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Andrographolides and traditionally used Andrographis paniculata as potential adaptogens: Implications for therapeutic innovation

Thakur, Ajit Kumar;Chatterjee, Shyam Sunder;Kumar, Vikas

  • Received : 2014.01.06
  • Accepted : 2014.07.15
  • Published : 2014.08.31

Abstract

Andrographis paniculata (Burm. F.) Wall. Ex Nees (Family: Anthaceae) is a traditionally known Ayurvedic medicinal plant. Several well-controlled clinical trials conducted during recent years have consistently reconfirmed that Andrographis paniculata extracts are effective in suppressing cardinal symptoms of diverse inflammatory and infectious diseases. Despite extensive efforts though, many questions concerning bioactive constituents of such extracts and their modes of actions still remain unanswered. Amongst diverse diterpene lactones isolated to date from such extracts, andrographolide is often considered to be the major, representative, or bioactive secondary metabolite of the plant. Therefore, it has attracted considerable attention of several drug discovery laboratories as a lead molecule potentially useful for identifying structurally and functionally novel drug. Critical analysis of available preclinical and clinical information on Andrographis paniculata extracts and pure andrographolide strongly suggest that they are pharmacologically polyvalent and that they possess adaptogenic properties. Aim of this communication is to summarize and critically analyze such data, and to point out some possibilities for more rationally exploiting their adaptogenic properties for discovering novel therapeutic leads, or for obtaining pharmacologically better standardized phyto-pharmaceuticals.

Keywords

Andrographis paniculata;andrographolide;adaptogen;phyto-pharmaceuticals

References

  1. Agarwal R, Sulaiman SA, Mohamed M. Open label clinical trial to study adverse effects and tolerance to dry powder of the aerial part of Andrographis paniculata in patients type 2 with diabetes mellitus. Malays J Med Sci. 2005;12:13-19.
  2. Allan JJ, Pore MP, Deepak M, Murali B, Mayachari AS, Agarwal A. Reproductive and fertility effects of an extract of Andrographis paniculata in male Wistar rats. Int J Toxicol. 2009;28:308-317. https://doi.org/10.1177/1091581809339631
  3. Awang K, Abdullah NH, Hadi AH, Fong YS. Cardiovascular activity of labdane diterpenes from Andrographis paniculata in isolated rat hearts. J Biomed Biotechnol. 2012;2012:876458.
  4. Basak A, Cooper S, Roberge AG, Banik UK, Chretien M, Seidah NG. Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters. Biochem J. 1999;338:107-113. https://doi.org/10.1042/0264-6021:3380107
  5. Bond RA. Can intellectualism stifle scientific discovery? Nat Rev Drug Discov. 2002;1:825-829. https://doi.org/10.1038/nrd918
  6. Behrens M, Brockhoff A, Batram C, Kuhn C, Appendino G, Meyerhof W. The human bitter taste receptor hTAS2R50 is activated by the two natural bitter terpenoids andrographolide and amarogentin. J Agric Food Chem. 2009;57:9860-9866. https://doi.org/10.1021/jf9014334
  7. Bensky D, Gamble A. Chinese Herbal Medicine Materia Medica. 1st ed. (Washington, USA: Eastland Press), p. 136, 1986.
  8. Bond RA. Is paradoxical pharmacology a strategy worth pursuing? Trends Pharmacol Sci. 2001;22:273-276. https://doi.org/10.1016/S0165-6147(00)01711-9
  9. Bone K, Mills S. Principles and practice of phytotherapy: Modern herbal medicine. (London, UK: Churchill Livingston), p. 360, 2012.
