There are strong demands to develop new immunomodulatory drugs to combat chronic diseases. In the broadest sense, we need to inhibit specific arms of the immune system in inflammatory diseases, neurodegeneration and hematological cancers, or enhance them in solid cancers. Most current efforts aim at biologic drugs (antibodies, cytokines, decoy receptors etc.) that are highly specific for extracellular targets, mostly cytokines and their receptors. Biologics are considered faster and less risky to develop than small-molecule drugs, and biologic antagonists of cytokines and paracrine signals are blockbuster medicines in inflammation and cancer. However, small molecules still offer important benefits. Notably, they are much easier to manufacture and more affordable once they come off patent, which suits global needs. One small-molecule class, kinase inhibitors, has been extensively explored for immunomodulation, and inhibitors of JAK, BTK, and SYK kinases have been approved to downregulate specific immune pathways in various diseases (Zarrin et al., 2021). There is also great interest in adding small molecules in combination to help patient subgroups that are insufficiently responsive to single biologics (Adams et al., 2015; van der Zanden et al., 2020; Ahmed et al., 2021).

Here, we discuss the potential of Traditional Chinese Medicines (TCM) and other herbal medicine traditions as starting points for new immunomodulatory drugs from a specific perspective: that plant-derived molecules may have low oral bioavailability and restricted distribution that lead to organ-specific pharmacology. In standard oral pharmacology models, drugs are efficiently adsorbed into the bloodstream and then act throughout the body via transport in blood. This standard model is often assumed for active molecules present in traditional medicines. We will argue that for some TCM molecules, their chemical nature and the xenobiotic defense systems in the human body point to an alternative model, where the drug acts locally to induce circulating mediators with systemic immunomodulatory activity.

In this review we will not address two important areas in TCM pharmacology, combinatorial drug action and modulation of the gut microbiome. Combining ingredients with complementary actions is central to the TCM philosophy (Zhang et al., 2014), which prompted the application of systems pharmacology approaches to rationally decipher existing combinations and develop new ones (Li et al., 2012; Ru et al., 2014). The physical emulsions naturally present in herbal extracts may also increase oral bioavailability of active components compared to pure molecules (Zhao et al., 2020). However, drug approval in the West usually requires a pure molecule with a precisely defined formulation to demonstrate single agent activity before combinations can be tested, and we are convinced that many TCM molecules with useful single agent activity remain to be discovered. Modulation of the gut microbiome by TCMs is an important research frontier (Lin et al., 2019b; Lin et al., 2021; Zhang et al., 2020a; Li et al., 2021b). Here, we will only touch on this topic in the context of immune regulators that act locally in the gut.

Xenobiotic defenses and their role in TCM pharmacology

Traditional TCM prescriptions mainly consist of dried plant and fungal ingredients boiled in water and administered as oral decoctions. Thus, consideration of oral bioavailability is paramount in discussing their mechanisms and pharmacology. Western drugs designed for oral dosing are usually optimized using synthetic chemistry and formulation methodology to maximize adsorption through the gut wall and minimize metabolism by the liver. This leads to drugs with high oral bioavailability, long plasma half-life and high systemic exposure. A drug with these properties is said to display ‘good pharmacology’. Some famous plant-derived drugs display good pharmacology, such as morphine, digoxin, quinine and artemisinin. However, most TCM molecules display ‘poor pharmacology’, that is poor oral bioavailability, short plasma half-life and rapid metabolism by the gut and liver (Lin et al., 2019b; Chen et al., 2016). How molecules with these properties can achieve beneficial systemic action is a long-standing puzzle in TCM pharmacology. The gut microbiome may play a role in mediating systemic actions of some oral TCM components that are poorly absorbed (Chen et al., 2016). We will focus on an alternative model, that local action in the gut or liver generates systemic mediators.

The “poor pharmacology” of most TCM molecules is not a coincidence. Rather, it results from evolutionary fundamentals. Plants and fungi evolved complex, bioactive metabolites, which we will term “xenobiotics”, mainly to deter herbivores through bitter taste or/and poisonous actions. In parallel, animals evolved xenobiotic defenses to protect them from potential toxins in their diets (Florsheim et al., 2021). Animals that could safely digest toxic plants gained a competitive advantage in access to food resources. Xenobiotic defense systems evolved to protect animals against precisely the kinds of molecules present in TCM oral decoctions, which is why, in our view, most TCM molecules exhibit poor pharmacology. Here, we will argue that the detection-response arm of xenobiotic defenses may also help explain their therapeutic actions.

The first layer of xenobiotic defenses in animals are sensory cues, such as bitter taste or bright colors, which signal avoidance of potentially poisonous foods. The second is a series of barriers that prevent systemic exposure, of which the gut wall is the most important. The third is a complex series of detection, transport and metabolism systems which rapidly detoxify xenobiotics that enter the bloodstream and trigger protective gene expression in exposed organs. The latter are concentrated in the liver in humans and, to a lesser extent, in the kidney. The liver efficiently removes many xenobiotics from the portal circulation before they enter the systemic circulation. This is achieved by its filter-like anatomy, drug transporters expressed on the sinusoidal (blood facing) membrane of hepatocytes and enzymes that rapidly metabolize xenobiotics into derivatives that are less toxic and easier to be excreted. This filtering effect of the liver, which can be upregulated by prior exposure to xenobiotics, is called ‘first pass metabolism’ and is responsible for the poor pharmacology of many plant-derived xenobiotics that cross the gut barrier.

Importantly, the xenobiotic defense systems of the gut, liver and kidney are dynamic. Maintaining high levels of defense is metabolically costly, therefore these systems evolved to be inducible. Exposure to xenobiotics induces defense proteins, notably metabolic enzymes and transporters, at the transcriptional level in the gut, liver and other organs (Xie et al., 2004; Müller, 2000). Xenobiotics are detected in part by their toxic actions on cellular organelles and in part by dedicated receptor proteins which are thought to have evolved for xenobiotic sensing (Negishi et al., 2020; Hoffmann and Partridge, 2015). Examples of xenobiotic sensors that are prominent in hepatocytes include the nuclear receptors PXR (Pregnane X receptor), FXR (Farnesoid X receptor) and AHR (Aryl Hydrocarbon Receptor). These receptors bind xenobiotics through the ligand-binding domains, leading to allosteric activation of their gene expression domains (Mackowiak and Wang, 2016). The chaperone-like sensor KEAP1 (Kelch Like ECH Associated Protein 1) detects oxidizing and alkylating xenobiotics using thiol chemistry. Oxidation and alkylation of cysteines on KEAP1 cause it to be degraded, which releases and activates its client protein, the transcription factor NRF2 (Baird and Yamamoto, 2020). NRF2 then serves as a master activator of anti-oxidant and xenobiotic defenses. Activation of xenobiotic sensors in hepatocytes leads to induction of drug metabolizing enzymes, such as cytochrome P450s, as well as efflux pumps, anti-oxidant proteins and other defense factors. Induction of xenobiotic defenses, especially P450s, is an important cause of drug-drug interactions (Ma, 2008). This is one reason patients must inform their doctors of all the drugs they are taking, including herbal supplements and traditional medicines. Induction of xenobiotic defenses by drugs has been most studied in the liver, but it also occurs in the gut and other tissues (Dressman and Thelen, 2009; Stresser et al., 2021).

