| 24958869 |
Extensive sampling of basidiomycete genomes demonstrates inadequacy of the white-rot/brown-rot paradigm for wood decay fungi |
10.1073/pnas.1400592111. |
Proc Natl Acad Sci U S A |
Extensive sampling of basidiomycete genomes demonstrates inadequacy of the white-rot/brown-rot paradigm for wood decay fungi
Abstract
- Basidiomycota (basidiomycetes) make up 32% of the described fungi and include most wood-decaying species, as well as pathogens and mutualistic symbionts. Wood-decaying basidiomycetes have typically been classified as either white rot or brown rot, based on the ability (in white rot only) to degrade lignin along with cellulose and hemicellulose. Prior genomic comparisons suggested that the two decay modes can be distinguished based on the presence or absence of ligninolytic class II peroxidases (PODs), as well as the abundance of enzymes acting directly on crystalline cellulose (reduced in brown rot). To assess the generality of the white-rot/brown-rot classification paradigm, we compared the genomes of 33 basidiomycetes, including four newly sequenced wood decayers, and performed phylogenetically informed principal-components analysis (PCA) of a broad range of gene families encoding plant biomass-degrading enzymes. The newly sequenced Botryobasidium botryosum and Jaapia argillacea genomes lack PODs but possess diverse enzymes acting on crystalline cellulose, and they group close to the model white-rot species Phanerochaete chrysosporium in the PCA. Furthermore, laboratory assays showed that both B. botryosum and J. argillacea can degrade all polymeric components of woody plant cell walls, a characteristic of white rot. We also found expansions in reducing polyketide synthase genes specific to the brown-rot fungi. Our results suggest a continuum rather than a dichotomy between the white-rot and brown-rot modes of wood decay. A more nuanced categorization of rot types is needed, based on an improved understanding of the genomics and biochemistry of wood decay.
|
| 24970816 |
The subcellular distribution and function of MTA1 in cancer differentiation |
10.18632/oncotarget.2095. |
Oncotarget |
The subcellular distribution and function of MTA1 in cancer differentiation
Abstract
- The functions and mechanisms of metastasis-associated protein 1 (MTA1) in cancer progression are still unclear due to a lagged recognition of the subcellular localization. In the present study, using multiple molecular technologies we confirmed for the first time that MTA1 localizes to the nucleus, cytoplasm and nuclear envelope. MTA1 is primarily localized in the nucleus of normal adult tissues but in the cytoplasm of embryonic tissues. While in colon cancer, both distributions have been described. Further investigation revealed that MTA1 localizes on the nuclear envelope in a translocated promoter region (TPR)-dependent manner, while in the cytoplasm, MTA1 shows an obvious localization on microtubules. Both nuclear and cytoplasmic MTA1 are associated with cancer progression. However, these functions may be associated with different mechanisms because only nuclear MTA1 has been associated with cancer differentiation. Overexpression of MTA1 in HCT116 cells inhibited differentiation and promoted proliferation, whereas MTA1 knockdown resulted in cell differentiation and death. Theses results not only suggest that nuclear MTA1 is a good marker for cancer differentiation diagnosis and a potential target for the treatment of cancers but also reveal the necessity to differentially examine the functions of nuclear and cytoplasmic MTA1.
|
| 24972671 |
Non-ribosomal peptides produced by Planktothrix agardhii from Siemianówka Dam Reservoir SDR (northeast Poland) |
10.1007/s00203-014-1008-9. |
Arch Microbiol |
Non-ribosomal peptides produced by Planktothrix agardhii from Siemianówka Dam Reservoir SDR (northeast Poland)
Abstract
- Planktothtrix agardhii (Oscillatoriales) is a filamentous cyanobacterium, which frequently forms blooms in shallow, polymictic and eutrophicated waters. This species is also a rich source of unique linear and cyclic peptides. In the current study, the profile of the peptides in samples from the P. agardhii-dominated Siemianówka Dam Reservoir (SDR) (northeast Poland) was analyzed for four subsequent years (2009-2012). The LC-MS/MS analyses revealed the presence of 33 peptides. Twelve of the most abundant ones, including five microcystins, five anabaenopeptins, one aeruginosin and one planktocyclin, were present in all field samples collected during the study. The detection of different peptides in two P. agardhii isolates indicated that the SDR population was composed of several chemotypes, characterized by different peptide patterns. The total concentration of microcystins (MCs) positively correlated with the biomass of P. agardhii. Between subsequent years, the changes in the ratio of the total MCs concentration to the biomass of P. agardhii were noticed, but they were less than threefold. This is the first study on the production of different classes of non-ribosomal peptides by freshwater cyanobacteria in Poland.
