Isatis Leaf

• How It Works

  Isatis leaf has not been shown to treat or prevent cancer.

  Isatis leaf extract is derived from the same plant from which indigo dye is made. It is used in combination with isatis root and other herbs both in Traditional Chinese Medicine and in Ayurveda to treat the common cold, sore throat, mumps, respiratory ailments, other febrile diseases, hepatitis, and malignant tumors. Isatis root has both similar and different properties from isatis leaf.

  Isatis leaf has anti-inflammatory properties. Laboratory studies suggest that indirubin, an active compound in isatis, stops cell duplication and therefore may be useful in cancer treatment. Other lab experiments show that isatis extract can kill certain viruses and counteract some symptoms and tissue damage from bacterial infections. Qing Dai, the pulverised form of isatis leaf, has been shown useful for the treatment of psoriasis. It was also found effective against ulcerative colitis, but its use has been associated with pulmonary arterial hypertension. However, the symptoms resolved after discontinuing Qing Dai.

• Purported Uses
  • To prevent and treat cancer
    Lab studies show that an active compound in isatis stops cell duplication, but there is no evidence from clinical trials that it can prevent or treat cancer. In China, isatis is used in combination with other botanicals to treat chronic myelogenous leukemia.
  • To treat diarrhea or gastrointestinal disorders
    Isatis extracts have anti-inflammatory activity in the laboratory setting. A pulverized version of the extract is used in China to treat ulcerative colitis.
  • To treat hepatitis
    Isatis extracts have anti-inflammatory effects.
  • To treat HIV and AIDS
    There is no scientific evidence to support this claim.
  • To treat respiratory infections
    Although isatis has antiviral activity, there is no evidence from clinical trials that it can effectively treat infections.
• Side Effects
  • Pulmonary arterial hypertension has been associated with use of Qing Dai in patients with ulcerative colitis. Symptoms improved after discontinuing use.
    
  • Colitis involving wall thickening and edema that affected the large bowel, abdominal pain and bloody diarrhea were associated with the use of Qing Dai in patients with ulcerative colitis. Symptoms improved after stopping use.
• Scientific Name

  Isatidis baphicacanthi, Isatis tinctoria, Isatis indigotica, Folium isatidis

• Clinical Summary

  Isatis leaf is derived from the isatis plant and is a source of indigo dye. In both traditional Chinese medicine (TCM) and Ayurveda, it is used in combination with isatis root and other herbs to treat the common cold, sore throat, mumps, respiratory ailments, other febrile diseases, hepatitis, and malignant tumors ^(1) (2). Isatis root has both overlapping and different properties from isatis leaf.

  Isatis leaf is one of the ingredients used in PC-SPES, an herbal formula used to treat prostate cancer. It is also used in Danggui Longhui Wan, a formula used to treat chronic myelocytic leukemia (CML) in China ⁽⁴⁾. In vitro and in vivo studies indicate that isatis has antimicrobial, antiendotoxic ⁽⁵⁾, antiviral ^{(6) (7) (8)}, immunostimulatory ⁽⁹⁾, anti-inflammatory ^(10) (11), and chemotherapeutic ⁽¹²⁾ properties. In several instances, the pharmacologic effects of isatis leaves were found to be greater than that of the roots ^(5) (8). A preliminary study in healthy volunteers reported anti-inflammatory ⁽¹³⁾ effects with use of topical isatis leaf.

  The pulverized form of isatis leaf, known as Qing Dai, has been used in small studies for the treatment of ulcerative colitis that showed benefit ^(3) (20). A randomized controlled trial also reported effectiveness ⁽²¹⁾; however, the study was terminated following a report of pulmonary arterial hypertension (PAH) in a patient (not a study participant) who self-medicated with Qing Dai. Additional cases of Qing Dai-associated PAH have been reported in patients with ulcerative colitis, but symptoms improved after discontinuing use ^(22) (23).
  In other studies, topical use of Qing Dai was found useful for the treatment of psoriasis ^{(24) (25) (26)}.