  10. Bothiraja C, Pawar A, Shende V, Joshi P. Acute and subacute toxicity study of andrographolide bioactive in rodents: Evidence for the medicinal use as an alternative medicine. Comp Clin Pathol. 2013;22:1123-1128. https://doi.org/10.1007/s00580-012-1539-x
  11. Brencic A, Winans SC. Detection of and response to signals involved in host-microbe interactions by plant-associated bacteria. Microbiol Mol Biol Rev. 2005;69:155-194. https://doi.org/10.1128/MMBR.69.1.155-194.2005
  12. Burgos RA, Caballero EE, Sanchez NS, Schroeder RA, Wikman GK, Hancke JL. Testicular toxicity assessment of Andrographis paniculata dried extract in rats. J Ethnopharmacol. 1997;58:219-224. https://doi.org/10.1016/S0378-8741(97)00099-8
  13. Burgos RA, Hancke JL, Bertoglio JC, Aguirre V, Arriagada S, Calvo M, Caceres DD. Efficacy of an Andrographis paniculata composition for the relief of rheumatoid arthritis symptoms: a prospective randomized placebo-controlled trial. Clin Rheumatol. 2009;28:931-946. https://doi.org/10.1007/s10067-009-1180-5
  14. Burgos RA, Seguel K, Perez M, Meneses A, Ortega M, Guarda MI, Loaiza A, Hancke JL. Andrographolide inhibits IFN-gamma and IL-2 cytokine production and protects against cell apoptosis. Planta Med. 2005;71:429-434. https://doi.org/10.1055/s-2005-864138
  15. Calabrese V, Cornelius C, Dinkova-Kostova AT, Calabrese EJ, Mattson MP. Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid Redox Signal 1. 2010b;13:1763-1811. https://doi.org/10.1089/ars.2009.3074
  16. Calabrese C, Berman SH, Babish JG, Ma X, Shinto L, Dorr M, Wells K, Wenner CA, Standish LJ. A phase I trial of andrographolide in HIV positive patients and normal volunteers. Phytother Res. 2000;14:333-338. https://doi.org/10.1002/1099-1573(200008)14:5<333::AID-PTR584>3.0.CO;2-D
  17. Calabrese EJ. Hormesis: a revolution in toxicology, risk assessment and medicine. EMBO Rep. 2004;5:S37-S40. https://doi.org/10.1038/sj.embor.7400222
  18. Calabrese EJ, Mattson MP, Calabrese V. Resveratrol commonly displays hormesis: occurrence and biomedical significance. Hum Exp Toxicol. 2010a;29:980-1015. https://doi.org/10.1177/0960327110383625
  19. Cani PD, Delzenne NM. The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des. 2009;15:1546-1558. https://doi.org/10.2174/138161209788168164
  20. Carretta MD, Alarcon P, Jara E, Solis L, Hancke JL, Concha II, Hidalgo MA, Burgos RA. Andrographolide reduces IL-2 production in T-cells by interfering with NFAT and MAPK activation. Eur J Pharmacol. 2009;602:413-421. https://doi.org/10.1016/j.ejphar.2008.11.011
  21. Chakravarti RN, Chakravarti D. Andrographolide, the active constituent of Andrographis paniculata Nees; a preliminary communication. Ind Med Gaz. 1951;86:96-97.
  22. Chan SJ, Wong WS, Wong PT, Bian JS. Neuroprotective effects of andrographolide in a rat model of permanent cerebral ischaemia. Br J Pharmacol. 2010;161:668-679. https://doi.org/10.1111/j.1476-5381.2010.00906.x
  23. Chander R, Srivastava V, Tandon JS, Kapoor NK. Antihepatotoxic activity of diterpenes of Andrographis paniculata (Kal-Megh) against Plasmodium berghei induced hepatic damage in Mastomys natalensis. Pharm Biol. 1995;33:35-138. https://doi.org/10.3109/13880209509067086
  24. Chao WW, Lin BF. Isolation and identification of bioactive compounds in Andrographis paniculata (Chuanxinlian). Chin Med. 2010;5:17. https://doi.org/10.1186/1749-8546-5-17
  25. Chandrasekaran CV, Gupta A, Agarwal A. Effect of an extract of Andrographis paniculata leaves on inflammatory and allergic mediators in vitro. J Ethnopharmacol. 2010;129:203-207. https://doi.org/10.1016/j.jep.2010.03.007
  26. Chandrasekaran CV, Thiyagarajan P, Deepak HB, Agarwal A. In vitro modulation of LPS/calcimycin induced inflammatory and allergic mediators by pure compounds of Andrographis paniculata (King of bitters) extract. Int Immunopharmacol. 2011;11:79-84. https://doi.org/10.1016/j.intimp.2010.10.009
