Lan Tang

Chemical and Biological Aspects of Marine Sponges of the Genus Xestospongia

Contents1. Introduction2. Chemical Constituents2.1. Alkaloids2.2. Quinones2.3. Terpenoids2.4. Sterols2.5. Fatty Acids3. Biological Activities3.1. Cardiovascular Activity3.2. Cytotoxic and Antitumor Activities3.3. HIV Protease Inhibitory Activity3.4. Other Enzyme Inhibitory Activities3.5. Antimicrobial and Insecticidal Activities3.6. Other Activities4. Concluding Remarks1. Introduction. – Marine sponges (phylum Porifera) are sessile marine filterfeeders that have developed efficient defense mechanisms against foreign attackerssuch as viruses, bacteria, or eukaryotic organisms, by production of secondarymetabolitestorepelthem[1].Theyareamongtherichestsourcesofpharmacologicallyactive chemicals isolated from marine organisms. The Xestospongia species (classDesmospongia, order Haplosclerida, family Petrosiidae), known as barrel sponges, arelarge and common members of the coral reef communities at depths greater than 10 m,all over the Indo-Pacific Ocean and the Caribbean Sea. Since the 1970s, with thedevelopment of the investigations of marine natural products, the analysis of thechemical constituents of Xestospongia sponges has been carried out consecutively allover the world, particularly in the USA, Japan, and Australia. Xestospongia spongeshave been established as a rich source of diverse secondary metabolites, including

CHEMICAL CONSTITUENTS FROM THE ROOTS OF Actinidia chinensis

C NMR spectra were identical to thosereported in the literature [11].1) Key Laboratory of Marine Bioresources Sustainable Utilization, South China Sea Institute of Oceanology, ChineseAcademy of Sciences, Guangzhou 510301, P. R. China; 2) Faculty of Pharmaceutical Sciences, Tongji Medical College ofHuazhong University of Science and Technology, Wuhan 430030, P. R. China, fax: +86 27 83692739; e-mail: z peng_1979@163.com;3) School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, P. R. China. Published in KhimiyaPrirodnykh Soedinenii, No. 2, pp. 258–259, March–April, 2010. Original article submitted November 12, 2008.

The interleukin-18 inhibitory activities of echinocystic acid and its saponins from Impatiens pritzellii var. hupehensis.

1 Echinocystic acid (), an echinocystic acid saponin, 2, and four of its ester saponins, 3 - 6, obtained from the active fraction of Impatiens pritzellii var. hupehensis, an traditional Chinese medicine for rheumatoid arthritis, were investigated for their effects on lipopolysaccharide (LPS)-induced interleukin (IL)-18 in human peripheral blood mononuclear cells. Three of them, 1, 2 and 6, showed obvious activity to inhibit the production of IL-18, especially the ester saponins with a sugar chain at C-28, 6. Structure-activity relationships are discussed in brief

Relation of Transcriptional Factors to the Expression and Activity of Cytochrome P450 and UDP-Glucuronosyltransferases 1A in Human Liver: Co-Expression Network Analysis

Cytochrome P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) play important roles in the metabolism of exogenous and endogenous compounds. The gene transcription of CYPs and UGTs can be enhanced or reduced by transcription factors (TFs). This study aims to explore novel TFs involved in the regulatory network of human hepatic UGTs/CYPs. Correlations between the transcription levels of 683 key TFs and CYPs/UGTs in three different human liver expression profiles (n = 640) were calculated first. Supervised weighted correlation network analysis (sWGCNA) was employed to define hub genes among the selected TFs. The relationship among 17 defined TFs, CYPs/UGTs expression, and activity were evaluated in 30 liver samples from Chinese patients. The positive controls (e.g., PPARA, NR1I2, NR1I3) and hub TFs (NFIA, NR3C2, and AR) in the GreysWGCNA Module were significantly and positively associated with CYPs/UGTs expression. And the cancer- or inflammation-related TFs (TEAD4, NFKB2, and NFKB1) were negatively associated with mRNA expression of CYP2C9/CYP2E1/UGT1A9. Furthermore, the effect of NR1I2, NR1I3, AR, TEAD4, and NFKB2 on CYP450/UGT1A gene transcription translated into moderate influences on enzyme activities. To our knowledge, this is the first study to integrate Gene Expression Omnibus (GEO) datasets and supervised weighted correlation network analysis (sWGCNA) for defining TFs potentially related to CYPs/UGTs. We detected several novel TFs involved in the regulatory network of hepatic CYPs and UGTs in humans. Further validation and investigation may reveal their exact mechanism of CYPs/UGTs regulation.

The independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and the metabolism of atorvastatin.

To evaluate the independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and atorvastatin metabolism, the relationships among three levels of factors, namely (1) clinical characteristics, CYP3A4/5 genotypes, and miRNAs, (2) CYP3A4 and CYP3A5 mRNAs, and (3) CYP3A activity, as well as their individual impacts on atorvastatin metabolism, were assessed in 55 human liver tissues. MiR-27b, miR-206, and CYP3A4 mRNA respectively accounted for 20.0%, 5.8%, and 9.5% of the interindividual variations in CYP3A activity. MiR-142 was an independent contributor to the expressions of CYP3A4 mRNA (partial R2 = 0.12, P = 0.002) and CYP3A5 mRNA (partial R2 = 0.09, P = 0.005) but not CYP3A activity or atorvastatin metabolism. CYP3A activity was a unique independent predictor of variability of atorvastatin metabolism, explaining the majority of the variance in reduction of atorvastatin (60.0%) and formation of ortho-hydroxy atorvastatin (78.8%) and para-hydroxy atorvastatin (83.9%). MiR-27b and miR-206 were found to repress CYP3A4 gene expression and CYP3A activity by directly binding to CYP3A4 3′-UTR, while miR-142 was found to indirectly repress CYP3A activity. Our study indicates that miRNAs play significant roles in bridging the gap between epigenetic effects and missing heritability in CYP3A functionality.

Cytotoxic and Antibacterial Eremophilane Sesquiterpenes from the Marine-Derived Fungus Cochliobolus lunatus SCSIO41401

Three new eremophilane sesquiterpenes, dendryphiellins H-J (1-3), and three new phthalide natural products (4-6) were isolated from the marine-derived fungus Cochliobolus lunatus SCSIO41401. Their structures including absolute configurations were determined by spectroscopic and calculated ECD analyses. Dendryphiellin I (2) showed cytotoxic and antibacterial activities against five cancer cell lines (IC50 1.4 to 4.3 μM) and three bacterial species (MIC 1.5 to 13 μg/mL), respectively. Dendryphiellin J (3), a rare naturally occurring aldoxime analogue, displayed cytotoxicities against ACHN and HepG-2 cells with IC50 values of 3.1 and 5.9 μM, respectively. Further studies indicated that 3 induced apoptosis in ACHN cells in a dose- and time-dependent manner.

Nitrobenzoyl Sesquiterpenoids with Cytotoxic Activities from a Marine-Derived Aspergillus ochraceus Fungus

Nitrobenzoyl sesquiterpenoids are rare from natural sources. Two new nitrobenzoyl sesquiterpenoids, insulicolide B (1) and insulicolide C (3), and the new natural product 14-O-acetylinsulicolide A (2) were isolated from culture extracts of the marine-derived fungus Aspergillus ochraceus Jcma1F17, together with three known nitrobenzoyl sesquiterpenoids (4-6) and a derivative sesquiterpenoid (7). The structures of the new compounds, including their absolute configurations, were determined by NMR and MS spectroscopic data analyses and comparison between the calculated and experimental ECD spectra. The nitrobenzoyl sesquiterpenoids (1-6) were evaluated for their cytotoxicities against three renal carcinoma cell lines, ACHN, OS-RC-2, and 786-O cells, and compounds 2, 4, and 5 displayed activities with IC50 values of 0.89 to 8.2 μM. Further studies indicated that 2 arrested the cell cycle at the G0/G1 phase at a concentration of 1 μM and induced late apoptosis at a concentration of 2 μM after a 72 h treatment of 786-O cells.

Oxidative metabolism of koumine is mainly catalyzed by microsomal CYP3A4/3A5

Abstract 1. Gelsemium elegans Benth (Loganiaceae) is a toxic plant that can be used for committing suicide besides alleviating pains. Its anti-inflammatory and analgesic effect mainly come from its active ingredient, namely koumine. Koumine, an indole alkaloid, possesses widely pharmacological effects especially inhibition of neuropathic pain. 2. This study aimed to investigate the metabolic profile of koumine using human liver microsomes (HLMs), selective chemical inhibitors and recombinant human CYP isoforms. Ultra-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS) was used to detect and identify metabolites. 3. Four major metabolites of koumine were found after incubation with HLMs or individual CYP isoforms. The metabolic pathways of koumine included demethylation, dehydrogenation, oxidation and demethyl-dehydrogenation. Chemical inhibition study showed that the inhibitor of CYP3A4/3A5 significantly decreased (93%) the formation of koumine metabolites. Further, CYP3A4/3A5 was shown as the most efficient isoform in biotransformation of koumine, among a series of CYP isoforms tested. 4. In conclusion, koumine was metabolized into four oxidative metabolites in HLMs. And CYP3A4/3A5 was probably the main contributor to the hepatic oxidative metabolism of koumine.

