The anticancer and antiobesity effects of Mediterranean diet.

Cancers have been the leading cause of death worldwide and the prevalence of obesity is also increasing in these few decades. Interestingly, there is a direct association between cancer and obesity. Each year, more than 90,000 cancer deaths are caused by obesity or overweight. The dietary pattern in Crete, referred as the traditional Mediterranean diet, is believed to confer Crete people the low mortality rates from cancers. Nevertheless, the antiobesity effect of the Mediterranean diet is less studied. Given the causal relationship between obesity and cancer, the antiobesity effect of traditional Mediterranean diet might contribute to its anticancer effects. In this regard, we will critically review the anticancer and antiobesity effects of this diet and its dietary factors. The possible mechanisms underlying these effects will also be discussed.

Subcutaneous adipocytes promote melanoma cell growth by activating the Akt signaling pathway: role of palmitic acid.

Tumorigenesis involves constant communication between tumor cells and neighboring normal cells such as adipocytes. The canonical function of adipocytes is to store triglyceride and release fatty acids for other tissues. This study was aimed to find out if adipocytes promoted melanoma cell growth and to investigate the underlying mechanism. Here we isolated adipocytes from inguinal adipose tissue in mice and co-cultured with melanoma cells. We found that the co-cultured melanoma had higher lipid accumulation compared with mono-cultured melanoma. In addition, fluorescently labeled fatty acid BODIPY® FLC16 signal was detected in melanoma co-cultured with the adipocytes that had been loaded with the fluorescent dye, suggesting that the adipocytes provide fatty acids to melanoma cells. Compared with mono-cultured melanoma, co-cultured melanoma cells had a higher proliferation and phospho-Akt (Ser-473 and Thr-450) expression. Overexpression of Akt mutants in melanoma cells reduced the co-culture-enhanced proliferation. A lipidomic study showed that the co-cultured melanoma had an elevated palmitic acid level. Interestingly, we found that palmitic acid stimulated melanoma cell proliferation, changed the cell cycle distribution, and increased phospho-Akt (Ser-473 and Thr-450) and PI3K but not phospho-PTEN (phosphophosphatase and tensin homolog) expressions. More importantly, the palmitic acid-stimulated proliferation was further enhanced in the Akt-overexpressed melanoma cells and was reduced by LY294002 or knockdown of endogenous Akt or overexpression of Akt mutants. We also found that palmitic acid-pretreated B16F10 cells were grown to a significantly larger tumor in mice compared with control cells. Taken together, we suggest that adipocytes may serve as an exogenous source of palmitic acid that promotes melanoma cell growth by activating Akt.

The herbal compound cryptotanshinone restores sensitivity in cancer cells that are resistant to the tumor necrosis factor-related apoptosis-inducing ligand.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis and kills cancer cells but not normal cells. However, TRAIL resistance due to low level of TRAIL receptor expression is widely found in cancer cells and hampers its development for cancer treatment. Thus, the agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are urgently needed. We investigated whether tanshinones, the major bioactive compounds of Salvia miltiorrhiza (danshen), can up-regulate TRAIL receptor expression. Among the major tanshinones being tested, cryptotanshinone (CT) showed the best ability to induce TRAIL receptor 2 (DR5) expression. We further showed that CT was capable of promoting TRAIL-induced cell death and apoptosis in A375 melanoma cells. CT-induced DR5 induction was not cell type-specific, as DR5 induction was observed in other cancer cell types. DR5 knockdown abolished the enhancing effect of CT on TRAIL responses. Mechanistically, induction of the DR5 by CT was found to be p53-independent but dependent on the induction of CCAAT/enhancer-binding protein-homologous protein (CHOP). Knockdown of CHOP abolished CT-induced DR5 expression and the associated potentiation of TRAIL-mediated cell death. In addition, CT-induced ROS production preceded up-regulation of CHOP and DR5 and consequent sensitization of cells to TRAIL. Interestingly, CT also converted TRAIL-resistant lung A549 cancer cells into TRAIL-sensitive cells. Taken together, our results indicate that CT can potentiate TRAIL-induced apoptosis through up-regulation of DR5.