The most important cell type for detecting and responding to xenobiotics is the hepatocyte. Research on xenobiotic sensors and the protective genes that they regulate has focused on two functions that are local to hepatocytes, that is, regulation of drug metabolism (Guengerich, 2017) and protection from the cytopathic effects of toxins, particularly by the KEAP1-NRF2 system (Taguchi and Kensler, 2020). Their roles in regulating inflammatory pathways and promoting whole-organism homeostasis have been much less studied. Of particular importance to this review is that activation of xenobiotic sensors in the gut or liver can induce secreted proteins, whose effects extend to the whole body. Signaling proteins secreted by the gut or liver are termed, respectively, enterokines and hepatokines. A systematic analysis of drug- and toxin-induced changes in rat liver gene expression revealed that many xenobiotics induce or repress hepatokines with known systemic actions, including IGF1, IGFALS, IGFBP, and GDF15 (Shimada and Mitchison, 2019). This regulation implies that xenobiotic sensors in the liver can mobilize the whole human body to regulate feeding, metabolism and other physiological processes. The same is likely true of the gut, although this has been less studied. Activation of xenobiotic defenses has been implicated in healthy aging of entire organisms (Hoffmann and Partridge, 2015). Here, we will link it to the action of herbal medicines. Xenobiotic sensors also monitor gut microbiome metabolites (Stockinger et al., 2021), so they are a point of integration between direct- and microbiome-mediated effects of small molecules on the human body.

The innate immune system can detect and respond to xenobiotics and we believe this system plays an important role in immunomodulation by herbal medicines, especially for molecules that lack oral bioavailability and act locally in the gut. This is a newer area of research compared to xenobiotic defenses in hepatocytes and much remains to be learned. Macrophages and dendritic cells in the lamina propria continuously sample the gut luminal contents by extending phagocytic processes directly into the gut lumen (‘periscoping’) and also by receiving material that is transcytosed out of the lumen by Microfold cells (M cells) (Bain and Schridde, 2018; Strober, 2009). This sampling is important for monitoring the microbiome and triggering immune responses in the gut. We propose it also constitutes a path by which insoluble xenobiotics that are unable to cross the gut wall due to their particulate form can access the immune system. Xenobiotic receptors in gut macrophages that have been implicated in sensing both microbiome metabolites and xenobiotics include AHR (Stockinger et al., 2021) and Toll-like receptors (TLRs) (Abreu, 2010). TLRs are usually thought of as receptors for pathogen-derived molecules, but as we will discuss below, they can also bind TCM polysaccharides. Modulation of gut macrophages and dendritic cells by luminal TCM molecules is expected to modulate inflammation locally, which may be important in treatment of gut inflammatory diseases, as discussed below. It can also give rise to systemic effects in at least two ways, by triggering secretion of circulating cytokines and by trafficking of educated leukocytes from the gut to other organs. We speculate both are important for relaying the effects of xenobiotic exposure from the gut to distant sites.

Figure 1 illustrates a series of models to explain how TCM molecules with ‘poor pharmacology’ can act both locally and systemically. The green line on the far left, labeled ‘direct actions’, is the standard oral pharmacology paradigm, where a molecule with ‘good pharmacology’ is absorbed through the gut wall, distributed by the bloodstream and acts directly on target cells throughout the body. Circulating metabolites, usually generated by the liver, may also contribute to systemic action in this model. The other lines illustrate a series of potential indirect action models that may apply to TCM molecules with ‘poor pharmacology’. In these models, the TCM molecule acts locally in the gut or liver to generate mediators that act systemically. These mediators can, in principle, be small molecules, signaling proteins, or immune cells that have been educated by drug exposure or carry insoluble drug particles in their lysosomes. Below, we will explore roles of these indirect mechanisms in the immunomodulatory effects of specific components of traditional herbal medicines. Our emphasis in this review is on pathways in human cells and organs. The blue arrow in Figure 1 indicates direct action of TCM molecules on gut microbes, which is an important research frontier that we do not discuss. For reviews see Lin et al., 2019b; Lin et al., 2021; Zhang et al., 2020a; Li et al., 2021b; Chen et al., 2016.

Figure 1

Download asset Open asset

Before discussing specific exemplars of local pharmacology, we must sound a note of caution. In recent years, TCM has evolved in the direction of injectable formulations that bypass the gut barrier and achieve plasma concentrations that are much higher than those achieved by traditional oral dosing (Li et al., 2018; Jiabo, 2010). For example, an injectable formulation of Panax ginseng extract can achieve transient plasma concentrations and systemic exposure (AUC) values of the ginsenoside active ingredients that are many hundreds-fold higher than an oral decoction of the same herb, due to the poor oral bioavailability of ginsenosides (Choi et al., 2020; Zhang et al., 2020b). Injection of TCM ingredients allows for much stronger direct, systemic actions, but at significant risk. The safety of TCM prescriptions is mostly based on experience from traditional oral dosing so it is important to critically evaluate the potential for toxicity when systemic exposure is drastically increased (Li et al., 2019).

Below, we discuss four examples of plant- and fungus-derived molecules with immunomodulatory activity, where we believe restricted distribution and organ-specific pharmacology are central to their therapeutic mechanism. The pharmacology concepts exemplified by these molecules may have much broader implications.

