An oxanthroquinone derivative that disrupts RAS plasma membrane localization inhibits cancer cell growth

Oncogenic RAS proteins are commonly expressed in human cancer. To be functional, RAS proteins must undergo post-translational modification and localize to the plasma membrane (PM). Therefore, compounds that prevent RAS PM targeting have potential as putative RAS inhibitors. Here we examine the mechanism of action of oxanthroquinone G01 (G01), a recently described inhibitor of KRAS PM localization. We show that G01 mislocalizes HRAS and KRAS from the PM with similar potency and disrupts the spatial organization of RAS proteins remaining on the PM. G01 also inhibited recycling of epidermal growth factor receptor and transferrin receptor, but did not impair internalization of cholera toxin, indicating suppression of recycling endosome function. In searching for the mechanism of impaired endosomal recycling we observed that G01 also enhanced cellular sphingomyelin (SM) and ceramide levels and disrupted the localization of several lipid and cholesterol reporters, suggesting that the G01 molecular target may involve SM metabolism. Indeed, G01 exhibited potent synergy with other compounds that target SM metabolism in KRAS localization assays. Furthermore, G01 significantly abrogated RAS-RAF-MAPK signaling in MDCK cells expressing constitutively activated, oncogenic mutant RASG12V. G01 also inhibited the proliferation of RAS-less mouse embryo fibroblasts (MEFs) expressing oncogenic mutant KRASG12V or KRASG12D but not RAS-less MEFs expressing oncogenic mutant BRAFV600E. Consistent with these effects, G01 selectively inhibited the proliferation of KRAS-transformed pancreatic, colon, and endometrial cancer cells. Taken together, these results suggest that G01 should undergo further evaluation as a potential anti-RAS therapeutic

Lipid core peptide/poly(lactic-co-glycolic acid) as a highly potent intranasal vaccine delivery system against Group A streptococcus

Rheumatic heart disease represents a leading cause of mortality caused by Group A Streptococcus (GAS) infections transmitted through the respiratory route. Although GAS infections can be treated with antibiotics these are often inadequate. An efficacious GAS vaccine holds more promise, with intranasal vaccination especially attractive, as it mimics the natural route of infections and should be able to induce mucosal IgA and systemic IgG immunity. Nanoparticles were prepared by either encapsulating or coating lipopeptide-based vaccine candidate (LCP-1) on the surface of poly(lactic-co-glycolic acid) (PLGA). In vitro study showed that encapsulation of LCP-1 vaccine into nanoparticles improved uptake and maturations of antigen-presenting cells. The immunogenicity of lipopeptide incorporated PLGA-based nanoparticles was compared with peptides co-administered with mucosal adjuvant cholera toxin B in mice upon intranasal administration. Higher levels of J14-specific salivary mucosal IgA and systemic antibody IgG titres were observed for groups immunized with encapsulated LCP-1 compared to LCP-1 coated nanoparticles or free LCP-1. Systemic antibodies obtained from LCP-1 encapsulated PLGA NPs inhibited the growth of bacteria in six different GAS strains. Our results show that PLGA-based lipopeptide delivery is a promising approach for rational design of a simple, effective and patient friendly intranasal GAS vaccine resulting in mucosal IgA response

The history, geography, and sociology of slums and the health problems of people who live in slums

Massive slums have become major features of cities in many low-income and middle-income countries. Here, in the first in a Series of two papers, we discuss why slums are unhealthy places with especially high risks of infection and injury. We show that children are especially vulnerable, and that the combination of malnutrition and recurrent diarrhoea leads to stunted growth and longer-term effects on cognitive development. We find that the scientific literature on slum health is underdeveloped in comparison to urban health, and poverty and health. This shortcoming is important because health is affected by factors arising from the shared physical and social environment, which have effects beyond those of poverty alone. In the second paper we will consider what can be done to improve health and make recommendations for the development of slum health as a field of study

Improving the health and welfare of people who live in slums

In the first paper in this Series we assessed theoretical and empirical evidence and concluded that the health of people living in slums is a function not only of poverty but of intimately shared physical and social environments. In this paper we extend the theory of so-called neighbourhood effects. Slums offer high returns on investment because beneficial effects are shared across many people in densely populated neighbourhoods. Neighbourhood effects also help explain how and why the benefits of interventions vary between slum and non-slum spaces and between slums. We build on this spatial concept of slums to argue that, in all low-income and-middle-income countries, census tracts should henceforth be designated slum or non-slum both to inform local policy and as the basis for research surveys that build on censuses. We argue that slum health should be promoted as a topic of enquiry alongside poverty and health

Polyglutamic acid-trimethyl chitosan-based intranasal peptide nano-vaccine induces potent immune responses against group A streptococcus

