INDEX

Dì huáng (Rehmannia glutinosa Dì huáng)

Indications

Allergic, inflammatory, and autoimmune conditions including asthma, urticaria, eczema, hayfever, rheumatoid arthritis, chronic renal disease, thyroid disease, and multiple sclerosis.

Mechanism of Action

Oligosaccharides: Rehmannia contains raffinose family oligosaccharides that are found in many plants and are credited with immune-stimulating properties.1 Raffinose oligosaccharides are difficult to digest and often produce flatulence, another reason why many traditional Rehmannia formulations steam processed the roots.2 Stachyose and verbascoside are raffnose oligosaccharides shown to significantly stimulate fibroblast proliferation.3 Immune polysaccharides including stachyose, raffinose, and verbascose may exert immune modulation via effects on gastrointestinal microbiota.4 Like inulin and other more vigorously studied oligosaccharides, these compounds are referred to as “prebiotics” because of their support of beneficial intestinal bacteria. The oligosaccharides5 and the ionone glycosides in Rehmannia are both credited with hepatoprotective activities.6

Iridoid Glycosides: Rehmannia also contains at least 11 iridoid glycosides, called rehmaglutosides A–K; these glycosides are also known by individual names as many of the related compounds also occur in other plants. Rehmataglutosides A–K include catalpol, geniposide, acteoside, hydroxyaeginetic acid leucosceptoside, martynoside, isomartynoside, purpureaside, geniposidic acid,7 jionoside, rehmapicroside, and rehmanpicrogenin.

Rehmannia also contains the ionone glycosides dihydroxy-β-ionone and trihydroxy-β-ionone8; three phenethylalcohol glycosides; and one furfural derivative,9 feruloyl ajugol and ajugol isomers; the carotenoid glycosides neo-rehmannioside and oxyrehmonioside,10 a polyoxygenated triterpene named glutinolic acid; and two new aeginetic acid quinovosides.11

The iridoid glycosides, particularly catalpol, are the most studied compounds in Rehmannia. Catalpol occurs in other plants (Buddleja, Pikrorrhiza, Catalpa, Chelone, Callicarpa), and when isolated it is shown to affect T-cell balance, modulating T helper-to-T regulatory cell ratios in animal models of allergic airway disease.12 Catalpol has been shown to affect DNA polymerase enzymes and thereby affect DNA metabolism including replication, repair, transcription, recombination, and chromosome segregation during mitosis, thought to contribute to anticancer effects.13

Molecular research on iridoid alkaloids has provided a good example of how whole plants can exert a tonic or modulating effect on the immune system. Whereas catalpol may support inflammatory proliferation of epidermal cells, its metabolites l-shikonin and paeonol are shown to inhibit T-cell–induced proliferation.14 Furthermore, catalpol and acubin, when hydrolyzed, have shown apoptotic effects on leukemia cells, but when not hydrolyzed they have not,15 supporting the traditional practice of steaming or processing Rehmannia roots.

The numerous immune-modulating effects of catalpol and other iridoids glycosides are via inhibitory effects on proinflammatory pathways including NADPH oxidase enzymes,16 nitric oxide (NO) production, and the expression of inducible NO synthase, cyclooxygenase, prostaglandin E2, proinflammatory interleukins,17 tumor necrosis factor (TNF)-α, and activation of nuclear factor-κB (NF-κB)18,19,20 in tandem with promotion of anti-inflammatory pathways and compounds including superoxide dismutase and glutathione.21,22

All of these modulating effects on T-cell, cytokine, chemokine, and inflammatory pathways are credited with analgesic effects and an ability to reduce neuropathic pain.23 However, iridoid glycosides may also provide analgesia by antinociceptive actions. Catalpol and geniposide are shown to bind a nociceptive pain receptor call glucagon-like peptide 1 (GLP-1R). Catalpol and geniposide are reported to be agonists of GLP-1Rs, yet they block the activation and resulting pain by inhibiting formalin- and hydrogen peroxide–induced inflammation.24

Anticancer Effects: Many of these same T-cell and immune-modulating mechanisms are credited with some of catalpol’s anticancer and apoptotic effects in cancer cells. Catalpol may induce apoptosis via promotion of caspase and polymerase enzymes, shown to deter human bladder cancer.25 Animal and cell culture studies show Rehmannia to optimized T-lymphocyte release of cytokines including up-regulating interleukin and interferon production (in bone marrow–derived dendritic cells).26 Rehmannia polysaccharide B is noted to increase the release of interleukin 2 from cytotoxic T lymphocytes, an effect credited with antitumor effects.27