(1) Indigo – gut-restricted stimulation of AHR by insoluble drug particles

The plant Indigo naturalis is best known as a source of blue dye, but it also has traditional medicinal uses in China. Its main bioactive components are the bis-indoles indigo and indirubin, which are formed by non-biological reactions during processing (Sun et al., 2021). Therapeutic benefit of Indigo naturalis in ulcerative colitis (UC, a common inflammatory disease of the colon) was proven by recent clinical trials (Naganuma et al., 2018; Naganuma et al., 2020; Uchiyama et al., 2020). Response rates for the herbal medicine were comparable to the most effective western drugs, including biologics that target TNFα, and patients whose disease was not well-managed by western drugs responded well to the herbal preparation (Naganuma et al., 2020). The active ingredients in Indigo Naturalis, Indigo and indirubin, are almost insoluble in water and have very poor oral bioavailability (Sun et al., 2021). They are thought to act directly in the gut, where their concentration is locally high following ingestion of Indigo naturalis powder. Both are potent agonist ligands of the prototypical xenobiotic sensor AHR (Adachi et al., 2001) and tests in knockout mice showed that AHR expression is required for the therapeutic activity of both Indigo naturalis and pure indigo (Kawai et al., 2017). Therapeutic action is thought to proceed via secretion of the protective cytokines IL-10 and IL-22 from gut-associated immune cells (Lin et al., 2019a; Figure 2). The insolubility of indigo makes a traditional oral absorption route unlikely. We propose that indigo particles are delivered to gut macrophages and dendritic cells by phagocytosis, either directly from the gut lumen or following transcytosis by M cells (Bain and Schridde, 2018; Strober, 2009). Once ingested, active molecule slowly leaches from the phagocytosed particle to activate AHR. Limited clinical evidence suggests that the beneficial effects of Indigo naturalis power can extend systemically (Sun et al., 2021). This is unlikely to occur by systemic distribution of indigo itself, again due to its insolubility. Rather, it may involve one of the indirect action pathways proposed in Figure 1, such as trafficking of indigo-loaded immune cells from the gut into the systemic immune system. Systemic activation of AHR carries toxicity risk, as exemplified by the reference AHR agonist TCDD-dioxin (Bock and Köhle, 2006). The gut-restricted distribution of the indigo molecule, which we propose is due to its insoluble nature and selective delivery to gut by transcytosis and phagocytosis of particles, may be key to the therapeutic index of Indigo naturalis power. One of the proposed functions of AHR in gut macrophages is to monitor the gut microbiome and its metabolites (Stockinger et al., 2021). From this perspective, the therapeutic action of indigo in UC can be viewed as restoring balance to an endogenous immuno-regulatory circuit that monitors the gut microbiome.

Figure 2

Download asset Open asset

(3) Colchicine - induction of anti-inflammatory hepatokines

The alkaloid colchicine has a long history as a herbal medicine through use of Colchicum autumnale in the West and Gloriosa superba in Africa and Asia. It is still widely prescribed as a pure molecule for treating gout, Familial Mediterranean Fever and other inflammatory diseases and is being actively explored as a preventive in cardiovascular disease (Dasgeb et al., 2018; Tardif et al., 2019; Cocco et al., 2010). Colchicine targets tubulin, the subunit of microtubules, and promotes their depolymerization (Borisy and Taylor, 1967). Following oral dosing in humans, it reduces the adhesiveness of circulating myeloid cells and inhibits their recruitment to inflamed tissues (Fordham et al., 1981; Malawista, 1968). Colchicine has a high oral bioavailability and the standard model for its systemic anti-inflammatory action proposes that it acts on circulating myeloid cells to inhibit chemotaxis and IL-1β secretion (Dasgeb et al., 2018). However, this model is problematic. Colchicine is rapidly cleared from the blood to the liver (Thomas et al., 1989; Hunter and Klaassen, 1975). This rapid clearance, combined with its very slow association rate constant for tubulin binding, resulted in very low systemic exposure at safe doses, and microtubules in circulating leukocytes were not damaged following a safe, anti-inflammatory dose in mice (Weng et al., 2021). The same is likely true in humans, since colchicine at safe doses lacks anti-mitotic side effects, such as neutropenia and alopecia. In mice, colchicine damaged microtubules selectively in hepatocytes, presumably because it is concentrated across the sinusoidal membrane by xenobiotic transporters (Weng et al., 2021). Microtubule damage in hepatocytes activated NRF2, a master regulator of xenobiotic defenses, leading to induction of cytoprotective defense proteins (Figure 3). NRF2 activation also caused secretion of a novel form of GDF15 that acts systemically to inhibit inflammatory signaling in circulating myeloid cells (Weng et al., 2021). This new, indirect action model for colchicine has not been validated in humans and the anti-inflammatory form of GDF15 produced by the liver requires further characterization. Nevertheless, the concept that a plant-derived molecule with poor pharmacology can systemically modulate the immune system by inducing hepatokines has broad implications for the pharmacology of plant-derived molecules which enter the blood and act in the liver. The signature clinical activity of colchicine is relieving the symptoms of gout, a common rheumatic disease caused by the buildup of urate crystals in joints. Multiple TCM prescriptions are effective for gout treatment (Chi et al., 2020) and one demonstrated equal efficacy and superior therapeutic index when compared to colchicine in a double-blind trial (Wang et al., 2014). It would be interesting to test whether the active molecules in gout-active TCM prescriptions share colchicine’s ability to induce protective hepatokines.

Figure 3

Download asset Open asset

We believe that TCM is a viable starting point in the hunt for new immunomodulators but that previous research was handicapped by assuming systemic exposure, pre-selecting molecules with particular physical properties during fractionation and lack of realistic immune models. Below, we provide a short list of strategies designed to broaden the hunt and discovery of immune-active TCM molecules that were previously overlooked. The TCM field has made huge progress in chemistry and pharmacology in recent decades and powerful strategies for identification of bioactive molecules have been described elsewhere. Therefore, the suggestions below, based on the concepts in Figure 1, are not intended as a universal approach, but rather to supplement current approaches to fractionation and bioactivity analysis.

(2) Comprehensive and disease-specific immuno-profiling

TCM-derived molecules have often been tested for activity on immune cells in culture, but these tests were typically restricted to one single cell type and measurement. The human immune system is immensely complex and a single measurement is clearly insufficient to predict the immunomodulatory activity of a molecule in vivo. It is now possible to reconstitute many of the cell types and processes that constitute our immune systems in culture, but a comprehensive panel of assays is required (Figure 4). On this point, it is instructive to read papers from pharmaceutical companies which report comprehensive immuno-profiling of small-molecule immunomodulators, such as kinase inhibitors, using a battery of assays with multiple immune cell types, inputs and outputs (Braselmann et al., 2006; Zhu et al., 2007; Blomgren et al., 2020).

