Licorice-Yuanhua Herbal Pair Induces Ileum Injuries Through Weakening Epithelial and Mucous Barrier Functions: Saponins, Flavonoids, and Di-Terpenes All Involved
Jingao YuDong-Bo ZhangYanni LiangZhen ZhangJianming GuoYan‐Yan ChenYafeng YanHongbo LiuLiyan LeiZheng WangZhishu TangYuping TangJin‐Ao Duan
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In traditional Chinese Medicine (TCM), the licorice-yuanhua herbal pair is one of the most representative incompatible herbal pairs recorded in the "eighteen incompatible herbal pairs" theory. Previous studies of our research group have demonstrated several gut-related side-effects induced by the licorice-yuanhua herbal pair. In this study, we investigated whether and why this incompatible herbal pair could induce gut tissue damage. After licorice-yuanhua treatment, the duodenum, ileum, and colon and serum biomarkers of mice were examined by pathological staining, Western blot, and ELISA assays. The IEC-6 cells and LS174T cells were treated with licorice saponins, yuanhua flavonoids, and di-terpenes; iTRAQ-labeled proteomic technology was then used to explore their synergistic effects on mucosa cells, followed by verification of ZO-1 and MUC-2 protein expressions. The results showed that the licorice-yuanhua herbal pair induced ileum tissue injuries, including epithelial integrity loss, inflammation, and edema. These injuries were verified to be related to epithelial and mucous barrier weakening, such as downregulated ileum ZO-1 and MUC-2 protein expressions. Proteomic analysis also suggested that glycyrrhizic acid and genkwanin synergistically influence tight junction pathways in LS174T cells. Furthermore, licorice saponins, yuanhua flavonoids, and di-terpenes dose/structure-dependently downregulate ZO-1 and MUC-2 protein expressions in mucosa cells. Our study provides different insights into the incompatibility mechanisms and material basis of the licorice-yuanhua herbal pair, especially that besides toxic di-terpenes, licorice saponins and yuanhua flavonoids, which are commonly known to be non-toxic compounds, can also take part in the gut damage induced by the licorice-yuanhua herbal pair.Keywords:
Terpene
Terpene
Eucalyptol
Degradation
Pinene
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Terpenes are naturally occurring compounds produced by plants that are of great commercial interest in the food, agricultural, cosmetic, and pharmaceutical industries due to their broad spectra of antibacterial, antifungal, anthelmintic, membrane permeation enhancement, and antioxidant biological activities. Applications of terpenes are often limited by their volatility and the need for surfactants or alcohols to produce stable, soluble (non-precipitated) products. Yeast particles (YPs) are hollow, porous microspheres that have been used for the encapsulation of terpenes (YP terpenes) by passive diffusion of terpenes through the porous YP cell walls. We here report the development of a second generation YP encapsulated terpene technology that incorporates the stimuli-responsive control of terpene release using biodegradable pro-terpene compounds (YP pro-terpenes). YP terpenes and YP pro-terpenes were both produced, in which high levels of carvacrol, eugenol, thymol and geraniol were encapsulated. The YP pro-terpenes show higher encapsulation stability than YP terpenes due to pro-terpenes being non-volatile solids at room temperature and stable in suspensions at neutral pH. YP pro-terpenes and YP terpenes were evaluated for biological activity in antibacterial, antifungal and anthelmintic assays. The YP pro-terpenes retained the full biological activity of the parent terpene compound.
