National Center for Complementary and Alternative Medicine (NCCAM)

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NCCAM High-Priority Topics for Mechanistic Research on CAM Natural Products (R01) RFA-AT-11-001

NCCAM has identified a number of research areas, listed below, of particular interest as they relate to RFA-AT-11-001. This should not be considered an exclusive list. It is important to emphasize that NCCAM is interested in studying the mechanisms of action for natural products as part of this RFA and NOT their clinical efficacy. Furthermore, the posted topics may change over time to reflect emerging science and evolving priorities.

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Ashwagandha (Withania somnifera)

Ashwagandha is an herb used in Ayurvedic medicine. Many compounds have been identified from this plant, but activity is most often associated with the withanolides and other steroid lactones. Reported bioactivities include effects on carbohydrate and lipid metabolism, anti-leishmanial activity, immune modulation, decreased anxiety, and prevention of neurodegenerative diseases and cancer. Such an extensive list of possible health benefits for this plant raises the possibility that a more systemic effect could be at work. An examination of the changes in gene, protein, or regulatory RNA expression or localization in response to this herb would help to identify possible explanations for such diverse activity. Examples of responsive projects include:

  • Characterization of bioavailability and pharmacokinetics/pharmacodynamics of bioactive constituents
  • Immunomodulatory mechanisms
  • Elucidation of potential targets that might be relevant to prevention of neurodegenerative diseases or cancer, especially clarification of relevance of in vitro data to in vivo activities
  • Assessment of potential changes in gene or protein expression (including changes in posttranslational modifications and localization) in response to W. somnifera or its isolated components

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Astragalus (Astragalus membranaceus)

A. membranaceus has a long history of use in traditional Chinesemedicine as an immune-modulating herb. Modern research has shown that astragalus possesses in vitro antitumor activity and is capable of potentiating the activity of interleukin-2. It has also been studied for diabetic nephropathy and viral myocarditis. Interest in this plant has increased substantially over the last 5 years, as evidenced by the rapid rise in publications. A number of known classes of active compounds have been identified including polysaccharides, isoflavones, and saponin glycosides. However, more work on the following aspects is needed to fully characterize the bioactive compounds in this plant as well as their associated activities and mechanisms of action, particularly with regard to the complex polysaccharides. Examples of responsive projects include:

  • Identification of bioactive constituents
  • Characterization and standardization of polysaccharide components
  • Mechanisms of immune modulation

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Beta-glucans

Fungal and yeast β‑(1–3) glucans are widely used in Asia as an adjuvant treatment for a number of cancers and have been shown to modulate innate immunity and produce possible antitumor responses. However, as large and inherently heterogeneous natural products, glucan polymers have been notoriously difficult to characterize and standardize. New methods for structure determination are required. Also needed is a detailed assessment of mechanisms of immune modulation, as well as elucidation of translational potential of direct antitumor activities reported in vitro. Examples of responsive projects include:

  • Improved approaches for isolation, fractionation, and/or characterization of (primarily) β‑(1,3) glucans
  • Elucidation of direct anti-tumor activities of β‑(1,3) glucans
  • Application of new approaches to synthesis of purified glucan elements of known structure
  • Analysis of the functional role of β‑(1,4) and β‑(1,6) branching

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Coenzyme Q10

Mounting evidence indicates that coenzyme Q10 (CoQ10) supplementation may have a positive impact on cardiovascular and neurodegenerative diseases. Mitochondrial dysfunction is implicated as a major factor in the progression of these diseases. The primary route of activity for CoQ10 appears to be through modification of mitochondrial bioenergetics, thus providing a plausible hypothesis for its mechanism of action. However, a more thorough understanding is still needed. Individuals with the aforementioned medical conditions who choose to take CoQ10 almost certainly will be on pharmaceutical management as well. As such, it is important to ascertain any interactions that may take place when using CoQ10 in conjunction with prescription medication. Examples of responsive projects include:

  • Herb/drug interactions
  • Mechanisms of cardio and neuroprotection
  • Identification of in vivo markers of effect

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Devil’s Claw (Harpagophytum procumbens)

The anti-inflammatory mechanisms of devil’s claw have been the subject of in vitro and animal studies, yet the identification of a biological signature or biomarker of its anti-inflammatory activity is needed for future human clinical studies. While some of the biological activity of devil’s claw has been attributed to the harpagoside compound, additional components of the botanical that may have anti-inflammatory effects deserve further investigation. In addition, the purported analgesic properties, the mechanisms of the analgesic effects, and which compounds in the botanical are responsible for these effects have not been well-studied. Examples of responsive projects include:

  • Identification of a biological signature or biomarker for anti-inflammatory activity
  • Thorough analysis of anti-inflammatory constituents
  • Study of purported analgesic activity, including identification of active components and mechanism of action

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Echinacea (Echinacea purpurea)

