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Induced effects of CYP3A4 promoter mediated via PXR by SGD, SY and GC in HepG2 (a) and Caco2 (b). There is a significant increase in positive control RIF group and most prescriptions groups when compared with 0.1% DMSO treatment group (p < 0.05). There is no significant decrease in negative control PCN group when compared to the DMSO group (p > 0.05). VC1: cells were transfected with pcDNA3.1-PXR, PRL-SV40, pGL4.17; VC2: cells were transfected with pcDNA3.1, PRL-SV40, pGL4.17-CYP3A4; other groups: cells were transiently transfected with pcDNA3.1-PXR, PRL-SV40, pGL4.17-CYP3A4. All data were obtained from three independent experiments performed by triplicate and expressed as mean ± S.E.M. Statistical significance was determined by one-way ANOVA with Welch correction, followed by the Games Howell test for pairwise comparisons. One-way ANOVA with Welch’s correction revealed significant differences among the groups (Welch’s p < 0.001). *p < 0.05, **p < 0.01, ***p < 0.001 compared with the DMSO group; ▲p < 0.05 represents GC group compared to SY group with the same concentration
Source publication
Background
Chinese herbal formula Shaoyao Gancao decoction (SGD) is often used as an adjuvant with chemotherapeutic agents to treat cancer. Due to the herb-drug interactions, the alternations of drug metabolic enzyme and drug transporters induced by SGD deserve to be explored. We aimed to investigate the effect of SGD on the pregnane X receptor (PX...
Similar publications
• Pregnane X receptor (PXR) as a ligand dependent transcription factor, is capable of regulating gene expression of cytochromes P450 and transporters involved in xenobiotic/drug metabolism and elimination. Due to the species differences in the regulatory specificity of PXR, gene regulation should not be extrapolated from mammal to fish without rese...
Citations
... [14][15][16][17] In vitro studies have shown that Gancao extract activated PXR and induced CYP3A4 expression. 18,19 GZ and GA in Gancao have been considered as PXR activators based on in vitro data. [20][21][22][23] However, the data from these previous reports are equivocal due to the lack of demonstration of dose-response in PXR activation, lack of in vivo validation, and inconsistencies among different research groups. ...
Background and aims
The herbal supplement Gancao, also known as licorice, belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect. Recent studies have raised concerns about potential herb-drug interactions associated with Gancao via pregnane X receptor (PXR)-mediated induction of hepatic cytochrome P450 3A4 (CYP3A4). The current work aimed to determine the phytochemicals in Gancao that activate PXR and induce CYP3A4.
Methods
DPX2 cells were used for cell-based PXR reporter assays. The phytochemicals in Gancao extract were identified using a metabolomics approach. The effects of PXR activators identified from in vitro studies were further investigated in PXR- and CYP3A4-humanized mouse models.
Results
Gancao was verified to be a PXR-activating herb. Two major phytochemicals in Gancao, glycyrrhizin (GZ) and glycyrrhetinic acid (GA), did not activate PXR in the cell-based reporter assays. However, glabridin was shown to activate PXR in a dose-dependent manner. In vivo studies confirmed that GZ is not a PXR activator and glabridin is a weak PXR activator. Although GA did not active PXR in vitro, it induced CYP3A4 expression in a PXR-dependent manner in the PXR- and CYP3A4-humanized mice.
Conclusions
GZ is not a PXR activator. GA could not activate PXR in cell-based reporter assays but it could activate PXR in vivo. Glabridin is a weak PXR activator. This work provides novel insights into the underlying mechanisms of Gancao-related herb-drug interactions via PXR.
... The herbal mixture is a mixed combination of five commonly used herbal medicines with different proportions including: Paeoniae Radix Alba (42%), licorice (28%), dandelion (28%), and tea polyphenols (2%). The ratio of Paeoniae Radix Alba and licorice was revised on the basis of the traditional Chinese medicine prescription "Shaoyao Gancao Decoction" (25). In addition, the combination of licorice and dandelion has the functions of antioxidant, anti-inflammatory and antibacterial (26). ...