|
| 25010489 |
Tyrosine sulfation of human trypsin steers S2' subsite selectivity towards basic amino acids |
10.1371/journal.pone.0102063. |
PLoS One |
Tyrosine sulfation of human trypsin steers S2' subsite selectivity towards basic amino acids
Abstract
- Human cationic and anionic trypsins are sulfated on Tyr154, a residue which helps to shape the prime side substrate-binding subsites. Here, we used phage display technology to assess the significance of tyrosine sulfation for the specificity of human trypsins. The prime side residues P1'-P4' in the binding loop of bovine pancreatic trypsin inhibitor (BPTI) were fully randomized and tight binding inhibitor phages were selected against non-sulfated and sulfated human cationic trypsin. The selection pattern for the two targets differed mostly at the P2' position, where variants selected against non-sulfated trypsin contained primarily aliphatic residues (Leu, Ile, Met), while variants selected against sulfated trypsin were enriched also for Arg. BPTI variants carrying Arg, Lys, Ile, Leu or Ala at the P2' position of the binding loop were purified and equilibrium dissociation constants were determined against non-sulfated and sulfated cationic and anionic human trypsins. BPTI variants harboring apolar residues at P2' exhibited 3-12-fold lower affinity to sulfated trypsin relative to the non-sulfated enzyme, whereas BPTI variants containing basic residues at P2' had comparable affinity to both trypsin forms. Taken together, the observations demonstrate that the tyrosyl sulfate in human trypsins interacts with the P2' position of the substrate-like inhibitor and this modification increases P2' selectivity towards basic side chains.
|
| 25022972 |
Bicyclic tetrapeptides as potent HDAC inhibitors: effect of aliphatic loop position and hydrophobicity on inhibitory activity |
10.1016/j.bmc.2014.06.031. |
Bioorg Med Chem |
Bicyclic tetrapeptides as potent HDAC inhibitors: effect of aliphatic loop position and hydrophobicity on inhibitory activity
Abstract
- Several histone deacetylase (HDAC) inhibiting bicyclic tetrapeptides have been designed and synthesized through intramolecular ring-closing metathesis (RCM) reaction and peptide cyclization. We designed bicyclic tetrapeptides based on CHAP31, trapoxin B and HC-toxin I. The HDAC inhibitory and p21 promoter assay results showed that the aliphatic loop position as well as the hydrophobicity plays an important role toward the activity of the bicyclic tetrapeptide HDAC inhibitors.
|
| 25045430 |
Condom and oral contraceptive use and risk of cervical intraepithelial neoplasia in Australian women |
10.3802/jgo.2014.25.3.183. |
J Gynecol Oncol |
Condom and oral contraceptive use and risk of cervical intraepithelial neoplasia in Australian women
Abstract
- To assess the association between condom use and oral contraceptive consumption and the risk of cervical intraepithelial neoplasia (CIN).
A cross-sectional study was conducted in Perth clinics. A total of 348 women responded to the structured questionnaire. Information sought included demographic and lifestyle characteristics such as the use of condom for contraception, consumption of oral contraceptive, and duration of oral contraceptive usage. Crude and adjusted odds ratio (OR) and associated 95% confidence interval (CI) were calculated using unconditional logistic regression models and reported as estimates of the relative risk.
The prevalence of CIN was found to be 15.8%. The duration of oral contraceptive consumption among women with abnormal Papanicolaou (Pap) smear result indicating CIN was significantly shorter than those without abnormal Pap smear result (mean±SD, 5.6±5.2 years vs. 8.2±7.6 years; p=0.002). Comparing to ≤3 years usage, prolonged consumption of oral contraceptive for ≥10 years reduced the risk of CIN (p=0.012). However, use of condom for contraception might not be associated with a reduced risk of CIN after accounting for the effects of confounding factors (adjusted OR, 0.52; 95% CI, 0.05 to 5.11; p=0.577).