  27. Chandrasekaran CV, Thiyagarajan P, Sundarajan K, Goudar KS, Deepak M, Murali B, Allan JJ, Agarwal A. Evaluation of the genotoxic potential and acute oral toxicity of standardized extract of Andrographis paniculata (KalmCold). Food Chem Toxicol. 2009;47:1892-1902. https://doi.org/10.1016/j.fct.2009.05.006
  28. Chatterjee SS, Kumar V. Holistic psychopharmacology and promiscuous plants and principles of Ayurveda. Am J Plant Sci. 2012;3:1015-1021. https://doi.org/10.4236/ajps.2012.327120
  29. Clark AA, Liggett SB, Munger SD. Extraoral bitter taste receptors as mediators of off-target drug effects. FASEB J. 2012;26:4827-4831. https://doi.org/10.1096/fj.12-215087
  30. Colagiuri S. Diabesity: therapeutic options. Diabetes Obes Metab. 2010;12:463-473. https://doi.org/10.1111/j.1463-1326.2009.01182.x
  31. Coon JT, Ernst E. Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med. 2004;70:293-298. https://doi.org/10.1055/s-2004-818938
  32. Das S, Cordis GA, Maulik N, Das DK. Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation. Am J Physiol Heart Circ Physiol. 2005;288:H328-H335. https://doi.org/10.1152/ajpheart.00453.2004
  33. Farah M, Meyboom R, Ploen M. Acute Hypersensitivity Reactions to Andrographis paniculata Containing Products, as Reported in International Pharmacovigilance. Drug Saf. 2008;31:885.
  34. Das S, Gautam N, Dey SK, Maiti T, Roy S. Oxidative stress in the brain of nicotine-induced toxicity: protective role of Andrographis paniculata Nees and vitamin E. Appl Physiol Nutr Metab. 2009;34:124-135. https://doi.org/10.1139/H08-147
  35. Dinan TG, Cryan JF. Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology. 2012;37:1369-1378. https://doi.org/10.1016/j.psyneuen.2012.03.007
  36. European Medicines Agency/Committee on Herbal Medicinal Products. Reflection paper on the adaptogenic concept. (London, UK: European Medicines Agency), 2007.
  37. Gorter MK. The bitter constituent of Andrographis paniculata Nees. Rec Trav Chim. 1911;30:151-160.
  38. Govindarajan R, Vijayakumar M, Pushpangadan P. Antioxidant approach to disease management and the role of 'Rasayana' herbs of Ayurveda. J Ethnopharmacol. 2005;99:165-178. https://doi.org/10.1016/j.jep.2005.02.035
  39. Guo W, Liu W, Chen G, Hong S, Qian C, Xie N, Yang X, Sun Y, Xu Q. Water-soluble andrographolide sulfonate exerts antisepsis action in mice through down-regulating p38 MAPK, STAT3 and NF-kappaB pathways. Int Immunopharmacol. 2012;14:613-619. https://doi.org/10.1016/j.intimp.2012.09.002
  40. Gupta S, Yadava JNS, Tandon JS. Antisecretory (Antidiarrhoeal) Activity of Indian Medicinal Plants Against Escherichia Coli Enterotoxin-Induced Secretion in Rabbit and Guinea Pig Ileal Loop Models. Pharm Biol. 1993;31:198-204. https://doi.org/10.3109/13880209309082942
  41. Hapuarachchi SD, Ali Z, Abe N, Sugandhika ST, Sandun ST, Khan IA. Andrographidine G, a new flavone glucoside from Andrographis paniculata. Nat Prod Commun. 2013;8:333-334.
  42. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: underlying mechanisms and clinical application. Atherosclerosis. 2009;204:334-341. https://doi.org/10.1016/j.atherosclerosis.2008.10.029
  43. Jarukamjorn K, Nemoto N. Pharmacological aspects of Andrographis paniculata on health and its major diterpenoid constituent Andrographolide. J Health Sci. 2008;54:370-381. https://doi.org/10.1248/jhs.54.370
  44. He X, Li J, Gao H, Qiu F, Cui X, Yao X. Six new andrographolide metabolites in rats. Chem Pharm Bull (Tokyo). 2003;51:586-589. https://doi.org/10.1248/cpb.51.586
  45. Hidalgo MA, Hanke JL, Bertoglio JC, Burgos RA. Andrographolide a new potential drug for long term treatment of Rheumatoid Arthritis disease. In Innovative Rheumatology, Hiroaki M ed. (Hampshire, UK: InTech), pp. 247-270, 2013.
