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In the present study, we successfully assembled a high-quality genome of Planiliza haematocheila (redlip mullet) based on Oxford Nanopore long read, single-tube long fragment read (stLFR), and Hi-C chromatin interaction sequencing. The size of the P. haematocheila genome was 652.91 Mb. More than 93.8% of BUSCO genes were detected, and the N50 lengths of contigs and scaffolds reached 7.21 Mb and 28.01 Mb, respectively, thus demonstrating outstanding genome completeness and sequence continuity. A total of 21 045 protein-coding genes were predicted in the assembled genome, and 99.77% of those genes were functionally annotated. Comparative genomic and phylogenetic analyses revealed the adaptability of P. haematocheila to complex living environments at the genomic level, highlighting its broad adaptability and resistance to multiple stresses as an important economic fish. The high-quality reference chromosome-level genome of P. haematocheila provides a powerful genomic resource for further systematic study of Mugilidae.

A thiazole-containing cyclic depsipeptide with 11 amino acid residues, named pagoamide A (1), was isolated from laboratory cultures of a marine Chlorophyte, Derbesia sp. This green algal sample was collected from America Samoa, and pagoamide A was isolated using guidance by MS/MS-based molecular networking. Cultures were grown in a light- and temperature-controlled environment and harvested after several months of growth. The planar structure of pagoamide A (1) was characterized by detailed 1D and 2D NMR experiments along with MS and UV analysis. The absolute configurations of its amino acid residues were determined by advanced Marfey’s analysis following chemical hydrolysis and hydrazinolysis reactions. Two of the residues in pagoamide A (1), phenylalanine and serine, each occurred twice in the molecule, once in the d- and once in the l-configuration. The biosynthetic origin of pagoamide A (1) was considered in light of other natural products investigations with coenocytic green algae.

Two new 1,3-benzodioxole derivatives, leucandioxoles A and B (1–2), together with two known related compounds (3–4), have been isolated from the South China Sea sponge Leucandra sp. The structures ...

The Arctic fungus Eutypella sp. D-1, previously found to produce a variety of cytotoxic cyclopropyl-fused and cyclobutyl-fused pimarane diterpenoids when grown in the defined medium, was induced to produce unusual metabolites by growing on solid rice medium. A chemical investigation on the rice medium extract led to the isolation of four new meroterpenoids, eutypellacytosporins A-D (1-4), along with the known biogenetically related compound cytosporin D (5). The structures of the new compounds were elucidated by their detailed spectroscopic analysis and modified Mosher's method. Compounds 1-4 may be formed by the 12,32-ester linkage of two moieties, cytosporin D (5) and decipienolide A or B. All isolated compounds, except 5, showed weak cytotoxicity against DU145, SW1990, Huh7, and PANC-1 cell lines with IC50 values ranging from 4.9 to 17.1 μM.

Background the incidence of distant metastases is over 30% in advanced non-small cell lung cancer (NSCLC) patients. In particular, bone is reported as the most common site of distant metastasis NSCLC. Bone metastases (BM) have a consequence of serious skeletal-related events (SREs) leading to the reduced overall survival (OS) and quality of life of NSCLC patients. Inhibition of osteolytic lesions and regulation crosstalk between metastatic NSCLC cells and bone microenvironment are the key to treating NSCLC. Due to the lack of effective treatments against NSCLC with bone metastasis, screening and identification of novel agents against both NSCLC and osteoclast effects are critically needed. Methods We assessed the effects of Aspernolide A (AA) on osteolysis and RANKL-induced pathways activation, bone resorption and F-actin ring formation in vitro. We evaluated AA effects on NCI-H460 and A549 cells in vitro through wound healing assay and transwell assay. Furthermore, we assessed the effects of AA in vivo using an intratibial xenograft NSCLC nude mouse model, followed by micro-computed tomography(micro-CT) and TRAcP staining. Results in our study, AA, a soft coral-derived agent, was shown to inhibit osteoclastogenesis via suppression of nuclear factor (NF)-κBp65, ERK, AKT and P38 phosphorylation, and then suppress the RANKL-induced c-Fos and NFATc1 activities in bone marrow macrophages (BMMs). Furthermore, AA reduced the migration and invasion of NSCLC cells through diminishing the expression of MMP9, MMP7, and N-cadherin proteins and upregulating E-cadherin expression in vitro, as well as inhibited the phosphorylation of ERK, AKT, P38, and NF-κBp65. It was also demonstrated that administration of AA could help prevent NSCLC-induced bone destruction by attenuating NSCLC development and osteoclast activity in vivo. Conclusions collectively, these findings indicated that Aspernolide A is a potential candidate for NSCLC-induced osteolytic bone destruction.

Nine new linear lipopeptides, microcolins E-M (1-9), together with four known related compounds, microcolins A-D (10-13), were isolated from the marine cyanobacterium Moorea producens using bioassay-guided and LC-MS/MS molecular networking approaches. Catalytic hydrogenation of microcolins A-D (10-13) yielded two known compounds, 3,4-dihydromicrocolins A and B (14, 15), and two new derivatives, 3,4-dihydromicrocolins C and D (16, 17), respectively. The structures of these new compounds were determined by a combination of spectroscopic and advanced Marfey's analysis. Structurally unusual amino acid units, 4-methyl-2-(methylamino)pent-3-enoic (Mpe) acid and 2-amino-4-methylhexanoic acid (N-Me-homoisoleucine), in compounds 1-3 and 8, respectively, are rare residues in naturally occurring peptides. These metabolites showed significant cytotoxic activity against H-460 human lung cancer cells with IC50 values ranging from 6 nM to 5.0 μM. The variations in structure and attendant biological activities provided fresh insights concerning structure-activity relationships for the microcolin class of lipopeptides.

Three new sesquiterpene quinones/hydroquinones, 20-demethoxy-20-isopentylaminodactyloquinone D (1), 20-demethoxy-20-isobutylaminodactyloquinone D (2), and 19-methoxy-dictyoceratin-A (3), and five k...