Use of oral contraceptives, but not condoms, for contraception appeared to be inversely associated with CIN. Prolonged use of oral contraceptive demonstrated its benefits of reducing the risk of CIN.
|
| 25058475 |
Apicidin F: characterization and genetic manipulation of a new secondary metabolite gene cluster in the rice pathogen Fusarium fujikuroi |
10.1371/journal.pone.0103336. |
PLoS One |
Apicidin F: characterization and genetic manipulation of a new secondary metabolite gene cluster in the rice pathogen Fusarium fujikuroi
Abstract
- The fungus F. fujikuroi is well known for its production of gibberellins causing the 'bakanae' disease of rice. Besides these plant hormones, it is able to produce other secondary metabolites (SMs), such as pigments and mycotoxins. Genome sequencing revealed altogether 45 potential SM gene clusters, most of which are cryptic and silent. In this study we characterize a new non-ribosomal peptide synthetase (NRPS) gene cluster that is responsible for the production of the cyclic tetrapeptide apicidin F (APF). This new SM has structural similarities to the known histone deacetylase inhibitor apicidin. To gain insight into the biosynthetic pathway, most of the 11 cluster genes were deleted, and the mutants were analyzed by HPLC-DAD and HPLC-HRMS for their ability to produce APF or new derivatives. Structure elucidation was carried out be HPLC-HRMS and NMR analysis. We identified two new derivatives of APF named apicidin J and K. Furthermore, we studied the regulation of APF biosynthesis and showed that the cluster genes are expressed under conditions of high nitrogen and acidic pH in a manner dependent on the nitrogen regulator AreB, and the pH regulator PacC. In addition, over-expression of the atypical pathway-specific transcription factor (TF)-encoding gene APF2 led to elevated expression of the cluster genes under inducing and even repressing conditions and to significantly increased product yields. Bioinformatic analyses allowed the identification of a putative Apf2 DNA-binding ("Api-box") motif in the promoters of the APF genes. Point mutations in this sequence motif caused a drastic decrease of APF production indicating that this motif is essential for activating the cluster genes. Finally, we provide a model of the APF biosynthetic pathway based on chemical identification of derivatives in the cultures of deletion mutants.
|
| 25060168 |
Investigational drugs targeting somatostatin receptors for treatment of acromegaly and neuroendocrine tumors |
10.1517/13543784.2014.942728. |
Expert Opin Investig Drugs |
Investigational drugs targeting somatostatin receptors for treatment of acromegaly and neuroendocrine tumors
Abstract
- Octreotide long-acting release (LAR) and lanreotide Autogel (ATG) are the two somatostatin analogs currently approved for treatment of acromegaly and neuroendocrine tumors (NETs). The strength of these drugs has been their specificity for somatostatin receptor subtype 2. However, this peculiarity may become a weakness in some patients with tumors harboring somatostatin receptors different from the subtype 2. Another clinically relevant aspect related to the use of octreotide LAR and lanreotide ATG is the burden of injectable drug regimen that may adversely impact the quality of life of patients with acromegaly and NETs.
The authors review the recently published evidence on novel drugs targeting somatostatin receptors developed for treating acromegaly and NETs. Within this article, the authors discuss: i) the pharmacology of somatostatin and traditional somatostatin analogs; ii) the efficacy and safety of multireceptor-targeted somatostatin analogs in acromegaly and NETs; iii) the efficacy of chimeric molecules in acromegaly and NETs; iv) the preliminary data on the use of new injectable, oral and transdermal formulations of octreotide in acromegaly.
The development of new somatostatin analogs and new formulations has opened a new scenario for treatment of acromegaly and NETs. That being said, even though there have been big steps taken in the development of new therapies for acromegaly, there are still a number of unresolved issues, while more trials are necessary for the use of somatostatin anaologs in the treatment of NETs.
|
| 25072108 |
Cyclic Hexapeptides from the Deep South China Sea-Derived Streptomyces scopuliridis SCSIO ZJ46 Active Against Pathogenic Gram-Positive Bacteria |
10.1021/np500399v. |
J Nat Prod |
Cyclic Hexapeptides from the Deep South China Sea-Derived Streptomyces scopuliridis SCSIO ZJ46 Active Against Pathogenic Gram-Positive Bacteria
Abstract
- Three new cyclohexapeptides, desotamides B-D (2-4), and the known desotamide (1) were isolated from marine microbe Streptomyces scopuliridis SCSIO ZJ46. The sequences and absolute configurations of 2-4 were elucidated on the basis of high-resolution spectroscopic data, Marfey's method, and chiral-phase HPLC data. Desotamide C (3) contains a unique N-formyl-kynurenine residue, whereas 4 lacks formylation at the same site. Compounds 1 and 2 displayed notable antibacterial activities against strains of Streptococcus pnuemoniae, Staphylococcus aureus, and methicillin-resistant Staphylococcus epidermidis (MRSE), and structure activity relationship studies revealed the indispensability of the Trp component for antibacterial activity within this new scaffold.