Gender Differences in the Hepatotoxicity and Toxicokinetics of Emodin: The Potential Mechanisms Mediated by UGT2B7 and MRP2

Emodin is a main anthraquinone compound which exists in Chinese traditional medicines including Polygonum multiflorum and Rhubarb. It is documented to have obvious liver and kidney toxicity. This study aims to (a) estimate gender differences of the hepatotoxicity and toxicokinetics in rats after oral administration of emodin (60 and 150 mg/kg/d) for a consecutive 28 days and (b) clarify relative mechanisms caused by glucuronidation and disposition. Hepatotoxicity was significantly higher in female rats than that in male rats, as evidenced by histopathological and biochemical tests. Similarly, the toxicokinetic profiles of emodin have time and gender differences, which could cause time and gender differences in hepatotoxicity. The metabolic and transcriptomics data of 55 human liver and 36 human kidney samples demonstrated that UDP-glucuronosyltransferase 2B7 (UGT2B7) was the predominant enzyme for emodin glucuronidation. A genome-wide association study (GWAS) identified that rs11726899 located within ∼50 kb of the transcript of UGT2B could significantly affect emodin metabolism. Knockdown of UGT2B7 in HepG2 cells significantly decreased emodin glucuronidation and increased cytotoxicity of emodin. The gene expression and protein levels of UGT2B7 were decreased, but those of the multidrug-resistant-protein 2 (MRP2) were increased in HepG2 cells after being treated with 50 μM emodin for 48 h. Long-term use of emodin could decrease the intrinsic clearance (CLint, decreased by 18.5%-35.4%) values of zidovidue (UGT2B7 substrate) glucuronide in both male and female liver microsomes from rats administrated with emodin for 28 days, thus causing the accumulation of emodin. However, higher self-induced MRP2 expression and lower hepatotoxicity were observed in emodin-treated male rats compared to that in female rats. Therefore, gender differences in the hepatotoxicity and toxicokinetics of emodin are potentially mediated by the coupling of UGT2B7 and MRP2 in vivo.

Hepatic and renal metabolism of genistein: An individual-based model to predict glucuronidation behavior of genistein in different organs

HIGHLIGHTSDeveloped an individual‐based model to predict the glucuronidation characteristics of genistein in different organs using quite a small size of tissue.Clarified the enzymologic characterization of genistein in liver and kidney.Determined the expression level of UGT isoform in human liver and kidney by real‐time quantitative PCR.Clarified the explanation percentage of UGTs expression variations in genistein glucuronidation variations. ABSTRACT The present study aims to develop an individual‐based model to predict the glucuronidation characteristics of genistein in 45 human livers. The model was validated in 18 human kidneys. Ten UDP‐glucuronosyltransferases (UGTs) were expressed in liver abundantly. Among them, UGT1A1, UGT1A3, UGT1A6, UGT1A9 and UGT2B7 contributed 95.6% to genistein glucuronidation in human liver, with significant correlation between gene expression of the five UGTs and the glucuronidation of genistein. The genistein glucuronidation differences between individuals were varied enormously; meanwhile the expression variations can explain 24.7% total metabolic variation in livers. In kidney, UGT1A6, UGT1A9 and UGT2B7 were amply expressed. Their gene expressions and glucuronidation rates of genistein had high correlations. Expression variations of UGT1A9/2B7 can explain up to 40.9% of the total variation of genistein glucuronidation in kidney. The model was therefore established based on UGT expression between individuals taking into account an important assessment which is the ratio of metabolic rate of each recombinant UGT isoform. Excellent linear correlations between predicted and observed glucuronidation rate revealed that the model could predict metabolic activity of genistein using quite a small size of tissue. In conclusion, the individual‐based model can be employed for predicting individual glucuronidation behavior of genistein in different organs.