The gut microbiota-aromatic hydrocarbon receptor (AhR) axis mediates the anticolitic effect of polyphenol-rich extracts from Sanghuangporus.

Inflammatory bowel disease (IBD) is a significant global health concern. The gut microbiota plays an essential role in the onset and development of IBD. Sanghuangporus (SH), a traditional Chinese medicinal mushroom, has excellent anti-inflammatory effects and is effective at modulating the gut microbiota. Despite these attributes, the specific anticolitic effects of SH and the mechanisms through which the gut microbiota mediates its benefits remain unclear. Herein, we demonstrated that polyphenol-rich extract from SH effectively alleviated the pathological symptoms of dextran sodium sulfate (DSS)-induced colitis in mice by modulating the gut microbiota. Treatment with SH distinctly enriched Alistipes, especially Alistipes onderdonkii, and its metabolite 5-hydroxyindole-3-acetic acid (5HIAA). Oral gavage of live A. onderdonkii or 5HIAA potently mitigated DSS-induced colitis in mice. Moreover, both 5HIAA and SH significantly activated the aromatic hydrocarbon receptor (AhR), and the administration of an AhR antagonist abrogated their protective effects against colitis. These results underscore the potent efficacy of SH in diminishing DSS-induced colitis through the promotion of A. onderdonkii and 5HIAA, ultimately activating AhR signaling. This study unveils potential avenues for developing therapeutic strategies for colitis based on the interplay between SH and the gut microbiota.

Ovarian Microcystic Stromal Tumor with Significant Nestin Expression: A Unique Case.

Ovary microcystic stromal tumor (MCST) is an extremely rare subtype of sex cord-stromal neoplasm, and only 57 cases have been reported. We herein report a unique case of ovarian MCST with positive nestin expression in a 39-year-old Chinese woman. The tumor showed microcystic stromal histological structures and characteristically expressed the CD10, WT-1, and Ki67 proteins. A molecular analysis identified a point mutation (c.110C > T) in exon 3 of the CTNNB1 gene. To our knowledge, no report has described a case of ovarian MCST with positive staining for nestin protein. Our study provides new insights into the tumor biology of ovarian MCST.

Oral Intake of Inosine 5'-Monophosphate in Mice Promotes the Absorption of Exogenous Fatty Acids and Their Conversion into Triglycerides though Enhancing the Phosphorylation of Adenosine 5'-Monophosphate-Activated Protein Kinase in the Liver, Leading to Lipohyperplasia.

Inosine 5'-monophoaphate (IMP) is a food additive that promotes serious lipohyperplasia in the liver of C57/KsJ-db/db (db/db) mice. Thus, IMP taken orally by healthy mice might also damage their health. To date, how IMP affects health after being taken by healthy animals is still unclear. Therefore, we investigated the health of C57BL/6J mice affected by IMP intake. Our data revealed that C57BL/6J mice administered 255 µM IMP daily via oral gavage for 4 months caused hyperlipidemia and an increase in body fat rate. The expressions of acetyl-CoA carboxylase 1 (ACC1) and phosphorylated acetyl-CoA carboxylase 2 (ACC2) in hepatocytes increased though the administration of IMP, promoting the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). The conversion of acetyl-CoA into triglycerides (TGs) was promoted by ACC1. These TGs were transported from the hepatocytes to avoid the development of non-alcoholic fatty liver disease (NAFLD), causing a deficiency of acetyl-CoA in the liver, and then, the increased phosphorylated ACC2 promoted the cytoplasm fatty acids entering the mitochondria and conversion into acetyl-CoA through the fatty acid ß-oxidation pathway, causing a deficiency in fatty acids. Therefore, the liver showed enhanced absorption of exogenous fatty acids, which were converted into TGs, causing lipohyperplasia. In conclusion, an excessive IMP intake promotes metabolic dysfunction in adipose tissue.

Zearalenone-14-glucoside specifically promotes dysplasia of Gut-Associated Lymphoid Tissue: A natural product for constructing intestinal nodular lymphatic hyperplasia model.

