Ashitaba

NutraPedia - Evidence-Based Supplement Research

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Health Goals: detox immunity digestion

Research Overview

Across the provided abstracts, Ashitaba (Angelica keiskei) research is dominated by mechanistic and preclinical studies focused on its prenylated chalcones—primarily 4‑hydroxyderricin and xanthoangelol. The most studied areas include metabolic regulation (skeletal muscle glucose uptake/GLUT4 translocation; inhibition of protein tyrosine phosphatase 1B as a diabetes-relevant target), inflammation (macrophage LPS models assessing NO, TNF‑α, iNOS/COX‑2 and transcription factor signaling), and muscle biology (prevention of glucocorticoid/dexamethasone-induced muscle proteolysis via glucocorticoid receptor antagonism and downstream ubiquitin ligases). Additional animal work explores neuroprotection in a cuprizone demyelination model (MS-relevant outcomes such as demyelination scores, TNF‑α, BDNF, and behavior) and male reproductive protection under heat stress (sperm parameters and induction of heat shock proteins/antioxidant enzymes). Safety-related work includes GLP genotoxicity assays (negative) and a 90‑day rat study noting physiological effects on coagulation parameters and plasma lipids at higher doses; an EFSA novel food assessment is also referenced, indicating regulatory interest in ashitaba sap as a food ingredient.

The strongest evidence supported by these abstracts is that Ashitaba chalcones exert measurable biological effects in cell systems and mouse/rat models, particularly on glucose handling and catabolic muscle signaling. In vitro, 4‑hydroxyderricin and xanthoangelol increase glucose uptake and GLUT4 presence at the plasma membrane in muscle cells, and an oral glucose tolerance test in mice suggests an acute antihyperglycemic effect of a chalcone-enriched extract. Anti-inflammatory activity is supported by reduced LPS-induced NO and TNF‑α and suppression of iNOS/COX‑2 expression in macrophages, with signaling effects that appear to involve AP‑1 modulation (and phosphorylation changes in NF‑κB p65) rather than broad NF‑κB DNA-binding inhibition. For muscle wasting, both cell and mouse data indicate protection against dexamethasone-induced atrophy consistent with glucocorticoid receptor antagonism and reduced expression of ubiquitin ligases (e.g., MuRF‑1, Cbl‑b), providing a coherent mechanistic chain from receptor interaction to phenotypic outcome.

Key gaps are translational: most findings are preclinical, and the abstracts do not provide controlled human trials establishing efficacy, dose–response, durability of benefit, or clinically meaningful endpoints (e.g., HbA1c, insulin sensitivity by clamp, inflammatory biomarkers in patients, functional muscle outcomes, fertility outcomes, or MS-related clinical measures). More research is also needed to clarify pharmacokinetics/bioavailability of individual chalcones, standardization of extracts (content variability, active constituents beyond the two major chalcones), and mechanism (e.g., the non-canonical pathway driving GLUT4 translocation). Safety requires further characterization in humans, particularly given reported effects on coagulation parameters and plasma lipids in subchronic rat studies and the likelihood of interactions with anticoagulants/antiplatelet agents or metabolic drugs. Overall, the evidence base is strongest for mechanistic plausibility and animal-model efficacy in metabolic and muscle-related domains, while robust human efficacy and comprehensive safety profiling remain the primary unmet needs.

1. What conditions has Ashitaba been studied for?

  • Blood glucose control / diabetes-related outcomes: Skeletal muscle glucose uptake and acute hyperglycemia in oral glucose tolerance tests (OGTT) in mice; mechanistic targets relevant to insulin signaling (GLUT4 translocation) and insulin resistance (PTP1B inhibition).

  • Multiple sclerosis (MS)-like demyelination: Cuprizone-induced demyelination and cognitive impairment in C57BL/6 mice.

  • Inflammation: LPS-stimulated inflammatory responses in RAW264 macrophages (NO, TNF-α, iNOS, COX-2; AP-1/NF-κB signaling).

  • Thrombosis / prothrombotic state: Regulation of plasminogen activator inhibitor-1 (PAI-1) in inflammatory models and obese diabetic mice; platelet-related effects in mouse tail-bleeding models (anti-platelet activity in vivo).