Two new polyketides, palitantins B and C (1 and 2), along with one known related compound (+)-palitantin (3) were obtained from the culture of the Antarctic fungus Geomyces sp. 3-1. The structures of the new compounds were elucidated by detailed analysis of HRESIMS, NMR, CD, and ECD data. Compound 3 showed potent PTP1B inhibitory activity with an IC50 value of 7.9 ��M (ursolic acid as positive control, IC50 = 8.3 ��M).

Echinococcosis is an important parasitic disease that threats human health and animal husbandry worldwide. However, the low cure rate of clinical drugs for this disease is a challenge. Hence, novel compounds and specific drug targets are urgently needed. In this study, we identified drug targets of amino alcohols with effects on Echinococcus species. The drug targets were predicted with the idTarget web server. Corresponding three-dimensional structures of the drug targets were built after sequence BLAST analysis and homology modeling. After further screening by molecular docking, the activities of the candidate targets were validated in vitro. We ultimately identified glycogen phosphorylase as a potential drug target for amino alcohols. There are two genes coding glycogen phosphorylase in Echinococcus granulosus (EgGp1 and EgGp2). EgGp1 was abundant in E. granulosus PSCs, while EgGp2 was abundant in the cysts. These proteins were located at suckers and somas of E. granulosus PSCs and near the rostellum of cysts developed from PSCs. The effective compounds docked into a pocket consisting of E124, K543 and K654 and affected (either inhibited or enhanced) the activity of E. granulosus glycogen phosphorylase. In this study, we designed a method to predict drug targets for echinococcosis treatment based on inverse docking. The candidate targets found by this method can contribute not only to understanding of the modes of action of amino alcohols but also to modeling-aided drug design based on targets.

Alveolar echinococcosis, caused by the larval (metacestode) stage of the tapeworm Echinococcus multilocularis, is a lethal parasitosis of the liver prevalent in the Northern Hemisphere. For chemotherapy the benzimidazole derivatives mebendazole and albendazole were introduced, which were found to disrupt the microtubules by inhibition of the polymerization of tubulin into microtubules, and β-tubulin was determined to be the drug target molecule. In the present study, we evaluated the chemosensitivity of E. multilocularis protoscoleces tubulin to mebendazole and RNA interference in vitro, and to explore whether the molecular level and ultrastructure of E. multilocularis protoscoleces microtubules change post-mebendazole and RNA interference. We identified that mebendazole is parasitostatic to E. multilocularis protoscoleces through suppression the tubulin expression and change the flame cell morphology in molecular level, besides RNA interference indicated that β 2 tubulin is probably one of the vital tubulin gene to form the flame cell and the protonephridial system tubules (collective tubes) of E. multilocularis protoscoleces. Molecular level and ultrastructure detection were performed by reverse transcription-PCR, western blotting and transmission electron microscope. The RNA interference would be probably as a parasitocidal method to disrupt the survival of PSCs, extend that the relevant tubulin maybe as potential target for drug development against AE.

High quality genome is of great significance for the mining of biological information resources of species. Up to now, the genomic information of several important economic flatfishes has been well explained. All these fishes are eyes on left side-type, and no high-quality genome of eyes on right side-type species has been reported. In this study, we applied a combined strategy involving stLFR and Hi-C technologies to generate sequencing data for constructing the chromosomal genome of Verasper variegates, which belongs to Pleuronectidae with characteristic of eyes on right side. The size of genome of V. variegatus is 556 Mb. More than 97.2% of BUSCO genes were detected, and N50 lengths of the contigs and scaffolds reached 79.8 Kb and 23.8 Mb, respectively, demonstrating the outstanding completeness and sequence continuity of the genome. A total of 22,199 protein-coding genes were predicted in the assembled genome, and more than 95% of those genes could be functionally annotated. Meanwhile, the genomic collinearity, gene family and phylogenetic analyses of similar species in Pleuronectiformes were also investigated and portrayed for metamorphosis and benthic adaptation. Sex related genes mapping has also been achieved at the chromosome level. This study is the first chromosomal level genome of a Pleuronectidae fish (V. variegatus). The chromosomal genome assembly constructed in this work will not only be valuable for conservation and aquaculture studies of the V. variegatus but will also be of general interest in the phylogenetic and taxonomic studies of Pleuronectiformes.

Two new quinoline alkaloids, aaptolines A and B, were isolated from the marine sponge Aaptos aaptos. Their structures were determined by HR-ESI-MS data, NMR analysis, and X-ray crystallography. Structurally, aaptoline A is characterized as having a quinoline skeleton fused with a 1,4-dioxane motif at the C(7)-C(8) position, whereas aaptoline B possessed an intriguing 1H-pyrrolo[2,3-g]quinoline moiety. The cytotoxic assay of these compounds showed no cytotoxicity towards HepG2, A549, and PC9 cancer cell lines and had IC50 values greater than 20 μm.

Echinococcosis is a serious helminthic zoonosis with a great impact on human health and livestock husbandry. However, the clinically used drugs (benzimidazoles) have a low cure rate, so alternative drugs are urgently needed. Currently, drug screenings for echinococcosis are mainly phenotype-based, and the efficiency of identifying active compounds is very low. With a pharmacophore model generated from the structures of active amino alcohols, we performed a virtual screening to discover novel compounds with anti-echinococcal activity. Sixty-two compounds from the virtual screening were tested on Echinococcus multilocularis protoscoleces, and 10 of these compounds were found to be active. After further evaluation of their cytotoxicity, S6 was selected along with two active amino alcohols for in vivo pharmacodynamic and pharmacokinetic studies. At the two tested doses (50 and 25 mg/kg), S6 inhibited the growth of E. multilocularis in mice (14.43 and 9.53%), but no significant difference between the treatment groups and control group was observed. Treatment with BTB4 and HT3 was shown to be ineffective. During the 28 days of treatment, the death of mice in the mebendazole, HT3, and BTB4 groups indicated their toxicity. The plasma concentration of S6 administered by both methods was very low, with the Cmax being only 1 ng/ml after oral administration and below the detection limit after intramuscular administration. In addition, the plasma concentrations of BTB4 and HT3 in vitro did not reach high enough levels to kill the parasites. The toxicities of these two amino alcohols indicated that they are not suitable for further development as anti-echinococcal drugs. However, further attempts should be made to increase the bioavailability of S6 and modify its structure. In this study, we demonstrate that pharmacophore-based virtual screenings with high drug identification efficiency could be used to find novel drugs for treating echinococcosis.