INTRODUCTION: Zearalenone-14-glucoside (Z14G) is a modified mycotoxin that widely contaminates food across the world. Our preliminary experiment showed that Z14G degrades to zearalenone (ZEN) in the intestine exerting toxicity. Notably, oral administration of Z14G in rats induces intestinal nodular lymphatic hyperplasia. OBJECTIVES: To investigate the mechanism of Z14G intestinal toxicity and how it differs from ZEN toxicity. We conducted a precise toxicology study on the intestine of rats exposed to Z14G and ZEN using multi-omics technology. METHODS: Rats were exposed to ZEN (5 mg/kg), Z14G-L (5 mg/kg), Z14G-H (10 mg/kg), and pseudo germ free (PGF)-Z14G-H (10 mg/kg) for 14 days. Histopathological studies were performed on intestines from each group and compared. Metagenomic, metabolomic, and proteomic analyses were performed on rat feces, serum, and intestines, respectively. RESULTS: Histopathological studies showed that Z14G exposure resulted in dysplasia of gut-associated lymphoid tissue (GALT) compared to ZEN exposure. The elimination of gut microbes in the PGF-Z14G-H group alleviated or eliminated Z14G-induced intestinal toxicity and GALT dysplasia. Metagenomic analysis revealed that Z14G exposure significantly promoted the proliferation of Bifidobacterium and Bacteroides compared to ZEN. Metabolomic analysis showed that Z14G exposure significantly reduced bile acid, while proteomic analysis found that Z14G exposure significantly reduced the expression of C-type lectins compared to ZEN. CONCLUSIONS: Our experimental results and previous research suggest that Z14G is hydrolyzed to ZEN by Bifidobacterium and Bacteroides promoting their co-trophic proliferation. This leads to inactivation of lectins by hyperproliferative Bacteroides when ZEN caused intestinal involvement, resulting in abnormal lymphocyte homing and ultimately GALT dysplasia. It is noteworthy that Z14G is a promising model drug to establish rat models of intestinal nodular lymphatic hyperplasia (INLH), which is of great significance for studying the pathogenesis, drug screening and clinical application of INLH.

Adenosine-rich extract of Ganoderma lucidum: A safe and effective lipid-lowering substance.

Ganoderma lucidum is a traditional Chinese medicine with a variety of active compounds and possesses adequate lipid-lowering and anti-atherosclerotic effects. However, its main active components and potential mechanisms still remain unclear. Here, we evaluated the anti-hyperlipidemic effect of the adenosine extract from Ganoderma lucidum (AEGL) in high-fat-diet (HFD)-induced hyperlipidemic ApoE-/- mice and explored the underlying biological mechanism by multi-omics analysis. Treatment with AEGL for 8 weeks significantly decreased the serum levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-c) by 45.59%, 41.22%, and 39.02%, respectively, as well as reduced liver TC and TG by 44.15% and 76.23%, compared with the HFD-only group. We also observed significant amelioration of hepatic steatosis without liver and kidney damage after AEGL treatment. Regulating the expression and acetylation/crotonylation of proteins involved in the PPAR signaling pathway may be one of the potential mechanisms involved in the observed lipid-lowering effects of AEGL.

Whole-genome sequence of Phellinus gilvus (mulberry Sanghuang) reveals its unique medicinal values.