Figure 4

Download asset Open asset

While testing across a panel of normal immune cell types is much more informative than a single assay, testing cells only in their normal state may still not be sufficient. Immune cells exhibit specific forms of dis-regulation in disease contexts. If the therapeutic goal is to correct these aberrant cellular phenotypes, it is necessary to model them in culture. For example, there is a need for drugs that rejuvenate exhausted T cells in solid tumors to improve immunotherapy (Jiang et al., 2015). To identify such drug candidates, it is necessary to develop a cell culture model of exhausted T cells and assay their metabolic and cytotoxic activities. The closer the culture model matches the state of T cells in patient tumors, the more predictive the assay will be. Recent development of various single cell analysis methods has revolutionized our ability to profile and describe the variable states of immune cells in disease situations, which, as discussed above, often differ from any known healthy states of the same cells. These data should, in principle, help us model disease-specific states of the immune system in cell culture and then seek molecules that reverse them.

1. 1. Abreu MT

   (2010) Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function

   Nature Reviews. Immunology 10:131–144.

   https://doi.org/10.1038/nri2707

   • PubMed
   • Google Scholar
2. 1. Adachi J
   2. Mori Y
   3. Matsui S
   4. Takigami H
   5. Fujino J
   6. Kitagawa H
   7. Kato T
   8. Saeki K
   9. Matsuda T

   (2001) Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine

   The Journal of Biological Chemistry 276:31475–31478.

   https://doi.org/10.1074/jbc.C100238200

   • PubMed
   • Google Scholar
3. 1. Adams JL
   2. Smothers J
   3. Srinivasan R
   4. Hoos A

   (2015) Big opportunities for small molecules in immuno-oncology

   Nature Reviews. Drug Discovery 14:603–622.

   https://doi.org/10.1038/nrd4596

   • PubMed
   • Google Scholar
4. 1. Ahmed W
   2. Galati J
   3. Kumar A
   4. Christos PJ
   5. Longman R
   6. Lukin DJ
   7. Scherl E
   8. Battat R

   (2021) Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

   Clinical Gastroenterology and Hepatology 2021:34.

   https://doi.org/10.1016/j.cgh.2021.03.034

   • Google Scholar
5. 1. Bain CC
   2. Schridde A

   (2018) Origin, Differentiation, and Function of Intestinal Macrophages

   Frontiers in Immunology 9:2733.

   https://doi.org/10.3389/fimmu.2018.02733

   • PubMed
   • Google Scholar
6. 1. Baird L
   2. Yamamoto M

   (2020) The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

   Molecular and Cellular Biology 40:e00099-20.

   https://doi.org/10.1128/MCB.00099-20

   • PubMed
   • Google Scholar
7. 1. Benakis C
   2. Brea D
   3. Caballero S
   4. Faraco G
   5. Moore J
   6. Murphy M
   7. Sita G
   8. Racchumi G
   9. Ling L
   10. Pamer EG
   11. Iadecola C
   12. Anrather J

   (2016) Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells

   Nature Medicine 22:516–523.

   https://doi.org/10.1038/nm.4068

   • PubMed
   • Google Scholar
8. 1. Blomgren P
   2. Chandrasekhar J
   3. Di Paolo JA
   4. Fung W
   5. Geng G
   6. Ip C
   7. Jones R
   8. Kropf JE
   9. Lansdon EB
   10. Lee S
   11. Lo JR
   12. Mitchell SA
   13. Murray B
   14. Pohlmeyer C
   15. Schmitt A
   16. Suekawa-Pirrone K
   17. Wise S
   18. Xiong J-M
   19. Xu J
   20. Yu H
   21. Zhao Z
   22. Currie KS

   (2020) Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases

   ACS Medicinal Chemistry Letters 11:506–513.

   https://doi.org/10.1021/acsmedchemlett.9b00621

   • PubMed
   • Google Scholar
9. 1. Bock KW
   2. Köhle C

   (2006) Ah receptor: dioxin-mediated toxic responses as hints to deregulated physiologic functions

   Biochemical Pharmacology 72:393–404.

   https://doi.org/10.1016/j.bcp.2006.01.017

   • PubMed
   • Google Scholar
10. 1. Borisy GG
    2. Taylor EW

    (1967) The mechanism of action of colchicine Binding of colchincine-3H to cellular protein

    The Journal of Cell Biology 34:525–533.

    https://doi.org/10.1083/jcb.34.2.525

    • Google Scholar
11. 1. Braselmann S
    2. Taylor V
    3. Zhao H
    4. Wang S
    5. Sylvain C
    6. Baluom M
    7. Qu K
    8. Herlaar E
    9. Lau A
    10. Young C
    11. Wong BR
    12. Lovell S
    13. Sun T
    14. Park G
    15. Argade A
    16. Jurcevic S
    17. Pine P
    18. Singh R
    19. Grossbard EB
    20. Payan DG
    21. Masuda ES

    (2006) R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation

    The Journal of Pharmacology and Experimental Therapeutics 319:998–1008.

    https://doi.org/10.1124/jpet.106.109058

    • PubMed
    • Google Scholar
12. 1. Chai SC
    2. Cherian MT
    3. Wang YM
    4. Chen T

    (2016) Small-molecule modulators of PXR and CAR

    Biochimica et Biophysica Acta 1859:1141–1154.

    https://doi.org/10.1016/j.bbagrm.2016.02.013

    • PubMed
    • Google Scholar
13. 1. Chen F
    2. Wen Q
    3. Jiang J
    4. Li H-L
    5. Tan Y-F
    6. Li Y-H
    7. Zeng N-K

    (2016) Could the gut microbiota reconcile the oral bioavailability conundrum of traditional herbs?

    Journal of Ethnopharmacology 179:253–264.

    https://doi.org/10.1016/j.jep.2015.12.031

    • PubMed
    • Google Scholar
14. 1. Chi X
    2. Zhang H
    3. Zhang S
    4. Ma K

    (2020) Chinese herbal medicine for gout: a review of the clinical evidence and pharmacological mechanisms

    Chinese Medicine 15:17.

    https://doi.org/10.1186/s13020-020-0297-y

    • PubMed
    • Google Scholar
15. 1. Choi MK
    2. Jin S
    3. Jeon JH
    4. Kang WY
    5. Seong SJ
    6. Yoon YR
    7. Han YH
    8. Song IS

    (2020) Tolerability and pharmacokinetics of ginsenosides Rb1, Rb2, Rc, Rd, and compound K after single or multiple administration of red ginseng extract in human beings

    Journal of Ginseng Research 44:229–237.

    https://doi.org/10.1016/j.jgr.2018.10.006

    • PubMed
    • Google Scholar
16. 1. Cocco G
    2. Chu DCC
    3. Pandolfi S

    (2010) Colchicine in clinical medicine A guide for internists

    European Journal of Internal Medicine 21:503–508.

    https://doi.org/10.1016/j.ejim.2010.09.010

    • PubMed
    • Google Scholar
17. 1. Crutchfield CA
    2. Lu W
    3. Melamud E
    4. Rabinowitz JD