As a zoonotic parasitosis caused by the parasitism of Echinococcus larvae, echinococcosis imposes serious disease and economic burdens on human beings and society, and is thus a global public health issue. Its complex life history, wide distribution, the combined influence of various epidemic factors, coupled with the unique natural environment, customs, and religious beliefs in endemic areas, pose a huge challenge to the national echinococcosis control programme in China. Accurate early detection and confirmation of diagnosis of echinococcosis, the use of effective drugs, real-time surveillance of the infection status of populations and various hosts, controlling the source of infection, and blocking the route of transmission are of enormous significance for control. In this paper, the work by NIPD-CTDR on the prevention and control of echinococcosis in China is reviewed, with a view to providing reference for the further promotion of the national echinococcosis control programme.

Cystic echinococcosis is a globally distributed zoonotic disease, which is caused by the larval stage of Echinococcosus granulosus sensu lato. The chemotherapy of the disease is limited to the use of benzimidazoles. Recently, mefloquine and its analogues, aminoalcohol-carbazole, and some amino alcohol derivatives were reported to display inhibitory effects on parasites. Here, the activities of 130 amino alcohol compounds against E. granulosus were tested on protoscoleces and germinal cells at a concentration of 20 μg/ml over a period of three days. As a result, sixteen compounds totally were effective against both protoscoleces and germinal cells, and their IC50 and LC50 were also calculated respectively. Then effects of the most active compounds were observed on metacestodes over 14 days in vitro. Although the structure of active compounds were variable, hydroxyl and amino groups connected by two carbon atoms are held in common as the key feature of these compounds. The further investigation on metacestodes incubated with these active compounds revealed that the effects of JF16 and BTB4 were comparable to that of mefloquine and mebendazole. In addition, the ultrastructure alternations induced by these compounds on E. granulosus were confirmed by scanning electron microscopy and transmission electron microscopy observations. In conclusion, amino alcohols were a class of compounds with efficacy against E. granulosus. The most effective compounds JF16 and BTB4 indicated that their basic structure would be useful in the synthesis of new compound for the treatment of echinococcosis. However, their in vivo efficacy and toxicity need to be carefully evaluated in the future.

RNA modifications, as one of epigenetic mechanisms, are important and conserved mechanisms for maintaining the homeostasis of organisms. Little is known about RNA modifications in Echinococcus granulosus, an obligate parasite that inhabits mammals and gives rise to a huge public health and economic impact. Here, we focused on the RNA modification characteristics of E. granulosus for the first time by using mass spectrometry (UPLC-MS/MS) to qualitatively and quantitatively analyze 47 types of RNA modifications in E. granulosus total RNA. Furthermore, the E. granulosus homologs of writer enzymes preforming RNA modifications were identified, and their gene expression pattern at different developmental stages were analyzed by bioinformatics analysis. Finally, 23 types of RNA modifications were found in E. granulosus cysts total RNA, of which m1A, Ψ and m5C are the most abundant. The homologs of writer enzymes involved in these modifications were identified in the E. granulosus genome, with the dynamic gene expression during the different parasitic developmental stages. This work confirms that E. granulosus retains the conserved RNA modification mechanism during evolution, suggesting the important role of RNA modification in regulating its development and parasitic process. Moreover, the differences of amino acid sequences of RNA modification writer enzymes between parasite and host make it possible to use these enzymes as the candidate drug targets in the follow-up in-depth researches.

Eleganstone A (1), a rare diterpene possessing a 5/6/4/5 fused tetracyclic ring skeleton, along with its probable biogenetic precursor (2), one new dolabellane diterpene (3), and one known dolabellane diterpene (4), have been isolated from the marine sponge Dactylospongia elegans. As a pair of Z/E isomers, 2 can convert into 4 by the light-induced isomerization. Structure elucidations of all compounds were performed by spectroscopic analysis, ECD calculations, and comparison with the literature. These compounds were tested for their antibacterial and cytotoxic activities. Compounds 1–4 exhibited weak antibacterial activity against Escherichisa coli, Bacillus subtilis, and Staphylococcus aureus with MIC values of 32–64 μg/mL.

Six new bromopyrrole alkaloids, longamides D–F ( 1 – 3 ), 3-oxethyl-4-[1-(4,5-dibromopyrrole-2-yl)-formamido]-butanoic acid methyl ester ( 4 ), 2-oxethyl-3-[1-(4,5-dibromopyrrole-2-yl)-formamido]-methyl propionate ( 5 ), and 9-oxethyl-mukanadin F ( 6 ), along with two known metabolites, hanishin ( 7 ) and longamide B methyl ester ( 8 ), were isolated from the South China Sea sponge Agelas sp. The racemic mixtures 1 – 5 , 7 and 8 were resolved into seven pairs of enantiomers 1a/1b – 5a/5b , 7a/7b , and 8a/8b through HPLC using a Chiralcel OJ-RH column. The structures were elucidated on the basis of spectroscopic data. The absolute configurations of each enantiomer of (±)- 1 and (±)- 2 were established through the quantum mechanical calculations of the corresponding electronic circular dichroism (ECD) spectra and using the CD exciton chirality method, respectively, whereas the absolute configurations of 3a and 3b were confirmed by comparing the experimental CD spectra with that of (−)- S -longamide B methyl ester. Individual enantiomers (+)-(9 S , 10 R )- 1a , (−)- S - 2b , (+)- R - 3a , (+)- R - 7a , and (+)- R - 8a exhibited effective antifungal activity against Candida albicans in a Caenorhabditis elegans candidiasis model.