Peptide-based vaccines have the potential to overcome the limitations of classical vaccines; however, their use is hampered by a lack of carriers and adjuvants suitable for human use. In this study, an efficient self-adjuvanting peptide vaccine delivery system was developed based on the ionic interactions between cationic trimethyl chitosan (TMC) and a peptide antigen coupled with synthetically defined anionic α-poly-(L-glutamic acid) (PGA). The antigen, possessing a conserved B-cell epitope derived from the group A streptococcus (GAS) pathogen and a universal T-helper epitope, was conjugated to PGA using cycloaddition reaction. The produced anionic conjugate formed nanoparticles (NP-1) through interaction with cationic TMC. These NP-1 induced higher systemic and mucosal antibody titers compared to antigen adjuvanted with standard mucosal adjuvant cholera toxin B subunit or antigen mixed with TMC. The produced serum antibodies were also opsonic against clinically isolated GAS strains. Further, a reduction in bacterial burden was observed in nasal secretions, pharyngeal surface and nasopharyngeal-associated lymphoid tissue of mice immunized with NP-1 in GAS challenge studies. Thus, conjugation of defined-length anionic polymer to peptide antigen as a means of formulating ionic interaction-based nanoparticles with cationic polymer is a promising strategy for peptide antigen delivery. Statement of Significance: A self-adjuvanting delivery system is required for peptide vaccines to enhance antigen delivery to immune cells and generate systemic and mucosal immunity. Herein, we developed a novel self-adjuvanting nanoparticulate delivery system for peptide antigens by combining polymer-conjugation and complexation strategies. We conjugated peptide antigen with anionic α-poly-(L-glutamic acid) that in turn, formed nanoparticles with cationic trimethyl chitosan by ionic interactions, without using external crosslinker. On intranasal administration to mice, these nanoparticles induced systemic and mucosal immunity, at low dose. Additionally, nanoparticles provided protection to vaccinated mice against group A streptococcus infection. Thus, this concept should be particularly useful in developing nanoparticles for the delivery of peptide antigens

Predator‐induced changes in the chemical defence of a vertebrate

1. Inducible defences are ubiquitous in the animal kingdom, but little is known about facultative changes in chemical defences in response to predators, especially so in vertebrates. 2. We tested for predator‐induced changes in toxin production of larval common toads (Bufo bufo), which are known to synthesize bufadienolide compounds. 3. The experiment included larvae originating from three permanent and three temporary ponds reared in the presence or absence of chemical cues of three predators: dragonfly larvae, newts or fish. 4. Tadpoles raised with chemical cues of predation risk produced higher numbers of bufadienolide compounds and larger total bufadienolide quantities than predator‐ naive conspecifics. Further, the increase in intensity of chemical defence was greatest in response to fish, weakest to newts and intermediate to dragonfly larvae. Tadpoles originating from temporary and permanent ponds did not differ in their baseline toxin content or in the magnitude of their induced chemical responses. 5. These results provide the first compelling evidence for predator‐induced changes in chemical defence of a vertebrate that may have evolved to enhance survival under predation risk

Structure revision of the Penicillium alkaloids haenamindole and citreoindole

Herein, we describe the isolation of rare alkaloids, haenamindole and citreoindole, from a South China Sea deep-sea fungus, Penicillium citrinum (MF006), and their structure revision based on detailed spectroscopic and C-3 Marfey's analysis. (C) 2016 Elsevier Ltd. All rights reserved

Atropselective syntheses of (-) and (+) rugulotrosin A utilizing point-to-axial chirality transfer

Chiral, dimeric natural products containing complex structures and interesting biological properties have inspired chemists and biologists for decades. A seven-step total synthesis of the axially chiral, dimeric tetrahydroxanthone natural product rugulotrosin A is described. The synthesis employs a one-pot Suzuki coupling/dimerization to generate the requisite 2,2'-biaryl linkage. Highly selective point-to-axial chirality transfer was achieved using palladium catalysis with achiral phosphine ligands. Single X-ray crystal diffraction data were obtained to confirm both the atropisomeric configuration and absolute stereochemistry of rugulotrosin A. Computational studies are described to rationalize the atropselectivity observed in the key dimerization step. Comparison of the crude fungal extract with synthetic rugulotrosin A and its atropisomer verified that nature generates a single atropisomer of the natural product.P50 GM067041 - NIGMS NIH HHS; R01 GM099920 - NIGMS NIH HHS; GM-067041 - NIGMS NIH HHS; GM-099920 - NIGMS NIH HH

A tetrapeptide class of biased analgesics from an Australian fungus targets the μ-opioid receptor

An Australian estuarine isolate ofPenicilliumsp. MST-MF667 yielded3 tetrapeptides named the bilaids with an unusual alternating LDLDchirality. Given their resemblance to known short peptide opioidagonists, we elucidated that they were weak (Kilow micromolar)μ-opioid agonists, which led to the design of bilorphin, a potent andselectiveμ-opioid receptor (MOPr) agonist (Ki1.1 nM). In sharp con-trast to all-natural product opioid peptides that efficaciously recruitβ-arrestin, bilorphin is G protein biased, weakly phosphorylatingthe MOPr and marginally recruitingβ-arrestin, with no receptorinternalization. Importantly, bilorphin exhibits a similar G proteinbias to oliceridine, a small nonpeptide with improved overdosesafety. Molecular dynamics simulations of bilorphin and thestrongly arrestin-biased endomorphin-2 with the MOPr indicatedistinct receptor interactions and receptor conformations thatcould underlie their large differences in bias. Whereas bilorphinis systemically inactive, a glycosylated analog, bilactorphin, isorally active with similar in vivo potency to morphine. Bilorphinis both a unique molecular tool that enhances understanding ofMOPr biased signaling and a promising lead in the development ofnext generation analgesics