    (2010) Mass spectrometry-based metabolomics of yeast

    Methods in Enzymology 470:393–426.

    https://doi.org/10.1016/S0076-6879(10)70016-1

    • PubMed
    • Google Scholar
18. 1. Dasgeb B
    2. Kornreich D
    3. McGuinn K
    4. Okon L
    5. Brownell I
    6. Sackett DL

    (2018) Colchicine: an ancient drug with novel applications

    The British Journal of Dermatology 178:350–356.

    https://doi.org/10.1111/bjd.15896

    • PubMed
    • Google Scholar
19. 1. Dressman JB
    2. Thelen K

    (2009) Cytochrome P450-mediated metabolism in the human gut wall

    Journal of Pharmacy and Pharmacology 61:541–558.

    https://doi.org/10.1211/jpp/61.05.0002

    • Google Scholar
20. 1. Florsheim EB
    2. Sullivan ZA
    3. Khoury-Hanold W
    4. Medzhitov R

    (2021) Food allergy as a biological food quality control system

    Cell 184:1440–1454.

    https://doi.org/10.1016/j.cell.2020.12.007

    • PubMed
    • Google Scholar
21. 1. Fordham JN
    2. Kirwan J
    3. Cason J
    4. Currey HL

    (1981) Prolonged reduction in polymorphonuclear adhesion following oral colchicine

    Annals of the Rheumatic Diseases 40:605–608.

    https://doi.org/10.1136/ard.40.6.605

    • Google Scholar
22. 1. Fukata M
    2. Arditi M

    (2013) The role of pattern recognition receptors in intestinal inflammation

    Mucosal Immunology 6:451–463.

    https://doi.org/10.1038/mi.2013.13

    • PubMed
    • Google Scholar
23. 1. Gao Y
    2. Chu S
    3. Zhang Z
    4. Chen N

    (2017) Hepataprotective effects of ginsenoside Rg1 - A review

    Journal of Ethnopharmacology 206:178–183.

    https://doi.org/10.1016/j.jep.2017.04.012

    • PubMed
    • Google Scholar
24. 1. Guengerich FP

    (2017) Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions

    Chemical Research in Toxicology 30:2–12.

    https://doi.org/10.1021/acs.chemrestox.6b00226

    • PubMed
    • Google Scholar
25. 1. Hoffmann JM
    2. Partridge L

    (2015) Nuclear hormone receptors: Roles of xenobiotic detoxification and sterol homeostasis in healthy aging

    Critical Reviews in Biochemistry and Molecular Biology 50:380–392.

    https://doi.org/10.3109/10409238.2015.1067186

    • PubMed
    • Google Scholar
26. 1. Hunter AL
    2. Klaassen CD

    (1975)

    Biliary excretion of colchicine

    The Journal of Pharmacology and Experimental Therapeutics 192:605–617.

    • PubMed
    • Google Scholar
27. 1. Ina K
    2. Furuta R
    3. Kataoka T
    4. Kayukawa S
    5. Yoshida T
    6. Miwa T
    7. Yamamura Y
    8. Takeuchi Y

    (2011) Lentinan prolonged survival in patients with gastric cancer receiving S-1-based chemotherapy

    World Journal of Clinical Oncology 2:339–343.

    https://doi.org/10.5306/wjco.v2.i10.339

    • PubMed
    • Google Scholar
28. 1. Ina K
    2. Kataoka T
    3. Ando T

    (2013) The use of lentinan for treating gastric cancer

    Anti-Cancer Agents in Medicinal Chemistry 13:681–688.

    https://doi.org/10.2174/1871520611313050002

    • PubMed
    • Google Scholar
29. 1. Jiabo L

    (2010) Thinking About the Healthy Development of Traditional Chinese Medicine Injection

    World Science and Technology 12:497–501.

    https://doi.org/10.1016/S1876-3553(11)60023-9

    • Google Scholar
30. 1. Jiang Y
    2. Li Y
    3. Zhu B

    (2015) T-cell exhaustion in the tumor microenvironment

    Cell Death & Disease 6:e1792.

    https://doi.org/10.1038/cddis.2015.162

    • PubMed
    • Google Scholar
31. 1. Kawai S
    2. Iijima H
    3. Shinzaki S
    4. Hiyama S
    5. Yamaguchi T
    6. Araki M
    7. Iwatani S
    8. Shiraishi E
    9. Mukai A
    10. Inoue T
    11. Hayashi Y
    12. Tsujii M
    13. Motooka D
    14. Nakamura S
    15. Iida T
    16. Takehara T

    (2017) Indigo Naturalis ameliorates murine dextran sodium sulfate-induced colitis via aryl hydrocarbon receptor activation

    Journal of Gastroenterology 52:904–919.

    https://doi.org/10.1007/s00535-016-1292-z

    • PubMed
    • Google Scholar
32. 1. Kieser KJ
    2. Kagan JC

    (2017) Multi-receptor detection of individual bacterial products by the innate immune system

    Nature Reviews. Immunology 17:376–390.

    https://doi.org/10.1038/nri.2017.25

    • PubMed
    • Google Scholar
33. 1. Li J
    2. Lu C
    3. Jiang M
    4. Niu X
    5. Guo H
    6. Li L
    7. Bian Z
    8. Lin N
    9. Lu A

    (2012) Traditional chinese medicine-based network pharmacology could lead to new multicompound drug discovery

    Evidence-Based Complementary and Alternative Medicine 2012:149762.

    https://doi.org/10.1155/2012/149762

    • PubMed
    • Google Scholar
34. 1. Li H
    2. Wang S
    3. Yue Z
    4. Ren X
    5. Xia J

    (2018) Traditional Chinese herbal injection: Current status and future perspectives

    Fitoterapia 129:249–256.

    https://doi.org/10.1016/j.fitote.2018.07.009

    • PubMed
    • Google Scholar
35. 1. Li H
    2. Deng J
    3. Deng L
    4. Ren X
    5. Xia J

    (2019) Safety profile of traditional Chinese herbal injection: An analysis of a spontaneous reporting system in China

    Pharmacoepidemiology and Drug Safety 28:1002–1013.

    https://doi.org/10.1002/pds.4805

    • PubMed
    • Google Scholar
36. 1. Li B
    2. Nasser MI
    3. Masood M
    4. Adlat S
    5. Huang Y
    6. Yang B
    7. Luo C
    8. Jiang N

    (2020) Efficiency of Traditional Chinese medicine targeting the Nrf2/HO-1 signaling pathway

    Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 126:110074.

    https://doi.org/10.1016/j.biopha.2020.110074

    • PubMed
    • Google Scholar
37. 1. Li W
    2. Sun K
    3. Hu F
    4. Chen L
    5. Zhang X
    6. Wang F
    7. Yan B