• Purported Uses
  • Cancer treatment
  • Diarrhea
  • GI disorders
  • Hepatitis
  • HIV and AIDS
  • Respiratory infections
• Mechanism of Action

  Isatis leaf inhibits cyclooxygenase-2 (COX-2) with preferential effects on COX-2–catalysed prostaglandin synthesis, in vitro ⁽¹⁰⁾. The alkaloid tryptanthrin has been identified as the inhibitor of COX-2 ⁽¹⁰⁾ and 5-lipoxygenase (5-LOX) ^(13) (18). Indirubin, another active component, inhibits cyclin-dependent kinases (CDKs) and prevents proliferation by arresting cells in the G2/M phase ⁽⁴⁾. Other alkaloids isolated from isatis inhibit leukocyte function and attenuate the production of mediators related to inflammatory responses ⁽¹¹⁾. A compound derived from isatisine A showed moderate anti-HIV-1 activity ⁽⁷⁾. But better virucidal activity has been reported with leaf, not root extracts using a swine pseudorabies model ⁽⁸⁾.

  Animal models suggest that isatis leaf can reduce allergic airway inflammation and hyper-responsiveness by inhibiting production of Th2 cytokines IL-4 and IL-5, and RANTES ⁽⁹⁾. And when used as postexposure prophylaxis, isatis leaf attenuated lung tissue damage and reduce lung virus titers ⁽⁶⁾. Findings also showed induction of hepatocellular cancer cell death by isatis via a caspase-independent apoptotic pathway ⁽¹²⁾.

  In other mechanistic studies, Qing Dai was shown to prevent bisphosphonate-induced gastrointestinal injury by suppressing mitochondrial ROS production, the main cause of cellular lipid peroxidation ⁽²⁷⁾. Its anti-psoriatic effects are believed to be mediated by modulating the proliferation and differentiation of keratinocytes ⁽²⁸⁾, and by down regulating the IL-17 pathway ⁽²⁹⁾.

• Adverse Reactions
  • Pulmonary arterial hypertension has been associated with use of Qing Dai in patients with ulcerative colitis ^(22) (23). Symptoms improved after discontinuing use.
    
  • Colitis involving wall thickening and edema that affected the large bowel, abdominal pain and bloody diarrhea were associated with use of Qing Dai in patients with ulcerative colitis. Cessation of use resulted in symptom resolution ⁽³⁰⁾.
• References

  1. Zou P, Koh HL. Determination of indican, isatin, indirubin and indigotin in Isatis indigotica by liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom. 2007;21(7):1239-1246.

  2. Bensky D, Gamble A. Chinese Herbal Medicine: Materia Medica Revised ed. Seattle, WA: Eastland Press; 1993.

  3. Suzuki H, Kaneko T, Mizokami Y, et al. Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis. World J Gastroenterol. May 7 2013;19(17):2718-2722.

  4. Hoessel R, Leclerc S, Endicott JA, et al. Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat Cell Biol. May 1999;1(1):60-67.

  5. Wang Y, Qiao CZ, Liu S, et al. [Evaluation on antiendotoxic action and antiviral action in vitro of tetraploid Isatis indigotica]. Zhongguo Zhong Yao Za Zhi. Jun 2000;25(6):327-329.

  6. Deng YP, Liu YY, Liu Z, et al. Antiviral activity of Folium isatidis derived extracts in vitro and in vivo. Am J Chin Med. 2013;41(4):957-969.

  7. Liu JF, Jiang ZY, Wang RR, et al. Isatisine A, a novel alkaloid with an unprecedented skeleton from leaves of Isatis indigotica. Org Lett. Oct 11 2007;9(21):4127-4129.

  8. Hsuan SL, Chang SC, Wang SY, et al. The cytotoxicity to leukemia cells and antiviral effects of Isatis indigotica extracts on pseudorabies virus. J Ethnopharmacol. May 4 2009;123(1):61-67.

  9. Brattstrom A, Schapowal A, Kamal MA, et al. The plant extract Isatis tinctoria L. extract (ITE) inhibits allergen-induced airway inflammation and hyperreactivity in mice. Phytomedicine. Jul 2010;17(8-9):551-556.

  10. Danz H, Stoyanova S, Wippich P, et al. Identification and isolation of the cyclooxygenase-2 inhibitory principle in Isatis tinctoria. Planta Med. Jul 2001;67(5):411-416.

  11. Molina P, Tarraga A, Gonzalez-Tejero A, et al. Inhibition of leukocyte functions by the alkaloid isaindigotone from Isatis indigotica and some new synthetic derivatives. J Nat Prod. Oct 2001;64(10):1297-1300.

  12. Chung YC, Tang FY, Liao JW, et al. Isatis indigotica induces hepatocellular cancer cell death via caspase-independent apoptosis-inducing factor translocation apoptotic pathway in vitro and in vivo. Integr Cancer Ther. Jun 2011;10(2):201-214.

