Hypericin: A natural anthraquinone as promising therapeutic agent.

BACKGROUND: Hypericin is a prominent secondary metabolite mainly existing in genus Hypericum. It has become a research focus for a quiet long time owing to its extensively pharmacological activities especially the anti-cancer, anti-bacterial, anti-viral and neuroprotective effects. This review concentrated on summarizing and analyzing the existing studies of hypericin in a comprehensive perspective. METHODS: The literature with desired information about hypericin published after 2010 was gained from electronic databases including PubMed, SciFinder, Science Direct, Web of Science, China National Knowledge Infrastructure databases and Wan Fang DATA. RESULTS: According to extensive preclinical and clinical studies conducted on the hypericin, an organized and comprehensive summary of the natural and artificial sources, strategies for improving the bioactivities, pharmacological activities, drug combination of hypericin was presented to explore the future therapeutic potential of this active compound. CONCLUSIONS: Overall, this review offered a theoretical guidance for the follow-up research of hypericin. However, the pharmacological mechanisms, pharmacokinetics and structure activity relationship of hypericin should be further studied in future research.

Transcatheter Arterial Embolization Combined with Anti-vascular Agent Combretastatin A4 Phosphate Inhibits Growth and Vascularization of Liver Tumor in an Animal Model.

OBJECTIVE: This study aimed to investigate the effect of combretastatin A4 phosphate (CA4P) on proliferation, migration, and capillary tube formation of human umbilical vein endothelial cells (HUVECs) and the efficacy of transcatheter arterial embolization combined with CA4P in the treatment of rabbit VX2 liver tumor. METHODS: The effects of different concentrations of CA4P on proliferation, migration and capillary tube formation of HUVECs were investigated by cell proliferation assay, wound healing assay and capillary tube formation assay, respectively. Thirty-two rabbits implanted with liver VX2 tumors were randomly divided into 4 groups. After catheterization of the left hepatic artery, the infusion was performed using normal saline (group A), CA4P aqueous solution (group B), lipiodol and polyvinyl alcohol particles (group C), and CA4P lipiodol emulsion and polyvinyl alcohol particles (group D), respectively. Half of the animals in each group were euthanized for immunohistochemical analysis to evaluate microvessel density (MVD) at 3 days post-treatment. The other half were examined by MRI and histology to evaluate tumor growth and necrosis at 7 days post-treatment. RESULTS: CA4P could inhibit the proliferation, migration, and tube formation of HUVECs in cell experiments. After interventional treatment, the level of MVD in group D was lower than that in group C (P<0.01). The tumor volume in group C or D was lower than that in group A or B (P<0.01). The tumor necrosis rate was higher in group D than in the other groups. CONCLUSION: The study suggests that CA4P could inhibit the proliferation, migration, and capillary tube formation of HUVECs, and transcatheter arterial embolization combined with CA4P could inhibit the growth of VX2 tumor and obviously induce tumor necrosis.

Metabonomics Study on the Infertility Treated With Zishen Yutai Pills Combined With In Vitro Fertilization-embryo Transfer.

Zishen Yutai Pills (ZYP) is a safe and well quality-controlled TCM preparation with promising effects in many fields of reproduction, including prevention of miscarriage, increase of pregnancy rate during in vitro fertilization-embryo transfer (IVF-ET). The plasma of patients was collected from a clinical trial, namely, "Effect of Traditional Chinese Medicine vs placebo on live births among women undergoing in vitro fertilization, a multi-center randomized controlled trial." Plasma samples were analyzed with metabonomics method. UPLC-MS technology was used to establish the plasma metabolic fingerprint. Multivariate statistical analysis was applied for comparing the differences of plasma metabolites between ZYP group and placebo group, 44 potential metabolites were screen out and identified. Pathway analysis was conducted with database mining. Compared with placebo, chemicals were found to be significantly down-regulated on HCG trigger day and 14 days after embryo transplantation, including trihexosylceramide (d18:1/26:1), glucosylceramide(d18:1/26:0), TG(22:6/15:0/22:6), TG(22:4/20:4/18:4). Compared with placebo, some chemicals were found to be significantly up-regulated on HCG trigger day and 14 days after embryo transplantation, i.e., PIP3(16:0/16:1), PIP2(18:1/18:1), tauroursodeoxycholic acid, L-asparagine, L-glutamic acid, kynurenic acid, 11-deoxycorticosterone, melatonin glucuronide, hydroxytyrosol. These metabolites were highly enriched in pathways including sphingolipid metabolism, alanine, aspartic acid and glutamic acid metabolism, aminoacyl tRNA biosynthesis, taurine and hypotaurine metabolism. This study revealed metabolic differences between subjects administered with ZYP and placebo. Relating metabolites were identified and pathways were enriched, providing basis on the exploration on the underlying mechanisms of ZYP combined with IVF-ET in the treatment of infertility.