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Thymol
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This study investigated the effects of ammonia (NH3) exposure (0, 15, 25, and 35 ppm) on growth performance and cytokines in the serum, trachea, and ileum of broilers. A total of 288 22-day-old male broiler chickens were assigned to 4 treatment groups with 6 replicates of 12 chickens for a 21-D trial period. Growth performance and cytokines (IL-1β, IL-6, and IL-10) concentrations in the serum, trachea, and ileum were measured in response to 3, 7, 14, or 21 D of exposure to NH3. Correlations between cytokines in the serum, trachea, and ileum and growth performance, and between tracheal and ileal cytokines, were also analyzed. Results showed that exposure to 15 ppm NH3 did not influence the growth performance, but exposure to both 25 ppm and 35 ppm NH3 decreased the growth performance compared to that of the control group. Exposure to 15 ppm NH3 for 3 D increased IL-6 concentrations and induced an inflammatory response in the trachea and ileum, whereas exposure to 15 ppm NH3 for 7 D increased IL-10 concentrations and induced an anti-inflammatory response in the ileum. Exposure to 25 ppm NH3 induced an inflammatory response in the serum, trachea, and ileum after 3 D and induced an anti-inflammatory response in the ileum after 7 D. Exposure to 35 ppm NH3 for 3 D induced both inflammatory and anti-inflammatory responses in the trachea and ileum. Furthermore, increases in cytokines in the serum, trachea, or ileum were accompanied by a decrease in BW, ADFI, ADG, and an increase of feed/gain (F/G) from 7 D to 21 D. In addition, tracheal cytokine, especially IL-1β, was positively correlated with ileal cytokine IL-1β. These results indicated that the low growth performance associated with NH3 exposure may be due in part to an increase in cytokines, and the inflammatory response in the trachea and ileum may be related to cross-talk by cytokines such as IL-6, IL-10, and, in particular, IL-1β.
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Tight junctions form a belt‐like structure between adjacent cells whose degree of permeability changes according to external stimuli, physiological and pathological conditions. We have previously shown that alcohol increases tight junction permeability and disrupts tight junction proteins (ZO‐1 and claudin) in cultured airway epithelial cells through PKCα. It is well established that individuals who consume heavy and prolonged amounts of alcohol are more likely to suffer from pulmonary diseases and infections. Alcohol triggers tight junctions in airway epithelial cells to “leak”, which likely primes the airways for pulmonary infections. Thus, a second injury, such as viral or bacterial infection, is likely intensified by alcohol consumption. To date, very few studies have focused on the combination of alcohol and RSV infection. While both alcohol and RSV have been separately shown to disrupt tight junctions, little research has examined the combination of alcohol and RSV infection on tight junction function. We hypothesize that alcohol primes the airways for RSV infection and exacerbates RSV infection significantly increasing tight junction permeability and airway epithelial injury. Preliminary cell culture data demonstrates that Gö6976, a PKCαinhibitor, and Y27632, a Rho‐associated protein kinase (ROCK) inhibitor, prevent alcohol‐induced tight junction “leak”. In addition, the combination of alcohol exposure and RSV infection increase tight junction permeability considerably more than RSV or alcohol alone. Together our preliminary data suggest that alcohol‐induced tight junction disruption primes the airways for RSV infection. Grant Funding Source : Supported by I01BX000728 (TAW) and R01AA008769 (JHS)
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Objective To study the changes of expressions of intestinal mucosal tight junction proteins ZO-1 and Occludin in rats with acute intrahepatic cholestasis,and explore its mechanisms.Methods Forty SD rats aged 21 days were randomly divided into control group(n=10) and model group(n=30).A single dose(50 mg.kg-1) of α-naphthylisothiocyanate was administered by gavage to each experimental rats to induce acute intrahepatic cholestasis in model group.Rats in control group only administered with caster oil by gavage.At 24 hours,48 hours and 72 hours after gavage,immunohistochemistry and Western blot techniques were used to examine the distribution and expression of tight junction proteins(ZO-1,Occludin),and the results of Western blot were quantitatively analyzed by image analytical system.Results ZO-1 and Occludin were localized along the apical region of the lateral plasma membrane representing the region of tight junctions in surface and crypt epithelial cells.Compared with control group,the positive stainings of ZO-1 and Occludin in model group at 24 hours after gavage were decreased,the decrease was most obviously at 48 hours,and partly recovered at 72 hours.Western blot demonstrated consistent and significant reduction with immunohistochemistry.The expressions of ZO-1 and Occludin in model group were 0.129 4±0.048 1 and 0.195 0±0.044 1 at 24 hours,0.039 5±0.009 5 and 0.013 7±0.009 2 at 48 hours,0.202 4±0.049 8 and 0.149 4±0.035 5 at 72 hours,which were significantly lower than those in control group(ZO-1:0.288 7±0.023 7,Occludin:0.426 6±0.067 0)(Pa0.01).Conclusions Acute intrahepatic cholestasis induces the abnormal distribution of tight junction proteins and the alteration of their quantity,which affects the intestinal barrier integrity,resulting in impaired barrier function.