Four new norterpene cyclic peroxides (1-4), together with three known norterpene cyclic peroxides were isolated from the Xisha Islands Sponge Diacarnus megaspinorhabdosa. Their structures were elucidated on the basis of spectroscopic analyses and comparison with the related model compounds. The compounds (1-7) were evaluated for the inhibitory activity against the malaria parasite Plasmodium falciparum, all of them showed significant antimalarial activity with IC50 values in the range of 1.6-8.6 μM.

Chemical investigation on a marine sponge, Dactylospongia elegans, yielded five new &gamma, oxygenated butenolide sesterterpene derivatives, dactylospenes A&ndash, E (1&ndash, 5), as well as two known biosynthetically related compounds, luffariellolide (6) and furospinosulin B (7). The structures of these compounds were elucidated on the basis of their spectroscopic data, experimental and calculated electronic circular dichroism (ECD) analysis, as well as comparison of the NMR data with those of known analogs. These metabolites are the first &gamma, oxygenated butenolide sesterterpenes to be reported from this genus. These compounds were evaluated in antimicrobial, anti-inflammatory, and cytotoxic assays. Only compounds 1, 3, and 6 exhibited moderate cytotoxicity against DU145, SW1990, Huh7, and PANC-1 cancer cell lines with IC50 values in the range of 2.11&ndash, 13.35 &mu, M. Furthermore, compound 2, without cytotoxicity, exhibited significant inhibitory effects (inhibitory rate 77.5%) on nitric oxide production induced by lipopolysaccharide at 10 &mu, M.

Echinococcosis, which causes a high disease burden and is of great public health significance, is caused by the larval stage of Echinococcus species. It has been suggested that tubulin is the target of benzimidazoles, the only drugs for the treatment of echinococcosis. This study evaluated the characteristics of tubulins from Echinococcus granulosus. The full-length cDNAs of E. granulosus α- and β-tubulin isoforms were cloned by reverse transcription PCR from protoscolex RNA. Then, these two tubulin isoforms (α9 and β4) were recombinantly expressed as insoluble inclusion bodies in Escherichia coli. Nickel affinity chromatography was used to purify and refold the contents of these inclusion bodies as active proteins. The polymerization of tubulins was monitored by UV spectrophotometry (A350) and confirmed by confocal microscopy and transmission electron microscopy (TEM). Nucleotide sequence analysis revealed that E. granulosus 1356 bp α9-tubulin and 1332 bp β4-tubulin encode corresponding proteins of 451 and 443 amino acids. The average yields of α9- and β4-tubulin were 2.0–3.0 mg/L and 3.5–5.0 mg/L of culture, respectively. Moreover, recombinant α9- and β4-tubulin were capable of polymerizing into microtubule-like structures under appropriate conditions in vitro. These recombinant tubulins could be helpful for screening anti-Echinococcus compounds targeting the tubulins of E. granulosus.

Three new pimarane diterpenes, eutypellenoids A–C (1–3), together with a known compound, eutypenoid C (4), were isolated from the culture extract of Eutypella sp. D-1 derived from the Arctic region. Compounds 1–3 possessed an uncommon tetrahydrofuran-fused pimarane diterpene skeleton. The structures of all compounds were determined by detailed spectroscopic analysis, electronic circular dichroism (ECD) analysis, as well as a comparison with the literature data. Antibacterial, antifungal, and cytotoxic activities of these compounds were evaluated. Compound 2 displayed antibacterial activity against Staphylococcus aureus and Escherichia coli with MIC values of 8 and 8 μg/mL, respectively. Additionally, compound 2 showed antifungal activity against Candida parapsilosis, Candida albicans, Candida glabrata, and Candida tropicalis with MIC values of 8, 8, 16, and 32 μg/mL, respectively. Furthermore, compound 2 exhibited moderate cytotoxic activity against HCT-116 cell line with IC50 value of 3.7 μM.

Seven new pimarane-type diterpene derivatives, libertellenones O–S (1–5) and eutypellenones A and B (6 and 7), together with two known compounds (8 and 9), were isolated from the culture of Eutypella sp. D-1 obtained from high-latitude soil of the Arctic. Their structures were elucidated from spectroscopic data, as well as experimental and calculated electronic circular dichroism (ECD) analysis. Structurally, compounds 1–5 possess a cyclopropyl-fused pimarane diterpene moiety, whereas compounds 6 and 7 share an unusual cyclobutyl-fused pimarane diterpene skeleton. Compounds 1–9 exhibited cytotoxicities against HeLa, MCF-7, HCT-116, PANC-1, and SW1990 cells, with IC50 values in the range of 0.3 to 29.4 μM. Compounds 6 and 7 could dose-dependently inhibit the activity of NF-κB and exhibited significantly inhibitory effects on nitric oxide production induced by lipopolysaccharide.

This study was conducted to investigate the efficacy of a new formulation of MBZ oily suspension (MBZ-OS) in experimentally Echinococcus multilocularis-infected mice. MBZ-OS was prepared and administered to mice infected with E. multilocularis at 12.5 and 25 mg/kg for 14 consecutive days. Then, the cysts were collected, weighed and histologically examined. The results showed that the reduction rate of cyst weight induced by MBZ-OS at two doses was 95.23% and 92.67%, which was significantly higher than that of MBZ-1% tragacanth (positive control) at corresponding concentrations (87.41% and 69.47%), indicating that the treatment of alveolar echinococcosis at lower doses could be achieved by the use of MBZ-OS. This finding shows that MBZ-OS is also a promising formulation for alveolar echinococcosis as well as cystic echinococcosis and deserves to be investigated in clinical applications against echinococcosis.