  46. Iruretagoyena MI, Tobar JA, Gonzalez PA, Sepulveda SE, Figueroa CA, Burgos RA, Hancke JL, Kalergis AM. Andrographolide interferes with T cell activation and reduces experimental autoimmune encephalomyelitis in the mouse. J Pharmacol Exp Ther. 2005;312:366-372.
  47. Jayakumar T, Hsieh CY, Lee JJ Sheu JR. Experimental and clinical pharmacology of Andrographis paniculata and its major bioactive phytoconstituent andrographolide. Evid Based Complement Alternat Med 2013;2013:846740.
  48. Koteswara Rao Y, Vimalamma G, Rao CV, Tzeng YM. Flavonoids and andrographolides from Andrographis paniculata. Phytochemistry. 2004;65:2317-2321. https://doi.org/10.1016/j.phytochem.2004.05.008
  49. Kulkarni R, Girish KJ, Kumar A. Nootropic herbs (Medhya Rasayana) in Ayurveda: An update. Pharmacogn Rev. 2012;6:147-153. https://doi.org/10.4103/0973-7847.99949
  50. Kumar A, Dora J, Singh A, Tripathi R. A review on King of Bitter (Kalmegh). Int J Res Pharma Chem. 2012;2:116-124.
  51. Li J, Cheung HY, Zhang Z, Chan GK, Fong WF. Andrographolide induces cell cycle arrest at G2/M phase and cell death in HepG2 cells via alteration of reactive oxygen species. Eur J Pharmacol. 2007;568:31-44. https://doi.org/10.1016/j.ejphar.2007.04.027
  52. Lim JC, Chan TK, Ng DS, Sagineedu SR, Stanslas J, Wong WS. Andrographolide and its analogues: versatile bioactive molecules for combating inflammation and cancer. Clin Exp Pharmacol Physiol. 2012;39:300-310. https://doi.org/10.1111/j.1440-1681.2011.05633.x
  53. Mishra K, Dash AP, Swain BK, Dey N. Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin. Malar J. 2009;8:26. https://doi.org/10.1186/1475-2875-8-26
  54. Liu J, Wang ZT, Ji LL. In vivo and in vitro anti-inflammatory activities of neoandrographolide. Am J Chin Med. 2007;35:317-328. https://doi.org/10.1142/S0192415X07004849
  55. Mandal SC, Dhara AK, Maiti BC. Studies on psychopharmacological activity of Andrographis paniculata extract. Phytother Res. 2001;15:253-256. https://doi.org/10.1002/ptr.704
  56. Michelsen KS, Wong MH, Ko B, Thomas LS, Dhall D, Targan SR. HMPL-004 (Andrographis paniculata extract) prevents development of murine colitis by inhibiting T-cell proliferation and TH1/TH17 responses. Inflamm Bowel Dis. 2013;19:151-164.
