Nimbolide: promising agent for prevention and treatment of chronic diseases (recent update)

  • Peramaiyan Rajendran Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, Saudi Arabia;; and Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
  • Kaviyarasi Renu Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
  • Basem M. Abdallah Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, Saudi Arabia
  • Enas M. Ali Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, Saudi Arabia; and 3Department of Botany and Microbiology, Faculty of Science, Cairo University, Cairo, Egypt
  • Vishnu Priya Veeraraghavan Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India;
  • Kalaiselvi Sivalingam Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA;
  • Yashika Rustagi Centre for Cancer Genomics, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Salaheldin Abdelraouf Abdelsalam Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, Saudi Arabia; and Department of Zoology, Faculty of Science, Assiut University, Assiut, Egypt
  • Rashid Ismael Hag Ibrahim Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa, Saudi Arabia; and Department of Botany, Faculty of Science, University of Khartoum, Sudan
  • Saeed Yaseen Al-Ramadan Department of Anatomy, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
DOI: https://doi.org/10.29219/fnr.v68.9650
Keywords: chronic diseases, limonoids, Azadirachta indica, imbolide, EMT, Wnt-β/catenin

Abstract

Background: Nimbolide, a bioactive compound derived from the neem tree, has garnered attention as a potential breakthrough in the prevention and treatment of chronic diseases. Recent updates in research highlight its multifaceted pharmacological properties, demonstrating anti-inflammatory, antioxidant, and anticancer effects. With a rich history in traditional medicine, nimbolide efficacy in addressing the molecular complexities of conditions such as cardiovascular diseases, diabetes, and cancer positions it as a promising candidate for further exploration. As studies progress, the recent update underscores the growing optimism surrounding nimbolide as a valuable tool in the ongoing pursuit of innovative therapeutic strategies for chronic diseases.

Methods: The comprehensive search of the literature was done until September 2020 on the MEDLINE, Embase, Scopus and Web of Knowledge databases.

Results: Most studies have shown the Nimbolide is one of the most potent limonoids derived from the flowers and leaves of neem (Azadirachta indica), which is widely used to treat a variety of human diseases. In chronic diseases, nimbolide reported to modulate the key signaling pathways, such as Mitogen-activated protein kinases (MAPKs), Wingless-related integration site-β (Wnt-β)/catenin, NF-κB, PI3K/AKT, and signaling molecules, such as transforming growth factor (TGF-β), Matrix metalloproteinases (MMPs), Vascular Endothelial Growth Factor (VEGF), inflammatory cytokines, and epithelial-mesenchymal transition (EMT) proteins. Nimbolide has anti-inflammatory, anti-microbial, and anti-cancer properties, which make it an intriguing compound for research. Nimbolide demonstrated therapeutic potential for osteoarthritis, rheumatoid arthritis, cardiovascular, inflammation and cancer.

Conclusion: The current review mainly focused on understanding the molecular mechanisms underlying the therapecutic effects of nimbolide in chronic diseases.

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References


1.
Hathaway E. Chronic disease prevention in faith-based organizations. J Pastoral Care Counsel 2018; 72(3): 159–62. doi: 10.1177/1542305018798572


2.
Martín-Timón I, Sevillano-Collantes C, Segura-Galindo A, del Cañizo-Gómez FJ. Type 2 diabetes and cardiovascular disease: have all risk factors the same strength? World J Diabetes 2014; 5(4): 444. doi: 10.4239/wjd.v5.i4.444


3.
Shakya AK. Medicinal plants: future source of new drugs. Int J Herbal Med 2016; 4(4): 59–64.


4.
Dar RA, Shahnawaz M, Qazi PH. General overview of medicinal plants: a review. J Phytopharmacol 2017; 6(6): 349–51. https://doi.org/10.31254/phyto.2017.6608


5.
Islam MT, Sarkar C, El-Kersh DM, Jamaddar S, Uddin SJ, Shilpi JA, et al. Natural products and their derivatives against coronavirus: a review of the non-clinical and pre-clinical data. Phytother Res 2020; 34(10): 2471–92. doi: 10.1002/ptr.6700


6.
Owona BA, Abia WA, Moundipa PF. Natural compounds flavonoids as modulators of inflammasomes in chronic diseases. Int Immunopharmacol 2020; 84: 106498. doi: 10.1016/j.intimp.2020.106498


7.
Uddin MS, Nuri ZN, Khorshed M. Neem (Azadirachta indica) in health care: a review. Int J Unani Integr Med 2018; 2(2): 81–7. doi: 10.33545/2616454X.2018.v2.i2a.30


8.
Tewari DN. Monograph on neem (Azadirachta indica A. Juss.): International Book Distributors. Pearson education; 1992.


9.
Biswas K, Chattopadhyay I, Banerjee RK, Bandyopadhyay U. Biological activities and medicinal properties of neem (Azadirachta indica). Curr Sci 2002; 1336–45. Available from: https://www.jstor.org/stable/24106000 [cited 10 June 2002]


10.
Lakshmi T, Krishnan V, Rajendran R, Madhusudhanan N. Azadirachta indica: a herbal panacea in dentistry–an update. Pharmacogn Rev 2015; 9(17): 41. doi: 10.4103/0973–7847.156337


11.
Ahmad MF, Ansari MO, Jameel S, Parveen N, Siddique HR, Shadab G. Protective role of nimbolide against chemotherapeutic drug hydroxyurea induced genetic and oxidative damage in an animal model. Environ Toxicol Pharmacol 2018; 60: 91–9. doi: 10.1016/j.etap.2018.04.006


12.
Zhang L, Li Y, Sun D, Bai F. Protective effect of nimbolide against high fat diet-induced obesity in rats via Nrf2/HO-1 pathway. J Oleo Sci 2022; 71(5): 709–20. doi: 10.5650/jos.ess21389


13.
Baligar NS, Aladakatti RH, Ahmed M, Hiremath MB. Evaluation of acute toxicity of neem active constituent, nimbolide and its hepatoprotective activity against acute dose of carbon tetrachloride treated albino rats. Int J Pharm Sci Res 2014; 5(8): 3455. DOI: 10.13040/IJPSR.0975-8232.5(8).3455-66.