Antiallergy- and Autoimmune-Regulating Effects: Atopic conditions such as allergic airway diseases and eczema involve increase T-helper 2 cell responses, leading to increased serum immunoglobulin E and increased leukocyte infiltration. Rehmannia can help reduce atopic reactivity by reducing the secretion of cytokines, chemokines, and cellular adhesion molecules. Animal models of allergic dermatitis show Rehmannia to limit dermal infiltration of inflammatory cells when provoked by TNF-α and interferon-γ.28 Rehmannia decreases blood levels of TNF-α, interleukin-6, and other proinflammatory mediators, and it corrects elevated blood levels of superoxide dismutase in diabetic mice.29

Effect on AGEs: Advanced glycation products (AGEs) are formed from metabolic by-products or carbohydrate metabolism. When AGEs are bound to glycoprotein receptors on blood cells, endothelium, renal, and other tissues, they contribute to inflammation, cell death, and loss of function. Because of inadequate carbohydrate metabolism and processing, AGEs contribute to the inflammatory burden in diabetes; therefore, agents that inhibit AGE and cellular AGE receptors can decrease pathologic degeneration in chronic inflammatory diseases. Catalpol has been shown to suppress AGE-mediated inflammation by inhibiting the production or reactive oxygen species and NF-κB activation, which may help mitigate diabetic complications.30,31

Evidence-Based Research

Rehmannia may promote equilibrium within the immune system, helping to limit autoimmune activity and allergic hyperactivity without overly suppressing needed and healthy immune responsiveness.

Rehmannia’s immune-related characteristics are related to its capacity to increase leucocyte production and balance T- and B-lymphocyte biosynthesis. Its antioxidant properties can also aid in the prevention of oxidative damage to the liver. Rehmannia glutinosa has antioxidation, anti-inflammation, antiapoptosis actions.32 Compounds in Rehmannia are credited with neuroprotective,22,33 vascular endothelial protective,34 and hepatoprotective actions6,35 that are capable of protecting against ischemia and reperfusion injury,22 reducing inflammation in animal models of acute pancreatitis,20 and attenuating tissue injury in animal models of diabetes. Rehmannia may also benefit allergic and autoimmune hyperreactivity. Although immunosuppressive fractions36 have been identified in Rehmannia, overall the plant is demonstrated to be immune modulating, as have iridoids glycosides in general37, one of the main active molecular groups in Rehmannia.

Catalpol, an iridoid glucoside and one of the main active components of the dried Rehmannia roots, is reported to be altered or degraded when steam processed, but in the presence of the amino acids also found in the roots, the antioxidant properties of the metabolites are significantly increased,38 accounting for the use of steam dried roots in many traditional formulas. Catalpol in Rehmannia roots exerts anti-inflammatory, antitumor, and antiapoptotic effects. Catalpol also exerts neuroprotective effects and is shown to protect against levodopa-induced dyskinesia in animal models of Parkinson’s disease by modulating neurotransmitter signaling in the corpus striatum.39 Rehmannia oligosaccharides at a dose of 200 mg/kg have an ameliorating effect on stress-induced impaired glucose metabolism, in part, via neuroendocrine immunomodulation.40

Rehmannia leaves have also been used as a medicine, although less commonly than the roots, and one study has shown benefit in chronic glomerulonephritis in human subjects as a dose of 400 mg twice a day, improving proteinuria.41 Human trials have also shown Rehmannia root in combination with the angiotensin receptor blocker irbesartan improves proteinuria in chronic glomerulonephritis patients better than irbesartan alone.42

Safety in Pregnancy and Breastfeeding

There is no published or anecdotal evidence regarding the use of Rehmannia in pregnancy or lactation.

General Safety

Animal studies dosing Rehmannia have not noted toxicity or side effects.

Dosage

Rehmannia is generally considered safe, even at high doses up to 50 g/day. Traditional formulas have often included 10–50 g of Rehmannia or steamed Rehmannia root as a daily dose, often decocted with other herbs and taken as a tea on regular basis, but also with regular breaks in the treatment, anywhere from 1 day to 5 days to a month, depending on the dose and overall intended long-term duration of the course of therapy. Modern formulas typically mix Rehmannia root with similarly acting herbs such as Cordyceps and have between 75–500 mg of Rehmannia per dose. It is possible to concentrate the herbal constituents and get more activity with a smaller dose.