  57. Mishra SK, Sangwan NS, Sangwan RS. Andrographis paniculata (Kalmegh): A Review. Pharmacogn Rev 2007;1:283-298.
  58. Nagalekshmi R, Menon A, Chandrasekharan DK, Nair CK. Hepatoprotective activity of Andrographis paniculata and Swertia chirayita. Food Chem Toxicol. 2011;49:3367-3373. https://doi.org/10.1016/j.fct.2011.09.026
  59. Najib Nik ARN, Furuta T, Kojima S, Takane K, Ali Mohd M. Antimalarial activity of extracts of Malaysian medicinal plants. J Ethnopharmacol. 1999;64:249-254. https://doi.org/10.1016/S0378-8741(98)00135-4
  60. Nugroho AE, Andrie M, Warditiani NK, Siswanto E, Pramono S, Lukitaningsih E. Antidiabetic and antihiperlipidemic effect of Andrographis paniculata (Burm. f.) Nees and andrographolide in high-fructose-fat-fed rats. Indian J Pharmacol. 2012;44:377-381. https://doi.org/10.4103/0253-7613.96343
  61. Page C. Paradoxical pharmacology: turning our pharmacological models upside down. Trends Pharmacol Sci. 2011;32:197-200. https://doi.org/10.1016/j.tips.2011.02.006
  62. Pandey AK, Mandal AK. Variation in morphological characteristics and andrographolide content in Andrographis paniculata (Burm.f.) Nees of central India. Iranica J Energy Environ. 2010;1:165-169.
  63. Parichatikanond W, Suthisisang C, Dhepakson P, Herunsalee A. Study of anti-inflammatory activities of the pure compounds from Andrographis paniculata (burm.f.) Nees and their effects on gene expression. Int Immunopharmacol. 2010;10:1361-1373. https://doi.org/10.1016/j.intimp.2010.08.002
  64. Panossian A, Hovhannisyan A, Mamikonyan G, Abrahamian H, Hambardzumyan E, Gabrielian E, Goukasova G, Wikman G, Wagner H. Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. Phytomedicine. 2000;7:351-364. https://doi.org/10.1016/S0944-7113(00)80054-9
  65. Panossian A, Kochikian A, Gabrielian E, Muradian R, Stepanian H, Arsenian F, Wagner H. Effect of Andrographis paniculata extract on progesterone in blood plasma of pregnant rats. Phytomedicine. 1999;6:157-161. https://doi.org/10.1016/S0944-7113(99)80003-8
  66. Panossian A, Wikman G. Efficacy of Andrographis paniculata in Upper Respiratory Tract Infectious Diseases and the Mechanism of Action. In Evidence and Rational Based Research on Chinese Drugs, Wagner H, Ulrich-Merzenich G eds. (Vienna, Austria: Springer), pp. 137-179, 2013.
  67. Parixit B, Bharath Ch, Rajarajeshwari N, Ganapaty S. The Genus Andrographis- A review. Int J Pharm Sci. 2012;4:1835-1856.
  68. Pawar VS, Shivakumar H. Screening methods for evaluation of adaptogenic agents: A review. J Pharm Res. 2011;4:763-765.
  69. Pawar VS, Shivakumar H. A current status of adaptogens: Natural remedy to stress. Asian Pac J Trop Dis. 2012;2:S480-S490. https://doi.org/10.1016/S2222-1808(12)60207-2
  70. Pramanick S, Banerjee S, Achari B, Mukhopadhyay S. Phytochemicals from the genus Andrographis. In: Govil JN, Singh VK, Bhardwaj R eds. Recent Progress in Medicinal Plants: Phytomedicines. (Houston, USA: Studium Press LLC), pp. 339-387, 2007.
  71. Qin LH, Kong L, Shi GJ, Wang ZT, Ge BX. Andrographolide inhibits the production of TNF-alpha and interleukin-12 in lipopolysaccharide-stimulated macrophages: role of mitogen-activated protein kinases. Biol Pharm Bull. 2006;29:220-224. https://doi.org/10.1248/bpb.29.220
  72. Rook GAW, Raison CL, Lowry CA. Microbial "Old Friends", immunoregulation and psychiatric disorders. In The gut microbiome and the nervous system, Heidt PJ, Bienenstoc J, Rusch V eds. (Berlin, Germany: Old Herborn University), pp. 61-90, 2013.
  73. Radhika P, Annapurna A, Rao SN. Immunostimulant, cerebroprotective & nootropic activities of Andrographis paniculata leaves extract in normal & type 2 diabetic rats. Indian J Med Res. 2012a;135:636-641.
  74. Radhika P, Prasad YR, Sowjanya K. A new diterpene from the leaves of Andrographis paniculata Nees. Nat Prod Commun. 2012b;7:485-486.
