytochemicals and targets responsible for the treatment of lung-cancer. The present review provides a comprehensive information about the lung-cancer biomarkers under the classification of predictive, prognostic, and diagnostic type. Moreover, it discusses and enlists the phytochemicals with mode of action against different biomarkers, effective doses in in vitro, in vivo, and clinical studies, the limitations associated with usage of phytochemicals as a drug to prevent/cure lung-cancer and the latest techniques employed to overcome such issues.
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El Haouari M, Quintero JE, Rosado JA. Anticancer molecular mechanisms of oleocanthal. Phytother Res 2020; 34:2820-2834. [PMID: 32449241 DOI: 10.1002/ptr.6722] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/23/2020] [Accepted: 04/23/2020] [Indexed: 12/13/2022]
Abstract
Cancer is among the leading causes of mortality worldwide. Current cancer therapies are associated with serious side effects, which further damage patients' health. Therefore, the search for new anticancer agents with no toxic effects on normal and healthy cells is of great interest. Recently, we and other groups have demonstrated that oleocanthal (OLC), a phenolic compound from extra virgin olive oil, exhibits antitumor activity in various tumor models. However, the underlying mechanisms and intracellular targets of OLC remain to be completely elucidated. This review summarizes the current advancers concerning the anticancer activity of OLC, with particular emphasis on the molecular signaling pathways modulated by this compound in different tumor cell types. The major mechanisms of action of OLC include modulation of the apoptotic pathway, the HGF/c-Met pathway, and the signal transducer and activator of transcription 3 signaling pathway, among others. Furthermore, OLC has synergistic effects with anticancer drugs in vitro. Also discussed are OLC bioavailability and its concentration in olive oil. Data summarized here will represent a database for more extensive studies aimed at providing information on molecular mechanisms against cancer induced by OLC.
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Affiliation(s)
- Mohammed El Haouari
- Laboratoire d'Ingénierie Pédagogique et Didactique des Sciences (IPDSM), Centre Régional des Métiers de l'Education et de la Formation (CRMEF Fès-Meknès), Taza, Morocco.,Laboratoire Substances Naturelles, Pharmacologie, Environnement, Modélisation, Santé & Qualité de vie (SNAMOPEQ), Faculté Polydisciplinaire de Taza, Université Sidi Mohamed Ben Abdellah, Taza, Morocco
| | - Juan E Quintero
- Department of Physiology (Cell Physiology Research Group), Institute of Molecular Pathology Biomarkers, University of Extremadura, Cáceres, Spain
| | - Juan A Rosado
- Department of Physiology (Cell Physiology Research Group), Institute of Molecular Pathology Biomarkers, University of Extremadura, Cáceres, Spain
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Akkermansia muciniphila Aspartic Protease Amuc_1434* Inhibits Human Colorectal Cancer LS174T Cell Viability via TRAIL-Mediated Apoptosis Pathway. Int J Mol Sci 2020; 21:ijms21093385. [PMID: 32403433 PMCID: PMC7246985 DOI: 10.3390/ijms21093385] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/07/2020] [Accepted: 05/09/2020] [Indexed: 02/07/2023] Open
Abstract
Mucin2 (Muc2) is the main component of the intestinal mucosal layer and is highly expressed in mucous colorectal cancer. Previous studies conducted by our lab found that the recombinant protein Amuc_1434 (expressed in Escherichia coli prokaryote cell system, hereinafter termed Amuc_1434*), derived from Akkermansia muciniphila, can degrade Muc2. Thus, the main objective of this study was to explore the effects of Amuc_1434* on LS174T in colorectal cancer cells expressing Muc2. Results from this study demonstrated that Amuc_1434* inhibited the proliferation of LS174T cells, which was related to its ability to degrade Muc2. Amuc_1434* also blocked the G0/G1 phase of the cell cycle of LS174T cells and upregulated the expression of tumor protein 53 (p53), which is a cell cycle-related protein. In addition, Amuc_1434* promoted apoptosis of LS174T cells and increased mitochondrial ROS levels in LS174T cells. The mitochondrial membrane potential of LS174T cells was also downregulated by Amuc_1434*. Amuc_1434* can activate the death receptor pathway and mitochondrial pathway of apoptosis by upregulating tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL). In conclusion, our study was the first to demonstrate that the protein Amuc_1434* derived from Akkermansia muciniphila suppresses LS174T cell viability via TRAIL-mediated apoptosis pathway.