Lipidomics identification of metabolic biomarkers in chemically induced hypertriglyceridemic mice.

In this study, we aim to identify the potential biomarkers in hTG pathogenesis in schisandrin B-induced hTG mouse model. To investigate whether these identified biomarkers are only specific to schisandrin B-induced hTG mouse model, we also measured these biomarkers in a high fat diet (HFD)-induced hTG mouse model. We employed a LC/MS/MS-based lipidomic approach for the study. Mouse liver and serum metabolites were separated by reversed phase liquid chromatography. Metabolite candidates were identified by matching with marker retention times, isotope distribution patterns, and high-resolution MS/MS fragmentation patterns. Subsequently, target candidates were quantified by quantitative MS. In the schisandrin B-induced hTG mice, we found that the plasma fatty acids, diglyceroids, and phospholipids were significantly increased. Palmitic acid and stearic acid were increased in the plasma; oleic acid, linoleic acid, linolenic acid, arachidonic acid, and docosahexaenoic acid were increased in both the plasma and the liver. Acetyl-CoA, malonyl-CoA, and succinyl-CoA were increased only in the liver. The changes in levels of these identified markers were also observed in HFD-induced hTG mouse model. The consistent results obtained from both hTG models not only suggest novel biomarkers in hTG pathogenesis, but they also provide insight into the underlying mechanism of the schisandrin B-induced hTG.

Inhibition of DNA-dependent protein kinase reduced palmitate and oleate-induced lipid accumulation in HepG2 cells.

PURPOSE: The aim of this study is to investigate the involvement of DNA-dependent protein kinase (DNA-PK) in palmitate and oleate-induced lipid accumulation in hepatocytes. METHODS: We treated HepG2 with free fatty acids (FFA) (0.33 mM palmitate and 0.66 mM oleate) mixture to induce lipid accumulation. Cellular lipid was determined by Nile Red staining followed by flow cytometry detection as well as phase contrast and fluorescence microscope examination. Cell viability was detected by MTT assay. Apoptosis was detected by DAPI staining. Lipogenic gene expression was examined by real-time PCR at mRNA level and Western blotting at protein level. Promoter transcriptional activity was measured by dual luciferase assay. RESULTS: FFA treatment neither affected HepG2 cells viability nor induced DNA fragmentation, while induced cellular lipid accumulation was associated by the upregulation of sterol regulatory element-binding protein-1 (SREBP1) and fatty acid synthase (FAS) at both mRNA and protein levels. Interestingly, we also found that both the protein phosphatase 2A (PP2A) protein expression and DNA-PK activity were increased in these cells. Inhibition of PP2A by okadaic acid, knockdown of DNA-PK by siRNA or inhibition of DNA-PK by specific DNA-PK inhibitors curtailed the FFA-induced upregulations of the SREBP1 mRNA expression and the nuclear active SREBP1 protein expression, and reduced FFA-induced upregulation of FAS promoter transcriptional activity and lipid accumulation. CONCLUSION: This is the first time suggesting that inhibition of DNA-PK reduced FFA-induced lipid accumulation in hepatocytes. This finding might help us better understand non-alcoholic steatohepatitis pathogenesis.

A highly selective, label-free, homogenous luminescent switch-on probe for the detection of nanomolar transcription factor NF-kappaB.