  75. Rege NN, Thatte UM, Dahanukar SA. Adaptogenic properties of six rasayana herbs used in Ayurvedic medicine. Phytother Res. 1999;13:275-291. https://doi.org/10.1002/(SICI)1099-1573(199906)13:4<275::AID-PTR510>3.0.CO;2-S
  76. Samuelsson G, Bohlin L. Drugs of Natural Origin: A Treatise of Pharmacognosy. (Stockholm, Sweden: Swedish Pharmaceutical Press), p. 776, 2009.
  77. Sandborn WJ, Targan SR, Byers VS, Rutty DA, Mu H, Zhang X, Tang T. Andrographis paniculata extract (HMPL-004) for active ulcerative colitis. Am J Gastroenterol. 2013;108:90-98. https://doi.org/10.1038/ajg.2012.340
  78. Saranya P, Geetha A, Selvamathy SM. A biochemical study on the gastroprotective effect of andrographolide in rats induced with gastric ulcer. Indian J Pharm Sci. 2011;73:550-557. https://doi.org/10.4103/0250-474X.99012
  79. Saxena RC, Singh R, Kumar P, Yadav SC, Negi MP, Saxena VS, Joshua AJ, Vijayabalaji V, Goudar KS, Venkateshwarlu K, Amit A. A randomized double blind placebo controlled clinical evaluation of extract of Andrographis paniculata (KalmCold) in patients with uncomplicated upper respiratory tract infection. Phytomedicine. 2010;17:178-185. https://doi.org/10.1016/j.phymed.2009.12.001
  80. Schmidt MI, Duncan BB. Diabesity: an inflammatory metabolic condition. Clin Chem Lab Med. 2003;41:1120-1130.
  81. Selzner N, Boehnert M, Selzner M. Preconditioning, postconditioning, and remote conditioning in solid organ transplantation: basic mechanisms and translational applications. Transplant Rev (Orlando). 2012;26:115-124. https://doi.org/10.1016/j.trre.2011.07.003
  82. Sheeja K, Shihab PK, Kuttan G. Antioxidant and anti-inflammatory activities of the plant Andrographis paniculata Nees. Immunopharmacol Immunotoxicol. 2006;28:129-140. https://doi.org/10.1080/08923970600626007
  83. Sharma A, Lal K, Handa SS. Standardization of the indian crude drug kalmegh by high pressure liquid chromatographic determination of andrographolide. Phytochemical Anal. 1992;3:129-131. https://doi.org/10.1002/pca.2800030308
  84. Sheeja K, Guruvayoorappan C, Kuttan G. Antiangiogenic activity of Andrographis paniculata extract and andrographolide. Int Immunopharmacol. 2007;7:211-221. https://doi.org/10.1016/j.intimp.2006.10.002
  85. Sheeja K, Kuttan G. Ameliorating effects of Andrographis paniculata extract against cyclophosphamide-induced toxicity in mice. Asian Pac J Cancer Prev. 2006;7:609-614.
  86. Shen T, Yang WS, Yi YS, Sung GH, Rhee MH, Poo H, Kim MY, Kim KW, Kim JH, Cho JY. AP-1/IRF-3 targeted anti-inflammatory activity of andrographolide isolated from Andrographis paniculata. Evid Based Complement Alternat Med. 2013;2013:210736.
  87. Siripong P, Kongkathip B, Preechanukool K, Picha P, Tunsuwan K, Taylor WC. Cytotoxic diterpenoid constituents from Andrographis paniculata Nees leaves. J Sci Soc Thailand. 1992;18:187-194. https://doi.org/10.2306/scienceasia1513-1874.1992.18.187
  88. Smith AP. Effects of the common cold on mood, psychomotor performance, the encoding of new information, speed of working memory and semantic processing. Brain Behav Immun. 2012;26:1072-1076. https://doi.org/10.1016/j.bbi.2012.06.012
  89. Smith AP. Twenty-five years of research on the behavioural malaise associated with influenza and the common cold. Psychoneuroendocrinology. 2013;38:744-751. https://doi.org/10.1016/j.psyneuen.2012.09.002
  90. Subramanian R, Asmawi MZ, Sadikun A. In vitro alpha-glucosidase and alpha-amylase enzyme inhibitory effects of Andrographis paniculata extract and andrographolide. Acta Biochim Pol. 2008;55:391-398.
