Gaojushen：a novel anti-cancer drug prepared from SEC superantigen

1Clinicalobservations Gaojushenisanovelanti cancerdrugdeveloped byXieheBio pharmaceuticalCompany,Shenyang,China.Itispreparedandprocessedfromthefiltrateof Staphylococcusaureusculture.Theactivecomponent containedinithasbeenshowntobeaSECsuperanti genthatisam…     

Ethylbutyrate,a valproate-like compound,exhibits inositol-depleting effects — A potential mood-stabilizing drug

AimsTo screen for inositol-depleting valproate-like compounds as potential mood stabilizing drugs.Main methodsWe exploited the yeast Saccharomyces cerevisiae, as a model in which inositol de novo synthesis has been extensively characterized, to test the effects of ethyl butyrate (EB), 2-ethyl-butyric acid, sodium butyrate, and n-propyl hexanoate on inositol biosynthesis. Cell growth was followed by measuring the optical density of the cultures (spectrophotometrically), RNA abundance was determined by Northern blot analysis, intracellular inositol was measured by a fluorometric assay, and 1-d-myo-inositol-3-phosphate synthase activity was examined using a chromatographic method.Key findingsOf the tested compounds, only EB exhibited an inositol-depleting effect. The inositol-depleting effect of EB was achieved without significant adverse effect on cell growth, pointing to lesser toxicity compared to valproate.SignificanceThese results indicate that EB is a potential candidate for mood-stabilizing therapy.     

Antibody–drug conjugates as novel anti-cancer chemotherapeutics

Over the past couple of decades, antibody–drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics.     

Conformation of N-formyl-1,3-dihydroxy-Δ31-pentene,a model compound of sphingomyelin

The conformations of 2S,3R-2-(N-formyl)amino-l,3-dihydroxy-Δ³¹-pentene, a model compound of sphingomyelin, have been studied both by the classical potential function and by the INDO molecular orbital method. The results suggest that the preferred conformation of sphingomyelin in the membrane is such that the olefinic double bond of the γ-hydrocarbon chain and the planar amide group of the β-chain are parallel and stack in an antiparallel manner with dihedral angles β₁′(C3-C2-N21-C21) = ?100 ° and γ₁(C2-C3-C31-C32) = ?100 °.     

ψ-esters of depsidones with a lactole ring

The reaction of stictic, norstictic and salazinic acids with methanol, ethanol and tert-butanol has been investigated. 8′-O-Methylstictic acid is identical with methylstictic acid from Lobaria oregana. Ingolfdottir's vesuvianic acid from Stereocaulon vesuvianum and Handong's cetrariastrumin from Cetrariastrum nepalensis have been shown to be 8′-O-ethylstictic acid and 8′,9′-di-O-ethylsalazinic acid, respectively, by reaction of stictic and salazinic acids with ethanol.     

Are fingernail lead levels a reliable biomarker of lead internal dose?

BackgroundPotentially toxic elements, such as lead, can bioaccumulate and alter human physiology. Human biomonitoring is an essential tool to evaluate chemical exposures in different biological matrices (blood, urine, saliva, nails, and hair). Of these biological matrices, nails are favorable for their ease of sampling, transport and storage. The aim of this study was to investigate possible correlations between blood lead levels (BLL) and washed and non-washed fingernail lead levels (FLL) in 55 adults living in a lead-contaminated area.MethodVenous blood and fingernail (thumbs and forefingers) samples were collected. Nails from the left hand were washed with Triton X-100 (0.5 % m/v) and HNO₃ solution, while nails from the right hand were not submitted to the pre-analytical procedures. Samples were analyzed by graphite furnace atomic absorption spectrometry, and pairwise correlations were used to correlate lead concentrations between BLL and FLL; nails from fingers of the same hand and between washed and unwashed fingernails. Principal component analysis was performed and scatter diagrams were plotted to investigate correlations.ResultsA non-significant positive correlation was found between BLL and washed forefinger nails lead (r = 0.219, p = 0.112) and between BLL and thumbnail lead levels (r = 0.182, p = 0.191). Comparison of fingernails from the same hand (thumb and forefinger), showed that lead concentrations of non-washed nails varied widely, even on analyses of transversal fragments from the same nail. Lead levels in non-washed forefinger nails were not correlated with non-washed thumbnails (r = 0.169, p = 0.219). Conversely, washed thumb and forefinger nails were found to be correlated (r = 0.39, p = 0.003). Washed and non-washed nails were also found to be correlated (p < 0.0001).ConclusionIn conclusion, the results showed that non-washed nails are not a reliable biomarker for lead exposure. Although washing nails before analysis may reduce external contamination, the correlation of lead concentrations between fingers is poor for fingernail lead levels to serve as an internal dose biomarker to lead exposure. In addition, levels in washed nails were not significantly correlated with blood lead levels. Fingernail lead levels seem to serve as an indicator of lead exposure sources in contact with the individual, but not as a reliable biomarker of internal dose.     