14.
Ma Y, Xu S, Meng J, Li L. Protective effect of nimbolide against streptozotocin induced gestational diabetes mellitus in rats via alteration of inflammatory reaction, oxidative stress, and gut microbiota. Environ Toxicol 2022; 37(6): 1382–93. doi: 10.1002/tox.23491


15.
Shu X, Hu Y, Huang C, Wei N. Nimbolide ameliorates the streptozotocin-induced diabetic retinopathy in rats through the inhibition of TLR4/NF-κB signaling pathway. Saudi J Biol Sci 2021; 28(8): 4255–62. doi: 10.1016/j.sjbs.2021.06.039


16.
Bhagavathy S, Kancharla S. Wound healing and angiogenesis of silver nanoparticle from Azadirachta indica in diabetes induced mice. Int J Herb Med 2016; 4: 24–9. doi: 10.22271/flora


17.
Islas JF, Acosta E, Zuca G, Delgado-Gallegos JL, Moreno-Treviño MG, Escalante B, et al. An overview of Neem (Azadirachta indica) and its potential impact on health. Funct Foods 2020; 74: 104171. https://doi.org/10.1016/j.jff.2020.104171


18.
Li H, Xia B, Chen W, Zhang Y, Gao X, Chinnathambi A, et al. Nimbolide prevents myocardial damage by regulating cardiac biomarkers, antioxidant level, and apoptosis signaling against doxorubicin-induced cardiotoxicity in rats. J Biochem Mol Toxicol 2020; 34(9): e22543. doi: 10.1002/jbt.22543


19.
Zeenat F, Ravish MS, Ahmad W, Ahmad I. Therapeutic, phytochemistry and pharmacology of Azadirachta indica: a review. Int J Unani Integr Med 2018; 2(1): 20–8. doi: 10.33545/2616454X


20.
Zhang A, Yang C, Chen H, Pan L, Li J, Wang J. Anti-atherosclerotic activity of nimbolide in high fat diet induced atherosclerosis model rats. Latin Am J Pharm 2023; 42(3): 710–8. Available from: http://www.latamjpharm.org/resumenes/42/3/LAJOP_42_3_1_34.pdf [cited 10 April 2023]


21.
Alshammari GM, Balakrishnan A, Chinnasamy T. Nimbolide attenuate the lipid accumulation, oxidative stress and antioxidant in primary hepatocytes. Mol Biol Rep 2017; 44: 463–74. doi: 10.1007/s11033-017-4132-1


22.
Katola FO, Olajide OA. Nimbolide targets multiple signalling pathways to reduce neuroinflammation in BV-2 microglia. Mol Neurobiol 2022; 60(9): 5450–97. doi: 10.1007/s12035-023-03410-y


23.
Zhang J, Jung YY, Mohan CD, Deivasigamani A, Chinnathambi A, Alharbi SA, et al. Nimbolide enhances the antitumor effect of docetaxel via abrogation of the NF-κB signaling pathway in prostate cancer preclinical models. Biochim Biophys Acta (BBA)-Mol Cell Res. 2022; 1869(12): 119344. doi: 10.1016/j.bbamcr.2022.119344


24.
Elumalai P, Ezhilarasan D, Raghunandhakumar S. Molecular targets of nimbolide for anti-cancer therapy: an updated review. J Environ Pathol Toxicol Oncol 2022; 41(2): 69–88. doi: 10.1615/JEnvironPatholToxicolOncol.2021040263


25.
Awasthi M, Upadhyay AK, Singh S, Pandey VP, Dwivedi UN. Terpenoids as promising therapeutic molecules against Alzheimer’s disease: amyloid beta-and acetylcholinesterase-directed pharmacokinetic and molecular docking analyses. Mol Simulat 2018; 44(1): 1–11. doi: 10.1080/08927022.2017.1334880


26.
Vergoten G, Bailly C. Molecular docking study of GSK-3β interaction with nomilin, kihadanin B, and related limonoids and triterpenes with a furyl-δ-lactone core. J Biochem Mol Toxicol 2022; 36(9): e23130. doi: 10.1002/jbt.23130


27.
Kanaoujiya R, Srivastava S. Azadirachta Indica (neem): a review. 2020.


28.
Pandey A, Pare P. A review: antimicrobial activity of Azadirachta indica (Neem). Int J Pharm Life Sci 2018; 9(3): 5755–5756.