Traditional Uses

Rehmannia has been used for a variety of allergic, inflammatory, and autoimmune conditions in traditional Chinese medicine including asthma, urticaria, eczema, rheumatoid arthritis, and chronic renal disease. It is a traditional medicine listed in the Pharmacopoeia of the People’s Republic of China; however, it has not yet attracted great use in the western herbal arena. Rehmannia has often been combined with Astragalus for managing inflammatory and immune disorders and is included in many traditional formulas for allergy, autoimmune disease, liver support, and chronic inflammation including kyon-ok-ko formula.43 Qi-ju-di-huang-wan (Lycium berry, Chrysanthemum, and Rehmannia pill) is commonly prescribed to Sjögren׳s patients,44 and Zhi-Bai-Di-Huang-Wan (Anemarrhena, Phellodendron, and Rehmannia pill) is commonly prescribed to lupus erythematosus patients.45,46 The dried and steamed roots of Rehmannia glutinosa have different pharmacological functions and indications.

References

1

Phytochem Anal. 2012;23(6):607–12. Quantitation of α-galactosides in Rehmannia glutinosa by hydrophilic interaction chromatography-evaporative light scattering detector. Kim TB, Kim SH, Sung SH.

2 Plant Foods Hum Nutr. 1997;51(3):209–18. Effect of processing on flatus producing oligosaccharides in cowpea (Vigna unguiculata) and the tropical African yam bean (Sphenostylis stenocarpa). Nwinuka NM, Abbey BW, Ayalogu EO.

3 J Tradit Complement Med. 2012;2(3):227–34. Stachyose: One of the active fibroblast-proliferating components in the root of Rehmanniae Radix (dì huáng). Lai PK, To MH, Lau KM, Liu CL, Cheng L, Fung KP, Leung PC, Lau CB.

4 J Agric Food Chem. 2013;61(48):11825–31. Stachyose-enriched α-galacto-oligosaccharides regulate gut microbiota and relieve constipation in mice. Li T, Lu X, Yang X.

5 J Agric Food Chem. 2013;61(32):7786–93. Isolation, characterization, and hepatoprotective effects of the raffinose family oligosaccharides from Rehmannia glutinosa Libosch. Zhang R, Zhao Y, Sun Y, Lu X, Yang X.

6 J Asian Nat Prod Res. 2014;16(1):11–9. Ionone glycosides from the roots of Rehmannia glutinosa. Liu YF, Liang D, Luo H, Hao ZY, Wang Y, Zhang CL, Ni G, Chen RY, Yu DQ.

7 Zhongguo Zhong Yao Za Zhi. 2011;36(22):3125–9. Chemical constituents from Rehmannia glutinosa. Li X, Zhou M, Shen P, Zhang J, Chu C, Ge Z, Yan J.

8 Nat Prod Res. 2015;29(1):59–63. Two new ionone glycosides from the roots of Rehmannia glutinosa Libosch. Feng WS, Li M, Zheng XK, Zhang N, Song K, Wang JC, Kuang HX.

9 Food Chem. 2012;135(4):2277–86. Simultaneous determination of iridoid glycosides, phenethylalcohol glycosides and furfural derivatives in Rehmanniae Radix by high performance liquid chromatography coupled with triple-quadrupole mass spectrometry. Xu J, Wu J, Zhu LY, Shen H, Xu JD, Jensen SR, Jia XB, Zhang QW, Li SL.

10 Nat Prod Res. 2011;25(13):1213–8. A new carotenoid glycoside from Rehmannia glutinosa. Fu GM, Shi SP, Ip FC, Pang HH, Ip NY.

11 Chem Pharm Bull (Tokyo). 2011;59(6):742–6. A new polyoxygenated triterpene and two new aeginetic acid quinovosides from the roots of Rehmannia glutinosa. Lee SY, Kim JS, Choi RJ, Kim YS, Lee JH, Kang SS.

12 J Ethnopharmacol. 2015;164:368–77. Bu-Shen-Yi-Qi formulae suppress chronic airway inflammation and regulate Th17/Treg imbalance in the murine ovalbumin asthma model. Wei Y, Luo QL, Sun J, Chen MX, Liu F, Dong JC.

13 Bioorg Med Chem Lett. 2015;25(4):914–8. A new iridoid, verbascoside and derivatives with inhibitory activity against Taq DNA polymerase. Garro HA, García C, Martín VS, Tonn CE, Pungitore CR.

14 Zhonghua Yi Xue Za Zhi. 2014;94(16):1265–9. Effects of catalpol, L-shikonin and paeonol extracted from radix rehmanniae, radix arnebiae and cortex moutan on KGF-induced HaCaT cell proliferation. Lü J, Wang Y, Zhao W, Li N, Li H, Lu J, Zeng W, Bao S, Bai Y.