Transcription factors are involved in a number of important cellular processes. The transcription factor NF-κB has been linked with a number of cancers, autoimmune and inflammatory diseases. As a result, monitoring transcription factors potentially represents a means for the early detection and prevention of diseases. Most methods for transcription factor detection tend to be tedious and laborious and involve complicated sample preparation, and are not practical for routine detection. We describe herein the first label-free luminescence switch-on detection method for transcription factor activity using Exonuclease III and a luminescent ruthenium complex, [Ru(phen)(2)(dppz)](2+). As a proof of concept for this novel assay, we have designed a double-stranded DNA sequence bearing two NF-κB binding sites. The results show that the luminescence response was proportional to the concentration of the NF-κB subunit p50 present in the sample within a wide concentration range, with a nanomolar detection limit. In the presence of a known NF-κB inhibitor, oridonin, a reduction in the luminescence response of the ruthenium complex was observed. The reduced luminescence response of the ruthenium complex in the presence of small molecule inhibitors allows the assay to be applied to the high-throughput screening of chemical libraries to identify new antagonists of transcription factor DNA binding activity. This will allow the rapid and low cost identification and development of novel scaffolds for the treatment of diseases caused by the deregulation of transcription factor activity.

Alkylphenols from the roots of Ardisia brevicaulis induce G1 arrest and apoptosis through endoplasmic reticulum stress pathway in human non-small-cell lung cancer cells.

From the roots of Ardisia brevicaulis DIELS, two new alkylphenol derivatives, named ardisiphenol E (2) and F (3), have been isolated together with a known alkylphenol, ardisiphenol D (1). The structures of 1-3 were elucidated by chemical and spectroscopic techniques. Compounds 1 and 2 exhibited strong cytotoxicities on two human non-small-cell lung cancer cell lines (H1299 and A549). We found that compounds 1 and 2 upregulated mRNA and protein expressions of endoplasmic reticulum (ER) stress markers including C/EBP homologous protein (CHOP), binding immunoglobulin protein (Bip) and inositol-requiring enzyme 1 (IRE1) indicating 1 and 2 are novel natural ER stress inducers. Treatments with 1 and 5 µM of 1 or 2 triggered G1 arrest in H1299 and A549 cells with concomitant downregulation of ubiquitin fusion degradation protein 1 (Ufd1) and S-phase kinase-associated protein 2 (Skp2) proteins and the accumulation of p27, the key axes of ER stress-mediated G1 arrest. Compounds 1 and 2 also induced apoptosis at high concentrations (10, 20 µM) which was shown to be coupled with the upregulation of CHOP and Bim, the activation of caspase-9, caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage. These results indicate that compounds 1 and 2 induce ER stress that subsequently causes G1 arrest and apoptosis in human non-small-cell lung cancer cells and they may have potential anticancer effects.

Furanodienone inhibits cell proliferation and survival by suppressing ERα signaling in human breast cancer MCF-7 cells.

Estrogen receptor alpha (ERα) plays an important role in the development and progression of breast cancer and thus the attenuation of ERα activities is a promising treatment strategy. Furanodienone is one of the main bioactive chemical components of Rhizoma Curcumae which is commonly used in Chinese medicine for the treatment of cancer. In this study, we investigated the effects of furanodienone on human breast cancer MCF-7, T47D, and MDA-MB-231 cells. Our results showed that furanodienone could inhibit MCF-7, T47D, and MDA-MB-231 cells proliferation in a dose (10-160 µM) dependent manner. ERα-negative MDA-MB-231 cells were less sensitive to furanodienone than ERα-positive MCF-7 and T47D cells. Furanodienone could effectively block 17ß-estradiol (E2)-stimulated MCF-7 cell proliferation and cell cycle progression and induce apoptosis evidenced by the flow cytometric detection of sub-G1 DNA content and the appearance of apoptotic nuclei after DAPI staining. Furanodienone specifically down-regulated ERα protein and mRNA expression levels without altering ERß expression. Furanodienone treatment inhibited E2-stimulation of estrogen response element (ERE)-driven reporter plasmid activity and ablated E2-targeted gene (e.g., c-Myc, Bcl-2, and cyclin D1) expression which resulted in the inhibition of cell cycle progression and cell proliferation, and in the induction of apoptosis. Knockdown of ERα in MCF-7 cells by ERα-specific siRNA decreased the cell growth inhibitory effect of furanodienone. These findings suggest that effects of furanodienone on MCF-7 cells are mediated, at least in part, by inhibiting ERα signaling.