  91. Thakur AK, Chatterjee SS, Kumar V. Therapeutic potential of traditionally used medicinal plant Andrographis paniculata (Burm. F.) against diabesity: an experimental study in rats. TANG. 2014a;4:e7. https://doi.org/10.5667/tang.2014.0001
  92. Subramanian R, Zaini Asmawi M, Sadikun A. A bitter plant with a sweet future? A comprehensive review of an oriental medicinal plant: Andrographis paniculata. Phytochemistry Rev. 2012;11:39-75. https://doi.org/10.1007/s11101-011-9219-z
  93. Thakur AK, Chatterjee SS, Kumar V. General neuropharmacological screening of standardized extract of Andrographis paniculata in rodents. Ann Neurosci. 2012;19:S36-S37.
  94. Thakur AK, Chatterjee SS, Kumar V. Neuropsychopharmacology of a therapeutically used Andrographis paniculata extract: a preclinical study. Oriental Pharm Exp Med. 2013;14:181-191. https://doi.org/10.1007/s13596-013-0140-4
  95. Thakur AK, Chatterjee SS, Kumar V. Antidepressant-like activity of Andrographis paniculata in type-2 diabetic rats. Clin Pharmacol Biopharm. 2014b.
  96. Thakur AK, Shakya A, Husain GM, Emerald M, Kumar V. Gut-microbiota and mental health: current and future perspectives. J Pharmacol Clin Toxicol. 2014;2:1016.
  97. Thakur M, Weng A, Fuchs H, Sharma V, Bhargava CS, Chauhan NS, Dixit VK, Bhargava S. Rasayana properties of Ayurvedic herbs: are polysaccharides a major contributor. Carbohydr Polymers. 2012;87:3-15. https://doi.org/10.1016/j.carbpol.2011.08.035
  98. Thisoda P, Rangkadilok N, Pholphana N, Worasuttayangkurn L, Ruchirawat S, Satayavivad J. Inhibitory effect of Andrographis paniculata extract and its active diterpenoids on platelet aggregation. Eur J Pharmacol. 2006;553:39-45. https://doi.org/10.1016/j.ejphar.2006.09.052
  99. Valdiani A, Kadir MA, Tan SG, Talei D, Abdullah MP, Nikzad S. Nain-e Havandi Andrographis paniculata present yesterday, absent today: a plenary review on underutilized herb of Iran's pharmaceutical plants. Mol Biol Rep. 2012;39:5409-5424. https://doi.org/10.1007/s11033-011-1341-x
  100. Wiart C, Kumar K, Yusof MY, Hamimah H, Fauzi ZM, Sulaiman M. Antiviral properties of ent-labdene diterpenes of Andrographis paniculata nees, inhibitors of herpes simplex virus type 1. Phytother Res. 2005;19:1069-1070. https://doi.org/10.1002/ptr.1765
  101. Vissiennon C, Nieber K, Kelber O, Butterweck V. Route of administration determines the anxiolytic activity of the flavonols kaempferol, quercetin and myricetin-are they prodrugs? J Nutr Biochem. 2012;23:733-740. https://doi.org/10.1016/j.jnutbio.2011.03.017
  102. Wang T, Liu B, Zhang W, Wilson B, Hong JS. Andrographolide reduces inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuron-glia cultures by inhibiting microglial activation. J Pharmacol Exp Ther. 2004;308:975-983.
  103. WHO. Herba andrographidis. In WHO Monographs on Selected Medicinal Plants, WHO. (Geneva, Switzerland: World Health Organization), pp. 12-25, 2003.
  104. Williamson EM. Major Herbs of Ayurveda. (London, England: Churchill Livingstone), p. 361, 2002.
  105. Winston D, Maimes S. Adaptogens: Herbs for strength, stamina, and stress relief. (Vermont, USA: Healing Art Press), 2007.
  106. Wolowczuk I, Verwaerde C, Viltart O, Delanoye A, Delacre M, Pot B, Grangette C. Feeding Our Immune System: Impact on Metabolism. Clin Dev Immunol. 2008;2008:639803.