Weaning stress decreases the growth performance of piglets and is one of the main concerns of pig industries. Traditional Chinese herbal medicines have been used to reduce the adverse effects of weaning stress as both nutritional supplements and antibiotic substitutes. This study aimed to evaluate the effects of a Chinese herbal mixture (Kangtaile, which contained Paeonia lactiflora, licorice, dandelion, and tea polyphenols) on the growth performances, immune response, antioxidant capacity, and intestinal microbiota of weaned pigs. A total of 400 weaned pigs [Duroc × (Landrace × Yorkshire)] were randomly allocated into one of four treatments: the CON group, fed with basic diet; the HM1 group, fed with basal diet supplemented with 0.5 g herbal mixture/kg diet; the HM2 group, fed with basal diet supplemented with 1.0 g herbal mixture/kg diet; or the HM3 group, fed with basal diet supplemented with 1.5 g herbal mixture/kg diet. The results revealed that dietary supplementation with the herbal mixture for 28 days improved average daily gain and feed conversion ratio, while decreased the diarrhea rate of weaned pigs. Moreover, dietary supple-mentation with the herbal mixture improved the antioxidant capacity through increasing the activity of catalase (CAT) and the total antioxidant capacity (T-AOC) level, while decreasing the concentration of malondialdehyde (MDA) in the serum. Pigs supplemented with herbal mixture presented an increased serum immunoglobulin (Ig)M level on day 14 compared with control pigs. The herbal mixture altered the composition of intestinal microbiota by influencing the relative abundances of Firmicutes and Bacteroidetes at the phylum level. The relative abundances of the Firmicutes and Bacteroidetes were significantly related to the body weight gain of pigs. In conclusion, supplementation of herbal mixture to the diet improved growth performance, immunity, and antioxidant capacity and modified the composition of intestinal microbiota in weaning pigs. This study provided new insights into the nutritional regulation effects of the herbal mixtures on weaned pigs.
... SGD preparation was carried out in accordance with previously published literature. 8,35 Briefly, Baishao (100 g) and Gancao (100 g) were blended and distilled twice in water (at a ratio of 1:10, g/mL) for 1 h. The combination included the above two filtrates, and the concentration of SGD was determined to be 1g/mL. ...
Purpose:
Paclitaxel-induced peripheral neuropathy (PIPN) is increasingly becoming one of the most widespread adverse effects in the treatment of cancer patients, and further precipitate neuroinflammation in the nervous system. Interestingly, Shaoyao Gancao Decoction (SGD), a traditional Chinese analgesic prescription, has emerged as a primary adjuvant to chemotherapy in relieving side effects, especially in the case of PIPN. However, the underlying mechanism of SGD functioning in PIPN remains elusive. Accordingly, the current study set out to explore the potential axis implicated in the functioning of SGD in PIPN.
Methods:
First, network pharmacology was adopted to predict the role of the transient receptor potential vanilloid type 1 (TRPV1) protein in treating PIPN with SGD. Subsequently, the effects of SGD treatment on mechanical allodynia and thermal hyperalgesia were evaluated in rat PIPN models. Based on the bioinformatics information and current literature, paclitaxel activates toll-like receptor 4 (TLR4) induces the sensitization of TRPV1 mechanistically. Thereafter, TLR4-myeloid-differentiation response gene 88 (MyD88) signaling and TRPV1 expression patterns in dorsal root ganglias (DRGs) were measured by means of Western blotting, qPCR and immunofluorescence.
Results:
Initial bioinformatics reared a total of 105 bioactive compounds and 1075 target genes from SGD. In addition, 40 target genes intersected with PIPN were considered as potential therapeutic genes. Based on the network analysis, SGD was found to exert its analgesic effect by reducing the expression of TRPV1. Further experimentation validated that SGD exerted an analgesic effect on thermal hyperalgesia in PIPN models, such that this protective effect was associated with the suppression of TRPV1 and TLR4-MyD88 Signaling over-expression.
Conclusion:
Collectively, our findings indicated that SGD ameliorates PIPN by inhibiting the over-expression of TLR4-MyD88 Signaling and TRPV1, and further highlights the use of SGD as a potential alternative treatment for PIPN.
... Natural products and plant constituents with anti-inflammatory and antioxidant activities protect against organ toxicity caused by DOX [19,20]. Herbal medicines can augment drug chemosensitivity, diminish chemotherapy side effects, and thus help to prolong patient survival [21,22]. Globally, traditionally used medicinal plants number between 10,000 and 53,000; however, few of these remedies have been biologically evaluated and require further exploration to characterize their therapeutic potential [23,24]. ...
