Rapid Discovery of Substances with Anticancer Potential from Marine Fungi Based on a One Strain-Many Compounds Strategy and UPLC-QTOF-MS.

The secondary metabolites of marine fungi with rich chemical diversity and biological activity are an important and exciting target for natural product research. This study aimed to investigate the fungal community in Quanzhou Bay, Fujian, and identified 28 strains of marine fungi. A total of 28 strains of marine fungi were screened for small-scale fermentation by the OSMAC (One Strain-Many Compounds) strategy, and 77 EtOAc crude extracts were obtained and assayed for cancer cell inhibition rate. A total of six strains of marine fungi (P-WZ-2, P-WZ-3-2, P-WZ-4, P-WZ-5, P56, and P341) with significant changes in cancer cell inhibition induced by the OSMAC strategy were analysed by UPLC-QTOF-MS. The ACD/MS Structure ID Suite software was used to predict the possible structures with inhibitory effects on cancer cells. A total of 23 compounds were identified, of which 10 compounds have been reported to have potential anticancer activity or cytotoxicity. In this study, the OSMAC strategy was combined with an untargeted metabolomics approach based on UPLC-QTOF-MS to efficiently analyse the effect of changes in culture conditions on anticancer potentials and to rapidly find active substances that inhibit cancer cell growth.

A Terphenyllin Derivative CHNQD-00824 from the Marine Compound Library Induced DNA Damage as a Potential Anticancer Agent.

With the emergence of drug resistance and the consequential high morbidity and mortality rates, there is an urgent need to screen and identify new agents for the effective treatment of cancer. Terphenyls-a group of aromatic hydrocarbons consisting of a linear 1,4-diaryl-substituted benzene core-has exhibited a wide range of biological activities. In this study, we discovered a terphenyllin derivative-CHNQD-00824-derived from the marine compound library as a potential anticancer agent. The cytotoxic activities of the CHNQD-00824 compound were evaluated against 13 different cell lines with IC50 values from 0.16 to 7.64 µM. Further study showed that CHNQD-00824 inhibited the proliferation and migration of cancer cells, possibly by inducing DNA damage. Acridine orange staining demonstrated that CHNQD-00824 promoted apoptosis in zebrafish embryos. Notably, the anti-cancer effectiveness was verified in a doxycin hydrochloride (DOX)-induced liver-specific enlargement model in zebrafish. With Solafinib as a positive control, CHNQD-00824 markedly suppressed tumor growth at concentrations of 2.5 and 5 µM, further highlighting its potential as an effective anticancer agent.

Targeted isolation of antitubercular cycloheptapeptides and an unusual pyrroloindoline-containing new analog, asperpyrroindotide A, using LC-MS/MS-based molecular networking.

Further insights on the secondary metabolites of a soft coral-derived fungus Aspergillus versicolor under the guidance of MS/MS-based molecular networking led to the isolation of seven known cycloheptapeptides, namely, asperversiamides A-C (1-3) and asperheptatides A-D (4-7) and an unusual pyrroloindoline-containing new cycloheptapeptide, asperpyrroindotide A (8). The structure of 8 was elucidated by comprehensive spectroscopic data analysis, and its absolute configuration was determined by advanced Marfey's method. The semisynthetic transformation of 1 into 8 was successfully achieved and the reaction conditions were optimized. Additionally, a series of new derivatives (10-19) of asperversiamide A (1) was semi-synthesized and their anti-tubercular activities were evaluated against Mycobacterium tuberculosis H37Ra. The preliminary structure-activity relationships revealed that the serine hydroxy groups and the tryptophan residue are important to the activity. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-022-00157-8.

Integrating Activity-Guided Strategy and Fingerprint Analysis to Target Potent Cytotoxic Brefeldin A from a Fungal Library of the Medicinal Mangrove Acanthus ilicifolius.