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Chemopreventive Effects and Antioxidant Capacity of Combined Leaf Extracts of Sesamum angustifolium (Oliv.) Engl. and Hibiscus articulatus on Rhabdomyosarcoma. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:8567182. [PMID: 32308718 PMCID: PMC7136805 DOI: 10.1155/2020/8567182] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 02/05/2020] [Accepted: 03/06/2020] [Indexed: 01/09/2023]
Abstract
Sesamum angustifolium (Oliv.) Engl. and Hibiscus articulatus contain compounds that have antimutagenic properties. The rise in rhabdomyosarcoma in paediatrics and prognosis of the disease in infants compared to adults calls for newer, less toxic alternatives in treatment of the disease. The aim of this study was to determine the anticancer activity and antioxidant capacity of combined leaf extracts of Sesamum angustifolium (Oliv.) Engl. and Hibiscus articulatus (SAHA), against rhabdomyosarcoma (RMS) using rhabdomyosarcoma (RD) cell line and mouse (L20B) cell line. Cytotoxicity, morphology, apoptosis induction, and antioxidant capacity assays were done. Of the four solvents used for extraction, the dichloromethane SAHA extract was the most cytotoxic with IC50 of 106 μg/mL after doxorubicin, the reference anticancer drug with IC50 of 0.8 μg/mL. The SAHA extracts had a stronger cytotoxicity effect on the cancerous RD cells than on normal L20B cells. Morphological assessment showed untreated cells maintained their normal striated appearance of muscle cells whereas cells treated with doxorubicin or SAHA extracts exhibited cell shrinkage, loss of surface adherence, reduced cell density along with cell debris, which is a characteristic of apoptosis. Normal L20B cells when treated with doxorubicin or SAHA extracts, maintained their cell shape, and remained adherent to the surface. The apoptotic enzyme caspase-3 was induced in a concentration dependent manner upon treatment of the RD cells with SAHA extracts or doxorubicin. Induction of caspase-3 was ten times less in treated L20B cells compared to the RD cells. Low induction of caspase-9 enzyme was observed in both treated RD and L20B cells. Treatment of both RD and L20B cells with SAHA extracts or doxorubicin resulted in increased activity of peroxidase and reduction of oxidative stress. Results of the study show that the SAHA extracts are potential sources of compounds that may serve as useful agents for treatment of rhabdomyosarcoma.
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Hafezi K, Hemmati AA, Abbaszadeh H, Valizadeh A, Makvandi M. Anticancer activity and molecular mechanisms of α-conidendrin, a polyphenolic compound present in Taxus yunnanensis, on human breast cancer cell lines. Phytother Res 2020; 34:1397-1408. [PMID: 31971313 DOI: 10.1002/ptr.6613] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 12/18/2019] [Accepted: 12/31/2019] [Indexed: 12/14/2022]
Abstract
α-Conidendrin is a polyphenolic compound found mainly in Taxus yunnanensis, as the source of chemotherapy drug paclitaxel, which has been used in traditional medicine for treatment of cancer. This study aimed to investigate the anticancer activity and molecular mechanisms of α-conidendrin on breast cancer cell lines. The results of the present study show that α-conidendrin possesses potent antiproliferative effects on breast cancer cell lines MCF-7 and MDA-MB-231. α-Conidendrin significantly induced apoptosis in breast cancer cells via reactive oxygen species generation, upregulation of p53 and Bax, downregulation of Bcl-2, depolarization of mitochondrial membrane potential (MMP), release of cytochrome c from mitochondria, and activation of caspases-3 and -9. α-Conidendrin remarkably inhibited the proliferation of breast cancer cells through induction of cell cycle arrest by upregulating p53 and p21 and downregulating cyclin D1 and CDK4. Unlike breast cancer cells, the antiproliferative effect of α-conidendrin on human foreskin fibroblast cells (normal cells) was very small. In normal cells, reactive oxygen species levels, loss of MMP, release of cytochrome c, mRNA expression of p53, p21, cyclin D1, CDK4, Bax, and Bcl-2 as well as mRNA expression and activity of caspases-3 and -9 were significantly less affected by α-conidendrin compared with cancer cells. These results suggest that α-conidendrin can be a promising agent for treatment of breast cancer with little or no toxicity against normal cells.