Chocolate consumption and all-cause and cause-specific mortality in a US population: a post hoc analysis of the PLCO cancer screening trial.

Few studies with mixed results have examined the association between chocolate consumption and mortality. We aimed to examine this association in a US population. A population-based cohort of 91891 participants aged 55 to 74 years was identified. Chocolate consumption was assessed via a food frequency questionnaire. Cox regression was used to estimate risk estimates. After an average follow-up of 13.5 years, 19586 all-cause deaths were documented. Compared with no regular chocolate consumption, the maximally adjusted hazard ratios of all-cause mortality were 0.89 [95% confidence interval (CI) 0.84-0.94], 0.84 (95% CI 0.79-0.90), 0.86 (95% CI 0.81-0.93), and 0.87 (95% CI 0.82-0.93) for >0-0.5 servings/week, >0.5-1 serving/week, >1-2 servings/week, and >2 servings/week, respectively (Ptrend = 0.009). A somewhat stronger inverse association was observed for mortality from cardiovascular disease and Alzheimer's disease. A nonlinear dose-response pattern was found for all-cause and cardiovascular mortality (all Pnonlinearity < 0.01), with the lowest risk observed at chocolate consumption of 0.7 servings/week and 0.6 servings/week, respectively. The favorable associations with all-cause and cardiovascular mortality were found to be more pronounced in never smokers than in current or former smokers (all Pinteraction < 0.05). In conclusion, chocolate consumption confers reduced risks of mortality from all causes, cardiovascular disease, and Alzheimer's disease in this US population.

Qigong for women with breast cancer: An updated systematic review and meta-analysis.

OBJECTIVE: The purpose of this review was to evaluate the effectiveness of Qigong in improving the quality of life and relieving fatigue, sleep disturbance, and cancer-related emotional disturbances (distress, depression, and anxiety) in women with breast cancer. METHODS: The PubMed, Cochrane Central Register of Controlled Trials, Web of Science, Sinomed, Wanfang, VIP, and China National Knowledge Infrastructure databases were searched from their inceptions to March 2020 for controlled clinical trials. Two reviewers selected relevant trials that assessed the benefit of Qigong for breast cancer patients independently. A methodological quality assessment was conducted according to the criteria of the 12 Cochrane Back Review Group for risk of bias independently. A meta-analysis was performed by Review Manager 5.3. RESULTS: This review consisted of 17 trials, in which 1236 cases were enrolled. The quality of the included trials was generally low, as only five of them were rated high quality. The results showed significant effectiveness of Qigong on quality of life (n = 950, standardized mean difference (SMD), 0.65, 95 % confidence interval (CI) 0.23-1.08, P =  0.002). Depression (n = 540, SMD = -0.32, 95 % CI -0.59 to -0.04, P =  0.02) and anxiety (n = 439, SMD = -0.71, 95 % CI -1.32 to -0.10, P =  0.02) were also significantly relieved in the Qigong group. There was no significant benefit on fatigue (n = 401, SMD = -0.32, 95 % CI  0.71 to 0.07, P = 0.11) or sleep disturbance relief compared to that observed in the control group (n = 298, SMD = -0.11, 95 % CI  0.74 to 0.52, P = 0.73). CONCLUSION: This review shows that Qigong is beneficial for improving quality of lifeand relieving depression and anxiety; thus, Qigong should be encouraged in women with breast cancer.

Self-assembled aggregations in Coptidis Rhizoma decoction dynamically regulate intestinal tissue permeability through Peyer's patch-associated immunity.