Molecular weight of a germination-enhancing compound in smoke†

The active compound(s) in smoke responsible for promoting seed germination of a number of plant species has so far remained unknown. A germination-promoting fraction containing approximately ten compounds has been obtained from cellulose-derived smoke. Furthermore, activity has been associated with one of the compounds in this fraction. The UV absorbance maximum and molecular weight of the active compound has been established and the molecular formula has been tentatively assigned as C₈H₆O₃.     

Selective inhibitors of nuclear export (SINE)– a novel class of anti-cancer agents

Dysregulation of the nucleo-cytoplasmic transport of proteins plays an important role in carcinogenesis. The nuclear export of proteins depends on the activity of transport proteins, exportins. Exportins belong to the karyopherin β superfamily. Exportin-1 (XPO1), also known as chromosomal region maintenance 1 (CRM1), mediates transport of around 220 proteins. In this review, we summarized the development of a new class of antitumor drugs, collectively known as selective inhibitors of nuclear export (SINE). KPT-330 (selinexor) as an oral agent is showing activities in early clinical trials in both solid tumors and hematological malignancies.     

Characteristics and use as spin trapping agent of a β-phosphorylated nitroso compound,DEPNP

2-(Diethylphosphonate)-nitrosopropane (DEPNP), prepared by oxidation of the corresponding aminophosphonate, was found to essentially exist as monomer in both water and organic solvents. The mechanisms of its degradation under 80°C heating or visible light exposure were studied by EPR spectroscopy: its decomposition gave rise to paramagnetic by-products, which have been identified as DEPNP / ·C(CH₃)₂[P(O)(OC₂H₅)₂] and DEPNP / ·P(O)(OC₂H₅)₂ spin adducts. Despite this drawback, DEPNP was successfully used as spin trapping agents to scavenge various carbon — and phosphorus-centred free radicals both in aqueous and organic media, giving rise to intense EPR spectra characteristic of the species trapped.     

What makes a volatile organic compound a reliable indicator of insect herbivory?

Plants that are subject to insect herbivory emit a blend of so‐called herbivore‐induced plant volatiles (HIPVs), of which only a few serve as cues for the carnivorous enemies to locate their host. We lack understanding which HIPVs are reliable indicators of insect herbivory. Here, we take a modelling approach to elucidate which physicochemical and physiological properties contribute to the information value of a HIPV. A leaf‐level HIPV synthesis and emission model is developed and parameterized to poplar. Next, HIPV concentrations within the canopy are inferred as a function of dispersion, transport and chemical degradation of the compounds. We show that the ability of HIPVs to reveal herbivory varies from almost perfect to no better than chance and interacts with canopy conditions. Model predictions matched well with leaf‐emission measurements and field and laboratory assays. The chemical class a compound belongs to predicted the signalling ability of a compound only to a minor extent, whereas compound characteristics such as its reaction rate with atmospheric oxidants, biosynthesis rate upon herbivory and volatility were much more important predictors. This study shows the power of merging fields of plant–insect interactions and atmospheric chemistry research to increase our understanding of the ecological significance of HIPVs.     

Synthesis and characterization of selective dopamine D₂ receptor ligands using aripiprazole as the lead compound

A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D(?-like) dopamine receptors. These compounds also share structural elements with the classical D(?-like) dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D? receptor subtype with high affinity (K(i) values < 0.3 nM), (b) exhibit >50-fold D? versus D? receptor binding selectivity and (c) be partial agonists at both the D? and D? receptor subtype.     

Contribution of lead in soil to children’s lead burden,an update

Abstract

Blood lead levels in children in the USA have dropped dramatically since lead in food, air and drinking water was reduced. In inner cities and older residential areas, increased lead exposure may still be a problem because of dilapidated housing with high lead paint levels. In these areas, at mining sites and around smelters lead levels in soil may be very high. A review of many studies indicates that lead in soil or mine tailings does not make a meaningful contribution to lead absorption by children. The contribution of lead in soil to overall exposure, if any, lies within the variation of the analytical method for blood lead measurements. The results of exposure studies in the pediatric population reviewed in this article do not support exposure predictions for children under 6 years of age based on the US EPA Integrated Exposure Uptake Biokinetic Model (using default parameters or using results obtained with in vitro digestion models). They also do not support predictions based on the percent of solubility of lead in soil (accessibility studies).     