29.
Ahmad S, Maqbool A, Srivastava A, Gogol S. Biological detail and therapeutic effect of azadirachta indica (neem tree) products – a review. Evidence Based Med Healthcare 2019; 6(22): 1607–12. doi: 10.18410/jebmh/2019/324


30.
Cohen E, Quistad GB, Casida JE. Cytotoxicity of nimbolide, epoxyazadiradione and other limonoids from neem insecticide. Life Sci 1996; 58(13): 1075–81. doi: 10.1016/0024-3205(96)00061-6


31.
Elumalai P, Arunakaran J. Review on molecular and chemopreventive potential of nimbolide in cancer. Genom Inform 2014; 12(4): 156–64. doi: 10.5808/GI.2014.12.4.156


32.
Anand Solomon K, Malathi R, Rajan SS, Anitha G, Josepha Lourdu Raj J, Narasimhan S, et al. The isomeric compounds nimbolide and isonimbolide. Acta Crystallogr C Crystal Struct Commun 2005; 61(Pt 2): o70–2. doi: 10.1107/S0108270104031385


33.
Alzohairy MA. Therapeutics role of Azadirachta indica (Neem) and their active constituents in diseases prevention and treatment. Evidence-Based Complement Alternat Med 2016; 2016: 7382506. doi: 10.1155/2016/7382506


34.
Gupta A, Ansari S, Gupta S, Narwani M, Gupta M, Singh M. Therapeutics role of neem and its bioactive constituents in disease prevention and treatment. J Pharmacogn Phytochem 2019; 8(3): 680–91.


35.
Rahman MM, Bibi S, Rahaman MS, Rahman F, Islam F, Khan MS, et al. Natural therapeutics and nutraceuticals for lung diseases: traditional significance, phytochemistry, and pharmacology. Biomed Pharmacother 2022; 150: 113041. doi: 10.1016/j.biopha.2022.113041


36.
Alam A, Haldar S, Thulasiram HV, Kumar R, Goyal M, Iqbal MS, et al. Novel anti-inflammatory activity of epoxyazadiradione against macrophage migration inhibitory factor: inhibition of tautomerase and proinflammatory activities of macrophage migration inhibitory factor. J Biol Chem 2012; 287(29): 24844–61. doi: 10.1074/jbc.M112.341321


37.
Soares DG, Godin AM, Menezes RR, Nogueira RD, Brito AMS, Melo IS, et al. Anti-inflammatory and antinociceptive activities of azadirachtin in mice. Planta Medica 2014; 80(08/09): 630–6. doi: 10.1055/s-0034-1368507


38.
Schumacher M, Cerella C, Reuter S, Dicato M, Diederich M. Anti-inflammatory, pro-apoptotic, and anti-proliferative effects of a methanolic neem (Azadirachta indica) leaf extract are mediated via modulation of the nuclear factor-κB pathway. Genes Nutr 2011; 6(2): 149–60. doi: 10.1007/s12263-010-0194-6


39.
Priyadarsini RV, Manikandan P, Kumar GH, Nagini S. The neem limonoids azadirachtin and nimbolide inhibit hamster cheek pouch carcinogenesis by modulating xenobiotic-metabolizing enzymes, DNA damage, antioxidants, invasion and angiogenesis. Free Radical Res 2009; 43(5): 492–504. doi: 10.1080/10715760902870637


40.
Cui X, Wang R, Bian P, Wu Q, Seshadri VDD, Liu L. Evaluation of antiarthritic activity of nimbolide against Freund’s adjuvant induced arthritis in rats. Artific Cells Nanomed Biotechnol 2019; 47(1): 3391–8. doi: 10.1080/21691401.2019.1649269


41.
Zhang J, Ahn KS, Kim C, Shanmugam MK, Siveen KS, Arfuso F, et al. Nimbolide-induced oxidative stress abrogates STAT3 signaling cascade and inhibits tumor growth in transgenic adenocarcinoma of mouse prostate model. Antioxidants Redox Signal 2016; 24(11): 575–89. doi: 10.1089/ars.2015.6418


42.
Xia D, Chen D, Cai T, Zhu L, Lin Y, Yu S, et al. Nimbolide attenuated the inflammation in the liver of autoimmune hepatitis’s mice through regulation of HDAC3. Toxicol Appl Pharmacol 2022; 434: 115795. doi: 10.1016/j.taap.2021.115795


43.
Anchi P, Swamy V, Godugu C. Nimbolide exerts protective effects in complete Freund’s adjuvant induced inflammatory arthritis via abrogation of STAT-3/NF-κB/Notch-1 signaling. Life Sci 2021; 266: 118911. doi: 10.1016/j.lfs.2020.118911


44.
Sophia J, Kowshik J, Dwivedi A, Bhutia SK, Manavathi B, Mishra R, et al. Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer. Cell Death Dis 2018; 9(11): 1–18. doi: 10.1038/s41419-018-1126-4


45.
Raja Singh P, Sugantha Priya E, Balakrishnan S, Arunkumar R, Sharmila G, Rajalakshmi M, et al. Inhibition of cell survival and proliferation by nimbolide in human androgen-independent prostate cancer (PC-3) cells: involvement of the PI3K/Akt pathway. Mol Cell Biochem 2017; 427(1): 69–79. doi: 10.1007/s11010-016-2898-4


46.
Babykutty S, Priya PS, Nandini RJ, Kumar MS, Nair MS, Srinivas P, et al. Nimbolide retards tumor cell migration, invasion, and angiogenesis by downregulating MMP-2/9 expression via inhibiting ERK1/2 and reducing DNA-binding activity of NF-κB in colon cancer cells. Mol Carcinogenesis 2012; 51(6): 475–90. doi: 10.1002/mc.20812