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Affiliation(s)
- Katayoon Hafezi
- Department of Pharmacology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Asghar Hemmati
- Department of Pharmacology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hassan Abbaszadeh
- Department of Pharmacology, School of Pharmacy, Medicinal Plants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Armita Valizadeh
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Manoochehr Makvandi
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Modarresi M, Hajialyani M, Moasefi N, Ahmadi F, Hosseinzadeh L. Evaluation of the Cytotoxic and Apoptogenic Effects of Glabridin and Its Effect on Cytotoxicity and Apoptosis Induced by Doxorubicin Toward Cancerous Cells. Adv Pharm Bull 2019; 9:481-489. [PMID: 31592119 PMCID: PMC6773930 DOI: 10.15171/apb.2019.057] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 04/18/2019] [Accepted: 05/04/2019] [Indexed: 12/19/2022] Open
Abstract
Purposes: In the present study, we tried for the first time to examine the anti-proliferative and
anti-apoptogenic effect of Glabridin (Glab) toward three groups of cancer cells (SKNMC,
H1299, and A2780). Furthermore, the possibility of co-administration of Glab with doxorubicin
(DOX) to these cells was also examined to find out whether Glab can potentiate the cytotoxic
effect of this chemotherapy agent.
Methods: Different cellular assays (MTT, caspase-3 activity, MMP, RT-PCR analysis) were carried
out on the cancer cells treated with Glab.
Results: Cellular toxicity assay revealed that Glab can potentially reduce the viability of these
cells with IC50 concentrations up to 10, 12, and 38 μM toward A2780, SKNMC, and H1299 cell
lines, respectively. The results of MMP and caspase-3 activity assays, in association with the
results corresponding to the BAX and Bcl-2 gene expressions, altogether revealed that Glab can
exert apoptogenic effect on these cells. The intrinsic mitochondrial pathway was found to be
the main mechanism, in which Glab induced apoptosis toward H1299 cells and SKNMC cells,
while the apoptosis mechanism for A2780 cells could be probably through extrinsic pathway.
Glab also potentiated the cytotoxic effect of DOX and its accumulation in H1299 cell line.
Conclusion: The results of this study revealed the promising cytotoxic role of Glab on different
carcinoma cells. These data also suggested that co-chemotherapy method using Glab could be
effective for treatment of cancer, but further in-vivo and clinical studies are still needed to assure
these results.
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Affiliation(s)
- Masoud Modarresi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
| | - Marziyeh Hajialyani
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
| | - Narges Moasefi
- Medical Biology Research Center , Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farahnaz Ahmadi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
| | - Leila Hosseinzadeh
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6734667149, Iran
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Jayachandran M, Chung SSM, Xu B. A critical review of the relationship between dietary components, the gut microbe Akkermansia muciniphila, and human health. Crit Rev Food Sci Nutr 2019; 60:2265-2276. [DOI: 10.1080/10408398.2019.1632789] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Muthukumaran Jayachandran
- Food Science and Technology Programme, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China
| | - Stephen Sum Man Chung
- Food Science and Technology Programme, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China
| | - Baojun Xu
- Food Science and Technology Programme, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China
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Kaur V, Kumar M, Kumar A, Kaur S. Butea monosperma (Lam.) Taub. Bark fractions protect against free radicals and induce apoptosis in MCF-7 breast cancer cells via cell-cycle arrest and ROS-mediated pathway. Drug Chem Toxicol 2018; 43:398-408. [DOI: 10.1080/01480545.2018.1497051] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Varinder Kaur
- Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar, India
| | - Manish Kumar
- Department of Biology, S.D. College, Barnala, India
| | - Ajay Kumar
- Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar, India
| | - Satwinderjeet Kaur
- Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar, India
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Pandurangan AK, Divya T, Kumar K, Dineshbabu V, Velavan B, Sudhandiran G. Colorectal carcinogenesis: Insights into the cell death and signal transduction pathways: A review. World J Gastrointest Oncol 2018; 10:244-259. [PMID: 30254720 PMCID: PMC6147765 DOI: 10.4251/wjgo.v10.i9.244] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Revised: 06/05/2018] [Accepted: 06/28/2018] [Indexed: 02/05/2023] Open
Abstract
Colorectal carcinogenesis (CRC) imposes a major health burden in developing countries. It is the third major cause of cancer deaths. Despite several treatment strategies, novel drugs are warranted to reduce the severity of this disease. Adenomatous polyps in the colon are the major culprits in CRC and found in 45% of cancers, especially in patients 60 years of age. Inflammatory polyps are currently gaining attention in CRC, and a growing body of evidence denotes the role of inflammation in CRC. Several experimental models are being employed to investigate CRC in animals, which include the APCmin/+ mouse model, Azoxymethane, Dimethyl hydrazine, and a combination of Dextran sodium sulphate and dimethyl hydrazine. During CRC progression, several signal transduction pathways are activated. Among the major signal transduction pathways are p53, Transforming growth factor beta, Wnt/β-catenin, Delta Notch, Hippo signalling, nuclear factor erythroid 2-related factor 2 and Kelch-like ECH-associated protein 1 pathways. These signalling pathways collaborate with cell death mechanisms, which include apoptosis, necroptosis and autophagy, to determine cell fate. Extensive research has been carried out in our laboratory to investigate these signal transduction and cell death mechanistic pathways in CRC. This review summarizes CRC pathogenesis and the related cell death and signal transduction pathways.