Simple and convenient G-quadruplex-based turn-on fluorescence assay for 3' → 5' exonuclease activity.

A selective, oligonucleotide-based, label-free, turn-on fluorescence detection method for 3' → 5' exonuclease activity has been developed using crystal violet as a G-quadruplex-binding probe. The assay is highly simple and rapid, does not require the use of gel-based equipment or radioisotopic labeling, and is amenable to high-throughput and real-time detection. A proof-of-concept of this assay has been demonstrated for prokaryotic Exonuclease III (ExoIII) and human TREX1.

Baicalein inhibits formation of α-synuclein oligomers within living cells and prevents Aß peptide fibrillation and oligomerisation.

Abnormal protein aggregation in the brain is linked to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Recent studies revealed that the oligomeric form of aggregates is most likely the toxic species, and thus could be a good therapeutic target. To screen for potent inhibitors that can inhibit both oligomerisation and fibrillation of α-synuclein (α-syn), we systematically compared the antioligomeric and antifibrillar activities of eight compounds that were extracted from Chinese herbal medicines through three platforms that can monitor the formation of α-syn fibrils and oligomers in cell-free or cellular systems. Our results revealed that baicalein, a flavonoid extracted from the Chinese herbal medicine Scutellaria baicalensis Georgi ("huang qin" in Chinese), is a potent inhibitor of α-syn oligomerisation both in cell-free and cellular systems, and is also an effective inhibitor of α-syn fibrillation in cell-free systems. We further tested the protective effect of baicalein against α-syn-oligomer-induced toxicity in neuronal cells. Our data showed that baicalein inhibited the formation of α-syn oligomers in SH-SY5Y and Hela cells, and protected SH-SY5Y cells from α-syn-oligomer-induced toxicity. We also explored the effect of baicalein on amyloid-ß peptide (Aß) aggregation and toxicity. We found that baicalein can also inhibit Aß fibrillation and oligomerisation, disaggregate pre-formed Aß amyloid fibrils and prevent Aß fibril-induced toxicity in PC12 cells. Our study indicates that baicalein is a good inhibitor of amyloid protein aggregation and toxicity. Given the role of these processes in neurodegenerative diseases such as AD and PD, our results suggest that baicalein has potential as a therapeutic agent for the treatment of these devastating disorders.

Ethanol extract of fructus schisandrae decreases hepatic triglyceride level in mice fed with a high fat/cholesterol diet, with attention to acute toxicity.

Effects of the ethanol extract of Fructus Schisandrae (EtFSC) on serum and liver lipid contents were investigated in mice fed with high fat/cholesterol (HFC) diet for 8 or 15 days. The induction of hypercholesterolemia by HFC diet caused significant increases in serum and hepatic total cholesterol (TC) levels (up to 62% and 165%, resp.) and hepatic triglyceride (TG) levels (up to 528%) in mice. EtFSC treatment (1 or 5 g/kg/day for 7 days; from Day 1 to 7 or from Day 8 to 14, i.g.) significantly decreased the hepatic TG level (down to 35%) and slightly increased the hepatic index (by 8%) in hypercholesterolemic mice. Whereas fenofibrate treatment (0.1 g/kg/day for 7 days, i.g.) significantly lowered the hepatic TG level (by 61%), it elevated the hepatic index (by 77%) in hypercholesterolemic mice. Acute toxicity test showed that EtFSC was relatively non-toxic, with an LD(50) value of 35.63 ± 6.46 g/kg in mice. The results indicate that EtFSC treatment can invariably decrease hepatic TG in hypercholesterolemic mice, as assessed by both preventive and therapeutic protocols, suggesting its potential use for fatty liver treatment.

New perspectives on chinese herbal medicine (zhong-yao) research and development.