Objective: To investigate the dynamic regulation of self-assembled aggregations (SAA) in Coptidis Rhizoma decoction on the permeability of intestinal tissue and the mechanism underlying. Methods: The effects of SAA on berberine (Ber) absorption were respectively analyzed in an in situ intestinal perfusion model and in an Ussing Chamber jejunum model with or without Peyer's patches (PPs). The expression levels of ZO-1, Occludin and Claudin-1 were detected by immunofluorescence to evaluate the tight junction (TJ) between intestinal epithelium cells. The expression levels of T-box-containing protein expressed in T cells, signal transducers and activators of tranion-6, retinoic acid receptor-related orphan receptor γt and forkhead box P3 in PPs were detected by the reverse transcription-polymerase chain reaction and the secretions of interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-17 (IL-17) and transforming growth factor-ß (TGF-ß) in PPs were evaluated by immunohistochemistry, to reflect the differentiation of T lymphocyte in PPs to helper T (Th) cell 1, Th2, Th17 and regulatory T (Treg) cell. To confirm the correlation between SAA in Coptidis Rhizoma decoction, PPs-associated immunity and intestinal epithelium permeability, SAA were administrated on an Ussing Chamber jejunum model with immunosuppressed PPs and evaluated its influences on intestinal tissue permeability and TJ proteins expression. Results: SAA in Coptidis Rhizoma decoction could dose-dependently promote Ber absorption in jejunum segment, with the participation of PPs. The dose-dependent and dynamical regulations of SAA on permeability of intestinal tissue and TJ proteins expression level between intestinal epithelium cells occurred along with the dynamically changed T lymphocyte differentiation and immune effectors secretion in PPs. The administration of SAA on immunosuppressed PPs exhibited dose-dependent PPs activation, inducing dynamic promotion on intestinal tissue permeability and inhibition on TJ proteins expression. Conclusion: SAA can improve the Ber absorption in small intestine, through the PPs-associated immunity induced dynamic regulation on intestinal tissue permeability and TJ proteins expression. These findings might enlighten the research of traditional Chinese medicine decoction.

Reversible and Irreversible Inhibition of Cytochrome P450 Enzymes by Methylophiopogonanone A.

Methylophiopogonanone A (MOA), an abundant homoisoflavonoid bearing a methylenedioxyphenyl moiety, is one of the major constituents in the Chinese herb Ophiopogon japonicas This work aims to assess the inhibitory potentials of MOA against cytochrome P450 enzymes and to decipher the molecular mechanisms for P450 inhibition by MOA. The results showed that MOA concentration-dependently inhibited CYP1A, 2C8, 2C9, 2C19, and 3A in human liver microsomes (HLMs) in a reversible way, with IC50 values varying from 1.06 to 3.43 µM. By contrast, MOA time-, concentration-, and NADPH-dependently inhibited CYP2D6 and CYP2E1, along with KI and kinact values of 207 µM and 0.07 minute-1 for CYP2D6, as well as 20.9 µM and 0.03 minutes-1 for CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by glutathione in an HLM incubation system, and CYP2D6, 1A2, and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-quinone intermediate. Additionally, the potential risks of herb-drug interactions triggered by MOA or MOA-related products were also predicted. Collectively, our findings verify that MOA is a reversible inhibitor of CYP1A, 2C8, 2C9, 2C19, and 3A but acts as an inactivator of CYP2D6 and CYP2E1. SIGNIFICANCE STATEMENT: Methylophiopogonanone A (MOA), an abundant homoisoflavonoid isolated from the Chinese herb Ophiopogon japonicas, is a reversible inhibitor of CYP1A, 2C8, 2C9, 2C19, and 3A but acts as an inactivator of CYP2D6 and CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by glutathione in a human liver microsome incubation system, and CYP2D6, 1A2, and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-quinone intermediate.

Evidence for Shikonin acting as an active inhibitor of human carboxylesterases 2: Implications for herb-drug combination.

Shikonin, a natural naphthoquinone compound derived from the herb Lithospermum erythrorhizon, is widely used for its various pharmacological activities. However, its potential interactions with other medications by inhibiting human carboxylesterases 2 (hCE2) remain unknown. In this study, the inhibitory effects of shikonin on the activity of hCE2 in human liver microsomes are investigated by using fluorescein diacetate (FD), N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-phenalen-6-yl)-2-chloroacetamide (NCEN), and CPT-11 as substrates of hCE2. The results demonstrate that shikonin significantly inhibits the activity of hCE2 when FD and NCEN are used as substrates, whereas the half inhibition concentration value of shikonin increased by 5-30 times when CPT-11 was used as the substrate. The inhibition types of shikonin against hCE2 activity reflected by 3 substrates were all best fit to noncompetitive manners. In addition, shikonin was found to distinctly suppress endogenous hCE2 activity, characterized with attenuated fluorescence. Furthermore, for drugs metabolized by hCE2 with the similar binding sites with FD or NCEN, the estimated magnitudes of area under the curve variation were approximately 9-357% in the presence of shikonin. Also, the area under the curve of CPT-11 could be increased by 1-14% following administration of shikonin. These findings have clear clinical implications for the combination of shikonin and hCE2-metabolizing prodrugs.