  • Obesity / metabolic syndrome features: In obese diabetic (TSOD) mice, effects on body weight gain, fat mass, glucose/insulin, TNF-α, and food efficiency alongside PAI-1 changes.

  • Male fertility under heat stress: Heat stress–induced impairment in sperm density/quality in mice; testicular heat shock proteins (HSPs) and antioxidant enzyme expression.

  • Muscle wasting (steroid-induced): Dexamethasone-induced muscle loss in C2C12 myotubes and in male C57BL/6J mice; glucocorticoid receptor antagonism and ubiquitin ligase expression.

  • Safety/toxicology as a novel food ingredient: Genotoxicity assays and a 90-day repeated-dose oral gavage study in rats; EFSA novel food assessment is referenced (details not provided in the excerpt).

2. Does it work in treating those conditions? Summarize the evidence.

  • Glucose control: supportive preclinical evidence

    • In rat L6 muscle cells, the Ashitaba chalcones 4-hydroxyderricin and xanthoangelol increased 2-deoxyglucose uptake by ~1.9-fold at 10 μM and increased GLUT4 levels in the plasma membrane.

    • In mice, oral administration of a chalcone-enriched Ashitaba extract (standardized to ~150.6 mg/g 4-hydroxyderricin and ~146.0 mg/g xanthoangelol, dry base) suppressed acute hyperglycemia during OGTT.

    • Separately, multiple Ashitaba chalcones showed PTP1B inhibition in vitro (IC50 values reported in μg/mL range), a mechanistic target relevant to insulin signaling; however, this is biochemical evidence rather than clinical efficacy.

    • Limitations: Cell and mouse studies only in these abstracts; no human trials described; mechanism of GLUT4 translocation appeared independent of Akt/AMPK/PKCζ/λ in the cell study, leaving the in vivo pathway uncertain.

  • MS-like demyelination: supportive mouse evidence

    • In a cuprizone mouse model, Ashitaba chalcones (300 or 600 mg/kg/day) reduced demyelination in the corpus callosum and lowered TNFα in serum and brain vs cuprizone alone.

    • The higher dose (600 mg/kg/day) also improved Y-maze behavioral performance and increased BDNF in serum and brain.

    • Limitations: This is an animal model of demyelination, not human MS; dosing is high and may not translate to typical supplement use.

  • Inflammation: strong in vitro evidence, unclear clinical relevance

    • In RAW264 macrophages, 4-hydroxyderricin (10 μM) and xanthoangelol (5 μM) reduced LPS-induced nitric oxide and inhibited TNF-α secretion and expression of iNOS and COX-2.

    • Mechanistically, they suppressed AP-1 DNA-binding activity (but not NF-κB DNA-binding), while still reducing phosphorylation of NF-κB p65 (Ser536).

    • Limitations: Cell culture findings do not establish clinical anti-inflammatory effects in humans.

  • Thrombosis-related markers / platelet function: supportive preclinical evidence with a potential bleeding tradeoff

    • Ashitaba exudates (injected and orally administered long-term) suppressed LPS-induced increases in plasma PAI-1 in mice; several chalcones (including xanthoangelol, xanthoangelols B and D) inhibited TNFα-induced PAI-1 production in human endothelial cells (HUVECs).

    • In obese diabetic TSOD mice, Ashitaba yellow exudate reduced plasma PAI-1 and also decreased glucose, insulin, TNF-α, body weight gain, and fat weights (with little effect in lean controls).

    • In a mouse tail-bleeding model, Ashitaba exudate and xanthoangelol suppressed LPS-induced shortening of tail bleeding, consistent with an anti-platelet effect in vivo.

    • Limitations: These are animal and ex vivo endpoints; no human thrombosis or cardiovascular outcome trials are provided.

  • Male fertility under heat stress: supportive mouse evidence

    • In mice, dietary Ashitaba powder (57.5 mg/kg) completely prevented heat-induced impairment in multiple sperm parameters (including motile/progressive sperm density and motility metrics). Xanthoangelol (3 mg/kg) was partially protective but significantly improved most parameters.