Synthetic chemical drugs, while being efficacious in the clinical management of many diseases, are often associated with undesirable side effects in patients. It is now clear that the need of therapeutic intervention in many clinical conditions cannot be satisfactorily met by synthetic chemical drugs. Since the research and development of new chemical drugs remain time-consuming, capital-intensive and risky, much effort has been put in the search for alternative routes for drug discovery in China. This narrative review illustrates various approaches to the research and drug discovery in Chinese herbal medicine. Although this article focuses on Chinese traditional drugs, it is also conducive to the development of other traditional remedies and innovative drug discovery.

Acylated protopanaxadiol-type ginsenosides from the root of Panax ginseng.

Six new protopanaxadiol-type ginsenosides, named ginsenosides Ra(4) -Ra(9) (1-6, resp.), along with 14 known dammarane-type triterpene saponins, were isolated from the root of Panax ginseng, one of the most important Chinese medicinal herbs. The structures of the new compounds were determined by spectroscopic methods, including 1D- and 2D-NMR, HR-MS, and chemical transformation as (20S)- 3-O-{ß-D-6-O-[(E)-but-2-enoyl]glucopyranosyl-(1→2)-ß-D-glucopyranosyl}-20-O-[ß-D-xylopyranosyl-(1→4)-α-L-arabinopyranosyl-(1→6)-ß-D-glucopyranosyl]protopanaxadiol (1), (20S)-3-O-[ß-D-6-O-acetylglucopyranosyl-(1→2)-ß-D-glucopyranosyl]-20-O-[ß-D-xylopyranosyl-(1→4)-α-L-arabinopyranosyl-(1→6)-ß-D-glucopyranosyl]protopanaxadiol (2), (20S)-3-O-{ß-D-6-O-[(E)-but-2-enoyl]glucopyranosyl-(1→2)-ß-D-glucopyranosyl}-20-O-[ß-D-glucopyranosyl-(1→6)-ß-D-glucopyranosyl]protopanaxadiol (3), (20S)-3-O-{ß-D-6-O-[(E)-but-2-enoyl]glucopyranosyl-(1→2)-ß-D-glucopyranosyl}-20-O-[α-L-arabinopyranosyl-(1→6)-ß-D-glucopyranosyl]protopanaxadiol (4), (20S)-3-O-{ß-D-4-O-[(E)-but-2-enoyl]glucopyranosyl-(1→2)-ß-D-glucopyranosyl}-20-O-[α-L-arabinofuranosyl-(1→6)-ß-D-glucopyranosyl]protopanaxadiol (5), (20S)-3-O-{ß-D-6-O-[(E)-but-2-enoyl]glucopyranosyl-(1→2)-ß-D-glucopyranosyl}-20-O-[α-L-arabinofuranosyl-(1→6)-ß-D-glucopyranosyl]protopanaxadiol (6). The sugar moiety at C(3) of the aglycone of each new ginsenoside is butenoylated or acetylated.

ERp57 is up-regulated in free fatty acids-induced steatotic L-02 cells and human nonalcoholic fatty livers.

Pathogenesis of nonalcoholic fatty liver disease (NAFLD) is not clear. In this study we aimed to identify proteins involved in NAFLD development in free fatty acids (FFA)-induced hepatosteatotic cells and in human liver biopsies. Steatosis was induced by incubating a normal human hepatocyte-derived cell line L-02 with FFA. Differentially expressed proteins in the steatotic cells were analyzed by two-dimensional gel electrophoresis-based proteomics. Involvement of one of the up-regulated proteins in steatosis was characterized using the RNA interference approach with the steatotic cells. Protein expression levels in liver biopsies of patients with NAFLD were assessed by immunohistochemistry. Proteomic analysis of L-02 steatotic cells revealed the up-regulation of ERp57, a condition not previously implicated in NAFLD. Knockdown of ERp57 expression with siRNA significantly reduced fat accumulation in the steatotic cells. ERp57 expression was detected in 16 out of 17 patient biopsies and correlated with inflammation grades or fibrosis stages, while in 5 normal biopsies ERp57 expression was not detectable in hepatocytes. In conclusion, ERp57 was up-regulated in FFA-induced steatotic hepatic cells and in NAFLD patient livers and demonstrated steatotic properties in cultured cells. Further investigations are warranted to verify the involvement of ERp57 in NAFLD development.

