Assessment of Herb-Drug Interaction Potential of Five Common Species of Licorice and Their Phytochemical Constituents.

The dried roots and rhizomes of Glycyrrhiza species (G. glabra, G. uralensis and G. inflata), commonly known as licorice, have long been used in traditional medicine. In addition, two other species, G. echinata and G. lepidota are also considered "licorice" in select markets. Currently, licorice is an integral part of several botanical drugs and dietary supplements. To probe the botanicals' safety, herb-drug interaction potential of the hydroethanolic extracts of five Glycyrrhiza species and their key constituents was investigated by determining their effects on pregnane X receptor, aryl hydrocarbon receptor, two major cytochrome P450 isoforms (CYP3A4 and CYP1A2), and the metabolic clearance of antiviral drugs. All extracts enhanced transcriptional activity of PXR and AhR (>2-fold) and increased the enzyme activity of CYP3A4 and CYP1A2. The highest increase in CYP3A4 was seen with G. echinata (4-fold), and the highest increase in CYP1A2 was seen with G. uralensis (18-fold) and G. inflata (16-fold). Among the constituents, glabridin, licoisoflavone A, glyasperin C, and glycycoumarin activated PXR and AhR, glabridin being the most effective (6- and 27-fold increase, respectively). Licoisoflavone A, glyasperin C, and glycycoumarin increased CYP3A4 activity while glabridin, glyasperin C, glycycoumarin, and formononetin increased CYP1A2 activity (>2-fold). The metabolism of antiretroviral drugs (rilpivirine and dolutegravir) was increased by G. uralensis (2.0 and 2.5-fold) and its marker compound glycycoumarin (2.3 and 1.6-fold). The metabolism of dolutegravir was also increased by G. glabra (2.8-fold) but not by its marker compound, glabridin. These results suggest that licorice and its phytochemicals could affect the metabolism and clearance of certain drugs that are substrates of CYP3A4 and CYP1A2.Supplemental data for this article is available online at https://doi.org/10.1080/19390211.2022.2050875 .

Evaluation of the Herb-Drug Interaction Potential of Commonly Used Botanicals on the US Market with Regard to PXR- and AhR-Mediated Influences on CYP3A4 and CYP1A2.

In this study, hydroethanolic extracts of 30 top-selling botanicals (herbs) commonly used as ingredients of herbal dietary supplements in the US were screened for their potential to activate the human pregnane X receptor (hPXR) and human aryl hydrocarbon receptor (hAhR) and to increase the activities of hPXR- and hAhR-regulated drug metabolizing cytochrome P450 enzymes (i.e., CYP3A4 and CYP1A2, respectively). Of the 30 botanicals tested, 21 induced PXR and 29 induced AhR transcriptional activities. Out of the 21 botanicals that induced hPXR transcriptional activity, 14 yielded >50% induction in CYP3A4 activity at concentrations ranging from 6 to 60 µg/mL and 16 out of the 29 botanicals that activated hAhR yielded >50% induction in CYP1A2 activity at concentrations ranging from 3 to 30 µg/mL. Moreover, eight botanicals (G. gummi-gutta [garcinia], Hemp [low and high CBD content], H. perforatum [St. John's wort], M. vulgare [horehound], M. oleifera [moringa], O. vulgare [oregano], P. johimbe [yohimbe] and W. somnifera [ashwagandha]) yielded >50% induction in both CYP3A4 and CYP1A2 activity. Herbal products are mixtures of phytoconstituents, any of which could modulate drug metabolism. Our data reveals that several top-selling botanicals may pose herb-drug interaction (HDI) risks via CYP450 induction. While in vitro experiments can provide useful guidance in assessing a botanical's HDI potential, their clinical relevance needs to be investigated in vivo. Botanicals whose effects on hPXR/CYP3A4, and hAhR/CYP1A2 activity were most pronounced will be slated for further clinical investigation.

Possible Herb-Drug Interaction Risk of Some Nutritional and Beauty Supplements on Antiretroviral Therapy in HIV Patients.