Bioactive Components from Qingwen Baidu Decoction against LPS-Induced Acute Lung Injury in Rats.

Qingwen Baidu Decoction (QBD) is an extraordinarily "cold" formula. It was traditionally used to cure epidemic hemorrhagic fever, intestinal typhoid fever, influenza, sepsis and so on. The purpose of this study was to discover relationships between the change of the constituents in different extracts of QBD and the pharmacological effect in a rat model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). The study aimed to discover the changes in constituents of different QBD extracts and the pharmacological effects on acute lung injury (ALI) induced by LPS. The results demonstrated that high dose and middle dose of QBD had significantly potent anti-inflammatory effects and reduced pulmonary edema caused by ALI in rats (p < 0.05). To explore the underlying constituents of QBD, we assessed its influence of six different QBD extracts on ALI and analyzed the different constituents in the corresponding HPLC chromatograms by a Principal Component Analysis (PCA) method. The results showed that the pharmacological effect of QBD was related to the polarity of its extracts, and the medium polarity extracts E2 and E5 in particular displayed much better protective effects against ALI than other groups. Moreover, HPLC-DAD-ESI-MSn and PCA analysis showed that verbascoside and angoroside C played a key role in reducing pulmonary edema. In addition, the current study revealed that ethyl gallate, pentagalloylglucose, galloyl paeoniflorin, mudanpioside C and harpagoside can treat ALI mainly by reducing the total cells and infiltration of activated polymorphonuclear leukocytes (PMNs).

Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G, two lignan analogs derived from Schisandra chinensis.

Gomisin C (GC) and gomisin G (GG) are two lignan analogs isolated from the Traditional Chinese Medicine Schisandra chinensis which possesses multiple pharmacological activities. However, the potential herb-drug interactions (HDI) between these lignans and other drugs through inhibiting human cytochrome P450 3A4 (CYP3A4) and CYP3A5 remains unclear. In the present study, the inhibitory action of GC and GG on CYP3A4 and CYP3A5 were investigated. The results demonstrated that both GC and GG strongly inhibited CYP3A-mediated midazolam 1'-hydroxylation, nifedipine oxidation and testosterone 6ß-hydroxylation. Notably, the inhibitory intensity of GC towards CYP3A4 was stronger than CYP3A5 when using midazolam and nifedipine as substrates. While inhibition of GC towards CYP3A5 was weaker than CYP3A4 when using testosterone as substrate. In contrast, GG showed a stronger inhibitory activity on CYP3A5 than CYP3A4 without substrate-dependent behavior. In addition, docking simulations indicated that the π-π interaction between CYP3A4 and GC, and hydrogen-bond interaction between CYP3A5 and GG might result in their different inhibitory actions. Furthermore, the AUC of drugs metabolized by CYP3A was estimated to increase by 8%-321% and 2%-3190% in the presence of GC and GG, respectively. These findings strongly suggested that GC and GG showed high HDI potentials, and the position of methylenedioxy group determined their different inhibitory effect towards CYP3A4 and CYP3A5, which are of significance for the application of Schisandra chinensis-containing herbs.

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases.

Licochalcone A (LCA) is a major bioactive compound in Licorice, a widely used herbal medicine. In this study, the inhibitory effects of LCA against human UDP-glucuronosyltransferases (UGTs) and LCA associated herb-drug interactions were systematically investigated. Our results demonstrated that LCA displayed broad-spectrum inhibition against human UGTs. LCA exhibited strong inhibitory effects against UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A9, and 2B7 (both IC50 and Ki values lower than 5 µM), while showing moderate inhibitory effects against UGT1A8, 1A10, 2B4, 2B15, and 2B17. The inhibitory effects of LCA against two major UGTs, including UGT1A1 and 1A9, were further investigated in human liver microsomes (HLMs), where the potential risks of LCA via inhibition of UGT1A1 and 1A9 were predicted by combining the in vitro inhibitory data and physiological data. The results from this study also showed that several LCA-containing products were able to increase the area under the curve (AUC) of the substrates that were predominantly metabolized by UGT1A1 or 1A9. These findings together demonstrate that LCA has a potent and broad-spectrum inhibitory effect against most human UGTs and thus suggest that much caution should be exercised when high-dose LCA is co-administered with UGT substrates.