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Affiliation(s)
- Ashok kumar Pandurangan
- Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, India
- School of Life sciences, B.S. Abdur Rahman Crescent Institute of Science and Technology, Chennai 600048, India
| | - Thomas Divya
- Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, India
| | - Kalaivani Kumar
- School of Life sciences, B.S. Abdur Rahman Crescent Institute of Science and Technology, Chennai 600048, India
| | - Vadivel Dineshbabu
- Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, India
| | - Bakthavatchalam Velavan
- Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, India
| | - Ganapasam Sudhandiran
- Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, India
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Rahman HS. Phytochemical analysis and antioxidant and anticancer activities of mastic gum resin from Pistacia atlantica subspecies kurdica. Onco Targets Ther 2018; 11:4559-4572. [PMID: 30122948 PMCID: PMC6084073 DOI: 10.2147/ott.s170827] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The mastic gum resin has been used in traditional Kurdish medicine for treating various disorders such as topical wound and gastric ulcer. The study designed to evaluate the total polyphenol and flavonoid content, free radical scavenging activity, and anticancer effects of mastic gum resin derived from Pistacia atlantica subspecies kurdica. MATERIALS AND METHODS Folin -Ciocalteau and the aluminum chloride colorimetric assays were used to determine the total phenol and flavonoid contents in the mastic gum resin respectively. Whereas, DPPH and ABTS+ assays were used to determine the antioxidant activities of mastic gum resin. Regarding anticancer activities, the MTT assay was used to study the effect of mastic gum resin on the proliferation of various cancer cells and the morphological changes were identified after Acridine Orange/Propidium Iodide staining. Flow cytometry was applied to determine the influence of mastic gum resin on the apoptosis rate by Annexin V double staining and to investigate the influence on cell cycle progression. Caspase colorimetric assay was used to estimate the hallmark enzyme of apoptosis, and finally RNA were obtained from COLO205 cells and analyzed by qRT-PCR analyses. RESULTS The MTT results showed that the mastic gum resin at concentrations from 0.01 to 100 μM induced death of cancer cells in a dose and time-dependent manner. The mastic gum resin suppressed proliferation of human cancer cells with 72 h IC50 value of 15.34 ± 0.21, 11.52 ± 0.18, 8.11 ± 0.23 and 5.2 ± 0.8 μg/mL for bile duct cancer (cholangiocarcinoma) (KMBC), pancreatic carcinoma (PANC-1), gastric adenocarcinoma (CRL-1739), and colonic adenocarcinoma (COLO205) cells, respectively. Normal human colon fibroblast (CCD-18Co) cells were not adversely affected by resin treatment. Flow cytometry showed that the mastic gum resin significantly (P<0.05) arrested COLO205 cell proliferation at the G2/M phase of cell cycle. The resin caused apoptotic morphological changes in COLO205 cells. The apoptotic effect to mastic gum resin was via the mitochondrial as shown by the up-regulation of Bax, down-regulation of Bcl-2 genes, and activation of caspase-9 and -3 activities. CONCLUSION It was confirmed that the antiproliferative efficacy of the resin is positively correlated with its polyphenolic contents, suggesting a causal link related to exudate content of phenolic acid and flavonoids. The results revealed that the mastic gum resin has potential to be developed as an anticancer and antioxidant product due to its high content of polyphenol compounds.