Mangrove-associated fungi are rich sources of novel and bioactive compounds. A total of 102 fungal strains were isolated from the medicinal mangrove Acanthus ilicifolius collected from the South China Sea. Eighty-four independent culturable isolates were identified using a combination of morphological characteristics and internal transcribed spacer (ITS) sequence analyses, of which thirty-seven strains were selected for phylogenetic analysis. The identified fungi belonged to 22 genera within seven taxonomic orders of one phyla, of which four genera Verticillium, Neocosmospora, Valsa, and Pyrenochaeta were first isolated from mangroves. The cytotoxic activity of organic extracts from 55 identified fungi was evaluated against human lung cancer cell lines (A-549), human cervical carcinoma cell lines (HeLa), human hepatoma cells (HepG2), and human acute lymphoblastic leukemia cell lines (Jurkat). The crude extracts of 31 fungi (56.4%) displayed strong cytotoxicity at the concentration of 50 µg/mL. Furthermore, the fungus Penicillium sp. (HS-N-27) still showed strong cytotoxic activity at the concentration of 25 µg/mL. Integrating cytotoxic activity-guided strategy and fingerprint analysis, a well-known natural Golgi-disruptor and Arf-GEFs inhibitor, brefeldin A, was isolated from the target active strain HS-N-27. It displayed potential activity against A549, HeLa and HepG2 cell lines with the IC50 values of 101.2, 171.9 and 239.1 nM, respectively. Therefore, combining activity-guided strategy with fingerprint analysis as a discovery tool will be implemented as a systematic strategy for quick discovery of active compounds.

The production of broad-spectrum antibiotics from phytopathogen Epicoccum sorghinum by culturing in host edible mushroom Thelephora ganbajun extract.

Metabolism of special endophytes and phytopathogens can be induced by the symbiotic interactions with the host. A phytopathogen Epicoccum sorghinum cultured in host mushroom Thelephora ganbajun medium exhibited different metabolites compared with that of ordinary medium. An unprecedented scaffold possessing the same substructure as perylenequinone mycotoxin, a first methyl rearrangement product of phytotoxin, epoxydon 6-methylsalicylate ester, three undescribed compounds, and an undescribed natural product were isolated from E. sorghinum cultured in T. ganbajun. Episorin A and epicosorin A were produced from E. sorghinum induced by culturing in host medium. Episorin A was the first example of perylenequinone analogue in the natural products. These induced compounds and other metabolites showed notable antibiosis against endogenous fungi, and insect existing in mushroom. Induced episorin A showed significant inhibitory effects on nitric oxide production in LPS-activated macrophages, and anti-acetylcholinesterase with the IC50 at 5.40 ± 0.25 µM, and 4.32 µM, respectively, and cytotoxicity against HL-60, A-549, SMMC-7721, MCF-7 and SW480 with IC50 at 14.21 ± 0.53, 17.93 ± 0.22, 18.17 ± 0.63, 28.36 ± 0.43, and 18.20 ± 1.03 µM.

New Metabolites, Antifeedant, Insecticidal Activities, and Reciprocal Relationship Between Insect and Fungus from Endophyte Schizophyllum commune.

Five new bisabolane sesquiterpenes, a new polyketide, along with seven known compounds, were isolated from endophyte Schizophyllum commune associated with a famous medicinal and edible plant, Gastrodia elata. Most compounds 1-12, and extract indicated antifeedant activities against silkworm with feeding deterrence index (FDI) of 21-85 %, at concentrations of 20 µg/cm2 , 40 µg/cm2 , respectively. Compound 6 indicated obvious insecticidal activity with fatality rate of 60 %, at the concentration of 20 µg/cm2 . Five bisabolane sesquiterpenes, two ergosterols, and a glyceride showed insecticidal synergism by combining with abamectin. Interesting, ergosterol peroxide (13) distributed widely in mushrooms and fungi, was found to have feeding attractant activities on insects and antifungal activity against entomopathogen Beauveria bassiana. The reciprocal relationship should be occurred between S. commune and pests for the fungus produced ergosterol peroxide to attract the pests propagating spore, and its anti-entomopathogen activity was also benefit for the health of insects.