Interspecies variation in phase I metabolism of bufalin in hepatic microsomes from mouse, rat, dog, minipig, monkey, and human.

1. Bufalin (BF), one of the major bioactive compounds in traditional Chinese medicine (TCM) Chansu, has been found with various pharmacological and toxicological effects. This study aims to investigate the species differences in phase I metabolism of BF in hepatic microsomes from human and five common experimental animals. 2. Metabolite profiling demonstrated that two major metabolites were formed in liver microsomes from human and animal species in NADPH-generating system. Two major metabolites were identified as 5ß-hydroxyl-bufalin and 3-keto-bufalin, with the help of authentic standards. CYP3A was assigned as the main isoform involved in both 5ß-hydroxylation and 3-oxidation in all studied liver microsomes. The apparent kinetic parameters including substrate affinity and catalytic efficiency for 5ß-hydroxylation and 3-oxidation of BF were also determined. 3. In summary, CYP3A mediated 5ß-hydroxylation and 3-oxidation were two major metabolic pathways of BF in hepatic microsomes from human and five studied animals, but kinetic analysis demonstrated that the intrinsic clearances of these two metabolic pathways were much different among various species. The qualitative and quantitative interspecies study indicated that minipig exhibited the similar metabolic profile, kinetic behaviors and intrinsic metabolic clearances of BF phase I biotransformation in comparison with that of human.

Inhibition of human cytochrome P450 enzymes by licochalcone A, a naturally occurring constituent of licorice.

Licochalcone A (LCA) is a major bioactive compound in traditional Chinese herbal liquorice that possesses multiple pharmacological activities. However, the effects of the potential herb-drug interactions (HDIs) between LCA and therapeutic drugs on the inhibition of human cytochrome P450 (CYP) enzymes remain unclear. In the present study, the inhibitory effects of LCA on seven major human CYP isoforms, including CYP1A2, 2D6, 2E1, 2C19, 2C8, 2C9 and 3A4, were investigated in human liver microsomes (HLMs). The results demonstrated that LCA significantly inhibited the activities of CYP1A2, 2C19, 2C8, 2C9 and 3A4 and exhibited weak inhibitory effects on CYP2E1 and CYP2D6. Dixon and Lineweaver-Burk plots revealed that the inhibition types of LCA against CYP1A2, 2C9, 2C19 and 2C8 were best fit as mixed-type inhibitions, while LCA was a competitive inhibitor towards CYP3A4. The inhibition kinetic parameters (K(i)) were calculated to be 1.02 µM, 0.17 µM, 3.89 µM 0.89 µM, and 2.29 µM, for CYP1A2, 2C9, 2C19, 2C8, and 3A4, respectively. Furthermore, the areas under the plasma concentration-time curves (AUCs) of several drugs that are primarily metabolized by CYPs were estimated to increase by 2-398% in the presence of LCA, which suggested that LCA exhibited high HDI potentials via CYP inhibition. These data are significant for the clinical applications of LCA-containing herbs.

Characterization of phase I metabolism of resibufogenin and evaluation of the metabolic effects on its antitumor activity and toxicity.