    (2021a) Protective effects of natural compounds against oxidative stress in ischemic diseases and cancers via activating the Nrf2 signaling pathway: A mini review

    Journal of Biochemical and Molecular Toxicology 35:e22658.

    https://doi.org/10.1002/jbt.22658

    • PubMed
    • Google Scholar
38. 1. Li X
    2. Wu D
    3. Niu J
    4. Sun Y
    5. Wang Q
    6. Yang B
    7. Kuang H

    (2021b) Intestinal Flora: A Pivotal Role in Investigation of Traditional Chinese Medicine

    The American Journal of Chinese Medicine 49:237–268.

    https://doi.org/10.1142/S0192415X21500130

    • PubMed
    • Google Scholar
39. 1. Lin YH
    2. Luck H
    3. Khan S
    4. Schneeberger PHH
    5. Tsai S
    6. Clemente-Casares X
    7. Lei H
    8. Leu YL
    9. Chan YT
    10. Chen HY
    11. Yang SH
    12. Coburn B
    13. Winer S
    14. Winer DA

    (2019a) Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity

    Ternational Journal of Obesity 43:2407–2421.

    https://doi.org/10.1038/s41366-019-0340-1

    • PubMed
    • Google Scholar
40. 1. Lin L
    2. Luo L
    3. Zhong M
    4. Xie T
    5. Liu Y
    6. Li H
    7. Ni J

    (2019b) Gut microbiota: a new angle for traditional herbal medicine research

    RSC Advances 9:17457–17472.

    https://doi.org/10.1039/C9RA01838G

    • Google Scholar
41. 1. Lin T-L
    2. Lu C-C
    3. Lai W-F
    4. Wu T-S
    5. Lu J-J
    6. Chen Y-M
    7. Tzeng C-M
    8. Liu H-T
    9. Wei H
    10. Lai H-C

    (2021) Role of gut microbiota in identification of novel TCM-derived active metabolites

    Protein & Cell 12:394–410.

    https://doi.org/10.1007/s13238-020-00784-w

    • PubMed
    • Google Scholar
42. 1. Lu W
    2. Su X
    3. Klein MS
    4. Lewis IA
    5. Fiehn O
    6. Rabinowitz JD

    (2017) Metabolite Measurement: Pitfalls to Avoid and Practices to Follow

    Annual Review of Biochemistry 86:277–304.

    https://doi.org/10.1146/annurev-biochem-061516-044952

    • PubMed
    • Google Scholar
43. 1. Ma Q

    (2008) Xenobiotic-activated receptors: from transcription to drug metabolism to disease

    Chemical Research in Toxicology 1:1651–1671.

    https://doi.org/10.1021/tx800156s

    • PubMed
    • Google Scholar
44. 1. Mackowiak B
    2. Wang H

    (2016) Mechanisms of xenobiotic receptor activation: Direct vs. indirect

    Biochimica et Biophysica Acta 1859:1130–1140.

    https://doi.org/10.1016/j.bbagrm.2016.02.006

    • PubMed
    • Google Scholar
45. 1. Mainous MR
    2. Ertel W
    3. Chaudry IH
    4. Deitch EA

    (1995)

    The gut: a cytokine-generating organ in systemic inflammation?

    Shock 4:193–199.

    • PubMed
    • Google Scholar
46. 1. Malawista SE

    (1968) Colchicine: a common mechanism for its anti-inflammatory and anti-mitotic effects

    Arthritis & Rheumatism 11:191–197.

    https://doi.org/10.1002/art.1780110210

    • Google Scholar
47. 1. Müller M

    (2000) Transcriptional control of hepatocanalicular transporter gene expression

    Seminars in Liver Disease 20:323–337.

    https://doi.org/10.1055/s-2000-9387

    • PubMed
    • Google Scholar
48. 1. Naganuma M
    2. Sugimoto S
    3. Mitsuyama K
    4. Kobayashi T
    5. Yoshimura N
    6. Ohi H
    7. Tanaka S
    8. Andoh A
    9. Ohmiya N
    10. Saigusa K
    11. Yamamoto T
    12. Morohoshi Y
    13. Ichikawa H
    14. Matsuoka K
    15. Hisamatsu T
    16. Watanabe K
    17. Mizuno S
    18. Suda W
    19. Hattori M
    20. Fukuda S
    21. Hirayama A
    22. Abe T
    23. Watanabe M
    24. Hibi T
    25. Suzuki Y
    26. Kanai T
    27. INDIGO Study Group

    (2018) Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis

    Gastroenterology 154:935–947.

    https://doi.org/10.1053/j.gastro.2017.11.024

    • PubMed
    • Google Scholar
49. 1. Naganuma M
    2. Sugimoto S
    3. Fukuda T
    4. Mitsuyama K
    5. Kobayashi T
    6. Yoshimura N
    7. Ohi H
    8. Tanaka S
    9. Andoh A
    10. Ohmiya N
    11. Saigusa K
    12. Yamamoto T
    13. Morohoshi Y
    14. Ichikawa H
    15. Matsuoka K
    16. Hisamatsu T
    17. Watanabe K
    18. Mizuno S
    19. Abe T
    20. Suzuki Y
    21. Kanai T
    22. Group IS

    (2020) Indigo naturalis is effective even in treatment-refractory patients with ulcerative colitis: a post hoc analysis from the INDIGO study

    Journal of Gastroenterology 55:169–180.

    https://doi.org/10.1007/s00535-019-01625-2

    • PubMed
    • Google Scholar
50. 1. Nakano H
    2. Namatame K
    3. Nemoto H
    4. Motohashi H
    5. Nishiyama K
    6. Kumada K

    (1999)

    A multi-institutional prospective study of lentinan in advanced gastric cancer patients with unresectable and recurrent diseases: effect on prolongation of survival and improvement of quality of life Kanagawa Lentinan Research Group

    Hepato-Gastroenterology 46:2662–2668.