15 Phytother Res. 2015;29(3):434–43. The hydrolysed products of iridoid glycosides can enhance imatinib mesylate-induced apoptosis in human myeloid leukaemia cells. Kim MB, Kim C, Chung WS, Cho JH, Nam D, Kim SH, Ahn KS.

16 Zhongguo Zhong Yao Za Zhi. 2014;39(15):2936–41. Catalpol protect diabetic vascular endothelial function by inhibiting NADPH oxidase. Liu JY.

17 J Ethnopharmacol. 2012;143(3):867–75. Bioassay-guided isolation of anti-inflammatory components from the root of Rehmannia glutinosa and its underlying mechanism via inhibition of iNOS pathway. Liu CL, Cheng L, Ko CH, Wong CW, Cheng WH, Cheung DW, Leung PC, Fung KP, Bik-San Lau C.

18 Int Immunopharmacol. 2014;23(2):400–6. Protective effect of catalpol on lipopolysaccharide-induced acute lung injury in mice. Fu K, Piao T, Wang M, Zhang J, Jiang J, Wang X, Liu H.

19 J Med Food. 2012;15(6):505–10. 2,5-Dihydroxyacetophenone isolated from Rehmanniae Radix Preparata inhibits inflammatory responses in lipopolysaccharide-stimulated RAW264.7 macrophages. Han Y, Jung HW, Lee JY, Kim JS, Kang SS, Kim YS, Park YK.

20 Int J Mol Sci. 2014;15(7):11957–72. Catalpol ameliorates sodium taurocholate-induced acute pancreatitis in rats via inhibiting activation of nuclear factor kappa B. Xiao WQ, Yin GJ, Fan YT, Qiu L, Cang XF, Yu G, Hu YL, Xing M, Wu de Q, Wang XP, Hu GY, Wan R.

21 Pharm Biol. 2012;50(10):1226–32. The protective effect of picroside II against hypoxia/reoxygenation injury in neonatal rat cardiomyocytes. Meng FJ, Hou ZW, Li Y, Yang Y, Yu B.

22 J Pharm Pharmacol. 2014;66(9):1265–70. Catalpol provides protective effects against cerebral ischaemia/reperfusion injury in gerbils. Liu YR, Li PW, Suo JJ, Sun Y, Zhang BA, Lu H, Zhu HC, Zhang GB.

23 Cell Biochem Biophys. 2014;70(3):1565–71. Analgesic activity of catalpol in rodent models of neuropathic pain, and its spinal mechanism. Wang Y, Zhang R, Xie J, Lu J, Yue Z.

24 Neuropharmacology. 2014;84:31–45. Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors. Gong N, Fan H, Ma AN, Xiao Q, Wang YX.

25 Cell Biochem Biophys. 2015;71(3):1349–56. Catalpol inhibited the proliferation of T24 human bladder cancer cells by inducing apoptosis through the blockade of Akt-mediated anti-apoptotic signaling. Jin D, Cao M, Mu X, Yang G, Xue W, Huang Y, Chen H.

26 Carbohydr Polym. 2013;96(2):516–21. Immunoenhancement effect of rehmannia glutinosa polysaccharide on lymphocyte proliferation and dendritic cell. Huang Y, Jiang C, Hu Y, Zhao X, Shi C, Yu Y, Liu C, Tao Y, Pan H, Feng Y, Liu J, Wu Y, Wang D.

27 Zhongguo Yao Li Xue Bao. 1995;16(4):337–40. Effects of Rehmannia glutinosa polysaccharide b on T-lymphocytes in mice bearing sarcoma 180. Chen LZ, Feng XW, Zhou JH.

28 J Ethnopharmacol. 2011;134(1):37–44. Topical application of Rehmannia glutinosa extract inhibits mite allergen-induced atopic dermatitis in NC/Nga mice. Sung YY, Yoon T, Jang JY, Park SJ, Kim HK.

29 J Ethnopharmacol. 2015;164:229–38. Rehmannia glutinosa (Gaertn.) DC. polysaccharide ameliorates hyperglycemia, hyperlipemia and vascular inflammation in streptozotocin-induced diabetic mice. Zhou J, Xu G, Yan J, Li K, Bai Z, Cheng W, Huang K.

30 Fitoterapia. 2013;86:19–28. Catalpol suppresses advanced glycation end-products-induced inflammatory responses through inhibition of reactive oxygen species in human monocytic THP-1 cells. Choi HJ, Jang HJ, Chung TW, Jeong SI, Cha J, Choi JY, Han CW, Jang YS, Joo M, Jeong HS, Ha K.