This study was carried out to assess the drug interaction potential of a variety of beauty and sports/nutritional supplements when co-administered with antiviral drug therapy, especially anti-HIV drugs. Ethanolic extracts of seven dietary supplements (two beauty products, three nutritional protein supplement products and two weight loss/body building products) were examined in human liver cells (HepG2 cells and primary hepatocytes) for their influence on the hepatic metabolism of five antiviral drugs (elvitegravir, rilpivirine, tenofovir, dolutegravir, and cobicistat), all of which are substrates for a key drug metabolizing enzyme CYP3A4. Our results showed that six of the seven supplements caused a 1.5 - 2 fold induction in PXR transcriptional activity in HepG2 cells. PXR regulates the expression of key drug metabolizing enzymes including CYP3A4. Follow up studies indicated a 1.5 - 3 fold induction in CYP3A4 enzyme activity in HepG2 cells treated with these supplements. We further investigated the effects of the supplement on the metabolism of above mentioned anti-viral drugs in HepG2 cells and primary hepatocytes. Of the five drugs, rilpivirine and dolutegravir metabolism was increased by up to 2-folds over the no supplement control by some of the supplements. Our findings indicate that concomitant consumption of these products with anti-HIV drugs may compromise the efficacy of antivirals therapy due to supplement-induced metabolism via induction of CYP3A4 activity.

Macrophage activation by edible mushrooms is due to the collaborative interaction of toll-like receptor agonists and dectin-1b activating beta glucans derived from colonizing microorganisms.

Research supports the theory that the microbiome of plants and mushrooms produce potent activators of pathogen recognition receptors which are principal contributors to the stimulation of macrophages. We have previously reported that the in vitro macrophage stimulatory activity of water-soluble extracts from 13 different types of edible mushrooms is predominantly due to bacterial components originating from the naturally occurring bacterial communities within these materials. The purpose of the current study was to further investigate the bacterial-dependent activity of the water-soluble extracts and assess whether these 13 types of mushrooms contain water-insoluble beta glucans that activate the dectin-1b signaling pathway. Activity of the water-soluble extracts was predominantly due to Toll-like receptor 2 (TLR2) and TLR4 agonists. For dectin-1b-dependent activity (indicative of water-insoluble beta glucans), culinary mushrooms (Agaricus bisporus varieties) were essentially inactive, whereas most of the medicinal mushrooms (Lentinula edodes, Grifola frondosa, Hypsizygus marmoreus varieties, Flammulina velutipes) exhibited potent activation. A. bisporus samples with no detectable dectin-1b-dependent activity had yeast colony forming units that were 687 times lower than L. edodes exhibiting high activity, indicating that the active insoluble beta glucans are derived from colonizing yeast. In addition, co-stimulation of macrophages with the TLR agonists and insoluble beta glucan was found to result in a synergistic enhancement of in vitro cytokine production. Taken together, these findings indicate that the in vitro macrophage activating potential of edible mushrooms is due to the collaborative interaction of water-soluble TLR agonists (derived from colonizing bacteria) and water-insoluble beta glucans (derived from colonizing yeast).

Pharmacokinetics and Tissue Distribution of Aegeline after Oral Administration in Mice.

Aegeline is claimed to be a biologically active constituent of Aegle marmelos. Preclinical studies have reported possible therapeutic potential for aegeline against obesity and diabetes. In recent years, aegeline has been added to several weight loss products. However, the consumption of aegeline-containing supplements such as OxyELITE Pro and VERSA-1 has been linked to multiple cases of acute and chronic liver failure. This study was carried out to evaluate the pharmacokinetics and tissue distribution of aegeline in ND4 mice. Two doses of aegeline, a human equivalent dose (1×) 30 mg/kg and a 10× dose (300 mg/kg), were orally administered to the mice, and blood and tissue samples were collected over 8 h. The quantitative analysis of plasma and tissue homogenates (liver, kidney, and brain) was done by UHPLC-QTOF to determine aegeline concentrations. The peak plasma level of aegeline was achieved at a Tmax of 0.5 h, indicating its rapid absorption from the gastrointestinal tract. Aegeline was not detected in the plasma at 8 h after oral administration, with a half-life of 1.4 ± 0.01 and 1.3 ± 0.07 h for the 30 and 300 mg/kg doses, respectively. The half-life of aegeline in the liver was 1.2 h and 1.7 h for 30 and 300 mg/kg doses, respectively, with a Tmax of 1.9 h, which indicates relatively fast elimination of aegeline from the liver.

Plant microbiome-dependent immune enhancing action of Echinacea purpurea is enhanced by soil organic matter content.

We previously demonstrated that extracts from Echinacea purpurea material varied substantially in their ability to activate macrophages in vitro and that this variation was due to differences in their content of bacterial components. The purpose of the current study was to identify soil conditions (organic matter, nitrogen, and moisture content) that alter the macrophage activation potential of E. purpurea and determine whether these changes in activity correspond to shifts in the plant-associated microbiome. Increased levels of soil organic matter significantly enhanced macrophage activation exhibited by the root extracts of E. purpurea (p < 0.0001). A change in soil organic matter content from 5.6% to 67.4% led to a 4.2-fold increase in the macrophage activation potential of extracts from E. purpurea. Bacterial communities also differed significantly between root materials cultivated in soils with different levels of organic matter (p < 0.001). These results indicate that the level of soil organic matter is an agricultural factor that can alter the bacterial microbiome, and thereby the activity, of E. purpurea roots. Since ingestion of bacterial preparation (e.g., probiotics) is reported to impact human health, it is likely that the medicinal value of Echinacea is influenced by cultivation conditions that alter its associated bacterial community.