    • Both increased expression of heat shock proteins (Hspa1a, Hsp40) and glutathione synthase in non-stressed testes; Ashitaba powder prevented heat-stress reductions in testis-critical HSPs (Hspa1l, Hspa2).

    • Limitations: Heat-stress mouse model; not evidence for treating human infertility.

  • Steroid-induced muscle wasting: supportive cell and mouse evidence

    • In C2C12 myotubes, 4-hydroxyderricin and xanthoangelol prevented dexamethasone-induced protein degradation by suppressing ubiquitin ligases Cbl-b and MuRF-1.

    • They acted as glucocorticoid receptor antagonists, inhibiting dexamethasone binding and receptor nuclear translocation; they also suppressed phosphorylation of p38 and FoxO3a.

    • In male mice, an Ashitaba extract containing these chalcones suppressed dexamethasone-induced muscle mass wasting and reduced ubiquitin ligase expression, consistent with the proposed mechanism.

    • Limitations: No human trials; potential for interaction with prescribed glucocorticoids is plausible given receptor antagonism (see downsides).

3. What health benefits does it have?

  • Metabolic support (preclinical): Increased skeletal muscle glucose uptake and improved acute glucose tolerance in mice; PTP1B inhibition suggests a plausible insulin-sensitizing mechanism (biochemical evidence).

  • Anti-inflammatory activity (preclinical): Reduced LPS-induced NO and TNF-α and downregulated iNOS/COX-2 in macrophages; reduced TNFα in demyelination and obese diabetic mouse models.

  • Neuroprotective signals in a demyelination model (preclinical): Reduced demyelination and improved cognition-like behavior; increased BDNF in the higher-dose chalcone group.

  • Potential antithrombotic/pro-fibrinolytic effects (preclinical): Lowered PAI-1 in inflammatory and obese diabetic mouse models; inhibited TNFα-induced PAI-1 production in endothelial cells; in vivo anti-platelet activity shown for xanthoangelol in a tail-bleeding model.

  • Protection against heat stress–related sperm impairment (preclinical): Preserved sperm motility/quality in mice, potentially via induction of HSPs and antioxidant defenses.

  • Protection against steroid-induced muscle loss (preclinical): Reduced dexamethasone-induced muscle wasting in mice and protein degradation in myotubes via glucocorticoid receptor-related mechanisms.

Overall, the benefits described in these abstracts are largely mechanistic, cell-based, or animal-model findings. They support biological plausibility but do not establish clinical efficacy in humans.

4. Does it have any downsides or side effects?

  • Potential bleeding/antiplatelet implications (preclinical)

    • Ashitaba exudate and xanthoangelol showed anti-platelet activity in vivo (mouse tail-bleeding model) and Ashitaba products lowered PAI-1 in multiple models, consistent with a shift toward less clotting / more fibrinolysis.

    • Practical implication: This raises a plausible risk of increased bleeding tendency, especially if combined with anticoagulants/antiplatelet drugs, though human interaction data are not provided in the abstracts.

  • Toxicology findings in rats (GLP 90-day study of yellow sap powder with 8.45% chalcones)

    • No genotoxicity signals: Bacterial reverse mutation, chromosome aberration, and in vivo micronucleus assays were negative.

    • Physiologic effects: “Expected known physiological effects” on coagulation parameters and plasma lipids at 300 and 1000 mg/kg/day (direction and clinical relevance not specified in the abstract excerpt).

    • Pathology: Dose-related male rat-specific α2-urinary globulin nephropathy at 100–1000 mg/kg/day (a phenomenon generally considered species- and sex-specific to male rats), and jejunal lymphangiectasia in both sexes at 1000 mg/kg/day.

    • NOAEL: Reported as 300 mg/kg in male and female rats for that preparation and study design.

  • Potential drug interaction concern (mechanism-based)

    • Because 4-hydroxyderricin and xanthoangelol acted as glucocorticoid receptor antagonists in muscle-wasting models, there is a plausible risk they could counteract therapeutic glucocorticoids (e.g., prednisone/dexamethasone) or alter their effects. This is not proven clinically in the abstracts but is mechanistically relevant.