New perspectives on innovative drug discovery: an overview.

Despite advances in technology, drug discovery is still a lengthy, expensive, difficult, and inefficient process, with a low rate of success. Today, advances in biomedical science have brought about great strides in therapeutic interventions for a wide spectrum of diseases. The advent of biochemical techniques and cutting-edge bio/chemical technologies has made available a plethora of practical approaches to drug screening and design. In 2010, the total sales of the global pharmaceutical market will reach 600 billion US dollars and expand to over 975 billion dollars by 2013. The aim of this review is to summarize available information on contemporary approaches and strategies in the discovery of novel therapeutic agents, especially from the complementary and alternative medicines, including natural products and traditional remedies such as Chinese herbal medicine.

Long-term treatment with a Chinese herbal formula, Sheng-Mai-San, improves cardiac contractile function in aged rats: the role of Ca(2+) homeostasis.

A Chinese herbal formula Sheng-Mai-Yin (SMY), the liquid dosage form of Sheng-Mai-San, has been used clinically for treating heart failure, particularly in aged patients. To investigate the effect of SMY treatment on the contractile function of aged hearts, we first examined cardiac hemodynamics in aged rats. To define the mechanism involved in the enhancement of cardiac function, we investigated the effect of SMY treatment on Ca(2+) homeostasis in ventricular cardiomyocytes isolated from aged rats. Ca(2+) release was assessed by measurements of changes in cardiac Ca(2+) transients and Ca(2+) sparks, using laser scanning confocal microscopy. The functional status of Ca(2+)-release regulators, including L-type Ca(2+) channels, sarcoplasmic reticulum (SR) Ca(2+)-adenosine triphosphatase (ATPase), and ryanodine receptors (RyRs), was also assessed. The results indicated that SMY treatment (2 g/kg per day for 30 doses within 6 weeks, intragastically) significantly improved hemodynamic parameters in aged rats. SMY treatment markedly increased the amplitude and shortened the duration of Ca(2+) transients in aged cardiomyocytes, and reversed the age-related increase in frequency, decrease in amplitude, and changes in spatiotemporal properties of Ca(2+) sparks in cardiomyocytes. In addition, SMY treatment increased the L-type Ca(2+) current density, SR Ca(2+) content, and SR Ca(2+)-ATPase expression, and decreased the sensitivity of RyRs to Ca(2+), all of which are causally related to increases in the amplitude of Ca(2+) transients and the size of Ca(2+) sparks. In conclusion, the improvement in cardiac contractile function afforded by SMY treatment in aged rats is likely mediated by an increase in Ca(2+) release from the SR through L-type Ca(2+) current-activated RyRs.

cDNA microarray analysis of the differentially expressed genes involved in murine pre-osteoclast RAW264.7 cells proliferation stimulated by dexamethasone.

Glucocorticoids (GCs) are hormones with anti-inflammatory and immuno-suppressive effects. The use of hormonal medicine like GCs may cause systemic adverse effects. In the present study, the cellular response of murine pre-osteoclast cell line RAW264.7 to dexamethasone (DEX) was investigated and the result demonstrated that DEX may stimulate RAW264.7 cells proliferation. Changes in gene expression involved in RAW264.7 cells proliferation stimulated by dexamethasone were investigated using cDNA microarrays containing 1000 cDNAs. It was found that 67 genes were regulated by DEX and could be grouped into 8 functional categories, including cell cycle regulation, cell survival, metabolism, pro-inflammatory effect, cytoskeleton, proteasome, signaling transduction and transcription factors. Moreover, some signaling pathways that involve in modulation of DEX on RAW264.7 cells functions were identified, including p53, 14-3-3 gamma, MAPK, Elk-1, I kappa B and Ifn related pathways.

Methoxylation of 3',4'-aromatic side chains improves P-glycoprotein inhibitory and multidrug resistance reversal activities of 7,8-pyranocoumarin against cancer cells.