Semisynthesis and biological evaluation of (+)-sclerotiorin derivatives as antitumor agents for the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most common primary hepatic malignancy. Herein, a series of semisynthesized derivatives (2-30) of the natural product (+)-sclerotiorin (1) was prepared and evaluated the cytotoxic activities against six cancer cell lines. Among them, 3 and 5 were the most effective compounds against human hepatocellular carcinoma Bel-7402 cell line with IC50 values of 1.45 and 1.15 µM, respectively. Molecular mechanism study showed that 5 disrupted the mitochondrial membrane potential and induced apoptosis in a caspase-dependent manner. In addition, 5 affected AKT and ERK signaling pathways and induced AKT and ERK proteins degradation through ubiquitin-proteasome system. Furthermore, 5 displayed significant in vivo anticancer effects in the xenograft models with decreasing the tumor mass by 52.5%. The safety evaluation was confirmed by acute toxicity subchronic toxicity tests, paraffin sections of mice organ and blood routine examination. Taken together, 5 can be developed as a potential therapeutic agent for hepatocellular carcinoma.

Analgesic Activity of Jin Ling Zi Powder and Its Single Herbs: A Serum Metabonomics Study.

OBJECTIVE: To compare the analgesic effect of Jin Ling Zi Powder (JLZ) and its two single herbs. METHODS: The hot plate method was used to induce pain. Totally 36 mice were randomly divided into 6 groups by a complete random design, including control, model, aspirin (ASP, 0.14 g/kg body weight), JLZ (14 g/kg body weight), Corydalis yanhusuo (YHS, 14 g/kg body weight), and Toosendan Fructus (TF, 14 g/kg body weight) groups, 6 mice in each group. The mice in the control and model groups were given the same volume of saline, daily for 2 consecutive weeks. At 30, 60, 90, and 120 min after the last administration, the pain threshold of mice in each group was measured, and the improvement rate of pain threshold was calculated. Serum endogenous metabolites were analyzed by gas chromatography-mass spectrometry (GC-MS). RESULTS: There was no statistical difference in pain threshold among groups before administration (P>0.05). After 2 weeks of administration, compared with the model group, the pain threshold in JLZ, YHS, TF and ASP groups were increased to varying degrees (P<0.05). JLZ had the best analgesic effect and was superior to YHS and TF groups. A total of 14 potential biomarkers were screened in serum data analysis and potential biomarkers levels were all reversed to different degrees after the treatment with JLZ and its single herbs. These potential biomarkers were mainly related to glyoxylate and dicarboxylate metabolism, glycine, serine and threonine metabolism, valine, leucine and isoleucine biosynthesis, aminoacyl-tRNA biosynthesis and inositol phosphate metabolism. CONCLUSIONS: The analgesic mechanism of JLZ and YHS was mainly due to the combination of glycine and its receptor, producing post-synaptic potential, reducing the excitability of neurons, and weakening the afferent effect of painful information.

Brefeldin A Induces Apoptosis, Inhibits BCR-ABL Activation, and Triggers BCRABL Degradation in Chronic Myeloid Leukemia K562 Cells.