  13. Heinemann C, Schliemann-Willers S, Oberthur C, et al. Prevention of experimentally induced irritant contact dermatitis by extracts of Isatis tinctoria compared to pure tryptanthrin and its impact on UVB-induced erythema. Planta Med. May 2004;70(5):385-390.

  14. Zhang Q, Hong B, Zheng L, et al. Matrix solid-phase dispersion extraction followed by HPLC-diode array detection method for the determination of major constituents in a traditional Chinese medicine Folium isatidis (Da-qing-ye). J Sep Sci. Sep 2012;35(18):2453-2459.

  15. Mohn T, Plitzko I, Hamburger M. A comprehensive metabolite profiling of Isatis tinctoria leaf extracts. Phytochemistry. May 2009;70(7):924-934.

  16. Deng X, Gao G, Zheng S, et al. Qualitative and quantitative analysis of flavonoids in the leaves of Isatis indigatica Fort. by ultra-performance liquid chromatography with PDA and electrospray ionization tandem mass spectrometry detection. J Pharm Biomed Anal. Nov 4 2008;48(3):562-567.

  17. Condurso C, Verzera A, Romeo V, et al. The leaf volatile constituents of Isatis tinctoria by Solid-Phase Microextraction and Gas chromatography/Mass Spectrometry. Planta Med. Aug 2006;72(10):924-928.

  18. Danz H, Stoyanova S, Thomet OA, et al. Inhibitory activity of tryptanthrin on prostaglandin and leukotriene synthesis. Planta Med. Oct 2002;68(10):875-880.

  19. Huang KC. The Pharmacology of Chinese Herbs. Second ed. Boca Raton, FL: CRC Press, Taylor & Francis Group; 1998.

  20. Sugimoto S, Naganuma M, Kiyohara H, et al. Clinical Efficacy and Safety of Oral Qing-Dai in Patients with Ulcerative Colitis: A Single-Center Open-Label Prospective Study. Digestion. 2016;93(3):193-201.

  21. Naganuma M, Sugimoto S, Mitsuyama K, et al. Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis. Gastroenterology. 2018 Mar;154(4):935-947.

  22. Nishio M, Hirooka K, Doi Y. Chinese herbal drug natural indigo may cause pulmonary artery hypertension. Eur Heart J. 2016 Jul 1;37(25):1992.

  23. Misumi K, Ogo T, Ueda J, et al. Development of Pulmonary Arterial Hypertension in a Patient Treated with Qing-Dai (Chinese Herbal Medicine). Intern Med. 2019 Feb 1;58(3):395-399.

  24. Lin YK, Chang CJ, Chang YC, et al. Clinical assessment of patients with recalcitrant psoriasis in a randomized, observer-blind, vehicle-controlled trial using indigo naturalis. Arch Dermatol. 2008 Nov;144(11):1457-64.

  25. Lin YK, Chang YC, Hui RC, et al. A Chinese Herb, Indigo Naturalis, Extracted in Oil (Lindioil) Used Topically to Treat Psoriatic Nails: A Randomized Clinical Trial. JAMA Dermatol. 2015 Jun;151(6):672-4.

  26. Farahnik B, Sharma D, Alban J, Sivamani RK. Topical Botanical Agents for the Treatment of Psoriasis: A Systematic Review. Am J Clin Dermatol. 2017 Aug;18(4):451-468.

  27. Yasuda G, Ito H, Kurokawa H, et al. The preventive effect of Qing Dai on bisphosphonate-induced gastric cellular injuries. J Clin Biochem Nutr. 2019 Jan;64(1):45-51.

  28. Lin YK, Leu YL, Yang SH, Chen HW, Wang CT, Pang JH. Anti-psoriatic effects of indigo naturalis on the proliferation and differentiation of keratinocytes with indirubin as the active component. J Dermatol Sci. 2009 Jun;54(3):168-74.

  29. Cheng HM, Wu YC, Wang Q, et al. Clinical efficacy and IL-17 targeting mechanism of Indigo naturalis as a topical agent in moderate psoriasis. BMC Complement Altern Med. 2017 Sep 2;17(1):439.

  30. Kondo S, Araki T, Okita Y, et al. Colitis with wall thickening and edematous changes during oral administration of the powdered form of Qing-dai in patients with ulcerative colitis: a report of two cases. Clin J Gastroenterol. 2018 Aug;11(4):268-272.