The overexpression of P-glycoprotein (Pgp), an ATP-driven membrane exporter of hydrophobic xenobiotics, is one of the major causes of multidrug resistance (MDR) in cancer cells. Through extensive screening we have found that the extracts of Peucedanum praeruptorum Dunn. and one of the major components (+/-)-praeruptorin A (PA) may reverse Pgp-mediated multidrug resistance. Studies on novel PA derivatives have shown that (+/-)-3'-O,4'-O-dicinnamoyl-cis-khellactone (DCK) is more active than PA or verapamil and is a non-competitive inhibitor of Pgp. Here, we report that methoxylation of the cinnamoyl groups on DCK may further enhance its bioactivity. The structure-activity relationship is demonstrated by comparing two new pyranocoumarins (+/-)-3'-O,4'-O-bis(3,4-dimethoxycinnamoyl)-cis-khellactone (DMDCK) and (+/-)-3'-O,4'-O-bis(4-methoxycinnamoyl)-cis-khellactone (MMDCK). While the co-existence of 3- and 4-methoxy groups on cinnamoyl remarkably enhanced the Pgp-inhibitory activity, the lone existence of the 4-methoxy group on cinnamoyl reduced the activity. Contrary to DCK, DMDCK promoted the binding of UIC2 antibody to Pgp which signifies a conformational change of Pgp similar to that induced by transport substrates. While DCK moderately stimulated the basal Pgp-ATPase activity, DMDCK inhibited the activity. A pharmacophore search with verapamil-based template revealed that four functional groups of DMDCK could be simultaneously involved in interaction with Pgp whereas for DCK or MMDCK only three groups were involved. It is speculated that the additional 3-methoxy group on cinnamoyl allows DMDCK to interact more efficiently with Pgp substrate site(s). If DMDCK was tightly bind to Pgp substrate site(s) the complexes could be inactive with regard to transportation and ATP hydrolysis could also be inhibited.

Tenacigenin B derivatives reverse P-glycoprotein-mediated multidrug resistance inHepG2/Dox cells.

Tenacissimoside A (1) and 11alpha-O-benzoyl-12beta- O-acetyltenacigenin B (2), two derivatives of tenacigenin B (3) from the plant Marsdenia tenacissima, reversed multidrug resistance in P-glycoprotein (Pgp)-overexpressing multidrug-resistant cancer cells. The sensitivity of HepG2/Dox cells to the antitumor drugs doxorubicin, vinblastine, puromycin, and paclitexel was increased by 18-, 10-, 11-, and 6-fold by 20 microg/mL (or 25 microM) of 1 and 16-, 53-, 16-, and 326-fold by 20 microg/mL (or 39 microM) of 2, respectively. A preliminary mechanistic study has suggested that 1 might modulate Pgp-mediated multidrug resistance through directly interacting with the Pgp substrate site.

Schisandrin B from Schisandra chinensis reduces hepatic lipid contents in hypercholesterolaemic mice.

The effects of schisandrin B (Sch B) on liver and serum lipid contents were investigated in mice with experimentally-induced hypercholesterolaemia. Hypercholesterolaemia was induced either by oral administration of a cholesterol/bile salts mixture (2/0.5 g kg(-1)) for four days or by feeding a high fat/cholesterol/bile salts (10/1/0.3%, w/w) diet for seven days. Daily co-administration of Sch B (50-200 mg kg(-1), i.g.) for four or six days, respectively, decreased hepatic total cholesterol (TC) and triglyceride (TG) levels (by up to 50% and 52%, respectively) in hypercholesterolaemic mice. Sch B treatment also increased hepatic indices (14-84%) in hypercholesterolaemic mice. The results indicated that Sch B treatment could decrease hepatic TC and TG levels, and increase liver weight, in mouse models of hypercholesterolaemia. Fenofibrate treatment (100 mg kg(-1)) produced effects similar to those of Sch B on the hepatic index and lipid levels of hypercholesterolaemic mice.