Phellinus gilvus (Schwein.) Pat, a species of 'Sanghuang', has been well-documented for various medicinal uses, but the genome information and active constituents are largely unknown. Here, we sequenced the whole-genome of P. gilvus, identified phenylpropanoids as its key anti-cancer components, and deduced their biosynthesis pathways. A 41.11-Mb genome sequence was assembled and the heatmap created with high-throughput chromosome conformation capture techniques data suggested all bins could be clearly divided into 11 pseudochromosomes. Cellular experiments showed that P. gilvus fruiting body was more effective to inhibit hepatocellular carcinoma cells than mycelia. High resolution electrospray ionization mass spectroscopy (HR-ESI-MS) analysis revealed P. gilvus fruiting body was rich in phenylpropanoids, and several unique phenylpropanoids in Phellinus spp. exhibited potent anti-carcinogenesis activity. Based on genomic, HR-ESI-MS information and differentially expressed genes in transcriptome analysis, we deduced the biosynthesis pathway of four major phenylpropanoids in P. gilvus. Transcriptome analysis revealed the deduced genes expressions were synergistically changed with the production of phenylpropanoids. The optimal candidate genes of phenylpropanoids' synthesis pathway were screened by molecular docking analysis. Overall, our results provided a high-quality genomic data of P. gilvus and inferred biosynthesis pathways of four phenylpropanoids with potent anti-carcinogenesis activities. These will be a valuable resource for further genetic improvement and effective use of the P. gilvus.

Four-week administration of nicotinemoderately impacts blood metabolic profile and gut microbiota in a diet-dependent manner.

As the primary active component in tobacco, nicotine affects many aspects of human metabolism. Diet and gut microbiota are key factors that profoundly influence human lipid and glucose metabolism. However, the diet-based differential impacts of nicotine on blood lipid and glucose levels as well as on the gut microbiota are still largely unknown. Here we show that 4-week oral administration of nicotine (2 mg/kg) resulted in bodyweight and fat decrease in both normal-chow (NCD)- and high-fat diet (HFD)-fed mice. But nicotine showed little influence on the plasma levels of lipids, glucose and inflammatory cytokines in NCD-fed mice but moderately deteriorated these parameters in HFD-fed ones. 16S sequencing showed that nicotine perturbed bacterial diversity and community composition of gut microbiota more pronouncedly in HFD mice. At genus level, nicotine dramatically increased Ruminococcaceae UCG-009 in HFD condition but not in NCD feeding. Interestingly, co-treatment with antibiotics (ampicillin + norfloxacin) substantially abolished the lipid-enhancing effect of nicotine in HFD-fed mice, suggesting an important role of gut microbes in the lipid-modulatory effect of nicotine. Together, our results indicate that the harmful effects of nicotine on metabolism and systemic inflammation are diet-dependent. Chronic exposure to nicotine may alter the gut microbiota especially in HFD-fed animals.

Synthesis and In Vitro Evaluation of Caffeoylquinic Acid Derivatives as Potential Hypolipidemic Agents.

A series of novel caffeoylquinic acid derivatives of chlorogenic acid have been designed and synthesized. Biological evaluation indicated that several synthesized derivatives exhibited moderate to good lipid-lowering effects on oleic acid-elicited lipid accumulation in HepG2 liver cells. Particularly, derivatives 3d, 3g, 4c and 4d exhibited more potential lipid-lowering effect than the positive control simvastatin and chlorogenic acid. Further studies on the mechanism of 3d, 3g, 4c and 4d revealed that the lipid-lowering effects were related to their regulation of TG levels and merit further investigation.

The pandanus tectorius fruit extract (PTF) modulates the gut microbiota and exerts anti-hyperlipidaemic effects.