  107. Woo AY, Waye MM, Tsui SK, Yeung ST, Cheng CH. Andrographolide up-regulates cellular-reduced glutathione level and protects cardiomyocytes against hypoxia/reoxygenation injury. J Pharmacol Exp Ther. 2008;325:226-235. https://doi.org/10.1124/jpet.107.133918
  108. Wu TS, Chern HJ, Damu AG, Kuo PC, Su CR, Lee EJ, Teng CM. Flavonoids and ent-labdane diterpenoids from Andrographis paniculata and their antiplatelet aggregatory and vasorelaxing effects. J Asian Nat Prod Res. 2008;10:17-24. https://doi.org/10.1080/10286020701273627
  109. Yang T, Shi HX, Wang ZT, Wang CH. Hypolipidemic effects of andrographolide and neoandrographolide in mice and rats. Phytother Res. 2013a;27:618-623. https://doi.org/10.1002/ptr.4771
  110. Xia YF, Ye BQ, Li YD, Wang JG, He XJ, Lin X, Yao X, Ma D, Slungaard A, Hebbel RP, et al. Andrographolide attenuates inflammation by inhibition of NF-kappa B activation through covalent modification of reduced cysteine 62 of p50. J Immunol. 2004;173:4207-4217. https://doi.org/10.4049/jimmunol.173.6.4207
  111. Xu C, Chou GX, Wang ZT. A new diterpene from the leaves of Andrographis paniculata Nees. Fitoterapia. 2010;81:610-613. https://doi.org/10.1016/j.fitote.2010.03.003
  112. Yan X, Wang T, Ma Z, Zhang W, Duan J, Cai Y; Hutchison MediPharma Enterprises Limited (Nassau, New Providence, BS), assignee. Crude extracts from Andrographis paniculata. US patent 7341748 B2, 2008.
  113. Yang T, Xu C, Wang ZT, Wang CH. Comparative pharmacokinetic studies of andrographolide and its metabolite of 14-deoxy-12-hydroxy-andrographolide in rat by ultra-performance liquid chromatography-mass spectrometry. Biomed Chromatogr. 2013b;27:931-937. https://doi.org/10.1002/bmc.2884
  114. Ye L, Wang T, Tang L, Liu W, Yang Z, Zhou J, Zheng Z, Cai Z, Hu M, Liu Z. Poor oral bioavailability of a promising anticancer agent andrographolide is due to extensive metabolism and efflux by P-glycoprotein. J Pharm Sci. 2011;100:5007-5017. https://doi.org/10.1002/jps.22693
  115. Yunus MB. Fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes. Semin Arthritis Rheum. 2007;36:339-356. https://doi.org/10.1016/j.semarthrit.2006.12.009
  116. Yunus MB. Central sensitivity syndromes: An overview. J Musculoskelet Pain. 2009;17:400-408. https://doi.org/10.3109/10582450903284752
  117. Zhang CY, Tan BK. Mechanisms of cardiovascular activity of Andrographis paniculata in the anaesthetized rat. J Ethnopharmacol. 1997;56:97-101. https://doi.org/10.1016/S0378-8741(97)01509-2
  118. Zhang J, Zhou F, Lu M, Ji W, Niu F, Zha W, Wu X, Hao H, Wang G. Pharmacokinetics-pharmacology disconnection of herbal medicines and its potential solutions with cellular pharmacokinetic-pharmacodynamic strategy. Curr Drug Metab. 2012;13:558-576. https://doi.org/10.2174/1389200211209050558
  119. Zhang Q, Pi J, Woods CG, Jarabek AM, Clewell HJ, 3rd, Andersen ME. Hormesis and adaptive cellular control systems. Dose Response. 2008;6:196-208. https://doi.org/10.2203/dose-response.07-028.Zhang
  120. Zhang XF, Tan BK. Antihyperglycaemic and anti-oxidant properties of Andrographis paniculata in normal and diabetic rats. Clin Exp Pharmacol Physiol. 2000;27:358-363. https://doi.org/10.1046/j.1440-1681.2000.03253.x
  121. Zhou B, Zhang D, Wu X. Biological activities and corresponding SARs of andrographolide and its derivatives. Mini Rev Med Chem. 2013;13:298-309.