|
| 25089652 |
Trichormamides A and B with Antiproliferative Activity from the Cultured Freshwater Cyanobacterium Trichormus sp. UIC 10339 |
10.1021/np5003548. |
J Nat Prod |
Trichormamides A and B with Antiproliferative Activity from the Cultured Freshwater Cyanobacterium Trichormus sp. UIC 10339
Abstract
- Two new cyclic lipopeptides, trichormamides A (1) and B (2), were isolated from the cultured freshwater cyanobacterium Trichormus sp. UIC 10339. The strain was obtained from a sample collected in Raven Lake in Northern Wisconsin. The planar structures of trichormamides A (1) and B (2) were determined using a combination of spectroscopic analyses including HRESIMS and 1D and 2D NMR experiments. The absolute configurations of the amino acid residues were assigned by the advanced Marfey's method after acid hydrolysis. Trichormamide A (1) is a cyclic undecapeptide containing two D-amino acid residues (D-Tyr and D-Leu) and one β-amino acid residue (β-aminodecanoic acid). Trichormamide B (2) is a cyclic dodecapeptide characterized by the presence of four nonstandard α-amino acid residues (homoserine, N-methylisoleucine, and two 3-hydroxyleucines) and one β-amino acid residue (β-aminodecanoic acid). Trichormamide B (2) was cytotoxic against MDA-MB-435 and HT-29 cancer cell lines with IC50 values of 0.8 and 1.5 μM, respectively.
|
| 25093538 |
Total synthesis and conformational analysis of apratoxin C |
10.1021/jo501130b. |
J Org Chem |
Total synthesis and conformational analysis of apratoxin C
Abstract
- Total synthesis of apratoxin C, a cyanobacterial cyclodepsipeptide with highly potent cytotoxicity against some cancer cell lines, was achieved using the apratoxin A synthetic strategy developed by us. To elucidate the relationship between conformation and activity, the tertiary structure of apratoxin C was analyzed by NMR spectroscopy. We obtained 37 ROEs and five (3)JH,H values, which were translated into distance and dihedral angle constraints, respectively. Molecular modeling was performed with a restrained conformational search by a distance geometry method. The lowest energy structure indicated that the methyl group at C37 and the isopropyl group at C39 play critical roles in maintaining the conformation, whereas the methyl group at C34 does not. Moreover, we confirmed that apratoxin A and C possess similar conformations, providing a likely explanation for their nearly equivalent cytotoxicities.
|
| 25099014 |
Anticancer and toxic properties of cyclotides are dependent on phosphatidylethanolamine phospholipid targeting |
10.1002/cbic.201402144. |
Chembiochem |
Anticancer and toxic properties of cyclotides are dependent on phosphatidylethanolamine phospholipid targeting
Abstract
- Cyclotides, ultrastable disulfide-rich cyclic peptides, can be engineered to bind and inhibit specific cancer targets. In addition, some cyclotides are toxic to cancer cells, though not much is known about their mechanisms of action. Here we delineated the potential mode of action of cyclotides towards cancer cells. A novel set of analogues of kalata B1 (the prototypic cyclotide) and kalata B2 and cycloviolacin O2 were examined for their membrane-binding affinity and selectivity towards cancer cells. By using solution-state NMR, surface plasmon resonance, flow cytometry and bioassays we show that cyclotides are toxic against cancer and non-cancerous cells and their toxicity correlates with their ability to target and disrupt lipid bilayers that contain phosphatidylethanolamine phospholipids. Our results suggest that the potential of cyclotides as anticancer therapeutics might best be realised by combining their amenability to epitope engineering with their ability to bind cancer cell membranes.
|
| 25100358 |
Vipericidins: a novel family of cathelicidin-related peptides from the venom gland of South American pit vipers |
10.1007/s00726-014-1801-4. |
Amino Acids |
Vipericidins: a novel family of cathelicidin-related peptides from the venom gland of South American pit vipers
Abstract
- Cathelicidins are phylogenetically ancient, pleiotropic host defense peptides-also called antimicrobial peptides (AMPs)-expressed in numerous life forms for innate immunity. Since even the jawless hagfish expresses cathelicidins, these genetically encoded host defense peptides are at least 400 million years old. More recently, cathelicidins with varying antipathogenic activities and cytotoxicities were discovered in the venoms of poisonous snakes; for these creatures, cathelicidins may also serve as weapons against prey and predators, as well as for innate immunity. We report herein the expression of orthologous cathelicidin genes in the venoms of four different South American pit vipers (Bothrops atrox, Bothrops lutzi, Crotalus durissus terrificus, and Lachesis muta rhombeata)-distant relatives of Asian cobras and kraits, previously shown to express cathelicidins-and an elapid, Pseudonaja textilis. We identified six novel, genetically encoded peptides: four from pit vipers, collectively named vipericidins, and two from the elapid. These new venom-derived cathelicidins exhibited potent killing activity against a number of bacterial strains (S. pyogenes, A. baumannii, E. faecalis, S. aureus, E. coli, K. pneumoniae, and P. aeruginosa), mostly with relatively less potent hemolysis, indicating their possible usefulness as lead structures for the development of new anti-infective agents. It is worth noting that these South American snake venom peptides are comparable in cytotoxicity (e.g., hemolysis) to human cathelicidin LL-37, and much lower than other membrane-active peptides such as mastoparan 7 and melittin from bee venom. Overall, the excellent bactericidal profile of vipericidins suggests they are a promising template for the development of broad-spectrum peptide antibiotics.