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Affiliation(s)
- Heshu Sulaiman Rahman
- Department of Clinic and Internal Medicine, College of Veterinary Medicine, University of Sulaimani, Sulaimani, Kurdistan Region, Republic of Iraq,
- Department of Medical Laboratory Sciences, College of Science, Komar University of Science and Technology, Chaq-Chaq Qularaisee, Sarchinar District, Sulaimani, Kurdistan Region, Republic of Iraq,
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, University Putra Malaysia, Serdang, Selangor, Malaysia,
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Jogi H, Maheshwari R, Raval N, Kuche K, Tambe V, Mak KK, Pichika MR, Tekade RK. Carbon nanotubes in the delivery of anticancer herbal drugs. Nanomedicine (Lond) 2018; 13:1187-1220. [DOI: 10.2217/nnm-2017-0397] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cancer is estimated to be a significant health problem of the 21st century. The situation gets even tougher when it comes to its treatment using chemotherapy employing synthetic anticancer molecules with numerous side effects. Recently, there has been a paradigm shift toward the adoption of herbal drugs for the treatment of cancer. In this context, a suitable delivery system is principally warranted to deliver these herbal biomolecules specifically at the tumorous site. To achieve this goal, carbon nanotubes (CNTs) have been widely explored to deliver anticancer herbal molecules with improved therapeutic efficacy and safety. This review uniquely expounds the biopharmaceutical, clinical and safety aspects of different anticancer herbal drugs delivered through CNTs with a cross-talk on their outcomes. This review will serve as a one-stop-shop for the readers on various anticancer herbal drugs delivered through CNTs as a futuristic delivery device.
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Affiliation(s)
- Hardi Jogi
- National Institute of Pharmaceutical Education & Research (NIPER) – Ahmedabad, Opposite Air Force Station Palaj, Gandhinagar, Gujarat, 382355 India
| | - Rahul Maheshwari
- National Institute of Pharmaceutical Education & Research (NIPER) – Ahmedabad, Opposite Air Force Station Palaj, Gandhinagar, Gujarat, 382355 India
| | - Nidhi Raval
- National Institute of Pharmaceutical Education & Research (NIPER) – Ahmedabad, Opposite Air Force Station Palaj, Gandhinagar, Gujarat, 382355 India
| | - Kaushik Kuche
- National Institute of Pharmaceutical Education & Research (NIPER) – Ahmedabad, Opposite Air Force Station Palaj, Gandhinagar, Gujarat, 382355 India
| | - Vishakha Tambe
- National Institute of Pharmaceutical Education & Research (NIPER) – Ahmedabad, Opposite Air Force Station Palaj, Gandhinagar, Gujarat, 382355 India
| | - Kit-Kay Mak
- School of Postgraduate Studies & Research, International Medical University, Kuala Lumpur, Malaysia
| | - Mallikarjuna Rao Pichika
- Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Rakesh Kumar Tekade
- National Institute of Pharmaceutical Education & Research (NIPER) – Ahmedabad, Opposite Air Force Station Palaj, Gandhinagar, Gujarat, 382355 India
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Xie W, Zhang Z, Song L, Huang C, Guo Z, Hu X, Bi S, Yu R. Cordyceps militaris Fraction induces apoptosis and G2/M Arrest via c-Jun N-Terminal kinase signaling pathway in oral squamous carcinoma KB Cells. Pharmacogn Mag 2018; 14:116-123. [PMID: 29576711 PMCID: PMC5858231 DOI: 10.4103/pm.pm_63_17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 04/11/2017] [Indexed: 12/22/2022] Open
Abstract
Background: Cordyceps militaris fraction (CMF) has been shown to possess in vitro antitumor activity against human chronic myeloid leukemia K562 cells in our previous research. Materials and Methods: The in vitro inhibitory activities of CMF on the growth of KB cells were evaluated by viability assay. The apoptotic and cell cycle influences of CMF were detected by 4′,6-diamidino-2-phenylindole staining and flow cytometry assay. The expression of different apoptosis-associated proteins and cell cycle regulatory proteins was examined by Western blot assay. The nuclear localization of c-Jun was observed by fluorescence staining. Objective: The objective of this study was to investigate the antiproliferative effect of CMF as well as the mechanism underlying the apoptosis and cell cycle arrest it induces in KB cells. Results: CMF suppressed KB cells’ proliferation in a dose- and time-dependent manner. Flow cytometric analysis indicated that CMF induced G2/M cell cycle arrest and apoptosis. Western blot analysis revealed that CMF induced caspase-3, caspase-9, and PARP cleavages, and increased the Bax/Bcl-2 ratio. CMF also led to increased expression of p21, decreased expression of cyclin B1, mitotic phosphatase cdc25c, and mitotic kinase cdc2, as well as unchanged expression of p53. In addition, CMF stimulated c-Jun N-terminal kinases (JNK) protein phosphorylations, resulting in upregulated expression of c-Jun and nuclear localization of c-Jun. Pretreatment with JNK inhibitor SP600125 suppressed CMF-induced apoptosis and G2/M arrest. Conclusions: CMF is capable of modulating c-Jun caspase and Bcl-2 family proteins through JNK-dependent apoptosis, which results in G2/M phase arrest in KB cells. CMF could be developed as a promising candidate for the new antitumor agents. SUMMARY
CMF exhibited strong anticancer activity against oral squamous carcinoma KB cells CMF inhibited KB cells’ proliferation via induction of apoptosis and G2/M cell cycle arrest CMF activated JNK signaling pathway and promoted the nuclear localization of c-Jun CMF regulated the apoptosis- and cell cycle-related proteins in a manner dependent on JNK/c-Jun pathway. Abbreviations used: CMF: Cordyceps militaris fraction; OSCC: Oral squamous cell carcinoma; JNK: c-Jun N-terminal kinase.