47.
Lin H, Qiu S, Xie L, Liu C, Sun S. Nimbolide suppresses non-small cell lung cancer cell invasion and migration via manipulation of DUSP4 expression and ERK1/2 signaling. Biomed Pharmacother 2017; 92: 340–6. doi: 10.1016/j.biopha.2017.05.072


48.
Pooladanda V, Thatikonda S, Sunnapu O, Tiwary S, Vemula PK, Talluri MK, et al. iRGD conjugated nimbolide liposomes protect against endotoxin induced acute respiratory distress syndrome. Nanomed Nanotechnol Biol Med 2021; 33: 102351. doi: 10.1016/j.nano.2020.102351


49.
Kushwah APS, Gajendragadkar MP. The medicinal and therapeutical capacity of neem (Azadirachta indica): a review. Int J Sci Res 2022; 11(3): 200–4. doi: 10.21275/SR22127115821


50.
SaiRam M, Ilavazhagan G, Sharma S, Dhanraj S, Suresh B, Parida M, et al. Anti-microbial activity of a new vaginal contraceptive NIM-76 from neem oil (Azadirachta indica). J Ethnopharmacol 2000; 71(3): 377–82. doi: 10.1016/s0378-8741(99)00211-1


51.
Prashant G, Chandu G, Murulikrishna K, Shafiulla M. The effect of mango and neem extract on four organisms causing dental caries: Streptococcus mutans, Streptococcus salivavius, Streptococcus mitis, and Streptococcus sanguis: an in vitro study. Indian J Dent Res 2007; 18(4): 148. doi: 10.4103/0970-9290.35822


52.
Shubhi M, Ashwani KS, Shoma PN. Comparative antimicrobial activities of neem, amla, aloe, Assam tea and clove extracts against Vibrio cholerae, Staphylococcus aureus and Pseudomonas aeruginosa. J Med Plants Res 2010; 4(23): 2473–8.


53.
Kali A. Antibiotics and bioactive natural products in treatment of methicillin resistant Staphylococcus aureus: a brief review. Pharmacogn Rev 2015; 9(17): 29. doi: 10.4103/0973-7847.156329


54.
Maragathavalli S, Brindha S, Kaviyarasi N, Annadurai B, Gangwar S. Antimicrobial activity in leaf extract of neem (Azadirachta indica Linn.). Int J Sci Nat 2012; 3(1): 110–3.


55.
Vinothkumar TS, Rubin MI, Balaji L, Kandaswamy D. In vitro evaluation of five different herbal extracts as an antimicrobial endodontic irrigant using real time quantitative polymerase chain reaction. J Conserv Dent 2013; 16(2): 167. doi: 10.4103/0972-0707.108208


56.
Rosaline H, Kandaswamy D, Gogulnath D, Rubin M. Influence of various herbal irrigants as a final rinse on the adherence of Enterococcus faecalis by fluorescence confocal laser scanning microscope. J Conserv Dent 2013; 16(4): 352. doi: 10.4103/0972-0707.114365


57.
Harjai K, Bala A, Gupta RK, Sharma R. Leaf extract of Azadirachta indica (neem): a potential antibiofilm agent for Pseudomonas aeruginosa. Pathogens Dis 2013; 69(1): 62–5. doi: 10.1111/2049-632X.12050


58.
Isah A, Ibrahim Y, Iwalewa E. Evaluation of the antimalarial properties and standardization of tablets of Azadirachta indica (Meliaceae) in mice. Phytother Res 2003; 17(7): 807–10. doi: 10.1002/ptr.1231


59.
Badam L, Joshi S, Bedekar S. ‘In vitro’ antiviral activity of neem (Azadirachta indica. A. Juss) leaf extract against group B coxsackieviruses. J Commun Dis 1999; 31(2): 79–90.


60.
Pooladanda V, Thatikonda S, Bale S, Pattnaik B, Sigalapalli DK, Bathini NB, et al. Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation. Cell Death Dis 2019; 10(2): 81. doi: 10.1038/s41419-018-1247-9


61.
Han S, Mallampalli RK. The acute respiratory distress syndrome: from mechanism to translation. J Immunol 2015; 194(3): 855–60. doi: 10.4049/jimmunol.1402513


62.
Pooladanda V, Thatikonda S, Bale S, Pattnaik B, Sigalapalli DK, Bathini NB, et al. Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation. Cell Death Dis 2019; 10(2): 1–17. doi: 10.1038/s41419-018-1247-9


63.
Chan Y, MacLoughlin R, Zacconi FC, Tambuwala MM, Pabari RM, Singh SK, et al. Advances in nanotechnology-based drug delivery in targeting PI3K signaling in respiratory diseases. Future Med 2021; 16(16): 1351–5. doi: 10.2217/nnm-2021-0087


64.
Goud MP, Bale S, Pulivendala G, Godugu C. Therapeutic effects of nimbolide, an autophagy regulator, in ameliorating pulmonary fibrosis through attenuation of TGF-β1 driven epithelial-to-mesenchymal transition. Int Immunopharmacol 2019; 75: 105755. doi: 10.1016/j.intimp.2019.105755


65.
Diddi S, Bale S, Pulivendala G, Godugu C. Nimbolide ameliorates fibrosis and inflammation in experimental murine model of bleomycin-induced scleroderma. Inflammopharmacology 2019; 27: 139–49. doi: 10.1007/s10787-018-0527-4