Combination of microbial and chemical synthesis for the sustainable production of β-elemene,a promising plant-extracted anticancer compound

Beta-elemene, a class of sesquiterpene derived from the Chinese medicinal herb Curcuma wenyujin, is widely used in clinical medicine due to its broad-spectrum antitumor activity. However, the unsustainable plant extraction prompted the search for environmentally friendly strategies for β-elemene production. In this study, we designed a Yarrowia lipolytica cell factory that can continuously produce germacrene A, which is further converted into β-elemene with 100% yield through a Cope rearrangement reaction by shifting the temperature to 250°C. First, the productivity of four plant-derived germacrene A synthases was evaluated. After that, the metabolic flux of the precursor to germacrene A was maximized by optimizing the endogenous mevalonate pathway, inhibiting the competing squalene pathway, and expressing germacrene A synthase gene in multiple copies. Finally, the most promising strain achieved the highest β-elemene titer reported to date with 5.08 g/L. This sustainable and green method has the potential for industrial β-elemene production.     

Enzymatic synthesis of γ-l-glutamyl-S-allyl-l-cysteine,a naturally occurring organosulfur compound from garlic,by Bacillus licheniformis γ-glutamyltranspeptidase

In the practical application of Bacillus licheniformis γ-glutamyltranspeptidase (BlGGT), we describe a straightforward enzymatic synthesis of γ-L-glutamyl-S-allyl-L-cysteine (GSAC), a naturally occurring organosulfur compound found in garlic, based on a transpeptidation reaction involving glutamine as the γ-glutamyl donor and S-allyl-L-cysteine as the acceptor. With the help of thin layer chromatography technique and computer-assisted image analysis, we performed the quantitative determination of GSAC. The optimum conditions for a biocatalyzed synthesis of GSAC were 200 mM glutamine, 200 mM S-allyl-L-cysteine, 50 mM Tris–HCl buffer (pH 9.0), and BlGGT at a final concentration of 1.0 U/mL. After a 15-h incubation of the reaction mixture at 60 °C, the GSAC yield for the free and immobilized enzymes was 19.3% and 18.3%, respectively. The enzymatic synthesis of GSAC was repeated under optimal conditions at 1-mmol preparative level. The reaction products together with the commercially available GSAC were further subjected to an ESI-MS/MS analysis. A significant signal with m/z of 291.1 and the protonated fragments at m/z of 73.0, 130.1, 145.0, and 162.1 were observed in the positive ESI-MS/MS spectrum, which is consistent with those of the standard compound. These results confirm the successful synthesis of GSAC from glutamine and S-allyl-L-cysteine by BlGGT.     

Will telomere erosion lead to a loss of T-cell memory?

Evidence is accumulating that elderly individuals are more susceptible to infection with organisms to which they were previously immune. This indicates that there might be a limit to the persistence of immune memory. This fact is particularly disturbing because the average life expectancy of humans has almost doubled in the past 200 years and is still increasing. We discuss mechanisms that might constrain the persistence of memory T cells and consider whether humans will suffer from memory T-cell exhaustion as life expectancy increases.     

Determination and pharmacokinetics of a furosemide–amiloride drug combination

The study presents an accurate and precise HPLC assay for the determination of furosemide and amiloride in human specimens. Both drugs were extracted from human plasma with ethyl acetate; furosemide was extracted at pH 1 and amiloride at pH 12. While chromatographic separation conditions, i.e., column, mobile phase and flow-rate were the same for both investigated drugs, furosemide was detected using a UV absorbance detector, whereas amiloride, because of its very low therapeutic range, was detected with a spectrofluorimetric detector. The linearity of the furosemide and amiloride assays were confirmed over the range of 30–3000 ng/ml and 0.5–30 ng/ml, respectively. These concentrations correspond well with the therapeutic ranges of both drugs. The extraction recoveries, depending on concentration, exceed 80% for furosemide and 74% for amiloride. The reported methods were applied to pharmacokinetic investigations of the two compounds taken in form of a drug combination.     

Does the peroxide compound of cytochrome oxidase contain a ferryl iron?

The reaction of peroxide with cytochrome oxidase generates a peroxide compound having a Soret maximum at 428 nm. X-ray absorption spectroscopy analysis of the local structure of the active site iron shows marked similarity to that of the cytochrome c peroxidase intermediate Compound ES, which contains a short iron to proximal nitrogen distance compared to globins. Reductive titration of the 580 nm band of this compound indicates that the iron is one oxidizing equivalent above the resting oxidized form. These results support the presence of a ferryl iron (Fe(IV) = O) in the peroxide compound similar to that found for the peroxidases.