Benzimidazoles, including albendazole and mebendazole, are the major drugs for clinical chemotherapy of echinococcosis. They mainly exert parasitostatic effects depending on high dosages for long-term. Previous studies have identified carbazole aminoalcohols as novel anti-CE (cystic echinococcosis) agents. However, it is still to be confirmed whether it is effective on alveolar echinococcosis (AE) or not. In the present study, efficacies of novel carbazole aminoalcohols, propylamine, R-propylamine and S-propylamine were evaluated under in vitro and in vivo conditions. Carbazole aminoalcohols were tested against Echinococcus multilocularis (E. multilocularis) protoscoleces (PSC) in vitro. The effects of propylamine and R-propylamine exhibited a time-dependent manner at different concentrations, while the effect of S-propylamine was very poor. At a concentration of 20 μM, the mortality of PSC achieved to 100% on the 11th day after exposure to R-propylamine. The treatment of carbazole aminoalcohols to infected mice resulted in statistically significant reductions in the cyst weights compared with those obtained from negative control mice (p 0.05), and no significant differences were found between albendazole and carbazole aminoalcohols (p 0.05). The cytotoxicity examination in rat hepatoma (RH) cells indicated that propylamine and R/S-propylamine were lower that of albendazole at a low concentration (5 μM). In addition, histopathological observation of organs (liver, spleen and kidney) for experimental mice showed mild inflammatory changes in the liver and spleen. This study reveals the potential of carbazole aminoalcohols as a class of novel anti-AE agents.

Background Cystic echinococcosis is a global public health problem; however, the drugs (albendazole and mebendazole) currently recommended by WHO for its treatment, have limited efficacy. Therefore, novel drugs are required to provide more choices for the treatment of this disease. Methods The anthelmintic effects of ursolic acid (UA) were tested on Echinococcus granulosus protoscoleces, germinal cells and metacestodes in vitro. The in vivo efficacy of UA was investigated in mice following secondary infection with E. granulosus. Furthermore, the corresponding ultrastructural damage induced by UA was evaluated by electron microscopy. Results In vitro, 45.95 ± 5.30% of protoscoleces were killed by UA at 40 μg/ml, while the growth of more than 90% of germinal cells was inhibited by UA at 10 to 40 μg/ml. The same effect was observed in metacestodes 7 days after treatment with UA at 10, 20 and 40 μg/ml, and more than 50% of metacestodes showed loss of integrity at the end of the experiment. In vivo, metacestode weight was significantly reduced following oral administration of UA at 200 and 100 mg/kg (39.5 and 38.3%, respectively). Additionally, ultrastructural damage, such as alternations in germinal cell morphology and formation of vacuoles and lipid granules were observed in parasites treated with UA in vitro, while detachment of the germinal layer from the laminated layer was also seen in metacestodes in vivo. Conclusions UA was demonstrated to exert parasiticidal activity against E. granulosus in vitro and in vivo, thus implicating UA as a potential anti-echinococcosis agent.

Two new cyclohexanone derivatives, nectriatones A–B (1–2), and one new natural product, nectriatone C (3), together with three known phenolic sesquiterpene derivatives (4–6), were isolated from the culture of Nectria sp. B-13 obtained from high-latitude soil of the Arctic. The structures of all compounds were unambiguously elucidated by extensive spectroscopic analysis, as well as by comparison with the literature. These compounds were evaluated in cytotoxic and antibacterial activities. Compounds 1–6 showed cytotoxicities against SW1990, HCT-116, MCF-7, and K562 cells, with IC50 values in the range of 0.43 to 42.64 μM. Only compound 4 exhibited antibacterial activity against Escherichisa coli, Bacillus subtilis, and Staphylococcus aureus (MIC 4.0, 2.0, and 4.0 μg/ml, respectively).

A new furanone derivative, butanolide A (1), and a new sesquiterpene, guignarderemophilane F (2), together with six known compounds, were isolated from the fungus Penicillium sp. S-1-18 derived from Antarctic marine. The new structures were determined by spectroscopic studies such as 1D- and 2D-NMR and MS analyses. The absolute configuration of 1 was determined by the modified Mosher’s method, while the absolute configuration of 2 was determined by calculated ECD spectroscopy. The isolated secondary metabolites were evaluated for their protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. Compound 1 showed moderate inhibitory activity against PTP1B with IC50 value of 27.4 μM.

Introduction: Different results have been achieved in the evaluation of antiparasitic drug activity in Mongolian jirds, hamsters, and BALB/c mice infected with Babesia microti. The aims of the present study were to find a preferable method for drug screening and to re-evaluate the activity of several drugs against B. microti. Methodology: The activity of 19 drugs on B. microti-infected BALB/c mice was evaluated. The study was built on Peters' four-day suppressive test, and the pathogenicity of the blood from the treated mice was also used as indicator. Results: The results showed that 15 of the 19 drugs had little or no in vivo effect against B. microti. The inhibitory rates of atovaquone and azithromycin were high at all doses, but the microscopy-negative blood of recovered mice was still infectious. Similar to robenidine hydrochloride at 25 and 50 mg/kg, primaquine at 100 mg/kg had a 100% inhibitory rate. Robenidine hydrochloride achieved a 100% inhibitory rate at 100 mg/kg, and the blood of recovered mice did not result in parasitemia in subpassage experiments. Parasite-negative blood from mice treated with antimalarial drugs (clinically used for babesiosis) still caused parasitemia in subpassage experiments. This suggests that these drugs cannot eradicate the parasites. Conclusions: Peters' four-day suppressive test and the pathogenicity of the blood from the treated mice are suitable methods for preliminary investigating possible drugs against B. microti. Considering that robenidine hydrochloride achieved the best activity against B. microti in BALB/c mice in our study, further studies are needed.

Lygus pratensis distributes worldwide and is one of the common insect pests on cotton in Xinjiang Uygur Autonomous Region, the largest cotton growing region of China. This study assessed the effects of six constant temperatures (10, 15, 20, 25, 30 and 35 °C) at 60% relative humidity (RH) on egg and nymphal development of L. pratensis. Eggs failed to hatch and the newly-hatched nymphs could not normally develop at 10 °C. The developmental duration of egg and nymph decreased as temperature increased from 15 to 30 except 35 °C for egg. Based on the linear model, the lower developmental threshold and effective accumulated temperature were 10.68 °C and 150.2 DD for egg, and 12.08 °C and 208.3 DD for nymph, respectively. Among three non-linear models (Briere-1, Logan-6 and Lactin), Logan-6 provided the most accurate estimate for the mean optimum and lethal maximum temperatures (33.6 and 40.9 °C for egg, and 34.0 and 37.4 °C for nymphs). The interactive effects of three RH levels (45, 60 and 75%) and two temperatures (25 and 35 °C) on the immature developmental stages were tested. Temperature, RH and their interaction showed significant effects on egg and nymphal development. High relative humidity (75% RH) shortened the developmental duration of egg at 25 °C and nymph at 25 and 35 °C, whereas no significant difference was found for egg duration between different RH levels at 35 °C. The present study is useful for further predicting the phenology of L. pratensis and developing forecast and management strategies for this emerging mirid bug in China.

