immunomodulatory herbal drugs

we end by proposing research strategies for identification of novel immunomodulatory drugs from herbal medicine sources that are informed by the possibility of local action in the gut or liver, leading to generation of systemic immune mediators. the gut microbiome may play a role in mediating systemic actions of some oral tcm components that are poorly absorbed (chen et al., 2016). 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. 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. this is a newer area of research compared to xenobiotic defenses in hepatocytes and much remains to be learned. they are thought to act directly in the gut, where their concentration is locally high following ingestion of indigo naturalis powder. one of the proposed functions of ahr in gut macrophages is to monitor the gut microbiome and its metabolites (stockinger et al., 2021). the challenge and opportunity of developing this class of tcm molecules appear to be not so much in discovering new types of polysaccharides but in designing better clinical trials to evaluate their efficacy as well as benefit to overall patient wellness.

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. colchicine and oral ginsenosides both appear to provide therapeutic benefit by activating xenobiotic defenses in the liver, a proposed mechanism that is shared by many other tcm-derived molecules (li et al., 2021a; li et al., 2020). from these findings, we can infer that induction of xenobiotic defenses in the liver is likely to be a widespread mechanism by which tcm molecules influence the human body and promote therapeutic benefit. the human immune system is immensely complex and a single measurement is clearly insufficient to predict the immunomodulatory activity of a molecule in vivo. we urge scholars to also query secreted proteins that may mediate systemic action of a xenobiotic, especially in the liver given its high capacity to modify blood chemistry via secreted proteins (shimada and mitchison, 2019; weng et al., 2021). given the ‘poor pharmacology’ of many plant-derived molecules, local action in the gut and liver may be common, in some cases generating immune mediators that circulate in blood and are responsible for systemic benefit (figure 1). this article is distributed under the terms of the creative commons attribution license, which permits unrestricted use and redistribution provided that the original author and source are credited. progress in understanding these transport mechanisms has been hampered by the poor sensitivity and time-resolution of import assays.

most of immunostimulants and immunosuppressants in clinical use are the cytotoxic drugs which possess serious side effects. the function and efficiency of the immune system are influenced by various exogenous and endogenous factors resulting in either immunosuppression or immunostimulation. the prevention and treatment of disease using plant-based medicines has been reported in human history. the treatment of glioma cells with 25 μm curcumin reduced the binding of nf-κb and ap-1 (dhandapani et al., 2007). the attachment of t cells to endothelial and antigen presenting cells is dependent on cell adhesion molecules. the release of inflammatory cytokines (mip-1, il-6, il-1, and tnf-α) in c5a-activated mouse and human neutrophils was inhibited by the pre-incubation with resveratrol (10–40 m). the down-regulation of inos transcription and no production in macrophages is dependent on the inhibition of nf-κb. a green tea extract was approved as a prescription drug in 2006 for the topical treatment of anal and genital warts (condylomata acuminate). quercetin decreased the markers of inflammation (il-8 and tnf-α) in sarcoidosis patients (boots et al., 2011). in 1960s, colchicine played a key role for the initial characterization of tubulin subunits and microtubules (borisy and taylor, 1967). furthermore, capsaicin was found to inhibit nf-κb pathway, inos expression and cox-2 activity in the macrophages in a trpv1-independent manner (kim et al., 2003). the administration of andrographolide resulted in improved expression of cd markers and production of tnf-α, therefore increasing the cytotoxic potential of lymphocytes (rajagopal et al., 2003). besides, the efficacy and safety of andrographolide will also be evaluated for the treatment of colorectal cancer. genistein modulated th1-predominant immune response by increasing il-4 production and suppressing the secretion of ifn-γ in a collagen-induced rheumatoid arthritis rat (wang et al., 2008). natural products and folklore medicines are the main contributors of the leads in the design and development of therapeutic agents. a few plant derived compounds, including polysaccharides, are extremely diversified in terms of molecular weight and structure; therefore, it is challenging to produce the similar quality in every batch. bioavailability of curcumin: problems and promises. doi: 10.3945/ajcn.2009.28822 bandele, o. j., and osheroff, n. (2008). arzanol, a prenylated heterodimeric phloroglucinyl pyrone, inhibits eicosanoid biosynthesis and exhibits anti-inflammatory efficacy in vivo. anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin. quercetin reduces markers of oxidative stress and inflammation in sarcoidosis. medicinal chemistry and pharmacology of genus tripterygium (celastraceae). anti-inflammatory effects of isoflavones are dependent on flow and human endothelial cell ppar gamma. luteolin exhibits anti-inflammatory effects by blocking the activity of heat shock protein 90 in macrophages. doi: 10.1016/s0006-2952(00)00255-0 chiou, w. f., chen, c. f., and lin, j. j. mechanisms of inhibition of the ras-map kinase signaling pathway in 30.7b ras 12 cells by tea polyphenols (-)-epigallocatechin-3-gallate and theaflavin-3,3’-digallate. evidence for the efficacy of complementary and alternative medicines in the management of osteoarthritis: a systematic review. anti-inflammatory activity of baicalein in lps-stimulated raw264.7 macrophages via estrogen receptor and nf-κb-dependent pathways. immunomodulatory activity of curcumin: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production in vitro. anti-hepatitis b virus activity of wogonin in vitro and in vivo. the reduction of hypoxia-induced and reoxygenation-induced apoptosis in rat islets by epigallocatechin gallate. in vitro and in vivo modulation of cartilage degradation by a standardized centella asiatica fraction. genistein reduces the production of proinflammatory molecules in human chondrocytes. doi: 10.1016/j.bcp.2004.10.002 hu, j.-z., huang, j. h., xiao, z. m., li, j. h., li, x. m., and lu, h. b. j. med.