5. Is it beneficial or harmful for any genetic variations (pharmacogenomics)?

The provided abstracts do not report pharmacogenomic analyses (e.g., effects by genotype in humans, or variant-specific metabolism/response). No specific gene–supplement interactions are established here.

  • What can be inferred (hypothesis only, not demonstrated): Some mechanisms described (e.g., glucocorticoid receptor antagonism; effects on inflammatory signaling; coagulation-related endpoints) could, in principle, vary with genetic differences in pathways such as glucocorticoid receptor signaling, inflammatory mediators, or coagulation/fibrinolysis. However, the abstracts provide no data linking Ashitaba response or risk to specific variants.

  • Bottom line: No evidence from these abstracts that Ashitaba is uniquely beneficial or harmful for particular genetic variations.

References

  1. Prenylated chalcones 4-hydroxyderricin and xanthoangelol stimulate glucose uptake in skeletal muscle cells by inducing GLUT4 translocation.
    Kyuichi Kawabata, Keisuke Sawada, Kazunori Ikeda, Itsuko Fukuda, Kengo Kawasaki, Norio Yamamoto, Hitoshi Ashida (2011) - Molecular nutrition & food research
  2. The neuroprotective effects of Chalcones from Ashitaba on cuprizone-induced demyelination via modulation of brain-derived neurotrophic factor and tumor necrosis factor α.
    Soodeh Rowhanirad, Mahnaz Taherianfard (2023) - Brain and behavior
  3. Simultaneous Intake of
    Ran Okouchi, Shuang E, Kazushi Yamamoto, Toshikuni Ota, Kentarou Seki, Mayumi Imai, Ryuki Ota, Yuta Asayama, Ayaka Nakashima, Kengo Suzuki, Tsuyoshi Tsuduki (2019) - Nutrients
  4. A Chalcone from Ashitaba (
    Minson Kweon, Hyejin Lee, Cheol Park, Yung Hyun Choi, Jae-Ha Ryu (2019) - Nutrients
  5. Inhibitory effects of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide-induced inflammatory responses in RAW264 macrophages.
    Michiko Yasuda, Kyuichi Kawabata, Miki Miyashita, Mayu Okumura, Norio Yamamoto, Masakazu Takahashi, Hitoshi Ashida, Hajime Ohigashi (2014) - Journal of agricultural and food chemistry
  6. Safety of ashitaba sap as a Novel food pursuant to Regulation (EU) 2015/2283.
    Dominique Turck, Torsten Bohn, Jacqueline Castenmiller, Stefaan De Henauw, Karen Ildico Hirsch-Ernst, Alexandre Maciuk, Inge Mangelsdorf, Harry J McArdle, Androniki Naska, Kristina Pentieva, Alfonso Siani, Frank Thies, Sophia Tsabouri, Marco Vinceti, Margarita Aguilera-Gómez, Francesco Cubadda, Thomas Frenzel, Marina Heinonen, Miguel Prieto Maradona, Monika Neuhäuser-Berthold, Morten Poulsen, Josef Rudolf Schlatter, Alexandros Siskos, Henk van Loveren, Maria Glymenaki, Eirini Kouloura, Helle Katrine Knutsen (2024) - EFSA journal. European Food Safety Authority
  7. Angelica keiskei (Ashitaba) powder and its functional compound xanthoangelol prevent heat stress-induced impairment in sperm density and quality in mouse testes.
    Daichi Kokubu, Ryousuke Ooba, Yukiko Abe, Hana Ishizaki, Shigeki Yoshida, Atsushi Asano, Shin-Ichi Kashiwabara, Hitoshi Miyazaki (2019) - The Journal of reproduction and development
  8. 4-Hydroxyderricin and xanthoangelol isolated from Angelica keiskei prevent dexamethasone-induced muscle loss.