BACKGROUND: The gut microbiota plays a key role in the maintenance of human health and mediates the beneficial effects of natural products including polyphenols. Previous studies have demonstrated that the polyphenol-rich Pandanus tectorius fruit extract (PTF) was effective in ameliorating high-fat diet (HFD)-induced hyperlipidaemia, and polyphenols can significantly change the structure of the gut microbiota. PURPOSE: In this study, we assessed whether the modulation of the gut microbiota plays a key role in the PTF-induced anti-hyperlipidaemic effects. METHODS: Male C57BL/6 J mice were induced with hyperlipidaemia by consuming a high-fat diet (HFD) for 4 weeks. Then, the mice were orally administered PTF, antibiotics (ampicillin+ norfloxacin), PTF+antibiotics or vehicle for another 6 weeks. Body weights and 24-h food intake were assessed weekly. At the end of the experiment, fresh stools were collected for 16S RNA pyrosequencing, and blood and liver and fat tissue were collected for pharmacological analysis. RESULTS: PTF was effective in ameliorating high-fat diet (HFD)-induced hyperlipidaemia and significantly changed the structure of the gut microbiota. However, the anti-hyperlipidaemic effect of PTF was not influenced by the co-treatment with antibiotics (ampicillin+norfloxacin). A microbiological analysis of the gut microbiotas revealed that PTF selectively enhanced the relative abundance of Lactobacillus and decreased the relative abundance of Bacteroides and Alistipes. A correlation analysis between biochemical indexes and individual taxon showed that Lactobacillus was negatively associated with serum lipids and glucose while Bacteroides and Alistipes were positively associated with serum lipids and glucose. The modulatory effect of PTF on Lactobacillus, Bacteroides and Alistipes was not disturbed by the administration of antibiotics. CONCLUSION: These results demonstrated that the polyphenol-rich PTF as a unique gut microbiota modulating agent and highlighted the richness of Lactobacillus and the decreased abundance of Bacteroides and Alistipes as an effective indicator of the therapeutic effect of medicinal foods on hyperlipidaemia.

Cordycepin promotes browning of white adipose tissue through an AMP-activated protein kinase (AMPK)-dependent pathway.

Obesity is a worldwide epidemic. Promoting browning of white adipose tissue (WAT) contributes to increased energy expenditure and hence counteracts obesity. Here we show that cordycepin (Cpn), a natural derivative of adenosine, increases energy expenditure, inhibits weight gain, improves metabolic profile and glucose tolerance, decreases WAT mass and adipocyte size, and enhances cold tolerance in normal and high-fat diet-fed mice. Cpn markedly increases the surface temperature around the inguinal WAT and turns the inguinal fat browner. Further investigations show that Cpn induces the development of brown-like adipocytes in inguinal and, to a less degree, epididymal WAT depots. Cpn also increases the expression of uncoupling protein 1 (UCP1) and other thermogenic genes in WAT and 3T3-L1 differentiated adipocytes, in which AMP-activated protein kinase (AMPK) plays an important role. Our results provide novel insights into the function of Cpn in regulating energy balance, and suggest a potential utility of Cpn in the treatment of obesity.

Butylene fipronil induces apoptosis in PC12 murine nervous cells via activation of p16-CDK4/6-cyclin D1 and mitochondrial apoptotic pathway.

Butylene fipronil (BFPN) is a phenylpyrazole insecticide, acting at the γ-aminobutyric acid (GABA) receptor. Here, we show that BFPN inducedcytotoxicity in PC12 murinenervous cells, which lacks GABA receptor. Treatment with BFPN for 48 hours significantly enhanced G0/G1 arrest and induced apoptosis. BFPN decreased the expression of cyclin-dependent kinase (CDK4 and CDK6) and increased P16 and cyclin D1. Simultaneously, Bcl-2 protein was declined while Bax and cytochrome c were significantly enhanced in BFPN-treated groups. The apoptotic enzymes caspase-8, -9, and -3 were also activated by BFPN. Furthermore, treatment with BFPN significantly stimulated reactive oxygen species (ROS) generation, and pretreatment with antioxidant diphenyleneiodonium, substantially reduced cell death. Overall, these results suggest that BFPN is effective to induce G0/G1-phase arrest and apoptosis in PC12 murine nervous cell. Stimulating ROS generation and activation of P16-CDK4/6-cyclin D1 and mitochondrial apoptotic pathway may participate in the cytotoxicity of BFPN.

Agarwood Essential Oil Ameliorates Restrain Stress-Induced Anxiety and Depression by Inhibiting HPA Axis Hyperactivity.