66.
Lee J-W, Ryu HW, Park S-Y, Park HA, Kwon O-K, Yuk HJ, et al. Protective effects of neem (Azadirachta indica A. Juss.) leaf extract against cigarette smoke-and lipopolysaccharide-induced pulmonary inflammation. Int J Mol Med 2017; 40(6): 1932–40. doi: 10.3892/ijmm.2017.3178


67.
Sarkar S, Singh RP, Bhattacharya G. Exploring the role of Azadirachta indica (neem) and its active compounds in the regulation of biological pathways: an update on molecular approach. 3 Biotech 2021; 11(4): 1–12. doi: 10.1007/s13205-021-02745-4


68.
Roehlen N, Crouchet E, Baumert TF. Liver fibrosis: mechanistic concepts and therapeutic perspectives. Cells 2020; 9(4): 875. doi: 10.3390/cells9040875


69.
Wight TN, Potter-Perigo S. The extracellular matrix: an active or passive player in fibrosis? Am J Physiol Gastrointest Liver Physiol 2011; 301(6): G950–G5. doi: 10.1152/ajpgi.00132.2011


70.
Acharya P, Chouhan K, Weiskirchen S, Weiskirchen R. Cellular mechanisms of liver fibrosis. Front Pharmacol 2021; 12: 671640. doi: 10.3389/fphar.2021.671640


71.
Kumbar SB, Jadaramkunti UC, Aladakatti RH. In-vitro effect of nimbolide, an isoprenoid of neem leaf, on antioxidant system of rat cauda epididymal spermatozoa: a dose dependent study. J Appl Pharm Sci 2012: 2(5): 84–93. doi: 10.7324/JAPS.2012.2514


72.
Zahran Mohamed F, Saad Mohamed A, Mohamed Abd El-Galil F, Gamal Haikel N. Antitumor activity of neem leaf extract and nimbolide on ehrlich ascites carcinoma cells in mice. Biochem Lett 2015; 11(1): 27–41. doi: 10.21608/blj.2015.63390


73.
Nikolova G, Ananiev J, Ivanov V, Petkova-Parlapanska K, Georgieva E, Karamalakova Y. The Azadirachta indica (Neem) seed oil reduced chronic redox-homeostasis imbalance in a mice experimental model on ochratoxine a-induced hepatotoxicity. Antioxidants 2022; 11(9): 1678. doi: 10.3390/antiox11091678


74.
Ezz-Din D, Gabry MS, Farrag ARH, Abdel Moneim A. Physiological and histological impact of Azadirachta indica (neem) leaves extract in a rat model of cisplatin-induced hepato and nephrotoxicity. J Med Plants Res 2011; 5(23): 5499–506.


75.
Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol 2020; 72(2): 250–61. doi: 10.1016/j.jhep.2019.08.025


76.
Kavitha K, Priyadarsini RV, Anitha P, Ramalingam K, Sakthivel R, Purushothaman G, et al. Nimbolide, a neem limonoid abrogates canonical NF-κB and Wnt signaling to induce caspase-dependent apoptosis in human hepatocarcinoma (HepG2) cells. Eur J Pharmacol 2012; 681(1–3): 6–14. doi: 10.1016/j.ejphar.2012.01.024


77.
Yang YM, Kim SY, Seki E. Inflammation and liver cancer: molecular mechanisms and therapeutic targets. Semin Liver Dis 2019;39(1):26–42. doi: 10.1055/s-0038-1676806


78.
Ram AK, Vairappan B, Srinivas B. Nimbolide inhibits tumor growth by restoring hepatic tight junction protein expression and reduced inflammation in an experimental hepatocarcinogenesis. World J Gastroenterol 2020; 26(45): 7131. doi: 10.3748/wjg.v26.i45.7131


79.
Harding JL, Pavkov ME, Magliano DJ, Shaw JE, Gregg EW. Global trends in diabetes complications: a review of current evidence. Diabetologia 2019; 62(1): 3–16. doi: 10.1007/s00125-018-4711-2


80.
Park YG, Roh Y-J. New diagnostic and therapeutic approaches for preventing the progression of diabetic retinopathy. J Diabetes Res 2016; 2016: 1753584. doi: 10.1155/2016/1753584


81.
Juin SK, Pushpakumar S, Tyagi SC, Sen U. Glucosidase inhibitor, Nimbidiol ameliorates renal fibrosis and dysfunction in type-1 diabetes. Sci Rep 2022; 12(1): 21707. doi: 10.1038/s41598-022-25848-1


82.
Wang L, Zhang J, Ong P-S, Thuya WL, Soo R, Wong AL-A, et al. Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development. Oncotarget 2016; 7(28): 44790–802. doi: 10.18632/oncotarget.8316


83.
Nagini S, Nivetha R, Palrasu M, Mishra R. Nimbolide, a neem limonoid, is a promising candidate for the anticancer drug arsenal. J Med Chem 2021; 64(7): 3560–77. doi: 10.1021/acs.jmedchem.0c02239


84.
Patra A, Satpathy S, Hussain MD. Nanodelivery and anticancer effect of a limonoid, nimbolide, in breast and pancreatic cancer cells. Int J Nanomed 2019; 14: 8095. doi: 10.2147/IJN.S208540


85.
Arumugam A, Subramani R, Lakshmanaswamy R. Involvement of actin cytoskeletal modifications in the inhibition of triple-negative breast cancer growth and metastasis by nimbolide. Mol Ther Oncolyt 2021; 20: 596–606. doi: 10.1016/j.omto.2021.02.014