    • PubMed
    • Google Scholar
51. 1. Negishi M
    2. Kobayashi K
    3. Sakuma T
    4. Sueyoshi T

    (2020) Nuclear receptor phosphorylation in xenobiotic signal transduction

    The Journal of Biological Chemistry 295:15210–15225.

    https://doi.org/10.1074/jbc.REV120.007933

    • PubMed
    • Google Scholar
52. 1. Ning C
    2. Gao X
    3. Wang C
    4. Kong Y
    5. Liu Z
    6. Sun H
    7. Sun P
    8. Huo X
    9. Ma X
    10. Meng Q
    11. Liu K

    (2018) Ginsenoside Rg1 protects against acetaminophen-induced liver injury via activating Nrf2 signaling pathway in vivo and in vitro

    Regulatory Toxicology and Pharmacology 98:58–68.

    https://doi.org/10.1016/j.yrtph.2018.07.012

    • PubMed
    • Google Scholar
53. 1. Norris PC
    2. Serhan CN

    (2018) Metabololipidomic profiling of functional immunoresolvent clusters and eicosanoids in mammalian tissues

    Biochemical and Biophysical Research Communications 504:553–561.

    https://doi.org/10.1016/j.bbrc.2018.03.037

    • PubMed
    • Google Scholar
54. 1. Oba K
    2. Kobayashi M
    3. Matsui T
    4. Kodera Y
    5. Sakamoto J

    (2009)

    Individual patient based meta-analysis of lentinan for unresectable/recurrent gastric cancer

    Anticancer Research 29:2739–2745.

    • PubMed
    • Google Scholar
55. 1. Pal D
    2. Mitra AK

    (2006) MDR- and CYP3A4-mediated drug-herbal interactions

    Life Sciences 78:2131–2145.

    https://doi.org/10.1016/j.lfs.2005.12.010

    • PubMed
    • Google Scholar
56. 1. Peng Q
    2. Cai H
    3. Sun X
    4. Li X
    5. Mo Z
    6. Shi J
    7. Beeton C

    (2013) Alocasia cucullata exhibits strong antitumor effect in vivo by activating antitumor immunity

    PLOS ONE 8:e75328.

    https://doi.org/10.1371/journal.pone.0075328

    • Google Scholar
57. 1. Ren S
    2. Leng J
    3. Xu XY
    4. Jiang S
    5. Wang YP
    6. Yan XT
    7. Liu Z
    8. Chen C
    9. Wang Z
    10. Li W

    (2019) Ginsenoside Rb1, A Major Saponin from Panax ginseng, Exerts Protective Effects Against Acetaminophen-Induced Hepatotoxicity in Mice

    The American Journal of Chinese Medicine 47:1815–1831.

    https://doi.org/10.1142/S0192415X19500927

    • PubMed
    • Google Scholar
58. 1. Ru J
    2. Li P
    3. Wang J
    4. Zhou W
    5. Li B
    6. Huang C
    7. Li P
    8. Guo Z
    9. Tao W
    10. Yang Y
    11. Xu X
    12. Li Y
    13. Wang Y
    14. Yang L

    (2014) TCMSP: a database of systems pharmacology for drug discovery from herbal medicines

    Journal of Cheminformatics 6:13.

    https://doi.org/10.1186/1758-2946-6-13

    • PubMed
    • Google Scholar
59. 1. Samuelsson B
    2. Dahlén SE
    3. Lindgren JA
    4. Rouzer CA
    5. Serhan CN

    (1987) Leukotrienes and lipoxins: structures, biosynthesis, and biological effects

    Science 237:1171–1176.

    https://doi.org/10.1126/science.2820055

    • PubMed
    • Google Scholar
60. 1. Schirmer M
    2. Smeekens SP
    3. Vlamakis H
    4. Jaeger M
    5. Oosting M
    6. Franzosa EA
    7. Ter Horst R
    8. Jansen T
    9. Jacobs L
    10. Bonder MJ
    11. Kurilshikov A
    12. Fu J
    13. Joosten LAB
    14. Zhernakova A
    15. Huttenhower C
    16. Wijmenga C
    17. Netea MG
    18. Xavier RJ

    (2016) Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity

    Cell 167:1125–1136.

    https://doi.org/10.1016/j.cell.2016.10.020

    • PubMed
    • Google Scholar
61. 1. Shimada K
    2. Mitchison TJ

    (2019) Unsupervised identification of disease states from high-dimensional physiological and histopathological profiles

    Molecular Systems Biology 15:e8636.

    https://doi.org/10.15252/msb.20188636

    • PubMed
    • Google Scholar
62. 1. Stockinger B
    2. Shah K
    3. Wincent E

    (2021) AHR in the intestinal microenvironment: safeguarding barrier function

    Nature Reviews. Gastroenterology & Hepatology 18:559–570.

    https://doi.org/10.1038/s41575-021-00430-8

    • PubMed
    • Google Scholar
63. 1. Stresser DM
    2. Sun J
    3. Wilson SS

    (2021) Evaluation of Tissue Stem Cell-Derived Human Intestinal Organoids, a Physiologically Relevant Model to Evaluate Cytochrome P450 Induction in Gut

    Drug Metabolism and Disposition 49:245–253.

    https://doi.org/10.1124/dmd.120.000281

    • PubMed
    • Google Scholar
64. 1. Strober W

    (2009) The multifaceted influence of the mucosal microflora on mucosal dendritic cell responses

    Immunity 31:377–388.

    https://doi.org/10.1016/j.immuni.2009.09.001

    • PubMed
    • Google Scholar
65. 1. Sun Q
    2. Leng J
    3. Tang L
    4. Wang L
    5. Fu C

    (2021) A Comprehensive Review of the Chemistry, Pharmacokinetics, Pharmacology, Clinical Applications, Adverse Events, and Quality Control of Indigo Naturalis

    Frontiers in Pharmacology 12:664022.

    https://doi.org/10.3389/fphar.2021.664022

    • PubMed
    • Google Scholar
66. 1. Taguchi K
    2. Kensler TW

    (2020) Nrf2 in liver toxicology

    Archives of Pharmacal Research 43:337–349.

    https://doi.org/10.1007/s12272-019-01192-3

    • PubMed
    • Google Scholar
67. 1. Tardif JC
    2. Kouz S
    3. Waters DD
    4. Bertrand OF
    5. Diaz R
    6. Maggioni AP
    7. Pinto FJ
    8. Ibrahim R
    9. Gamra H
    10. Kiwan GS
    11. Berry C
    12. López-Sendón J
    13. Ostadal P
    14. Koenig W
    15. Angoulvant D
    16. Grégoire JC
    17. Lavoie MA
    18. Dubé MP
    19. Rhainds D
    20. Provencher M
    21. Blondeau L
    22. Orfanos A
    23. L’Allier PL
    24. Guertin MC
    25. Roubille F

    (2019) Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

    The New England Journal of Medicine 381:2497–2505.

    https://doi.org/10.1056/NEJMoa1912388

    • PubMed
    • Google Scholar
68. 1. Thomas G
    2. Girre C
    3. Scherrmann JM
    4. Francheteau P
    5. Steimer JL

    (1989) Zero-order absorption and linear disposition of oral colchicine in healthy volunteers