Echinococcus granulosus is a cestode parasite. The metacestode stage causes cystic echinococcosis (CE) mainly in the human liver and lung. Current chemotherapy against CE is based on mebendazole and albendazole. However, benzimidazoles result in a low cure rate or are ineffective in many patients; therefore, novel compounds for the treatment of this disease have been studied. Mefloquine was reported to be dramatically effective on cultured Echinococcus multilocularis metacestodes in vitro. And, nitazoxanide has a prominent protoscolicidal effect. However, these compounds have no impact on the growth of cysts harbored in mice. In this study, we investigated the in vitro and in vivo efficacy of mebendazole, mefloquine, and nitazoxanide against E. granulosus protoscoleces, germinal cells, and infected mice. The effect of mebendazole on protoscoleces and germinal cell was proved to be dose-dependent in vitro. And, a reduction of the cyst weight was also the found after oral application of mebendazole to infected mice. Mefloquine (5 and 10 μg/ml) caused death within 24 h of protoscoleces and germinal cells in vitro, whereas a lower concentration of 1 μg/ml was ineffective. In mice infected with E. granulosus, oral mefloquine (200 and 400 mg/kg twice weekly for 2 weeks) showed no reduction in parasite weight. Without affecting the viability of germinal cells and the growth of hydatid cysts, nitazoxanide only showed protoscolicidal effects in infected mice. In conclusion, mebendazole, mefloquine, and nitazoxanide showed various effects on E. granulosus under different conditions. These drugs could be useful to some extent in the treatment of CE.

Chemical investigation on CH2Cl2 extract of the marine sponge Diacarnus megaspinorhabdosa resulted in the isolation of two new farnesylacetone derivatives 1-2, a new γ-lactone 3, a known dinorditerpenone 4 and four known norsesterterpene peroxides 5-8. Their structures were elucidated by using one and two dimensional (1D and 2D)-NMR, high resolution-electrospray ionization (HR-ESI)-MS, and comparison with the literature. Compounds 1 and 2 were cis/trans-olefinic isomers and determined through nuclear Overhauser effect spectroscopy (NOESY) experiment. The absolute configuration of 3 was established by comparison of circular dichroism (CD) data with known lactones. The cytotoxic activities of the compounds were evaluated against five cancer cell lines, and compound 3 showed moderate cytotoxicity activities against cancer cell lines HeLa, H446, NCI-H460, SGC-7901 and MCF-7, with IC50 values in the range of 18.5 to 47.1 µM.

(±)-Quassidines I (1) and J (2), two pairs of new bis-β-carboline alkaloid enantiomers, were isolated from the stems of Picrasma quassioides. Their structures were determined by the analysis of spectroscopic data, including HRESIMS and 2D NMR, and confirmed by single-crystal X-ray diffraction analysis. The racemic mixtures of 1 and 2 were resolved into two pairs of enantiomers, (+)-S-1a and (-)-R-1b and (+)-S-2a and (-)-R-2b, by HPLC using a chiral Daicel IB-3 column, respectively, which represents the first successful example to resolve bis-β-carboline racemic mixtures. The absolute configurations of the two pairs of enantiomers were determined by comparison between the calculated and experimental ECD spectra. The cytotoxicity evaluation revealed that (+)-S-1a and (+)-S-2a showed more potent cytotoxicity against human cervical HeLa and gastric MKN-28 cancer cell lines with IC50 values of 4.03-6.30 μM than their enantiomers with IC50 values of 9.64-12.3 μM; however, the two (+)-S-quassidines showed similar activities to their enantiomers against the mouse melanoma B-16 cancer cell line.

An unusual meroterpenoid, dysidinoid A (1), was isolated from the South China Sea sponge Dysidea sp. Its structure was elucidated by extensive spectroscopic methods including HRESIMS and 2D NMR, and its absolute configuration was determined by single-crystal X-ray diffraction analysis. Dysidinoid A (1) is the first meroterpenoid from Nature bearing a 9,4-friedodrime skeleton and a 2,5-dionepyrrole unit. Dysidinoid A (1) showed potent antibacterial activity against two strains of pathogenic bacteria methicillin-resistant Staphylococcus aureus (MRSA) with MIC90 values of 8.0 μg/mL against both.

Background Echinococcosis is a serious, zoonotic, parasitic disease with worldwide distribution. According to a epidemiological survey in 2012 in China, there are 20,000 infected patients and more than 50 million people at the risk. As the dog is the main, definitive host, the Government of China encourages monthly praziquantel treatment of every dog. However, this is difficult to achieve in geographically challenging areas, such as the Tibetan plateau, where there are also many dogs without owners. To overcome these problems, we investigated the transmission blocking capacity of a slow-release formulation of praziquantel administered by subcutaneous injection. Methods The impact of a slow-release preparation of two pharmacokinetically stereoselective praziquantel enantiomers, i.e., R-(−)-praziquantel (R-PZQ) and S-(+)-praziquantel (S-PZQ) absorbed into a biodegradable polymer was studied in beagle dogs (N = 6). The preparation was given by subcutaneous injection using a single dose of 100 mg/kg. Chiral-selective, high-performance liquid chromatography (HPLC) and high-resolution mass spectrometry (HRMS) were applied to measure the praziquantel enantiomers in the plasma of the dogs. The lower limit for estimating plasma concentrations accurately for R-PZQ was 4 ng/ml and for S-PZQ 20 ng/ml. The pharmacokinetic parameters were calculated by a noncompartmental analysis model using Drug Analyze System (DAS) software 2.0. The SPSS 19.0 software was used for statistical analysis, and the statistical comparison between enantiomers was assessed using the two-tailed t-test. Results Two hours after administration, peak concentrations of R-PZQ and S-PZQ: 321 ± 26 and 719 ± 263 ng/ml, respectively, were achieved. After 180 days, the average plasma concentration of R-PZQ in the six dogs had decreased to 13 ng/ml. The average concentration value of S-PZQ was higher than that of R-PZQ in the first 90-day period but fell afterwards and could not be accurately estimated when dropping below 20 ng/ml (the lower methodological limit for this enantiomer). Taking all the dogs into account, the average maximum concentration (Cmax) of S-PZQ in plasma over the first 3 months was higher than that of R-PZQ by 114.0% (P