86.
Singh PR, Priya ES, Balakrishnan S, Arunkumar R, Sharmila G, Rajalakshmi M, et al. Nimbolide inhibits androgen independent prostate cancer cells survival and proliferation by modulating multiple pro-survival signaling pathways. Biomed Pharmacother 2016; 84: 1623–34. doi: 10.1016/j.biopha.2016.10.076


87.
Nivetha R, Arvindh S, Baba AB, Gade DR, Gopal G, Reddy KP, et al. Nimbolide, a neem limonoid, inhibits angiogenesis in breast cancer by abrogating aldose reductase mediated IGF-1/PI3K/Akt signalling. Anti-Cancer Agents Med Chem (Formerly Current Medicinal Chemistry-Anti-Cancer Agents) 2022; 22(14): 2619–36. doi: 10.2174/1871520622666220204115151


88.
Kowshik J, Mishra R, Sophia J, Rautray S, Anbarasu K, Reddy GD, et al. Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model. Sci Rep 2017; 7(1): 1–12. doi: 10.1038/s41598-017-01960-5


89.
Annaldas S, Saifi MA, Khurana A, Godugu C. Nimbolide ameliorates unilateral ureteral obstruction-induced renal fibrosis by inhibition of TGF-β and EMT/Slug signalling. Mol Immunol 2019; 112: 247–55. doi: 10.1016/j.molimm.2019.06.003


90.
Suarez-Carmona M, Lesage J, Cataldo D, Gilles C. EMT and inflammation: inseparable actors of cancer progression. Mol Oncol 2017; 11(7): 805–23. doi: 10.1002/1878-0261.12095


91.
Subramani R, Gonzalez E, Arumugam A, Nandy S, Gonzalez V, Medel J, et al. Nimbolide inhibits pancreatic cancer growth and metastasis through ROS-mediated apoptosis and inhibition of epithelial-to-mesenchymal transition. Sci Rep 2016; 6(1): 19819. doi: 10.1038/srep19819


92.
Kasala ER, Bodduluru LN, Barua CC. Nimbolide inhibits invasion of breast cancer. Cell Prolifer 2015; 48(2): 117–8. doi: 10.1111/cpr.12170


93.
Pooladanda V, Bandi S, Mondi SR, Gottumukkala KM, Godugu C. Nimbolide epigenetically regulates autophagy and apoptosis in breast cancer. Toxicol In Vitro 2018; 51: 114–28. doi: 10.1016/j.tiv.2018.05.010


94.
Jaiswara PK, Kumar A. Nimbolide retards T cell lymphoma progression by altering apoptosis, glucose metabolism, pH regulation, and ROS homeostasis. Environ Toxicol 2022; 37(6): 1445–57. doi: 10.1002/tox.23497


95.
Lange N, Tontsa AT, Wegscheid C, Mkounga P, Nkengfack AE, Loscher C, et al. The limonoids TS3 and Rubescin E induce apoptosis in human hepatoma cell lines and interfere with NF-κB signaling. PLoS One 2016; 11(8): e0160843. doi: 10.1371/journal.pone.0160843


96.
Gupta SC, Prasad S, Sethumadhavan DR, Nair MS, Mo Y-Y, Aggarwal BB. Nimbolide, a limonoid triterpene, inhibits growth of human colorectal cancer Xenografts by suppressing the proinflammatory microenvironment Nimbolide inhibits colorectal cancer growth. Clin Cancer Res 2013; 19(16): 4465–76. doi: 10.1158/1078-0432.CCR-13-0080


97.
Mondal S, Bandyopadhyay S, K Ghosh M, Mukhopadhyay S, Roy S, Mandal C. Natural products: promising resources for cancer drug discovery. Anti-Cancer Agents Med Chem (Formerly Current Medicinal Chemistry-Anti-Cancer Agents) 2012; 12(1): 49–75. doi: 10.2174/187152012798764697


98.
Prakobwong S, Gupta SC, Kim JH, Sung B, Pinlaor P, Hiraku Y, et al. Curcumin suppresses proliferation and induces apoptosis in human biliary cancer cells through modulation of multiple cell signaling pathways. Carcinogenesis 2011; 32(9): 1372–80. doi: 10.1093/carcin/bgr032


99.
Gupta SC, Francis SK, Nair MS, Mo Y-Y, Aggarwal BB. Azadirone, a limonoid tetranortriterpene, induces death receptors and sensitizes human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through a p53 protein-independent mechanism: evidence for the role of the ROS-ERK-CHOP-death receptor pathway. J Biol Chem 2013; 288(45): 32343–56. doi: 10.1074/jbc.M113.455188


100.
Zhao J, Lu Y, Shen H-M. Targeting p53 as a therapeutic strategy in sensitizing TRAIL-induced apoptosis in cancer cells. Cancer Lett 2012; 314(1): 8–23. doi: 10.1016/j.canlet.2011.09.040


101.
Zhang Y, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol 2020; 13(1): 1–16. doi: 10.1186/s13045-020-00990-3


102.
Sebio A, Kahn M, Lenz H-J. The potential of targeting Wnt/β-catenin in colon cancer. Expert Opin Therapeutic Targets 2014; 18(6): 611–5. doi: 10.1517/14728222.2014.906580


103.
Prosperi JR, Goss KH. A Wnt-ow of opportunity: targeting the Wnt/β-catenin pathway in breast cancer. Curr Drug Targets 2010; 11(9): 1074–88. doi: 10.2174/138945010792006780