BACKGROUND: Chronic Myeloid Leukemia (CML) is a myeloproliferative disease caused by BCR-ABL oncoprotein. Tyrosine kinase inhibitors have been developed to inhibit the activity of BCR-ABL; however, drug resistance and side effect occur in clinic application. Therefore, it is urgent to find novel drugs for CML treatment. Under the guidance of cytotoxic activity, crude extracts of 55 fungal strains from the medicinal mangrove Acanthus ilicifolius were evaluated, and one potent cytotoxic natural compound, brefeldin A (BFA), was discovered from Penicillium sp. (HS-N-29). OBJECTIVE: This study was aimed to determine the cytotoxic activity of BFA and the effect on the activation and expression of BCR-ABL in K562 cells. METHODS: We evaluated cytotoxic activity by MTT assay and soft agar clone assay; apoptosis and cell cycle distribution by Muse cell analyzer. The protein level of BCR-ABL and signaling molecules was detected by western blotting, and the mRNA level of BCR-ABL was determined by RT-PCR. RESULTS: BFA inhibited cell proliferation, induced G2/M cell cycle arrest, and stimulated cell apoptosis in K562 cells. Importantly, for the first time, we revealed that BFA inhibited the activation of BCR-ABL and consequently inhibited the activation of its downstream signaling molecules in K562 cells. Moreover, we found BFA degraded BCR-ABL without affecting its transcription in K562 cells, and BFA-induced BCR-ABL degradation was related to caspase activation, while not to autophagy or ubiquitinated proteasome degradation pathway. CONCLUSION: Our present results indicate that BFA acts as a dual functional inhibitor and degrader of BCR-ABL, and BFA is a potential compound for chemotherapeutics to overcome CML.

Transcriptomic analyses reveal antiinflammatory mechanism of withanolides derived from the fruits of Physalis alkekengi L. var. franchetii.

In China, the fruits of Physalis alkekengi L. var. franchetii, which are conventionally utilized as edible berry, have attracted wide attention due to its significant biological activities. In the present study, phytochemical studies on the fruits of Physalis plants afforded six compounds, including two new withanolides (1-2) and four known agnologues (3-6). The inhibitory effects of these compounds on the formation of nitric oxide (NO) stimulated by lipopolysaccharide (LPS) in RAW264.7 macrophages were evaluated. Physapubescin M (1), with IC50 value of 1.58 µM, was selected for further study. The protein expression of COX-2 and iNOS, and LPS-induced production of cytokines (IL-6, IL-1ß and TNF-α) were reduced by physapubescin M (1) in a dose-dependent way. In addition, transcriptomic analyses were conducted to profile gene expression alterations in LPS-induced RAW264.7 cells upon treatment of physapubescin M (1) and the potential antiinflammatory mechanism of withnolides was mentioned. These results provide broad view to the underlying antiinflammatory mechanism of withnolides, and give a theoretical basis for the utilization of the fruits of P. alkekengi L. var. franchetii.

Antifeedant and antiphytopathogenic metabolites from co-culture of endophyte Irpex lacteus, phytopathogen Nigrospora oryzae, and entomopathogen Beauveria bassiana.

Five new tremulane sesquiterpenoids were isolated from co-culture of endophyte Irpex lacteus, phytopathogen Nigrospora oryzae, and entomopathogen Beauveria bassiana. All compounds showed obvious antifeedant activities against silkworm with inhibition percentages of 73-99%, at concentrations of 50 µg/cm2. Compound 11 indicated notable antifeedant activity with inhibition percentage of 93% at concentration of 6.25 µg/cm2 among them. Compounds 2, 3, 4, 8, 9, 15 and 16 indicated anti-fungal activities against I. lacteus with MIC values ≤8 µg/mL, compounds 11, 12, 16-18 showed significant anti-fungal activity against N. oryzae with MICs ≤ 4 µg/mL, and compounds 2, 5, 12 and 18 indicated significant anti-fungal activity against B. bassiana with MICs ≤ 8 µg/mL. In addition, the I. lacteus should unite B. bassiana to inhibit the production of phytotoxins from N. oryzae in the ternary culture.

New lathyrane diterpenoids with anti-inflammatory activity isolated from the roots of Jatropha curcas L.