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Affiliation(s)
- Wangshi Xie
- Department of Pharmacology, College of Pharmacy, Jinan University, China
| | - Zhang Zhang
- Department of Pharmacology, College of Pharmacy, Jinan University, China
| | - Liyan Song
- Department of Pharmacology, College of Pharmacy, Jinan University, China
| | - Chunhua Huang
- Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou, China
| | - Zhongyi Guo
- Department of Pharmacology, College of Pharmacy, Jinan University, China
| | - Xianjing Hu
- Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou, China
| | - Sixue Bi
- Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou, China
| | - Rongmin Yu
- Department of Pharmacology, College of Pharmacy, Jinan University, China.,Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou, China
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Pharmacotherapeutic potential of phytochemicals: Implications in cancer chemoprevention and future perspectives. Biomed Pharmacother 2018; 97:564-586. [DOI: 10.1016/j.biopha.2017.10.124] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 10/14/2017] [Accepted: 10/23/2017] [Indexed: 12/17/2022] Open
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Curti V, Di Lorenzo A, Dacrema M, Xiao J, Nabavi SM, Daglia M. In vitro polyphenol effects on apoptosis: An update of literature data. Semin Cancer Biol 2017; 46:119-131. [PMID: 28830771 DOI: 10.1016/j.semcancer.2017.08.005] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 06/07/2017] [Accepted: 08/09/2017] [Indexed: 02/08/2023]
Abstract
Polyphenols are secondary plant metabolites which have been studied extensively for their health-promoting properties, and which could also exert pharmacological activities ranging from anti-inflammatory effects, to cytotoxic activity against cancer cells. The main mechanism for programmed cell death is represented by apoptosis, and its dysregulation is involved in the etiopathology of cancer. As such, substances able to induce apoptosis in cancer cells could be used as new anticancer agents. The aim of this paper is to review literature data on the apoptotic effects of polyphenols and the molecular mechanisms through which they induce these effects in cancer cells. In addition, a brief summary of the new delivery forms used to increase the bioavailability, and clinical impact of polyphenols is provided. The studies reported show that many polyphenol rich plant extracts, originating from food and herbal medicine, as well as isolated polyphenols administered individually or in combination, can regulate cell apoptosis primarily through intrinsic and extrinsic mechanisms of action in in vitro conditions. Due to these promising results, the use of polyphenols in the treatment of cancer should therefore be deeply investigated. In particular, because of the low number of clinical trials, further studies are required to evaluate the anticancer activity of polyphenols in in vivo conditions.
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Affiliation(s)
- Valeria Curti
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy; KOLINPHARMA S.p.A., Lainate, Corso Europa 5, 20020 Lainate, Italy
| | - Arianna Di Lorenzo
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy; KOLINPHARMA S.p.A., Lainate, Corso Europa 5, 20020 Lainate, Italy
| | - Marco Dacrema
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy
| | - Jianbo Xiao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Avenida da Universidade, Taipa, Macau
| | - Sayed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, PO Box 19395 5487, Iran.
| | - Maria Daglia
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy.