104.
Arend RC, Londoño-Joshi AI, Straughn Jr JM, Buchsbaum DJ. The Wnt/β-catenin pathway in ovarian cancer: a review. Gynecol Oncol 2013; 131(3): 772–9. doi: 10.1016/j.ygyno.2013.09.034


105.
Kypta RM, Waxman J. Wnt/β-catenin signalling in prostate cancer. Nat Rev Urol 2012; 9(8): 418–28. doi: 10.1038/nrurol.2012.116


106.
Kılıçaslan SMS, İncesu Z. Effects of integrin-linked kinase on protein kinase b, glycogen synthase kinase-3β, and β-catenin molecules in ovarian cancer cells. Iranian J Basic Med Sci 2021; 24(11): 1500. doi: 10.22038/IJBMS.2021.58716.13042


107.
Guarino M, Rubino B, Ballabio G. The role of epithelial-mesenchymal transition in cancer pathology. Pathology 2007; 39(3): 305–18. doi: 10.1080/00313020701329914


108.
Sophia J, Kiran Kishore TK, Kowshik J, Mishra R, Nagini S. Nimbolide, a neem limonoid inhibits Phosphatidyl Inositol-3 Kinase to activate Glycogen Synthase Kinase-3β in a hamster model of oral oncogenesis. Sci Rep 2016; 6: 22192. doi: 10.1038/srep22192


109.
Kavitha K, Vidya Priyadarsini R, Anitha P, Ramalingam K, Sakthivel R, Purushothaman G, et al. Nimbolide, a neem limonoid abrogates canonical NF-κB and Wnt signaling to induce caspase-dependent apoptosis in human hepatocarcinoma (HepG2) cells. Eur J Pharmacol 2012; 681(1–3): 6–14. doi: 10.1016/j.ejphar.2012.01.024


110.
Elumalai P, Arunkumar R, Benson CS, Sharmila G, Arunakaran J. Nimbolide inhibits IGF-I-mediated PI3K/Akt and MAPK signalling in human breast cancer cell lines (MCF-7 and MDA-MB-231). Cell Biochem Funct 2014; 32(5): 476–84. doi: 10.1002/cbf.3040


111.
Karkare S, Chhipa RR, Anderson J, Liu X, Henry H, Gasilina A, et al. Direct inhibition of retinoblastoma phosphorylation by nimbolide causes cell-cycle arrest and suppresses glioblastoma growth. Clin Cancer Res 2014; 20(1): 199–212. doi: 10.1158/1078-0432.CCR-13-0762


112.
Nagini S. Neem limonoids as anticancer agents: modulation of cancer hallmarks and oncogenic signaling. Enzymes 2014; 36: 131–47. doi: 10.1016/B978-0-12-802215-3.00007-0


113.
Chien SY, Hsu CH, Lin CC, Chuang YC, Lo YS, Hsi YT, et al. Nimbolide induces apoptosis in human nasopharyngeal cancer cells. Environ Toxicol 2017; 32(8): 2085–92. doi: 10.1002/tox.22423


114.
Elumalai P, Brindha Mercy A, Arunkamar R, Sharmila G, Bhat FA, Balakrishnan S, et al. Nimbolide inhibits invasion and migration, and down-regulates uPAR chemokine gene expression, in two breast cancer cell lines. Cell Proliferat 2014; 47(6): 540–52. doi: 10.1111/cpr.12148


115.
Nagini S, Nivetha R, Palrasu M, Mishra R. Nimbolide, a meem limonoid, is a promising candidate for the anticancer drug arsenal. J Med Chem 2021; 64(7): 3560–77. doi: 10.1021/acs.jmedchem.0c02239


116.
Li F, Sethi G. Targeting transcription factor NF-κB to overcome chemoresistance and radioresistance in cancer therapy. Biochim Biophys Acta (BBA) – Rev Cancer 2010; 1805(2): 167–80. doi: 10.1016/j.bbcan.2010.01.002


117.
Li F, Zhang J, Arfuso F, Chinnathambi A, Zayed M, Alharbi SA, et al. NF-κB in cancer therapy. Arch Toxicol 2015; 89(5): 711–31. doi: 10.1007/s00204-015-1470-4


118.
Puar YR, Shanmugam MK, Fan L, Arfuso F, Sethi G, Tergaonkar V. Evidence for the involvement of the master transcription factor NF-κB in cancer initiation and progression. Biomedicines 2018; 6(3): 82. doi: 10.3390/biomedicines6030082


119.
Shanmugam MK, Kumar AP, Tan BK, Sethi G. Role of NF-κB in tumorigenesis. Onco Therapeutics 2013; 4(2): 181–96. doi: 10.1615/ForumImmunDisTher.2013008382


120.
Kaltschmidt B, Greiner JF, Kadhim HM, Kaltschmidt C. Subunit-specific role of NF-κB in cancer. Biomedicines 2018; 6(2): 44. doi: 10.3390/biomedicines6020044


121.
Hseu Y-C, Lin Y-C, Rajendran P, Thigarajan V, Mathew DC, Lin K-Y, et al. Antrodia salmonea suppresses invasion and metastasis in triple-negative breast cancer cells by reversing EMT through the NF-κB and Wnt/β-catenin signaling pathway. Food Chem Toxicol 2019; 124: 219–30. doi: 10.1016/j.fct.2018.12.009