In our previous investigation, we found that agarwood essential oil (AEO) has a sedative-hypnotic effect. Sedative-hypnotic drugs usually have an anxiolytic effect, where concomitant anxiety and depression are a common comorbidity. Therefore, this study further investigated the anxiolytic and antidepressant effects of AEO using a series of animal behavior tests on a restraint stress-induced mice model. The elevated plus maze (EPM) test, the light dark exploration (LDE) test, and the open field (OF) test demonstrated that AEO has a significant anxiolytic effect. Simultaneously, the tail suspension (TS) test and the forced swimming (FS) test illuminated that AEO has an antidepressant effect with the immobility time decreased. Stress can cause cytokine and nitric oxide (NO) elevation, and further lead to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. AEO was shown to dose-dependently inhibit the levels of cytokines, including interleukin 1α (IL-1α), IL-1ß, and IL-6 in serum, significantly decrease the mRNA level of neural nitric oxide synthase (nNOS) in the cerebral cortex and hippocampus, and inhibit the nNOS protein level in the hippocampus. Concomitant measurements of the HPA axis upstream regulator corticotropin releasing factor (CRF) and its receptor CRFR found that AEO significantly decreases the gene expression of CRF, and significantly inhibits the gene transcription and protein expression of CRFR in the cerebral cortex and hippocampus. Additionally, AEO dose-dependently reduces the concentrations of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) downstream of the HPA axis, as measured by ELISA kits. These results together demonstrate that AEO exerts anxiolytic and antidepressant effects which are related to the inhibition of CRF and hyperactivity of the HPA axis.

The aqueous extract of Phellinus igniarius (SH) ameliorates dextran sodium sulfate-induced colitis in C57BL/6 mice.

Phellinus igniarius, which is called Sanghuang in Chinese, is a fungal herb widely used in Traditional Chinese Medicine to treat stomachache, inflammation and tumors. Recent studies have demonstrated the antitumor, anti-diabetic, anti-inflammatory and immunity-modulating activities of P. igniarius. In the present study, we investigated that ameliorating effect of the aqueous extract of P. igniarius fruiting body (SH) on dextran sodium sulfate (DSS)-induced colitis in C57BL/6 mice. Treatment with SH (250 and 400 mg/kg) for 8 weeks effectively alleviated the pathological indicators of colitis such as bodyweight reduction, disease activity index score, shortening of colon length and abnormal colon histology. The plasma levels of lipopolysaccharide (LPS) and inflammatory factors such as interleukin-6 (IL-6), IL-1ß and tumor necrosis factor (TNF)-α were all significantly reduced. Supplementation of SH (10 mg/L) also inhibited LPS-elicited IL-1ß production by RAW264.7 macrophages. Real-time PCR and western blot showed that treatment with SH significantly inhibited the phosphorylation of nuclear factor kappa B inhibitor alpha (IκBα) and decreased the expression of IL-6/IL-1ß-maturation genes such as apoptosis-associated speck-like protein (ASC3) and caspase-1 in the colon of DSS-induced colitis mice. These results suggest that SH is adequate for the treatment of colitis. Inhibiting the expression and release of inflammatory factors may participate in the colitis-ameliorating effect of SH.

Agarwood Essential Oil Displays Sedative-Hypnotic Effects through the GABAergic System.

Although agarwood has been used as a tranquilizer in Asian countries for hundreds of years, the underlying pharmacological basis is still unclear. This study investigated the sedative-hypnotic effect of agarwood essential oil (AEO) using locomotor activity and pentobarbital-induced sleeping assays in mice. Single (1-day) and multiple (7- and 14-days) administrations of 60 mg/kg AEO generated significant sedative effect on inhibiting locomotor activity and hypnotic effect on pentobarbital-induced sleeping in mice. Interestingly, prolonged AEO treatment did not result in obvious desensitization. Concoitant measurement of the levels of brain neurotransmitters using ultrafast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) indicated that AEO had no significant effect on the levels of glutamic acid (Glu) and γ-aminobutyric acid (GABA) in the brain. However, the sedative-hypnotic effects were blocked by the type A GABA (GABAA) receptor antagonists bicuculline and flumazenil. In addition, AEO significantly elevated the expression of GABAA receptor subunits and subtypes in the cerebral cortex. Furthermore, AEO increased chlorine ion (Cl-) influx through GABAA receptors in human neuroblastoma cells. These results together demonstrate that AEO exerts its sedative-hypnotic effects through regulating gene expression of GABAA receptors and potentiating GABAA receptor function.