Echinacea has a long history of use in North America and Europe for prevention or treatment of colds, yet clinical trials of echinacea have not confirmed clinical benefits. Nonetheless, there is evidence that some echinacea preparations modulate immune responses, and potentially may influence the development of symptoms. Interestingly, both immunostimulatory and immunosuppressive in vitro activity has been described depending on the part of the plant used and the extraction method employed. Important information needed to inform future studies includes: identification of the optimal species, means of extraction, and specific components associated with specific immune activities(be they stimulatory or inhibitory), marker components for echinacea standardization and determination of pharmacokinetics, and elucidation of an overall biological signature of the product. Additionally, it remains to be seen if dosages and effects observed in vitro can be achieved in human subjects. Examples of responsive projects include:

  • Identification of immunomodulatory components and their mechanisms of action
  • Comparison of the activity of different echinacea products on the immune system
  • Determination of the biological signature of echinacea

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Ginseng (Panax ginseng, Panax quinquefolius)

P. ginseng has been used in traditional Chinese medicine for centuries. Recently, a number of biological effects have been linked to the various Panax species, including disruption of quorum sensing in the human pathogen Pseudomonas aeruginosa, immune modulation, and direct inhibition of tumor growth. More research is needed to elucidate potential mechanisms of action of specific ginseng components in mediating such effects. This may include ways in which individual ginsenosides and ginseng-derived glycans or terpenoids from different ginseng species or preparations contribute to the biological effects of ginseng at the cellular and whole-animal levels. Application of systems biology approaches to deconvolute the contributions of specific components in specific biological contexts is encouraged. Examples of responsive projects include:

  • Characterization of immunomodulatory ginseng components and their mechanisms of action
  • Animal studies of bioavailability, pharmacokinetics, and pharmacodynamics of ginseng components with direct (including anti-angiogenic) tumor-inhibitory effects
  • Characterization of ginseng components with direct effects on human pathogens and elucidation of their mechanisms of action
  • Characterization of interactions between ginseng components or between ginseng components and commonly used pharmaceuticals, as well as optimization of ginseng extract preparation for components active in specific clinical contexts

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Hops (Humulus lupulus)

Hops have long been considered to have sedative properties. More recently, it was discovered that a number of phytoestrogens are present in this plant. The estrogenic activity is most often associated with 8‑prenylnaringenin, whereas the compound(s) responsible for the sedative activity are less clearly understood. One theory suggests that the estrogenic qualities of the plant could improve menopausal symptoms such as night sweats, thereby explaining the “sedative” activity in terms of improved sleep quality. A better understanding of the phytoestrogenic principles in hops, including any receptor or tissue specificity, is needed. Furthermore, despite the historic use of this plant as a sedative, it appears little is known about the components responsible for this activity or their mechanisms of action. Examples of responsive projects include:

  • Investigation of compounds responsible for sedative activity
  • Determination of sedative mechanism of action
  • Determination of tissue and receptor specificity of phytoestrogenic principles

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Milk Thistle (Silybum marianum)

S. marianum is the most extensively studied plant for the treatment of liver diseases such as alcoholic liver disease, acute and chronic viral hepatitis, and toxin-induced liver disease. Silymarin is an extract of milk thistle, composed of multiple flavonolignans including silybin A and B, silydianin, and silychristin. Silymarin may have antioxidant and antifibrotic activity and may inhibit binding of toxins to the hepatocytes, although this has not been clearly demonstrated in humans. Furthermore, the in vitro and in vivo activity of the components individually and collectively requires further investigation. Of particular interest are the mechanisms associated with the hepatoprotective and chemopreventive activities observed in cells and animals and whether or not these mechanisms translate into humans. For many possible indications, silymarin would be taken in conjunction with pharmaceutical interventions. Thus, it becomes important to fully understand its mechanisms and potential herb/drug interactions. Examples of responsive projects include:

  • Studies on the activity of components individually and collectively
  • Mechanism of action for possible hepatoprotective effects
  • Understanding of possible interactions with drugs used frequently by patients with liver disease

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Polyphenols (e.g., flavonoids, catechins, anthocyanins)

Polyphenols are a very diverse class of compounds ubiquitous in medicinal and food plants. Over the last 20 years, an incredibly broad array of bioactivities has been attributed to these compounds based on in vitro and animal studies. These include anti-cancer, anti-inflammatory, neuroprotective, and (widely touted) antioxidant activities. One possible explanation for such a wide range of biological effects is that these compounds exert their activity through a central mechanism that links all these targets. A systems biology approach may lead to a better comprehension of the various pathways that are influenced by polyphenols and could reveal a biological signature of effect. Possibly their activity is mediated through interactions with the host microbiome and subsequent generation of bioactive metabolites. It is known that polyphenols are rapidly metabolized, thereby producing a plethora of metabolic products, yet little is understood regarding the bioavailability and bioactivity of these metabolites. Examples of responsive projects include:

  • Understanding formation and biological activity of polyphenol metabolites
  • Investigation into possible central mechanisms of action
  • Identification of biological signatures
  • Systems biology study of polyphenols