Nine new sesquiterpene quinones/hydroquinones (1–7, 10, and 12), three solvent-generated artifacts (8, 9, and 11), and three known compounds, 5-epi-smenospongine (13), smenospongine (14), and smenospongiadine (15), were isolated from the marine sponge Spongia pertusa Esper. The planar structures of the new compounds were elucidated on the basis of spectroscopic analyses. Their absolute configurations were determined by comparison between the calculated and experimental ECD spectra. In the cytotoxicity bioassay, compounds 13–15 exhibited activities against the human cancer cell lines U937, HeLa, and HepG2, with most potent cytotoxicities to U937 cells with IC50 values of 2.8, 1.5, and 0.6 μM, respectively. In addition, compound 6 displayed CDK-2 affinity with a Kd value of 4.8 μM in a surface plasmon resonance assay.

Hipposponlachnins A (1) and B (2), possessing an unprecedented tetracyclo [9.3.0.02,8.03,7] tetradecane ring system, and the probable biogenetic precursor [3, (1R*,2E,4R*,7E,10S*,11S*,12R*)-10, 18-diacetoxydolabella-2,7-dien-6-one] of 1‒2 were isolated from the South China Sea marine sponge Hippospongia lachne. The structures of the novel compounds were determined using integrated spectroscopic methods in combination with single-crystal X-ray diffraction analysis. Compounds 1‒2 showed potent inhibitory activity on the release of β-hexosaminidase, a biomarker for degranulation, as well as the production of pro-inflammatory cytokine IL-4 and lipid mediator LTB4 in DNP-IgE-stimulated RBL-2H3 cells.

We isolated and identified a new sesquiterpene lactone which we named eut-Guaiane sesquiterpene (1), along with four cytochalasins from the fungus Eutypella sp. derived from the soil of high latitude of Arctic. The new structure was determined by spectroscopic studies such as 1D and 2D NMR and MS analyses, while the known compounds were identified by comparison of the NMR data with those in literatures. New compound 1 exhibited strong antibacterial activity against Escherichia coli, Bacillus subtilis and Staphylococcus aureus. Besides, it showed a little cytotoxicity against SGC7901 cell line.

Trip-step infrared spectroscopy, Fourier transform infrared spectroscopy combined with second derivative infrared spectroscopy (SD-IR) and two-dimensional correlation infrared spectroscopy (2DCOS-IR), was employed to characterize and discriminate nine China sponges. Sponges from different classes and different orders had respective unique IR macro-fingerprints. Their IR spectra suggested that the prime ingredient of calcareous sponges was calcium carbonate in calcite and/or aragonite forms, but that of demosponges was protein. Particularly, the sponges from the same genus which could not be identified by traditional spicule identification have been definitely discriminated. For sponges having highly similar chemical profile (IR spectral profile), SD-IR and 2DCOS-IR have been applied to enhance the spectral resolution to distinguish the sponges convincingly.

Dysidaminones A–M (1–13), thirteen new sesquiterpene aminoquinones, along with six known ones (14–19), were isolated from the South China Sea sponge Dysidea fragilis. The new structures were determined by extensive spectroscopic analyses, the absolute configurations of 1 and 2 were determined by single-crystal X-ray diffraction analysis, and the absolute configurations of 3–13 were assigned by comparing their CD spectra with those of 1 and 2. Dysidaminones C (3), E (5), H (8), and J (10), 18-methylaminoavarone (14), and 18-aminoavarone (16) showed cytotoxicity against mouse B16F10 melanoma and human NCI-H929 myeloma, HepG2 hepatoma, and SK-OV-3 ovarian cancer cell lines. In addition, these six cytotoxic compounds also exhibited NF-κB inhibitory activity with IC50 values of 0.05–0.27 μM. Preliminary structure–activity relationship analysis indicated that 18-aminosubstituted sesquiterpene quinones with exocyclic double bond (Δ4,11) are cytotoxic agents and NF-κB inhibitors.

Fifteen polyketides, including the first hydroxylated plakortone (12) and plakdiepoxide (15), the first polyketide to embed a vicinal diepoxide, have been isolated from the Chinese sponge Plakortis simplex. The structures of the new metabolites were elucidated by analysis of spectroscopic data, Mosher’s derivatization, and DFT computational calculations. The reactivity of the major endoperoxide of this sponge was investigated, suggesting that furan, furanylidene, and plakilactone derivatives, well-known classes of natural products, could actually be chemical degradation products. Plakdiepoxide is a potent and selective modulator of peroxisome proliferator-activated receptor (PPAR)-γ, while the diunsaturated C12 fatty acid monotriajaponide (13) activates both PPAR-α and PPAR-γ, a dual activity of potential great importance for the treatment of metabolic disorders.

Three new polyketides, woodylides A-C (1-3), were isolated from the ethanol extract of the South China Sea sponge Plakortis simplex. The structures were elucidated by spectroscopic data (IR, 1D and 2D NMR, and HRESIMS). The absolute configurations at C-3 of 1 and 3 were determined by the modified Mosher's method. Antifungal, cytotoxic, and PTP1B inhibitory activities of these polyketides were evaluated. Compounds 1 and 3 showed antifungal activity against fungi Cryptococcus neoformans with IC₅₀ values of 3.67 and 10.85 µg/mL, respectively. In the cytotoxicity test, compound 1 exhibited a moderate effect against the HeLa cell line with an IC₅₀ value of 11.2 µg/mL, and compound 3 showed cytotoxic activity against the HCT-116 human colon tumor cell line and PTP1B inhibitory activity with IC₅₀ values of 9.4 and 4.7 µg/mL, respectively.