Doxorubicin (DOX) is an effective anticancer agent with a wide spectrum of activities. However, it has many adverse effects on various organs especially on the liver. Thymol, one of the major components of thyme oil, has biological properties that include anti-inflammatory and antioxidant activities. Thus, this study was designed to examine thyme oil and thymol for their ability to prevent doxorubicin-induced hepatotoxicity in Wistar rats. Hepatotoxicity was induced by an intraperitoneal injection of doxorubicin, at a dose of 2 mg/kg bw/week, for seven weeks. Doxorubicin-injected rats were supplemented with thyme oil and thymol at doses 250 and 100 mg/kg bw, respectively, four times/week by oral gavage for the same period. Treatment of rats with thyme oil and thymol reversed the high serum activities of AST, ALT, and ALP and total bilirubin, AFP, and CA19.9 levels, caused by doxorubicin. Thyme oil and thymol also reduced the high levels of TNF-α and the decreased levels of both albumin and IL-4. These agents ameliorated doxorubicin-induced elevation in hepatic lipid peroxidation and associated reduction in GSH content and GST and GPx activities. Further, the supplementation with thyme oil and thymol significantly augmented mRNA expression of the level of antiapoptotic protein Bcl-2 and significantly downregulated nuclear and cytoplasmic levels of the hepatic apoptotic mediator p53. Thus, thyme oil and thymol successfully counteracted doxorubicin-induced experimental hepatotoxicity via their anti-inflammatory, antioxidant, and antiapoptotic properties.
... The pretreatment with Chinese medicine compound Shaoyao Gancao Decoction (SGD) for 2 weeks significantly reduced AUC (area under the curve) and increased CL (plasma clearance) of paclitaxel [2]. In vitro experiments showed that SGD could activate cytochrome P450 3A4 (CYP3A4) and drug transporter multidrug resistance protein 1 (MDR1) promoters and enhance mRNA expression, resulting in accelerated paclitaxel metabolism [3]. Ginkgo biloba combined with warfarin or aspirin may increase bleeding. ...
Terminalia chebula Retz. (TCR) is a medicinal material commonly used in Mongolian medicine. After consulting the literature at home and abroad, current research on TCR focuses on chemical composition, pharmacodynamics, and fingerprints. The pharmacokinetics of TCR has not been reported. Cytochrome P450 (CYP450) is the main drug-metabolizing enzyme, and its activity may be induced or inhibited by certain drugs, resulting in drug interactions in clinical applications. The objective of this study was to establish a high performance liquid chromatography (HPLC) method that can simultaneously detect multiple probe drugs to determine the effect of TCR on the activities of CYP450 enzymes CYP2C19, CYP2E1, CYP2D6, CYP2C9, CYP3A4, and CYP1A2. Wistar rats (male) were divided into 5 groups according to the randomization principle, namely the control group, the positive group, and the high, medium and low dose group. After 15 days of continuous administration, the mixed probe drug was injected into the vein, and then a small amount of blood was collected from the orbital vein at different time points. After the samples were processed, the blood concentration of each probe drug was measured by the established HPLC method. The pharmacokinetic parameters of each probe drug were calculated using DAS software. Compared with the control group, the plasma clearance (CL) of chlorzoxazone and omeprazole decreased, and the maximum plasma concentration (Cmax) and area under the curve (AUC) increased in the TCR group. The pharmacokinetic parameters of theophylline, midazolam, metoprolol, and tolbutamide did not differ significantly. The results indicated that TCR mainly inhibited the activities of CYP2E1 and CYP2C19, but had no effect on the activities of CYP1A2, CYP2C9, CYP3A4 and CYP2D6. Extra care should be taken when drugs metabolized by CYP2C19 and CYP2E1 enzymes are used in combination with TCR, as drug-herb interactions may occur. These results can guide the clinical application of related drugs and provide valuable information for drug interactions. The main component that affects enzyme activity may be tannins in the water extract.
... Shaoyaogancao decoction: Shaoyaogancao decoction has anti-inflammatory and antioxidant effects [75]. Shaoyaogancao decoction and its main components-shaoyao (Paeonia lactiflora Pall.) and liquorice (Glycyrrhiza uralensis Fisch.)-enhanced the activity of the MDR1 promoter in vitro in a concentration-dependent manner and upregulated the expression of MDR1 mRNA in hPXR-transfected LS174T cells [76]. Verapamil is an effective inhibitor of P-gp. ...