    Yasukiyo Yoshioka, Yumi Samukawa, Yoko Yamashita, Hitoshi Ashida (2020) - Food & function
  9. PTP1B inhibitors from stems of Angelica keiskei (Ashitaba).
    Jin-Long Li, Li-Xin Gao, Fan-Wang Meng, Chun-Lan Tang, Ru-Jun Zhang, Jing-Ya Li, Cheng Luo, Jia Li, Wei-Min Zhao (2015) - Bioorganic & medicinal chemistry letters
  10. Simultaneous Intake of Euglena Gracilis and Vegetables Synergistically Exerts an Anti-Inflammatory Effect and Attenuates Visceral Fat Accumulation by Affecting Gut Microbiota in Mice.
    Yuto Sakanoi, Shuang E, Kazushi Yamamoto, Toshikuni Ota, Kentarou Seki, Mayumi Imai, Ryuki Ota, Yuta Asayama, Ayaka Nakashima, Kengo Suzuki, Tsuyoshi Tsuduki (2018) - Nutrients
  11. Toxicological assessment of Ashitaba Chalcone.
    Robert R Maronpot (2015) - Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
  12. Xanthoangelols isolated from Angelica keiskei inhibit inflammatory-induced plasminogen activator inhibitor 1 (PAI-1) production.
    Naoki Ohkura, Yoshitaka Nakakuki, Masahiko Taniguchi, Shiho Kanai, Akiko Nakayama, Katsunori Ohnishi, Toshiyuki Sakata, Tomoyoshi Nohira, Juzo Matsuda, Kimiye Baba, Gen-Ichi Atsumi (2011) - BioFactors (Oxford, England)
  13. Possible antithrombotic effects of
    N Ohkura, G Atsumi, K Ohnishi, K Baba, M Taniguchi (2018) - Die Pharmazie
  14. Anti-platelet effects of chalcones from
    N Ohkura, K Ohnishi, M Taniguchi, A Nakayama, Y Usuba, M Fujita, A Fujii, K Ishibashi, K Baba, G Atsumi (2016) - Die Pharmazie
  15. The Ashitaba (
    Tianshun Zhang, Qiushi Wang, Mangaladoss Fredimoses, Ge Gao, Keke Wang, Hanyong Chen, Ting Wang, Naomi Oi, Tatyana A Zykova, Kanamata Reddy, Ke Yao, Weiya Ma, Xiaoyu Chang, Mee-Hyun Lee, Moeez Ghani Rathore, Ann M Bode, Hitoshi Ashida, Scott M Lippman, Zigang Dong (2018) - Cancer prevention research (Philadelphia, Pa.)
  16. Ashitaba (Angelica Keiskei) Exudate Prevents Increases in Plasminogen Activator Inhibitor-1 Induced by Obesity in Tsumura Suzuki Obese Diabetic Mice.
    Mitsuhiro Ohta, Aya Fujinami, Katsutaka Oishi, Norihiro Kobayashi, Katsunori Ohnishi, Naoki Ohkura (2019) - Journal of dietary supplements
  17. The ethanolic extract of ashitaba stem (
    Sri Agung Fitri Kusuma, Yoppi Iskandar, Mutiara Ayu Dewanti (2018) - Journal of advanced pharmaceutical technology & research
  18. Promotion effect of the propolis from Jeju Island, Korea, on NGF secretion in human glioblastoma cells.
    Kohsuke Shimomura, Hironari Kako, Hidehiko Yokogoshi, Mok-Ryeon Ahn, Shigenori Kumazawa (2021) - Journal of natural medicines
  19. Supplementation with Ashitaba (Angelica keiskei) Yellow Stem Exudate Prevents Aging-Induced Thrombotic Tendencies and Systemic Inflammation Without Affecting Body Weight Gain in Mice
    Naoki Ohkura, Riyo Morimoto-Kamata, Katsutaka Oishi, Sayaka Higo-Yamamoto, Aya Fujinami (2023)
  20. Exploring the underlying mechanisms of Ashitaba in the management of non-alcoholic fatty liver disease by integrating the analysis of transcriptomics and metabolomics.
    Huan Yang, Yunshan Li, Weihong Xu, Wenjuan Liu, Ying Xie (2023) - Frontiers in medicine


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