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Biazi BI, Zanetti TA, Baranoski A, Corveloni AC, Mantovani MS. Cis-Nerolidol Induces Endoplasmic Reticulum Stress and Cell Death in Human Hepatocellular Carcinoma Cells through Extensive CYP2C19 and CYP1A2 Oxidation. Basic Clin Pharmacol Toxicol 2017; 121:334-341. [PMID: 28256105 DOI: 10.1111/bcpt.12772] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 02/21/2017] [Indexed: 01/04/2025]
Abstract
Of late, many studies are attempting to find new molecules with anticancer properties, especially those with the capability to inhibit cell growth. The aim of this work was to evaluate nerolidol, a plant-based compound, as its cytotoxicity, genotoxicity, antiproliferative and apoptotic induction, cell cycle, mitochondrial membrane potential and RT-qPCR of transcripts related to those pathways in the human hepatocellular carcinoma cell line (HepG2/C3A). Only cis-nerolidol (C-NER) demonstrated cytotoxicity (100-250 μM) activity and was selected to conduct the following experiments. C-NER did not show genotoxic activity, but altered the mitochondrial membrane potential, reduced cell proliferation by arresting cell cycle in G1 phase and induced cell death. RT-qPCR showed that C-NER down-regulated genes related to apoptosis (BAK1, BAX, CAPN1, CASP8, CASP9, PARP1 and TP53), cell cycle (CCND1, CCNE1, CDK1 and CDK2), xenobiotic metabolism (CYP2D6 and CYP3A4) and paraptosis (IGF1R receptor). Up-regulation was seen in case of genes related to cell survival (BBC3 and MYC) and reticulum stress protein response (EIF2AK3 and ERN1) and xenobiotic metabolism (CYP1A2 and CYP2C19). We deduced that the antiproliferative activity of C-NER is attributable to its modulation of the cyclins and cyclin-dependent kinases as these proteins are necessary for G1/S phase transition. EIF2AK3, ERN1, CYP2C19 and CYP1A2 up-regulation suggests that endoplasmic reticulum stress was induced owing to the increased activity of cytochrome P450 enzymes. Caspase-independent cell death was also observed, indicating that another type of cell death, paraptosis, was triggered. Our results indicate that C-NER has considerable potential in anticancer therapy because it modulates important molecular targets of cell survival and proliferation.
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Affiliation(s)
- Bruna Isabela Biazi
- Laboratory of Toxicological Genetics, Department of General Biology, Biological Sciences Center, State University of Londrina - UEL, Londrina, Paraná, Brazil
| | - Thalita Alves Zanetti
- Laboratory of Toxicological Genetics, Department of General Biology, Biological Sciences Center, State University of Londrina - UEL, Londrina, Paraná, Brazil
| | - Adrivanio Baranoski
- Laboratory of Toxicological Genetics, Department of General Biology, Biological Sciences Center, State University of Londrina - UEL, Londrina, Paraná, Brazil
| | - Amanda Cristina Corveloni
- Laboratory of Toxicological Genetics, Department of General Biology, Biological Sciences Center, State University of Londrina - UEL, Londrina, Paraná, Brazil
| | - Mário Sérgio Mantovani
- Laboratory of Toxicological Genetics, Department of General Biology, Biological Sciences Center, State University of Londrina - UEL, Londrina, Paraná, Brazil
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33
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Kaur V, Kumar M, Kaur P, Kaur S, Kaur S. Inhibitory Activities of Butanol Fraction from Butea monosperma
(Lam
.) Taub
. Bark Against Free Radicals, Genotoxins and Cancer Cells. Chem Biodivers 2017; 14. [DOI: 10.1002/cbdv.201600484] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 02/13/2017] [Indexed: 11/09/2022]
Affiliation(s)
- Varinder Kaur
- Department of Botanical and Environmental Sciences; Guru Nanak Dev University; Amritsar Punjab 143005 India
| | - Manish Kumar
- Department of Botanical and Environmental Sciences; Guru Nanak Dev University; Amritsar Punjab 143005 India
- Akal College of Basic Sciences (Botany); Eternal University; Baru Sahib Sirmour Himachal Pradesh 173101 India
| | - Paramjeet Kaur
- Department of Botanical and Environmental Sciences; Guru Nanak Dev University; Amritsar Punjab 143005 India
| | - Sandeep Kaur
- Department of Botanical and Environmental Sciences; Guru Nanak Dev University; Amritsar Punjab 143005 India
| | - Satwinderjeet Kaur
- Department of Botanical and Environmental Sciences; Guru Nanak Dev University; Amritsar Punjab 143005 India
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Kaur V, Kumar M, Kaur P, Kaur S, Singh AP, Kaur S. Hepatoprotective activity of Butea monosperma bark against thioacetamide-induced liver injury in rats. Biomed Pharmacother 2017; 89:332-341. [PMID: 28237915 DOI: 10.1016/j.biopha.2017.01.165] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 01/27/2017] [Accepted: 01/29/2017] [Indexed: 12/18/2022] Open
Abstract