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Intestinal epithelium functions as a tissue barrier to prevent interaction between the internal compartment and the external milieu. Intestinal barrier function also determines epithelial polarity for the absorption of nutrients and the secretion of waste products. These vital functions require strong integrity of tight junction proteins. In fact, intestinal tight junctions that seal the paracellular space can restrict mucosal-to-serosal transport of hostile luminal contents. Tight junctions can form both an absolute barrier and a paracellular ion channel. Although defective tight junctions potentially lead to compromised intestinal barrier and the development and progression of gastrointestinal (GI) diseases, no FDA-approved therapies that recover the epithelial tight junction barrier are currently available in clinical practice. Here, we discuss the impacts and regulatory mechanisms of tight junction disruption in the gut and related diseases. We also provide an overview of potential therapeutic targets to restore the epithelial tight junction barrier in the GI tract.
Paracellular transport
Claudin
Barrier function
Septate junctions
Intestinal epithelium
Intestinal mucosa
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Summary Terpenes have been proposed as potential biomarkers in verifying the diets of grazing animals. A study of the relationships between the intake of terpenes and their presence in animal tissues (blood and milk) as well as in the final product (cheese) was conducted. Eight dairy sheep were divided into two equal groups, representing control (C) and treatment group (T). In T group oral administration of a mixture of terpenes, α‐pinene, limonene and β‐caryophyllene, was applied over a period of 18 days. Blood and milk samples were collected regularly and terpenes were identified by extraction using petroleum ether and the solid phase micro‐extraction (SPME) method, respectively, followed by GC‐MS analysis. Cheese was produced, from C and T animals separately, twice during the period of terpenes oral administration. Terpenes contents and chemical properties of the produced cheeses were investigated. Limonene and α‐pinene were found in all blood and milk samples of the T group after a lag‐phase of 2 days, while β‐caryophyllene was detected in few plasma samples and in all milk samples. None of the terpenes was traced in blood and milk of C animals. The contents of cheese, in dosed terpenes, presented a more complicated pattern suggesting terpenes non‐credible as biomarkers. We conclude terpenes can be used as biomarkers for authentification of ewes’ milk, but further research is required on factors affecting their transfer to dairy products from grazing diets.
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Caryophyllene
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The cannabis plant exerts its pharmaceutical activity primarily by the binding of cannabinoids to two G protein-coupled cannabinoid receptors, CB1 and CB2. The role that cannabis terpenes play in this activation has been considered and debated repeatedly, based on only limited experimental results. In the current study we used a controlled in-vitro heterologous expression system to quantify the activation of CB1 receptors by sixteen cannabis terpenes individually, by tetrahydrocannabinol (THC) alone and by THC-terpenes mixtures. The results demonstrate that all terpenes, when tested individually, activate CB1 receptors, at about 10–50% of the activation by THC alone. The combination of some of these terpenes with THC significantly increases the activity of the CB1 receptor, compared to THC alone. In some cases, several fold. Importantly, this amplification is evident at terpene to THC ratios similar to those in the cannabis plant, which reflect very low terpene concentrations. For some terpenes, the activation obtained by THC- terpene mixtures is notably greater than the sum of the activations by the individual components, suggesting a synergistic effect. Our results strongly support a modulatory effect of some of the terpenes on the interaction between THC and the CB1 receptor. As the most effective terpenes are not necessarily the most abundant ones in the cannabis plant, reaching "whole plant" or "full spectrum" composition is not necessarily an advantage. For enhanced therapeutic effects, desired compositions are attainable by enriching extracts with selected terpenes. These compositions adjust the treatment for various desired medicinal and personal needs.
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Tetrahydrocannabinol
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Abstract Hydrolysis of the β‐curcumene epoxide (I) affords the title compound (II) as a single homogeneous diastereomer.
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