ETHNOPHARMACOLOGICAL RELEVANCE: Jatropha curcas L. (Euphorbiaceae), as a drought resistant shrub mainly cultivated in tropical and subtropical areas worldwide, is widely used as traditional medicine to cure arthritis, dysentery, abscess and pneumonia in Asian, African and South American folklores. The methanolic extracts of the roots have been revealed the anti-inflammatory activity in vivo and vitro. AIM OF STUDY: This research aimed to provide promising anti-inflammatory candidates from the roots of J. curcas. In addition, RNA-Seq was conducted to give targeted genes involved in the anti-inflammatory action. MATERIALS AND METHODS: The diterpenoids were isolated from the CH2Cl2 fraction of the methanolic extract from the roots of J. curcas by column chromatography (CC): silica gel, Sephadex LH-20, ODS, semi-preparative reversed-phase high-performance liquid chromatography (HPLC). The structures were identified based on HR-ESI-MS and 1D, 2D-NMR spectroscopic analysis. Their anti-inflammatory effects were tested on lipopolysaccharide (LPS, 500 ng/mL)-stimulated murine RAW264.7 macrophages. Furthermore, we conducted transcriptome-wide RNA sequencing to profile gene expression alterations in LPS-induced RAW264.7 cells upon treatment with jatrocurcasenone I (4) and analyzed the underlying genes targeted by this compound. RESULTS: Six diterpenoids were obtained from J. curcas, and four of them were identified to be new lathyrane diterpenoids: jatrocurcasenones F-I (1-4). Compounds 3 and 4 exhibited potent inhibitory activities against LPS-induced nitric oxide (NO) production in RAW264.7 cells with IC50 values of 11.28 µM and 7.71 µM, respectively. Western blotting analysis showed that the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were suppressed with the supplementation of 3 and 4. The results of RNA-seq showed that 4 (20 µM) exhibited regulation on the 587 differentially expressed genes (DEGs) induced by LPS (500 ng/mL). Transcriptome-wide RNA sequencing indicated that the protective activity of 4 supplementation was most likely driven by modulating expression levels of IL-1α, IL-1ß, IL-1f6, IL-6, IL-1rn, IL-27, Ccl2, Ccl5, Ccl7, Ccl9, Ccl22, Cxcl10, Tnfsf12, Tnfsf15, Lta, Trim25, Bcl2a1a, Dusp1, Dusp2, Ptgs2, Edn1 and Nr4a1. CONCLUSIONS: This study offered four new lathyrane diterpenoids, of them, jatrocurcasenone I (4) showed significant anti-inflammatory activity. RNA-Seq suggested that jatrocurcasenone I (4) could be a candidate drug for the prevention inflammation-mediated diseases by modulating 24 candidate DEGs.

Paraverrucsins A-F, Antifeedant, and Antiphytopathogenic Polyketides from Rhizospheric Paraphaeosphaeria verruculosa and Induced Bioactivity Enhancement by Coculturing with Host Plant Dendrobium officinale.

Six new polyketides named paraverrucsins A-F (1-6) with oxabicyclic and dioxatricyclic skeletons, together with eight known metabolites (7-14), were discovered and isolated from the fermentation medium of Paraphaeosphaeria verruculosa. Paraverrucsin A-C possessed a novel decarboxylated skeleton compared with that of trichocladinols. Their structures were elucidated by extensive spectral analysis and DP4+ calculations. Paraverrucsins B/C and D/E were isolated as a mixture for the mutarotation occurred at C-2. Paraverrucsins B/C, D/E, F/trichocladinol B, 8, and 9 displayed antifeedant activities against silkworm larvae, with antifeedant index percentages ranging from 62.5 to 93.0%, at a concentration of 50 µg/cm2. Among them, Paraverrucsins B/C and 9 had EC50 values at 13.9 and 18.2 µg/cm2. Most compounds showed antifungal activities against phytopathogenic fungi with minimum inhibitory concentration (MIC) values of 16-64 µg/mL. Coculture of P. verruculosa and host plant Dendrobium officinale leads to the enhancement of antifeedant and antiphytopathogenic activities. Compounds 1, 2/3, 4/5, 6/14 were tested for cytotoxicity against five human carcinoma cell lines, HL-60, A549, MCF-7, SW480, and SMMC-7721, while they exhibited selected cytotoxicity against SW480 with inhibition ratios of 32-38% at a concentration of 40 µM.