For thousands of years, the plant-based natural products have been a source of curative agents for various ailments. Butea monosperma (Fabaceae) has an important place in Indian traditional system of medicine for curing number of disorders. The present study deals with evaluation of hepatoprotective properties of ethyl acetate fraction (Beac) from B. monosperma bark in rat model. In preliminary antioxidant studies, Beac demonstrated pronounced superoxide scavenging (IC50 88.85μg/ml) and anti-lipid peroxidation (IC50 131.66μg/ml) potential. In animal studies, Beac showed protective effect against thioacetamide-induced pathophysiology in liver of male Wistar rats. The levels of different parameters related to hepatic functions were altered by thioacetamide treatment (300mg/g bw) in rats. The pre-treatment of rats with Beac (50, 100 and 200mg/kg bw) was able to normalize the biochemical markers viz. serum bilirubin, SGOT, SGPT, albumin and ALP along with liver antioxidative molecules viz. SOD, CAT, GSH and GR. Results of histopathological and colorimetric studies revealed that Beac treatment also restored the markers of fibrosis i.e. collagen and hydroxyproline towards normal level. Beac considerably inhibited thioacetamide-induced expression of p-PI3K, p-Akt and p-mTOR in hepatocytes as revealed from immunohistochemical studies. This finding is the first evidence of inhibitory action of B. monosperma bark on these pro-carcinogenic proteins. HRMS analysis revealed the presence of quercetin, buteaspermin B and ononin in Beac fraction of Butea monosperma. From the results, it can be concluded that B. monosperma bark is a rich source of phytochemicals with in vitro and in vivo protective activities which deserves further mechanistic studies for its use as a hepatoprotective agent in the prevention of hepatic inflammation and its related malignancies.
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Affiliation(s)
- Varinder Kaur
- Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India
| | - Manish Kumar
- Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India; Akal College of Basic Sciences (Botany), Eternal University, Baru Sahib, Sirmour 173101, Himachal Pradesh, India
| | - Paramjeet Kaur
- Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India
| | - Sandeep Kaur
- Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India
| | - Amrit Pal Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India
| | - Satwinderjeet Kaur
- Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India.
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Mohammed A, Chiruvella KK, Rao YK, Geethangili M, Raghavan SC, Ghanta RG. In Vitro Production of Echioidinin, 7-O-Methywogonin from Callus Cultures of Andrographis lineata and Their Cytotoxicity on Cancer Cells. PLoS One 2015; 10:e0141154. [PMID: 26488879 PMCID: PMC4619555 DOI: 10.1371/journal.pone.0141154] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 10/03/2015] [Indexed: 11/19/2022] Open
Abstract
Andrographis lineata is an herbal medicinal plant used in traditional medicine as a substitute for Andrographis paniculata. Here, using mature leaf explants of A. lineata we demonstrate for the first time the callus induction established on MS medium containing 1.0 mg l-1 IAA. Dried callus was subjected to solvent extraction with acetone. Further the acetone residue was separated by silica gel column chromatography, crystallized and characterized on the basis of nuclear magnetic resonance (proton and c13) and liquid chromatographic mass spectroscopy. This analysis revealed the occurrence of two known flavones namely, 7-O-methylwogonin (MW) and Echioidinin (ED). Furthermore, these compounds were tested for their cytotoxicity against leukemic cell line, CEM. We identify that ED and MW induced cytotoxicity in a time- and concentration-dependent manner. Further increase in the LDH release upon treatment with ED and MW further confirmed our cytotoxicity results against leukemic cell line. Strikingly, MW was more potent than ED when compared by trypan blue and MTT assays. Our results recapitulate the utility of callus cultures for the production of plant specific bioactive secondary metabolites instead of using wild plants. Together, our in vitro studies provide new insights of A. lineata callus cultures serving as a source for cancer chemotherapeutic agents.
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Affiliation(s)
- Arifullah Mohammed
- Faculty of Agrobased Industry, Universiti Malaysia Kelantan, Jeli Campus, Locked bag-100, 17600, Jeli, Kelantan, Malaysia
- Division of Plant Tissue Culture, Department of Botany, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
- * E-mail:
| | - Kishore K. Chiruvella
- Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India
- Division of Plant Tissue Culture, Department of Botany, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
| | - Yerra Koteswara Rao
- Department of Applied Chemistry, Chaoyang University of Technology, Taichung, Taiwan
| | | | - Sathees C. Raghavan
- Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India
| | - Rama Gopal Ghanta
- Division of Plant Tissue Culture, Department of Botany, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
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