Three new aaptamine derivatives (1–3), together with six known related compounds (4–9), have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated on the basis of spectroscopic analyses. Compounds 1, 4, 5, 7, and 9 showed cytotoxic activities against HeLa, K562, MCF-7, and U937 cell lines with IC50 values in the range of 0.90–12.32 μM.

The aim of the present study was to assess the ultrastructural alterations of juvenile Schistosoma japonicum induced by mefloquine. Mice infected with 14-day-old S. japonicum were treated orally with mefloquine at a single dose of 400 mg/kg. Between 8 h and 7 days after treatment, groups of two mice were sacrificed, and schistosomula were recovered for transmission electron microscopic observations. Ultrastructural damage was seen in the tegument, subtegumental musculature, parenchymal tissues, and gut epithelial cell. It was already prominent 8 h after drug administration and increased in severity rapidly to reach a peak 3 days post-treatment. Tegumental alterations were characterized by emergence of irregular and elongated cytoplasmic processes, which further fused together accompanied by indistinction of matrix and roughness of external plasma membrane. Meanwhile, in the subtegument, damage to the syncytium, swelling, and lysis of muscle bundles and parenchymal tissues were universal, which further aggravated the lesion on the tegument, followed by collapse or disintegration of damaged tegument to form numerous fragment or debris of cytoplasmic process detached from the worm surface. Severe damage to the gut epithelial cell was also observed 8 h post-mefloquine treatment, which included focal lysis of cytoplasm accompanied by formation of vacuoles and degeneration of mitochondria, emergence of enlarged and contracted nucleus with indistinct or focal disrupted nuclear membrane, and decrease in microvilli. All these alterations further increased in severity and reached the peak 3 days post-treatment. The findings of our study indicate that mefloquine exhibits a fast and potent ability to cause extensive ultrastructural damage to juvenile S. japonicum, which correlates with its high efficacy against juvenile schistosomes.

Two novel polyketides, simplextones A (1) and B (2), were isolated from the sponge Plakortis simplex. Their structures were established by spectroscopic methods. The absolute configurations were assigned by modified Mosher's method, X-ray crystallographic analysis, and quantum mechanical calculation of the electronic circular dichroism (ECD) spectrum. Compounds 1 and 2 featured an unprecedented polyketide skeleton via the connection of a single carbon-carbon bond to form a cyclopentane. These compounds also exhibited moderate cytotoxicity.

Five new alkaloids of aaptamine family, compounds (1-5) and three known derivatives (6-8), have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated by spectroscopic analyses, as well as by comparison with the literature data. Compounds 1-2 are characterized with triazapyrene lactam skeleton, whereas compounds 4-5 share an imidazole-fused aaptamine moiety. These compounds were evaluated in antifungal and anti-HIV-1 assays. Compounds 3, 7, and 8 showed antifungal activity against six fungi, with MIC values in the range of 4 to 64 μg/mL. Compounds 7-8 exhibited anti-HIV-1 activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a concentration of 10 μM.

Background Cystic echinococcosis is a serious zoonotic infection worldwide caused by metacestodes of Echinococcus gruanulosus. Mebendazole and albendazole are the only two drugs used in the treatment of this disease with cure rates only about 30% due to the poor oral absorption. Thus an alternative treatment for this disease is needed. Methods A mebendazole oily suspension (MBZ-OS) was prepared and orally administrated to mice infected with echinococcus cysts for 8 months at 12.5 mg/kg and 25 mg/kg for 14 consecutive days. Mebendazole suspended in 1% tragacanth (MBZ-1% tragacanth) served as treated control. In addition, liver and serum samples were collected from these treated mice (25 mg/kg) for histopathology examination and liver function test. For pharmacokinetic analysis, plasma, parasite (cyst wall and cyst fluid) and tissue samples were collected at 0.25, 0.5, 1, 2, 4, 8, 16 and 24 h after orally administrating MBZ-OS and MBZ-1% tragacanth to E. granulosus-infected mice at 25 mg/kg. These samples were then processed and quantitatively analyzed by HPLC. Results The administration of MBZ-OS resulted in a treatment efficacy with the cyst weight reductions higher than 80%, significantly better than the corresponding MBZ-1% tragacanth groups. The better treatment efficacy of MBZ-OS was related to the higher drug concentration in plasma, parasites and tissues. It was also shown that the injury of the liver was not significantly altered by taking MBZ-OS compared to the untreated control. Conclusion These findings demonstrate that MBZ-OS is a promising new formulation of MBZ for treatment of hydatid diseases without showing significantly liver toxicity. Electronic supplementary material The online version of this article (doi:10.1186/s13071-014-0589-0) contains supplementary material, which is available to authorized users.

The ocean is a capacious area with the most abundant biological resources on the earth. The particularity of the marine ecological environment (high pressure, high salt, and hypoxia) makes the marine species survival competition fiercely, forcing many marine organisms in the process of life to produce a great deal of secondary metabolites with special structures and biological activities. In this article, 118 natural products which were isolated from four kinds of marine organisms, sponges, algae, soft corals and fungus, showing PTP1B inhibitory activity were summarized from 2010 to 2016, which may become the leading compounds towards treating Diabetes mellitus (DM). What's more, we briefly summarized the structure-activity relationship of PTP1B inhibitors.

Nine new aaptamine derivatives (1–9), together with three known related compounds (10–12), have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated on the basis of spectroscopic analyses. Structurally, compound 1 possesses a piperidinyl group fused to a demethyl(oxy)aaptamine moiety, whereas compounds 3–6 share an imidazole-fused 1H-benzo[de][1,6]naphthyridin-2(4H)-one skeleton. The cytotoxic activities of the compounds were evaluated against various human cancer cell lines, and compounds 2, 8, 11, and 12 showed potent cytotoxicities against HL60, K562, MCF-7, KB, HepG2, and HT-29 cells, with IC50 values in the range of 0.03 to 8.5 μM.