31 Inflammation. 2012;35(4):1232–41. Rehmannia glutinosa suppresses inflammatory responses elicited by advanced glycation end products. Baek GH, Jang YS, Jeong SI, Cha J, Joo M, Shin SW, Ha KT, Jeong HS.

32 Curr Med Chem. 2015;22(10):1278–91. Catalpol: A potential therapeutic for neurodegenerative diseases. Jiang B, Shen RF, Bi J, Tian XS, Hinchliffe T, Xia Y.

33 Br J Pharmacol. 2013;169(5):1140–52. Neuroprotective activities of catalpol against CaMKII-dependent apoptosis induced by LPS in PC12 cells. Chen W, Li X, Jia LQ, Wang J, Zhang L, Hou D, Wang J, Ren L.

34 Pharm Biol. 2012;50(10):1226–32. The protective effect of picroside II against hypoxia/reoxygenation injury in neonatal rat cardiomyocytes. Meng FJ, Hou ZW, Li Y, Yang Y, Yu B.

35 J Nat Prod. 2012;75(9):1625–31. Hepatoprotective iridoid glycosides from the roots of Rehmannia glutinosa. Liu YF, Liang D, Luo H, Hao ZY, Wang Y, Zhang CL, Zhang QJ, Chen RY, Yu DQ.

36 Zhong Yao Cai. 2013;36(12):1933–6. Fingerprint research on immunosuppressive fraction of Rehmanniae Radix by HPLC. Zheng XK, Jia YG, Feng ZY, Wang S, Zhang MH, Feng WS.

37 Int Immunopharmacol. 2011;11(1):128–35. Possible role of macrophages induced by an irridoid glycoside (RLJ-NE-299A) in host defense mechanism. Sidiq T, Khajuria A, Suden P, Sharma R, Singh S, Suri KA, Satti NK, Johri RK.

38 Pharmacogn Mag. 2014;10(Suppl 1):S122–9. Characteristics and kinetics of catalpol degradation and the effect of its degradation products on free radical scavenging. Wei GD, Wen XS.

39 Neural Regen Res. 2014;9(4):407–12. Compound formula Rehmannia alleviates levodopa-induced dyskinesia in Parkinson’s disease. Teng L, Hong F, Zhang C, He J, Wang H.

40 Phytomedicine. 2014;21(5):607–14. Ameliorating effect and potential mechanism of Rehmannia glutinosa oligosaccharides on the impaired glucose metabolism in chronic stress rats fed with high-fat diet. Zhang R, Zhou J, Li M, Ma H, Qiu J, Luo X, Jia Z.

41 Afr J Tradit Complement Altern Med. 2013;10(4):109–15. General acteoside of Rehmanniae leaves in the treatment of primary chronic glomerulonephritis: a randomized controlled trial. Qiu H, Fan W, Fu P, Zuo C, Feng P, Liu F, Zhou L, Chen F, Zhong H, Liang Y, Shi M.

42 Phytother Res. 2014;28(1):132–6. Treatment of primary chronic glomerulonephritis with Rehmannia glutinosa acteosides in combination with the angiotensin receptor blocker irbesartan: a randomized controlled trial. Qiu H, Fu P, Fan W, Zuo C, Feng P, Shi P, Cao L, Liu F, Zhou L, Chen F, Zhong H, Gou Z, Liang Y, Shi M.

43 PLoS One. 2014;9(2):e87623. Oriental medicine Kyung-Ok-Ko prevents and alleviates dehydroepiandrosterone-induced polycystic ovarian syndrome in rats. Jang M, Lee MJ, Lee JM, Bae CS, Kim SH, Ryu JH, Cho IH.

44 J Ethnopharmacol. 2014;155(1):435–42. The traditional Chinese medicine prescription patterns of Sjögren׳s patients in Taiwan: a population-based study. Yu MC, Lin SK, Lai JN, Wei JC, Cheng CY.

45 Complement Ther Med. 2014;22(3):481–8. A novel model for exploring the correlation between patterns and prescriptions in clinical practice of traditional Chinese medicine for systemic lupus erythematosus. Liu CY, Wu WH, Huang TP, Lee TY, Chang HH.

46 Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013;33(10):1315–9. Treatment of severe active systemic lupus erythematosus by PMC therapy combined langchuang fuzheng jiedu capsule: a clinical observation. Song XW, Tang WJ, Guan TR, Dai QD, Zhang Y, Wu YJ.