|
| 25115227 |
Identification of marker compounds for Japanese Pharmacopoeia non-conforming jujube seeds from Myanmar |
10.1007/s11418-014-0864-6. |
J Nat Med |
Identification of marker compounds for Japanese Pharmacopoeia non-conforming jujube seeds from Myanmar
Abstract
- Jujube seed is a crude drug defined as the seed of Ziziphus jujuba Miller var. spinosa Hu ex H.F. Chou (Rhamnaceae) in the Japanese Pharmacopoeia (JP). Most of the jujube seed in the Japanese markets is imported from China, with the rest obtained from other Asian countries. Here we confirmed the botanical origins of jujube seeds from both China and Myanmar by a DNA sequencing analysis. We found that the botanical origins of the crude drugs from China and Myanmar were Z. jujuba and Z. mauritiana, respectively. Although the jujube seed from China conforms to the JP, that from Myanmar does not. A method for discriminating jujube seeds from China and Myanmar using a chemical approach is thus desirable, and here we sought to identify a compound specific to Z. jujuba. Jujuboside A (1) was identified as a compound specific to Z. jujuba. To establish a purity test of Jujube Seed in the JP against Z. mauritiana, we fractionated the extract of Z. mauritiana seeds and identified frangufoline (2) and oleanolic acid (4) as the marker compounds specific to Z. mauritiana. Thin-layer chromatography (TLC) and gas chromatography-mass spectrometry analyses revealed that the latter compound was useful for testing by TLC analysis. The established TLC conditions were as follows: chromatographic support, silica gel; developing solvent, n-hexane:EtOAc:HCOOH = 10:5:1; developing length, 7 cm; visualization, diluted sulfuric acid; R f value, 0.43 (oleanolic acid).
|
| 25173836 |
Physiological interaction of Daphnia and Microcystis with regard to cyanobacterial secondary metabolites |
10.1016/j.aquatox.2014.08.003. |
Aquat Toxicol |
Physiological interaction of Daphnia and Microcystis with regard to cyanobacterial secondary metabolites
Abstract
- Cyanobacterial blooms in freshwater ecosystems are a matter of high concern with respect to human health and ecosystem services. Investigations on the role of cyanobacterial secondary metabolites have largely been confined to microcystins, although cyanobacteria produce a huge variety of toxic or inhibitory secondary metabolites. Mass occurrences of toxic cyanobacteria strongly impact freshwater zooplankton communities; especially the unselective filter feeder Daphnia. Daphnids have been shown to successfully suppress bloom formation. However, the opposite situation, i.e. the suppression of Daphnia populations by cyanobacteria can be observed as well. To understand these contradictory findings the elucidation of the underlying physiological mechanisms that help daphnids to cope with cyanotoxins is crucial. We fed Daphnia magna with the cyanobacterium Microcystis aeruginosa PCC7806 for 24h and used high-resolution LCMS analytics to analyze the Microcystis cells, the Daphnia tissue and the surrounding medium in order to investigate the fate of seven investigated cyanobacterial compounds (cyanopeptolins A-C, microcyclamide 7806A and aerucyclamides B-D). For of these bioactive compounds evidence for biotransformation or biodegradation by Daphnia were found. Instead feeding and subsequent release experiments point at the importance of transport mechanisms in Daphnia with regard to the cyanopeptolins A and C and microcyclamide 7806A. In addition we found hints for new inducible defense mechanism in Microcystis against predation by Daphnia. These putative defense mechanisms include the elevated production of toxic compounds other than microcystins, as could be demonstrated here for aerucyclamide B and D, cyanopoeptolin B and microcyclamide 7806A. Moreover, our data demonstrate the elevated active export of at least one cyanobacterial compound (microcyclamide 7806A) into the surrounding medium as a response to grazer presence, which might constitute an entirely new not yet described cyanobacterial defense mechanism.
|