Cordycepin stimulates autophagy in macrophages and prevents atherosclerotic plaque formation in ApoE-/- mice.

Autophagy in macrophages plays a key role in the pathogenesis and progression of atherosclerosis and has become a potential therapeutic target. Here we show that cordycepin (Cpn), a natural derivative of adenosine, markedly reduced atherosclerotic plaque and ameliorated associated symptoms such as dyslipidemia, hyperglycemia and inflammation in ApoE-/- mice. Supplementation of Cpn dose-dependently inhibited oxLDL-elicited foam cell formation and modulated intracellular cholesterol homeostasis by inhibiting cholesterol uptake and promoting cholesterol efflux in RAW264.7 macrophages. Notably, Cpn exhibited significant stimulating effect on macrophage autophagy, as estimated by western blotting, immunofluorescent staining and autophagic vacuoles observation by transmission electron microscopy. The inhibitive effects of Cpn on foam cell formation were dramatically deteriorated in the presence of various autophagy inhibitors, suggesting that autophagy participate, at least in part, in the atheroprotective role of Cpn. Further investigations using different autophagy inhibitors and specific siRNAs for AMP-activated protein kinase (AMPK) gamma1 subunit indicated that Cpn may stimulate macrophage autophagy through AMPK-mTOR pathway. Together, our results demonstrated Cpn as a potential therapeutic agent for the prevention and treatment of atherosclerosis, and the autophagic activity presents a novel mechanism for Cpn-mediated atheroprotection.

Asperlin Inhibits LPS-Evoked Foam Cell Formation and Prevents Atherosclerosis in ApoE-/- Mice.

Asperlin is a marine-derived natural product with antifungal and anti-inflammatory activities in vitro. In the present study, we isolated asperlin from a marine Aspergillus versicolor LZD4403 fungus and investigated its anti-atherosclerotic effects in vitro and in vivo. Asperlin significantly inhibited lipopolysaccharides (LPS)- but not oxidated low-density lipoprotein (oxLDL)-evoked foam cell formation and promoted cholesterol efflux in RAW264.7 macrophages. Supplementation with asperlin also suppressed LPS-elicited production of pro-inflammatory factors in RAW264.7 macrophages, decreased the expression levels of iNOS, IL-1ß and TNFα, and increased the expression of IL-10 and IL-4, indicating a remarkable shift in M1/M2 macrophages polarization. In vivo experiments in high-fat diet (HFD)-fed ApoE-/- mice showed that oral administration of asperlin for 12 weeks remarkably suppressed atherosclerotic plaque formation in the aorta, as revealed by the reduced aortic dilatation and decreased atherosclerotic lesion area. Asperlin also decreased serum levels of pro-inflammatory factors but showed little impact on blood lipids in ApoE-/- atherosclerotic mice. These results suggested that asperlin is adequate to prevent atherosclerosis in vivo. It may exert atheroprotective function through suppressing inflammation rather than ameliorating dyslipidemia.

Penipyridones A-F, Pyridone Alkaloids from Penicillium funiculosum.

Six new pyridone alkaloids, named penipyridones A-F (1-6), were isolated from the fermentation broth of an Antarctic moss-derived fungus, Penicillium funiculosum GWT2-24. Their structures were elucidated from extensive NMR and MS data. Although they possess the same major chromophore and some of them presented almost mirror ECD spectra, their absolute configurations were found to be uniformly S, as evidenced by X-ray single-crystal diffraction analysis, stereocontrolled total synthesis, and chemical conversions. TDDFT-ECD calculations of compounds 3 and 6 revealed that subtle conformational changes are responsible for the significantly different ECD curves. None of the compounds were cytotoxic (IC50 > 50 µM), while compounds 1, 2, 5, and 7 elicited lipid-lowering activity in HepG2 hepatocytes.