andrographolide interferes with t cell activation and reduces experimental autoimmune encephalomyelitis in the mouse. presence of an acidic glycoprotein in the serum of arthritic rats: modulation by capsaicin and curcumin. lycorine inhibits lipopolysaccharide-induced inos and cox-2 up-regulation in raw264.7 cells through suppressing p38 and stats activation and increases the survival rate of mice after lps challenge. molecular targets of celastrol derived from thunder of god vine: potential role in the treatment of inflammatory disorders and cancer. curcumin inhibits immunostimulatory function of dendritic cells: mapks and translocation of nf-κb as potential targets. anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models. effect of apigenin, kaempferol and resveratrol on the expression of interleukin-1beta and tumor necrosis factor-alpha genes in j774.2 macrophages. doi: 10.1016/j.jep.2004.03.004 kumar, s., ahuja, v., sankar, m. j., kumar, a., and moss, a. c. (2012). mechanisms for the inhibition of dna methyltransferases by tea catechins and bioflavonoids. doi: 10.1017/s000711450769936x lin, w. c., and lin, j. y. the unexpected side effects and safety of therapeutic monoclonal antibodies. doi: 10.1164/rccm.201408-1565oc maiti, k., gantait, a., mukherjee, k., saha, b., and mukherjee, p. k. (2006). immunomodulating and anticancer agents in the realm of macromycetes fungi (macrofungi). apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating nf-κb through the suppression of p65 phosphorylation. colchicine: its mechanism of action and efficacy in crystal-induced inflammation. unravelling the mystery of capsaicin: a tool to understand and treat pain. flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. effect of quercetin on traits of the metabolic syndrome, endothelial function and inflammation in men with different apoe isoforms. andrographolide inhibits the production of tnf-alpha and interleukin-12 in lipopolysaccharide-stimulated macrophages: role of mitogen-activated protein kinases. the green tea polyphenol, epigallocatechin-3-gallate inhibits telomerase and induces apoptosis in drug-resistant lung cancer cells. oral treatment with genistein reduces the expression of molecular and biochemical markers of inflammation in a rat model of chronic tnbs-induced colitis. role of quercetin (a natural herbal compound) in allergy and inflammation. doi: 10.1016/j.bbrc.2009.02.071 si, h., and liu, d. (2007). induction of secretory and tumoricidal activities in peritoneal macrophages by ginsan. recombinant and natural human interferons: analysis of the incidence and clinical impact of neutralizing antibodies. doi: 10.1016/s0027-5107(01)00183-x tang, t., targan, s. r., li, z. s., xu, c., byers, v. s., and sandborn, w. j. piperine suppresses cerebral ischemia–reperfusion-induced inflammation through the repression of cox-2, nos-2, and nf-κb in middle cerebral artery occlusion rat model. systematic review and recommendations on the use of resveratrol. inhibition of adipocyte inflammation and macrophage chemotaxis by butein. doi: 10.1016/j.ejphar.2014.05.031 wu, c. j., wang, y. h., lin, c. j., chen, h. h., and chen, y. j. doi: 10.1111/j.1440-1746.2006.04681 yamakuchi, m., bao, c., ferlito, m., and lowenstein, c. j. doi: 10.1515/bc.2008.095 yang, c. s., wang, h., li, g. x., yang, z., guan, f., and jin, h. (2011a). anti-inflammatory effects of rutin on hmgb1-induced inflammatory responses in vitro and in vivo. comparison of effects of epigallocatechin-3-gallate on hypoxia injury to human umbilical vein, rf/6a, and ecv304 cells induced by na(2)s(2)o(4). sophocarpine and matrine inhibit the production of tnf-α and il-6 in murine macrophages and prevent cachexia-related symptoms induced by colon26 adenocarcinoma in mice. the use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

we end by proposing research strategies for identification of novel immunomodulatory drugs from herbal medicine sources that are informed by recently the clinical potential of six plant-derived antiinflammatory compounds: curcumin, colchicine, resveratrol, capsaicin, epigallocatechin- immunomodulatory constituents with herbal origins are termed as phytochemicals, including flavonoids, glycosides, polysaccharides, terpenoids, essential oils,, immunomodulatory drugs, immunomodulatory drugs, natural immunomodulators, immunomodulatory foods, immunomodulators examples.

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