Elevated plasma D-dimer levels are associated with short-term poor outcome in patients with acute ischemic stroke: a prospective, observational study.

BACKGROUND: Elevated levels of plasma D-dimer increase the risk of ischemic stroke, stroke severity, and the progression of stroke status, but the association between plasma D-dimer level and functional outcome is unclear. The aim of this study is to investigate whether plasma D-dimer level is a determinant of short-term poor functional outcome in patients with acute ischemic stroke (AIS). METHODS: This prospective study included 877 Chinese patients with AIS admitted to Renmin Hospital of Wuhan University within 72 h of symptom onset. Patients were categorized by plasma D-dimer level: Quartile 1(≤0.24 mg/L), Quartile 2 (0.25-0.56 mg/L), Quartile 3 (0.57-1.78 mg/L), and Quartile 4 (> 1.78 mg/L). The medical record of each patient was reviewed, and demographic, clinical, laboratory and neuroimaging information was abstracted. Functional outcome at 90 days was assessed with the modified Rankin Scale. RESULTS: Poor outcome was present in 302 (34.4%) of the 877 patients that were included in the study (mean age, 64 years; male, 68.5%). After adjustment for potential confounding variables, higher plasma D-dimer level on admission was associated with poor outcome (adjusted odds ratio 2.257, 95% confidence interval 1.349-3.777 for Q4:Q1; P trend = 0.004). According to receiver operating characteristic (ROC) analysis, the best discriminating factor for poor outcome was a plasma D-dimer level ≥ 0.315 mg/L (area under the ROC curve 0.657; sensitivity 83.8%; specificity 41.4%). CONCLUSION: Elevated plasma D-dimer levels on admission are significantly associated with poor outcome after admission for AIS, suggesting the potential role of plasma D-dimer level as a predictive marker for short-term poor outcome in patients with AIS.

Clinicopathological significance of human leukocyte antigen F-associated transcript 10 expression in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract. The worldwide mortality rate of CRC is about one half of its morbidity. Ubiquitin is a key regulatory factor in the cell cycle and widely exists in eukaryotes. Human leukocyte antigen F-associated transcript 10 (FAT10), known as diubiquitin, is an 18 kDa protein with 29% and 36% homology with the N and C termini of ubiquitin. The function of FAT10 has not been fully elucidated, and some studies have shown that it plays an important role in various cell processes. AIM: To examine FAT10 expression and to analyze the relationship between FAT10 expression and the clinicopathological parameters of CRC. METHODS: FAT10 expression in 61 cases of CRC and para-cancer colorectal tissues was measured by immunohistochemistry and Western blotting. The relationship between FAT10 expression and clinicopathological parameters of CRC was statistically analyzed. RESULTS: Immunohistochemical analysis showed that the positive rate of FAT10 expression in CRC (63.93%) was significantly higher than that in tumor-adjacent tissues (9.84%, P < 0.05) and normal colorectal mucosal tissue (1.64%, P < 0.05). Western blotting also indicated that FAT10 expression was significantly higher in CRC than in tumor-adjacent tissue (P < 0.05). FAT10 expression was closely associated with clinical stage and lymphatic spread of CRC. FAT10 expression also positively correlated with p53 expression. CONCLUSION: FAT10 expression is highly upregulated in CRC. FAT10 expression is closely associated with clinical stage and lymphatic spread of CRC.

Dimericursones A and B: two unprecedented hexacyclic dimeric diterpenoids from the root barks of Jatropha curcas.

Dimericursones A and B (1 and 2), two unprecedented hexacyclic dimeric diterpenoids, were obtained from the root barks of Jatropha curcas. Their structures were elucidated by extensive spectroscopic analysis, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Dimericursone B (2) showed significant inhibition on nitric oxide production of lipopolysaccharide-induced RAW264.7 macrophages with IC50 values of 5.65 µM.

Two new farnesyl phenolic compounds with anti-inflammatory activities from Ganoderma duripora.