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Probiotics

In the United States, candidate probiotic strains can be marketed as food products and dietary supplements or developed as live biologic drugs for intended preventive or biotherapeutic use. Areas of research interest include the potential role of probiotic antimicrobial proteins and signaling pathways in altering immune function, changes in gut barrier function, and metagenomic-based examination of the effects of probiotics on the gut microflora. Additionally, improved identification and standardization of probiotic organisms relevant to human health and assays to assess their interactions with host microflora are of high interest. An important area for investigation is to elucidate safety and activity of probiotic organisms relative to commensal microbial communities. Examples of responsive projects include:

  • Investigation of probiotics and immune function
  • Studies on gut microflora changes in response to probiotics
  • Development of improved identification and standardization of probiotic organisms
  • Elucidation of safety and activity profiles of probiotics

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PUFAs

The field of omega‑3 fatty acid (FA) research has expanded rapidly to assess the effects of polyunsaturated fatty acids (PUFAs) on cardiovascular disease, cognition, mental health, and atopic/inflammatory diseases. While the areas of clinical research related to PUFAs are expanding, more research is needed on the possible mechanisms of action responsible for the diverse purported clinical benefits. Significant questions remain regarding determination of the appropriate markers for dietary omega‑3 intake and the effect of supplementation on biological processes. Important unresolved mechanistic questions exist about putative central nervous system activity, effects on lipid-signaling pathways, individual response variability (gene/nutrient interactions), and the effect that the ratios of different FAs (EPA, DHA, GLA) have on different tissue targets. Examples of responsive projects include:

  • Mechanism of action studies for different clinical indications
  • Establishment of appropriate biomarkers
  • Studies on different FA ratios and their impact on targets
  • Understanding of individual response variability

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Thunder God Vine (Tripterygium wilfordii)

Extracts of T. wilfordii have been used to treat a variety of autoimmune and inflammatory disorders and have been shown to inhibit expression of multiple proinflammatory genes. Although the safety and efficacy of specific Tripterygium extracts have been the subject of a number of clinical trials, uncertainty about both safety and efficacy persist. Triptolide is the most extensively studied anti-inflammatory and immunosuppressive constituent from this plant, but other compounds present may influence the overall activity. Interestingly, some activities associated with Tripterygium extracts were not seen with pure triptolide. Modulation of the NF-KB signaling pathway, including inhibition of pro-inflammatory cytokine production and suppressing expression of multiple pro-inflammatory enzymes, has been implicated as being responsible for the activity of thunder god vine. However, the mechanism of action for the potent activities observed has not been elucidated. Examples of responsive projects include:

  • Anti-inflammatory and immunosuppressive mechanism of action
  • Investigation of mechanisms associated with rheumatoid arthritis activity
  • Studies examining the potencies of bioactive compounds individually and collectively

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Turmeric (Curcuma longa)

Turmeric, and its major constituent curcumin, has demonstrated potent in vitro anti-inflammatory activities, with suggested protective activities for neurodegenerative diseases and cancer. Commercially available curcumin appears to be well tolerated by humans at oral doses up to several grams per day and contains a mixture of curcuminoids (curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin) with differing activities and potentially limited bioavailability. Curcumin has been reported to act on a range of molecular targets to modulate gene expression and biological functions ranging from angiogenesis and apoptosis through eicosanoid synthesis and neurotransmitter activity. Curcumin is currently in clinical trials for a variety of applications including cancer, psoriasis, and Alzheimer’s disease. Examples of responsive projects include:

  • Studies that increase our understanding of the metabolites responsible for activity and the tissue distribution and pharmacokinetics and pharmacodynamics (PK/PD) of these metabolites
  • Studies of the comparative bioavailability and PK/PD of individual curcuminoids as compared with mixtures of curcuminoids and turmeric extracts in different formulations and in different dietary contexts
  • Animal studies or proof of principle human studies to substantiate mechanisms of action previously demonstrated only in vitro or in animal models
  • Studies to clarify which relevant biological activities of curcumin are through direct effects (e.g., directly mediated by curcuminoid binding), as opposed to indirect effects

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Vitamin D

Awareness regarding the health implications of vitamin D status is growing. Further evidence indicates that racial and ethnic minority populations may have lower mean concentrations of serum 25-Hydroxyvitamin D [25(OH)D]—the principal measure of vitamin D status—within their communities. The meaning of those lower levels is not understood. Research is currently under way to investigate the possible contributing role of vitamin D deficiency in common diseases such as diabetic neuropathy, cardiovascular diseases, and certain cancers. While supplementation can be effective in raising serum levels of 25(OH)D, research on what doses might be most appropriate for what indications or which populations is lacking. There is also insufficient information regarding toxicity at higher dosages and proper dosage forms. While vitamin D’s effects on bone are fairly well established, additional research is needed regarding the mechanism of action for vitamin D outside of the musculoskeletal system. Examples of responsive projects include:

  • Dose-ranging studies
  • Identification of optimal dosage form
  • Investigation of appropriate dosage for indication and population

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