Resibufogenin (RB), one of the major active compounds of the traditional Chinese medicine Chansu, has displayed great potential as a chemotherapeutic agent in oncology. However, it is a digoxin-like compound that also exhibits extremely cardiotoxic effects. The present study aimed to characterize the metabolic behaviors of RB in humans as well as to evaluate the metabolic effects on its bioactivity and toxicity. The phase I metabolic profile in human liver microsomes was characterized systemically, and the major metabolite was identified as marinobufagenin (5ß-hydroxylresibufogenin, 5-HRB) by liquid chromatography-mass spectrometry and nuclear magnetic imaging techniques. Both cytochrome P450 (P450) reaction phenotyping and inhibition assays using P450-selective chemical inhibitors demonstrated that CYP3A4 was mainly involved in RB 5ß-hydroxylation with much higher selectivity than CYP3A5. Kinetic characterization demonstrated that RB 5ß-hydroxylation in both human liver microsomes and human recombinant CYP3A4 obeyed biphasic kinetics and displayed similar apparent kinetic parameters. Furthermore, 5-HRB could significantly induce cell growth inhibition and apoptosis in A549 and H1299 by facilitating apoptosome assembly and caspase activation. Meanwhile, 5-HRB displayed very weak cytotoxicity of human embryonic lung fibroblasts, and in mice there was a greater tolerance to acute toxicity. In summary, CYP3A4 dominantly mediated 5ß-hydroxylation and was found to be a major metabolic pathway of RB in the human liver, whereas its major metabolite (5-HRB) displayed better druglikeness than its parent compound RB. Our findings lay a solid foundation for RB metabolism studies in humans and encourage further research on the bioactive metabolite of RB.

A standardized extract from Paeonia lactiflora and Astragalus membranaceus induces apoptosis and inhibits the proliferation, migration and invasion of human hepatoma cell lines.

Paeonia lactiflora and Astragalus membranaceus are two traditional Chinese medicines, which are commonly used in Chinese herb prescription to treat liver diseases. The protective effects of the extract prepared from the roots of Paeonia lactiflora and Astragalus membranaceus (PAE) on liver fibrosis have been demonstrated in previous studies. However, its effect on hepatocellular carcinoma (HCC) has not been investigated to date. In this study, the effects of PAE on the apoptosis, proliferation, migration and invasion of the human hepatoma cell lines HepG2 and SMMC-7721 were investigated. Our data demonstrated that treatment with PAE (50-200 mg/l) caused an inhibitory effect on the proliferation of the hepatoma cell lines HepG2 and SMMC-7721. Furthermore, PAE induced apoptosis of HepG2 cells and SMMC-7721 cells, which was demonstrated by PI staining. In addition, immunocytochemistry and western blotting showed that PAE significantly decreased the expression of Bcl-2, while the expression of Bax and cleaved caspase-3 in HepG2 cells and SMMC-7721 cells was significantly increased after treatment with PAE. These results clearly demonstrated that PAE induced hepatoma cell apoptosis through increasing the Bax-to-Bcl-2 ratio and upregulating the activation of caspase-3. In addition, the results of wound healing assay and Matrigel invasion assay showed that PAE displayed inhibitory activity on the migration and invasion of HCC cells. Taken together, the present data provides evidence that PAE is a potent antineoplastic drug candidate for the treatment of HCC.

Interactions between phytochemicals from traditional Chinese medicines and human cytochrome P450 enzymes.

Traditional Chinese medicine (TCM) formulas with fixed combinations rely on "sovereign, minister, assistant and guide" and fuzzy mathematical quantitative law, leading to greater challenges for the identification of active ingredients. Transformation and metabolic studies involving the Phase I drug-metabolizing enzyme cytochrome P450 (CYP) might potentially solve some of these challenges. The pharmacological effects can not be attributed to one active ingredient in TCMs, but integrated effects resulting from the combined actions of multiple ingredients. However, it is only after long-term administration that most ingredients exert their actions, which can result in prolonged exposure to herbs in vivo. Therefore, interactions between herbal compounds and CYPs appear to be inevitable. Yet unlike Western drugs, experimental determination of the absorption and disposition properties is not commonly carried out for TCMs. Moreover, the use of TCM as injections is an innovation aimed to improve efficiency in extensive clinical use in Mainland China. Therefore, in recent years, cases of adverse drug reactions (ADR) mainly concerning allergic reactions involving TCMs such as ShenMai injection and QingKaiLing injection have been reported, which have attracted attention with regard to the legal responsibilities for TCM approval. The lack of information on the ADME characteristics, especially the metabolic stability and interaction potential between CYPs and herbs, increases ADR occurrence due to TCMs. In this article, we review the most common herbs used in TCM prescriptions and fixed combinations of their usable frequency, and summarize the current understanding of the ability of phytochemical ingredients to act as substrates, inhibitors or inducers of human CYP enzymes, through which the key role of CYP enzymes on the herb disposition and toxicity is highlighted. The potential interaction between herbal phytochemicals and CYP enzymes dominates the target exposure, which further helps to elucidate the herbal pharmacological basis, assess the individual toxic risk of herbal remedies and gain mechanistic insight into herb-drug interactions (HDIs).