Bacterial components are the major contributors to the macrophage stimulating activity exhibited by extracts of common edible mushrooms.

Recent studies have indicated that a major contributor to the innate immune enhancing properties of some medicinal plants is derived from the cell wall components of bacteria colonizing these plants. The purpose of the current study was to assess if the bacteria present within edible and medicinal mushrooms substantially contribute to the innate immune stimulating potential of these mushrooms. Whole mushrooms from thirteen types of edible fungi and individual parts from Agaricus bisporus were analyzed for in vitro macrophage activation as well as bacterial lipopolysaccharides (LPS) content, cell load, and community composition. Substantial variation between samples was observed in macrophage activation (over 500-fold), total bacterial load (over 200-fold), and LPS content (over 10 million-fold). Both LPS content (ρ = 0.832, p < 0.0001) and total bacterial load (ρ = 0.701, p < 0.0001) correlated significantly with macrophage activation in the whole mushroom extracts. Extract activity was negated by treatment with NaOH, conditions that inactivate LPS and other bacterial components. Significant correlations between macrophage activation and total bacterial load (ρ = 0.723, p = 0.0001) and LPS content (ρ = 0.951, p < 0.0001) were also observed between different tissues of Agaricus bisporus. Pseudomonas and Flavobacterium were the most prevalent genera identified in the different tissue parts and these taxa were significantly correlated with in vitro macrophage activation (ρ = 0.697, p < 0.0001 and ρ = 0.659, p = 0.0001, respectively). These results indicate that components derived from mushroom associated bacteria contribute substantially to the innate immune enhancing activity exhibited by mushrooms and may result in similar therapeutic actions as reported for ingestion of bacterial preparations such as probiotics.

Activities and Prevalence of Proteobacteria Members Colonizing Echinacea purpurea Fully Account for Macrophage Activation Exhibited by Extracts of This Botanical.

Evidence supports the theory that bacterial communities colonizing Echinacea purpurea contribute to the innate immune enhancing activity of this botanical. Previously, we reported that only about half of the variation in in vitro monocyte stimulating activity exhibited by E. purpurea extracts could be accounted for by total bacterial load within the plant material. In the current study, we test the hypothesis that the type of bacteria, in addition to bacterial load, is necessary to fully account for extract activity. Bacterial community composition within commercial and freshly harvested (wild and cultivated) E. purpurea aerial samples was determined using high-throughput 16S rRNA gene pyrosequencing. Bacterial isolates representing 38 different taxa identified to be present within E. purpurea were acquired, and the activity exhibited by the extracts of these isolates varied by over 8000-fold. Members of the Proteobacteria exhibited the highest potency for in vitro macrophage activation and were the most predominant taxa. Furthermore, the mean activity exhibited by the Echinacea extracts could be solely accounted for by the activities and prevalence of Proteobacteria members comprising the plant-associated bacterial community. The efficacy of E. purpurea material for use against respiratory infections may be determined by the Proteobacterial community composition of this plant, since ingestion of bacteria (probiotics) is reported to have a protective effect against this health condition.

Oral administration of a Spirulina extract enriched for Braun-type lipoproteins protects mice against influenza A (H1N1) virus infection.

A growing body of research indicates that oral administration of bacteria (such as probiotics) can exhibit a protective effect against influenza A (H1N1) viral infection in mice. In the present study, we used a mouse model to examine whether oral administration of Immulina(®), a commercial extract from the cyanobacteria Arthrospira (Spirulina) platensis, can reduce the severity of illness resulting from influenza A (H1N1) viral infection. The main active compounds within Immulina(®) are bacterial Braun-type lipoproteins that activate innate immune cells through a toll-like receptor (TLR) 2-dependent pathway. Mice that were fed Immulina(®) for 30 days before and 21 days after infection with influenza A (H1N1) virus exhibited a statistically significant reduction in the severity of infection. Compared to the control group, Immulina(®)-fed mice exhibited less weight loss, increased appetite, decreased clinical signs of disease, and lower lung histopathology scores. The results from the present study adds to the increasing evidence that oral administration of bacterial components that activate innate immune cells, whether derived from a bacterial preparation (probiotics or cyanobacteria) or from plant material containing endophytic bacteria, can exhibit a protective effect against influenza A (H1N1) viral infection.