Ganoderma fungi have long been used as a famous traditional medicine and food in country of East Asia. In this work, two new farnesyl phenolic compounds, ganoduriporols A and B (1 and 2), were isolated from the fruiting bodies of Ganoderma duripora, and their structures were elucidated using various spectroscopic methods. Anti-inflammatory activities were assayed and evaluated for the two compounds. Ganoduriporols A and B exhibited dose-dependent anti-inflammatory effects in RAW 264.7 cells. Furthermore, ganoduriporol A was demonstrated to inhibit the production of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and prostaglandin E2 (PGE2) through the suppression of COX-2, MAPK and NF-κB signaling pathway in LPS-induced macrophage cells. These results suggested that these two new farnesyl phenolic compounds and the fruiting body of G. duripora could serve as anti-inflammatory agents for medicinal use or functional food.

Three new withanolides from the calyces of Nicandra physaloides.

Chemical investigation on ethyl acetate extract of the calyces of Nicandra physaloides resulted in the isolation of three new withanolides named as nicphysatone A (1), nicphysatone B (2), nicphysatone C (3), together with five known withanolides, nic 17 (4), nic 7 (5), nic 2 (6), withahisolide G (7) and nicaphysalin B (8). The structures were determined by comprehensive spectroscopic experiments. The discovery enriched the diversity of natural withanolides and could serve as scaffolds for the synthesis of more potent modified withanolides.

Anti-atherosclerotic effect of hesperidin in LDLr-/- mice and its possible mechanism.

Hesperidin, a citrus bioflavonoid, exerts numerous pharmacological activities. However, its protective effect against atherosclerosis in vivo remains poorly understood. In the present study, we aimed to observe the effects of hesperidin on high fat diet (HFD)-induced atherosclerosis using LDL receptor deficient (LDLr-/-) mice. After 12 weeks of treatment, the animals were sacrificed. The blood samples were collected for further analysis. Mouse peritoneal macrophages were collected. Hepatic lipid content, quantification of atherosclerosis, assessment of oxidative stress and inflammation, gene expressions were performed on liver and aorta samples. The data showed that hesperidin ameliorated HFD-induced weight gain, improved insulin resistance and ameliorated hyperlipidemia. Hesperidin suppressed HFD-induced hepatic steatosis, atherosclerotic plaque area and macrophage foam cell formation. Further study showed that hesperidin down-regulated expressions of acetyl coenzyme A carboxylase alpha (ACCα) and fatty acid synthase (FAS) which are two key enzymes in fatty acid and triglyceride synthesis in liver; and upregulated expression of hepatic ATP-binding cassette transporters G8 (ABCG8), macrophage ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) which are transporters involved in the process of reverse cholesterol transport. Hesperidin also reduced oxidative stress by normalizing activities of antioxidant enzymes and inflammation in HFD-fed LDLr-/- mice. These findings suggest that hesperidin reduced atherosclerosis via its pleiotropic effects, including improvement of insulin resistance, amelioration of lipid profiles, inhibition of macrophage foam cell formation, anti-oxidative effect and anti-inflammatory action.

Preparation, Structure, and Potent Antifouling Activity of Sclerotioramine Derivatives.

A series of 30 sclerotioramine derivatives (2-31) of the natural compound, (+)-sclerotiorin (1), has been successfully semi-synthesized by a one-step reaction with high yields (up to 80%). The structures of these new derivatives were established by extensive spectroscopic methods and single-crystal X-ray diffraction analysis for 3, 6, and 10. (+)-Sclerotiorin (1) and its semisynthetic derivatives (2-31) were evaluated for their antifouling activity. Most of them except 6, 7, 8, 12, and 28 showed potent antifouling activity against the larval settlement of the barnacle Balanus amphitrite. More interestingly, most of the aromatic amino-derivatives (13-17, 19-21, 23, 25-27, and 29-31) showed strong antifouling activity; however, only two aliphatic amino-derivatives (5 and 10) had the activity.