    European Journal of Clinical Pharmacology 37:79–84.

    https://doi.org/10.1007/BF00609430

    • PubMed
    • Google Scholar
69. 1. Uchiyama K
    2. Takami S
    3. Suzuki H
    4. Umeki K
    5. Mochizuki S
    6. Kakinoki N
    7. Iwamoto J
    8. Hoshino Y
    9. Omori J
    10. Fujimori S
    11. Yanaka A
    12. Mizokami Y
    13. Ohkusa T

    (2020) Efficacy and safety of short-term therapy with indigo naturalis for ulcerative colitis: An investigator-initiated multicenter double-blind clinical trial

    PLOS ONE 15:e0241337.

    https://doi.org/10.1371/journal.pone.0241337

    • PubMed
    • Google Scholar
70. 1. van der Zanden SY
    2. Luimstra JJ
    3. Neefjes J
    4. Borst J
    5. Ovaa H

    (2020) Opportunities for Small Molecules in Cancer Immunotherapy

    Trends in Immunology 41:493–511.

    https://doi.org/10.1016/j.it.2020.04.004

    • PubMed
    • Google Scholar
71. 1. Wang Y
    2. Wang L
    3. Li E
    4. Li Y
    5. Wang Z
    6. Sun X
    7. Yu X
    8. Ma L
    9. Wang Y
    10. Wang Y

    (2014) Chuanhu anti-gout mixture versus colchicine for acute gouty arthritis: a randomized, double-blind, double-dummy, non-inferiority trial

    Ternational Journal of Medical Sciences 11:880–885.

    https://doi.org/10.7150/ijms.9165

    • PubMed
    • Google Scholar
72. 1. Weng JH
    2. Koch PD
    3. Luan HH
    4. Tu HC
    5. Shimada K
    6. Ngan I
    7. Ventura R
    8. Jiang R
    9. Mitchison TJ

    (2021) Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation

    Nature Metabolism 3:513–522.

    https://doi.org/10.1038/s42255-021-00366-y

    • PubMed
    • Google Scholar
73. 1. Xie W
    2. Uppal H
    3. Saini SPS
    4. Mu Y
    5. Little JM
    6. Radominska-Pandya A
    7. Zemaitis MA

    (2004) Orphan nuclear receptor-mediated xenobiotic regulation in drug metabolism

    Drug Discovery Today 9:442–449.

    https://doi.org/10.1016/S1359-6446(04)03061-2

    • PubMed
    • Google Scholar
74. 1. Zarrin AA
    2. Bao K
    3. Lupardus P
    4. Vucic D

    (2021) Kinase inhibition in autoimmunity and inflammation

    Nature Reviews. Drug Discovery 20:39–63.

    https://doi.org/10.1038/s41573-020-0082-8

    • PubMed
    • Google Scholar
75. 1. Zhang A
    2. Sun H
    3. Wang X

    (2014) Potentiating therapeutic effects by enhancing synergism based on active constituents from traditional medicine

    Phytotherapy Research 28:526–533.

    https://doi.org/10.1002/ptr.5032

    • PubMed
    • Google Scholar
76. 1. Zhang J
    2. Cao L
    3. Wang H
    4. Cheng X
    5. Wang L
    6. Zhu L
    7. Yan T
    8. Xie Y
    9. Wu Y
    10. Zhao M
    11. Ma S
    12. Wu M
    13. Wang G
    14. Hao H

    (2015) Ginsenosides Regulate PXR/NF-κB Signaling and Attenuate Dextran Sulfate Sodium-Induced Colitis

    Drug Metabolism and Disposition 43:1181–1189.

    https://doi.org/10.1124/dmd.115.063800

    • PubMed
    • Google Scholar
77. 1. Zhang R
    2. Gao X
    3. Bai H
    4. Ning K

    (2020a) Traditional Chinese Medicine and Gut Microbiome: Their Respective and Concert Effects on Healthcare

    Frontiers in Pharmacology 11:538.

    https://doi.org/10.3389/fphar.2020.00538

    • PubMed
    • Google Scholar
78. 1. Zhang HY
    2. Niu W
    3. Olaleye OE
    4. Du FF
    5. Wang FQ
    6. Huang YH
    7. Yuan L
    8. Li YF
    9. Liu GP
    10. Xu F
    11. Yang JL
    12. Li C

    (2020b) Comparison of intramuscular and intravenous pharmacokinetics of ginsenosides in humans after dosing XueShuanTong, a lyophilized extract of Panax notoginseng roots

    Journal of Ethnopharmacology 253:112658.

    https://doi.org/10.1016/j.jep.2020.112658

    • PubMed
    • Google Scholar
79. 1. Zhao Q
    2. Luan X
    3. Zheng M
    4. Tian X-H
    5. Zhao J
    6. Zhang W-D
    7. Ma B-L

    (2020) Synergistic Mechanisms of Constituents in Herbal Extracts during Intestinal Absorption: Focus on Natural Occurring Nanoparticles

    Pharmaceutics 12:E128.

    https://doi.org/10.3390/pharmaceutics12020128

    • PubMed
    • Google Scholar
80. 1. Zhou L
    2. Liu Z
    3. Wang Z
    4. Yu S
    5. Long T
    6. Zhou X
    7. Bao Y

    (2017) Astragalus polysaccharides exerts immunomodulatory effects via TLR4-mediated MyD88-dependent signaling pathway in vitro and in vivo

    Scientific Reports 7:44822.

    https://doi.org/10.1038/srep44822

    • PubMed
    • Google Scholar
81. 1. Zhu Y
    2. Herlaar E
    3. Masuda ES
    4. Burleson GR
    5. Nelson AJ
    6. Grossbard EB
    7. Clemens GR

    (2007) Immunotoxicity assessment for the novel Spleen tyrosine kinase inhibitor R406

    Toxicology and Applied Pharmacology 221:268–277.

    https://doi.org/10.1016/j.taap.2007.03.027

    • Google Scholar

Author details

1. Jue Shi

   Centre for Quantitative Systems Biology, Department of Physics and Department of Biology, Hong Kong Baptist University, Hong Kong, China

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing

   For correspondence

   jshi@hkbu.edu.hk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4061-3496

2. Jui-Hsia Weng

   1. Department of Systems Biology, Harvard Medical School, Boston, United States
   2. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

   Contribution

   Conceptualization, Data curation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

3. Timothy J Mitchison

   Department of Systems Biology, Harvard Medical School, Boston, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Writing – original draft, Writing – review and editing

   For correspondence

   Timothy_Mitchison@hms.harvard.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7781-1897

• 3,098

  views

• 492

  downloads

• 18

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.