122.
Hseu YC, Chang GR, Pan JY, Rajendran P, Mathew DC, Li ML, et al. Antrodia camphorata inhibits epithelial-to-mesenchymal transition by targeting multiple pathways in triple-negative breast cancers. J Cell Physiol 2019; 234(4): 4125–39. doi: 10.1002/jcp.27222


123.
Raja Singh P, Arunkumar R, Sivakamasundari V, Sharmila G, Elumalai P, Suganthapriya E, et al. Anti-proliferative and apoptosis inducing effect of nimbolide by altering molecules involved in apoptosis and IGF signalling via PI3K/Akt in prostate cancer (PC-3) cell line. Cell Biochem Funct 2014; 32(3): 217–28. doi: 10.1002/cbf.2993


124.
Lee CH. Reversal of epithelial–mesenchymal transition by natural anti-inflammatory and pro-resolving lipids. Cancers 2019; 11(12): 1841. doi: 10.3390/cancers11121841


125.
Dhingra N, Sharma R, Kar A. Oxidative stress and carcinogenesis: prevention by antioxidative phytochemicals acting on different molecular targets. Int J Pharm Sci Rev Res 2014; 41: 236–45.


126.
Majidinia M, Aghazadeh J, Jahanban-Esfahlani R, Yousefi B. The roles of Wnt/β-catenin pathway in tissue development and regenerative medicine. J Cell Physiol 2018; 233(8): 5598–612. doi: 10.1002/jcp.26265


127.
Siddavaram N, Ramamurthi VP. Apoptosis induction by nimbolide, a limonoid from Azadirachta indica: molecular targets and signaling networks. Novel apoptotic regulators in carcinogenesis. Oxford: Springer; 2012, pp. 27–43.


128.
Xiao W, Li J, Hu J, Wang L, Huang JR, Sethi G, et al. Circular RNAs in cell cycle regulation: mechanisms to clinical significance. Cell Proliferat 2021; 54(12): e13143. doi: 10.1111/cpr.13143


129.
Chong Q-Y, Kok Z-H, Xiang X, Wong AL-A, Yong W-P, Sethi G, et al. A unique CDK4/6 inhibitor: current and future therapeutic strategies of abemaciclib. Pharmacol Res 2020; 156: 104686. doi: 10.1016/j.phrs.2020.104686


130.
Shin S-S, Hwang B, Muhammad K, Gho Y, Song J-H, Kim W-J, et al. Nimbolide represses the proliferation, migration, and invasion of bladder carcinoma cells via Chk2-mediated G2/M phase cell cycle arrest, altered signaling pathways, and reduced transcription factors-associated MMP-9 expression. Evidence Based Complement Alternat Med 2019; 2019: 3753587. doi: 10.1155/2019/3753587


131.
Roy MK, Kobori M, Takenaka M, Nakahara K, Shinmoto H, Tsushida T. Inhibition of colon cancer (HT-29) cell proliferation by a triterpenoid isolated from Azadirachta indica is accompanied by cell cycle arrest and up-regulation of p21. Planta Medica 2006; 72(10): 917–23. doi: 10.1055/s-2006-946694


132.
Roy MK, Kobori M, Takenaka M, Nakahara K, Shinmoto H, Isobe S, et al. Antiproliferative effect on human cancer cell lines after treatment with nimbolide extracted from an edible part of the neem tree (Azadirachta indica). Phytother Res 2007; 21(3): 245–50. doi: 10.1002/ptr.2058


133.
Priyadarsini RV, Murugan RS, Sripriya P, Karunagaran D, Nagini S. The neem limonoids azadirachtin and nimbolide induce cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells. Free Radical Res 2010; 44(6): 624–34. doi: 10.3109/10715761003692503


134.
Sophia J, Kowshik J, Dwivedi A, Bhutia SK, Manavathi B, Mishra R, et al. Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer. Cell Death Dis 2018; 9(11): 1087. doi: 10.1038/s41419-018-1126-4


135.
Rahmani A, Almatroudi A, Alrumaihi F, Khan A. Pharmacological and therapeutic potential of neem (Azadirachta indica). Pharmacogn Rev 2018; 12(24): 250–5. doi: 10.4103/phrev.phrev_8_18


136.
Kandhare AD, Mukherjee AA, Bodhankar SL. Neuroprotective effect of Azadirachta indica standardized extract in partial sciatic nerve injury in rats: evidence from anti-inflammatory, antioxidant and anti-apoptotic studies. EXCLI J 2017; 16: 546. doi: 10.17179/excli2017-161


137.
Moneim AEA. Azadirachta indica attenuates cisplatin-induced neurotoxicity in rats. Indian J Pharmacol 2014; 46(3): 316. doi: 10.4103/0253-7613.132182


138.
Israr M, Naseem N, Akhtar T, Aftab U, Zafar MS, Faheem MA, et al. Nimbolide attenuates complete Freund’s adjuvant induced arthritis through expression regulation of toll-like receptors signaling pathway. Phytother Res 2023; 37(3): 903–12. doi: 10.1002/ptr.7672
Published
2024-03-18
How to Cite
Rajendran P., Renu K., M. Abdallah B., M. Ali E., Veeraraghavan V. P., Sivalingam K., Rustagi Y., Abdelraouf Abdelsalam S., Ismael Hag Ibrahim R., & Al-Ramadan S. Y. (2024). Nimbolide: promising agent for prevention and treatment of chronic diseases (recent update). Food & Nutrition Research, 68. https://doi.org/10.29219/fnr.v68.9650
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Vol 68 (2024)
Section
Original Articles
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