MAPKs are not involved in triptolide-induced cell growth inhibition and apoptosis in prostate cancer cell lines with different p53 status.

Triptolide showed excellent antitumor activity against several solid tumors. However, its mechanism has not been fully understood. To further elucidate it, the effects of mitogen activated protein kinases (MAPKs) on the activity of triptolide towards prostate cancer cell lines were investigated in the present study using both LNCaP (p53 positive and androgen-dependent) and PC-3 (p53 deficient and androgen-independent) cells. Our results showed that triptolide exerted potent growth inhibitory and apoptotic effects on both cell lines, and the effects were independent of the expression of p53. Although upregulation of ERK and JNK phosphorylation was observed after the triptolide treatment, the results with inhibitors showed that these MAPKs were not involved in the mechanism of triptolide activity in human prostate cancer cell lines with different p53 status.

Cycloartane triterpenoids from Cimicifuga yunnanensis induce apoptosis of breast cancer cells (MCF7) via p53-dependent mitochondrial signaling pathway.

The present study was carried out to investigate the antitumor activity of five cycloartane triterpenoids isolated from Cimicifuga yunnanensis on the breast cancer cell line MCF7 and its corresponding drug resistant subline R-MCF7, including cimigenol-3-O-ß-D-xylopyranoside (compound 1), 25-O-acetylcimigenol-3-O-ß-D-xylopyranoside (compound 2), 25-chlorodeoxycimigenol-3-O-ß-D-xylopyranoside (compound 3), 25-O-acetylcimigenol-3-O-α-L-arabinopyranoside (compound 4) and 23-O-acetylcimigenol-3-O-ß-D-xylopyranoside (compound 5). The results showed that compounds 2-5 have relatively high antitumor activity on both MCF7 and R-MCF7 cells. The involvement of apoptosis as a major cause of cycloartane triterpenoids-induced cell death was further confirmed. The results of RT-PCR showed that compounds 2-5 increased the expression of p53 and bax, which led to the loss of mitochondrial potential and then resulted in the activation of caspase-7. These findings collectively demonstrated that compounds 2-5 induced apoptosis of MCF7 via p53-dependent mitochondrial pathway.

The use of zein and Shuanghuangbu for periodontal tissue engineering / 国际口腔科学杂志·英文版

<p><b>AIM</b>Tissue engineering is a promising area with a broad range of applications in the fields of regenerative medicine and human health. The emergence of periodontal tissue engineering for clinical treatment of periodontal disease has opened a new therapeutic avenue. The choice of scaffold is crucial. This study was conducted to prepare zein scaffold and explore the suitability of zein and Shuanghuangbu for periodontal tissue engineering.</p><p><b>METHODOLOGY</b>A zein scaffold was made using the solvent casting/particulate leaching method with sodium chloride (NaCl) particles as the porogen. The physical properties of the zein scaffold were evaluated by observing its shape and determining its pore structure and porosity. Cytotoxicity testing of the scaffold was carried out via in vitro cell culture experiments, including a liquid extraction experiment and the direct contact assay. Also, the Chinese medicine Shuanghuangbu, as a growth factor, was diluted by scaffold extract into different concentrations. This Shuanghuangbu-scaffold extract was then added to periodontal ligament cells (PDLCs) in order to determine its effect on cell proliferation.</p><p><b>RESULTS</b>The zein scaffold displayed a sponge-like structure with a high porosity and sufficient thickness. The porosity and pore size of the zein scaffold can be controlled by changing the porogen particles dosage and size. The porosity was up to 64.1%-78.0%. The pores were well-distributed, interconnected, and porous. The toxicity of the zein scaffold was graded as 0-1. Furthermore, PDLCs displayed full stretching and vigorous growth under scanning electronic microscope (SEM). Shuanghuangbu-scaffold extract could reinforce proliferation activity of PDLCs compared to the control group, especially at 100 microg x mL(-1) (P < 0.01).</p><p><b>CONCLUSION</b>A zein scaffold with high porosity, open pore wall structure, and good biocompatibility is conducive to the growth of PDLCs. Zein could be used as scaffold to repair periodontal tissue defects. Also, Shuanghuangbu-scaffold extract can enhance the proliferation activity of PDLCs. Altogether, these findings provide the basis for in vivo testing on animals.</p>