Spiromastixones Inhibit Foam Cell Formation via Regulation of Cholesterol Efflux and Uptake in RAW264.7 Macrophages.

Bioassay-guided evaluation shows that a deep sea-derived fungus, Spiromastix sp. MCCC 3A00308, possesses lipid-lowering activity. Chromatographic separation of a culture broth resulted in the isolation of 15 known depsidone-based analogues, labeled spiromastixones A-O (1-15). Each of these compounds was tested for its ability to inhibit oxidized low-density lipoprotein (oxLDL)-induced foam cell formation in RAW264.7 macrophages. Spiromastixones 6-8 and 12-14 significantly decreased oxLDL-induced lipid over-accumulation, reduced cell surface area, and reduced intracellular cholesterol concentration. Of these compounds, spiromastixones 6 and 14 exerted the strongest inhibitory effects. Spiromastixones 6 and 14 dramatically inhibited cholesterol uptake and stimulated cholesterol efflux to apolipoprotein A1 (ApoA1) and high-density lipoprotein (HDL) in RAW264.7 macrophages. Mechanistic investigation indicated that spiromastixones 6, 7, 12 and 14 significantly up-regulated the mRNA levels of ATP-binding cassette sub-family A1 (ABCA1) and down-regulated those of scavenger receptor CD36, while the transcription of ATP-binding cassette sub-family A1 (ABCG1) and proliferator-activated receptor gamma (PPARγ) were selectively up-regulated by 6 and 14. A transactivation reporter assay revealed that spiromastixones 6 and 14 remarkably enhanced the transcriptional activity of PPARγ. These results suggest that spiromastixones inhibit foam cell formation through upregulation of PPARγ and ABCA1/G1 and downregulation of CD36, indicating that spiromastixones 6 and 14 are promising lead compounds for further development as anti-atherogenic agents.

Varioxiranols A-G and 19-O-Methyl-22-methoxypre-shamixanthone, PKS and Hybrid PKS-Derived Metabolites from a Sponge-Associated Emericella variecolor Fungus.

Chemical examination of a sponge (Cinachyrella sp.)-associated Emericella variecolor fungus resulted in the isolation of seven new polyketide derivatives, namely, varioxiranols A-G (1-7), and a new hybrid PKS-isoprenoid metabolite, 19-O-methyl-22-methoxypre-shamixanthone (8), together with nine known analogues. Their structures were elucidated on the basis of extensive spectroscopic analyses, including ECD effects, Mosher's method, X-ray diffraction, and chemical conversion for the determination of absolute configurations. Varioxiranols F and G were found for the first time to link a xanthone moiety with a benzyl alcohol via an ether bond, while the dioxolanone group of 5 is unusual in nature. A cell-based lipid-lowering assay revealed that pre-shamixanthone (12) exerted significant inhibition against lipid accumulation in HepG2 cells without cytotoxic effects, accompanying the potent reduction of total cholesterol and triglycerides. Real-time quantitative PCR indicated that pre-shamixanthone (12) mediated the reduction of lipid accumulation related to the down-regulation of the expression of the key lipogenic transcriptional factor SREBP-1c and its downstream genes encoding FAS and ACC.

Lipid-lowering polyketides from a soft coral-derived fungus Cladosporium sp. TZP29.

Two new C12 polyketides, cladospolides E and F (1 and 2), together with four known derivatives seco-patulolides A and C (3 and 4), 11-hydroxy-γ-dodecalactone (5) and iso-cladospolide B (6), were isolated from a soft coral-derived fungus Cladosporium sp. TZP-29. Their structures, including the absolute configurations, were elucidated by spectroscopic analysis, modified Mosher's method, and the analysis of their biogenesis. All compounds were non-cytotoxic while compounds 1 and 3-5 showed potent lipid-lowering activity in HepG2 hepatocytes.