The incidence and mortality of coronary heart disease (CHD) continue to increase every year in China. It has become a serious public health concern, threatening people's health. The combination of herbs and drugs has become a common mode of treatment for various chronic diseases such as CHD and chronic lung disease. Clinical studies have shown that the combination of herbs and drugs can bring more clinical benefits in the treatment of CHD. However, safety issues caused by the interaction between herbs and drugs deserve attention. Recent findings indicate that many herbs and their active ingredients can affect the activities of cytochrome P450 enzyme system (CYP450s) and transporters related to drug metabolism, thus changing the metabolic process of combined drugs, leading to an increase or a decrease in plasma drug concentrations, finally increasing the uncertainty of clinical efficacy and the possibility of adverse events. This review aimed to discuss in detail the effect of herbs on CYP450s and/or transporters in the treatment of CHD and the potential herb-drugs interaction, thus providing the basis for the clinical rational combination of drugs.
... Many herbs have antioxidant potential by scavenging and counteracting free radicals or oxidants produced during various biochemical pathways (Rufino et al., 2009;Rahal et al., 2014). In addition, herbal medicine can enhance the response rate or chemosensitivity of drugs, reduce side-effects of chemotherapy, and prolong the survival time of patients with cancer diseases (Ben-Arye et al., 2017;Feng et al., 2018). Thymus vulgaris, "thyme", is a well-known herb with aromatic characteristics, and it is frequently used as a spice and herbal remedies since ancient times (Aljabeili et al., 2018). ...
This study aimed to assess the preventive effects of thyme oil and thymol on doxorubicin (DOX)-induced renotoxicity, cardiotoxicity, and oxidative stress in Wistar rats. Thyme oil was subjected to GC-MS analysis, which indicated that thymol was the major constituent representing 33.896%. Rats intraperitoneally injected with DOX at a dose of 2 mg/kg b.w./one per week for 7 weeks were co-treated with thyme oil and its major constituent, thymol, at doses 250 and 100 mg/kg b.w./every other day, respectively, by oral gavage for the same period. Thyme oil and thymol markedly ameliorated the raised levels of serum urea, uric acid, and creatinine in DOX-administered rats. They also reduced the elevated activities of serum CK-MB and LDH. Thyme oil was more effective than thymol in decreasing the elevated serum creatinine level and serum CK-MB activity in DOX-administered rats, thereby reflecting its more potent effect on kidney and heart functions. Lipid peroxidation significantly decreased while GSH level and GST and GPx activities significantly increased in kidney and heart of DOX-administered rats treated with thyme oil and thymol. The DOX-induced perturbed kidney histological changes including congestion of glomerulus tuft, inflammatory cells infiltration, protein cast in lumina of the renal tubule, and thickening of the parietal layer of Bowman's capsule were remarkably ameliorated as a result of treatment with thyme oil and thymol; thyme oil was more effective. In addition, DOX-induced deleterious heart histological alterations, including intramuscular infiltration of inflammatory cells, focal necrosis of cardiac myocytes, and edema, were remarkably reduced by treatment with thyme oil and thymol. Thus, it can be concluded that DOX could induce marked toxicity in kidney and heart, and the treatment with thyme oil or thymol produced potential improvement of kidney and heart function and histological integrity via repression of oxidative stress and enhancement of antioxidant defense mechanisms. BIOCELL 2020 44(1): 41-53
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide. Effective treatments against COVID-19 remain urgently in need although vaccination significantly reduces the incidence, hospitalization, and mortality. At present, antiviral drugs including Nirmatrelvir/Ritonavir (PaxlovidTM), Remdesivir, and Molnupiravir have been authorized to treat COVID-19 and become more globally available. On the other hand, traditional Chinese medicine (TCM) has been used for the treatment of epidemic diseases for a long history. Currently, various TCM formulae against COVID-19 such as Qingfei Paidu decoction, Xuanfei Baidu granule, Huashi Baidu granule, Jinhua Qinggan granule, Lianhua Qingwen capsule, and Xuebijing injection have been widely used in clinical practice in China, which may cause potential herb-drug interactions (HDIs) in patients under treatment with antiviral drugs and affect the efficacy and safety of medicines. However, information on potential HDIs between the above anti-COVID-19 drugs and TCM formulae is lacking, and thus this work seeks to summarize and highlight potential HDIs between antiviral drugs and TCM formulae against COVID-19, and especially pharmacokinetic HDIs mediated by metabolizing enzymes and/or transporters. These well-characterized HDIs could provide useful information on clinical concomitant medicine use to maximize clinical outcomes and minimize adverse and toxic effects.
