Anti-staphylococcal activity of C-methyl flavanones from propolis of Australian stingless bees (Tetragonula carbonaria) and fruit resins of Corymbia torelliana (Myrtaceae)

Propolis of Australian stingless bees (Tetragonula carbonaria, Meliponini) originating from Corymbia torelliana (Myrtaceae) fruit resins was tested for its antimicrobial activities as well as its flavonoid contents. This study aimed at the isolation, structural elucidation and antibacterial testing of flavanones of C. torelliana fruit resins that are incorporated into stingless bee propolis. Flavanones of this study were elucidated by spectroscopic and spectrometric methods including UV, 1D and 2D NMR, EI-MS, ESI-MS and HR-MS. The results indicated known C-methylated flavanones namely, 1 (2S)-cryptostrobin, its regioisomer 2 (2S)- stroboponin, 3 (2S)- cryptostrobin 7-methyl ether, and 6 (2S)- desmethoxymatteucinol, and known flavanones 4 (2S)- pinostrobin and 5 (2S)- pinocembrin as markers for C. torelliana fruit resins and one propolis type. Ethanolic preparations of propolis were shown to be active against Staphylococcus aureus (ATCC 25923) and to a lesser extent against Pseudomonas aeruginosa (ATCC 27853). C. torelliana flavanones inhibited the growth of S. aureus therefore contributing to the antibacterial effects observed for Australian stingless bee propolis extracts.

Atmospheric pressure gas plasma-induced colorectal cancer cell death is mediated by Nox2-ASK1 apoptosis pathways and oxidative stress is mitigated by Srx-Nrf2 anti-oxidant system

Atmospheric pressure gas plasma (AGP) generates reactive oxygen species (ROS) that induce apoptosis in cultured cancer cells. The majority of cancer cells develop a ROS-scavenging anti-oxidant system regulated by Nrf2, which confers resistance to ROS-mediated cancer cell death. Generation of ROS is involved in the AGP-induced cancer cell death of several colorectal cancer cells (Caco2, HCT116 and SW480) by activation of ASK1-mediated apoptosis signaling pathway without affecting control cells (human colonic sub-epithelial myofibroblasts; CO18, human fetal lung fibroblast; MRC5 and fetal human colon; FHC). However, the identity of an oxidase participating in AGP-induced cancer cell death is unknown. Here, we report that AGP up-regulates the expression of Nox2 (NADPH oxidase) to produce ROS. RNA interference designed to target Nox2 effectively inhibits the AGP-induced ROS production and cancer cell death. In some cases both colorectal cancer HT29 and control cells showed resistance to AGP treatment. Compared to AGP-sensitive Caco2 cells, HT29 cells show a higher basal level of the anti-oxidant system transcriptional regulator Nrf2 and its target protein sulfiredoxin (Srx) which are involved in cellular redox homeostasis. Silencing of both Nrf2 and Srx sensitized HT29 cells, leads to ROS overproduction and decreased cell viability. This indicates that in HT29 cells, Nrf2/Srx axis is a protective factor against AGP-induced oxidative stress. The inhibition of Nrf2/Srx signaling should be considered as a central target in drug-resistant colorectal cancer treatments.

SERS-barcoded colloidal gold NP assemblies as imaging agents for use in biodiagnostics

There is a growing need for new biodiagnostics that combine high throughput with enhanced spatial resolution and sensitivity. Gold nanoparticle (NP) assemblies with sub-10 nm particle spacing have the benefits of improving detection sensitivity via Surface enhanced Raman scattering (SERS) and being of potential use in biomedicine due to their colloidal stability. A promising and versatile approach to form solution-stable NP assemblies involves the use of multi-branched molecular linkers which allows tailoring of the assembly size, hot-spot density and interparticle distance. We have shown that linkers with multiple anchoring end-groups can be successfully employed as a linker to assemble gold NPs into dimers, linear NP chains and clustered NP assemblies. These NP assemblies with diameters of 30-120 nm are stable in solution and perform better as SERS substrates compared with single gold NPs, due to an increased hot-spot density. Thus, tailored gold NP assemblies are potential candidates for use as biomedical imaging agents. We observed that the hot-spot density and in-turn the SERS enhancement is a function of the linker polymer concentration and polymer architecture. New deep Raman techniques like Spatially Offset Raman Spectroscopy (SORS) have emerged that allow detection from beneath diffusely scattering opaque materials, including biological media such as animal tissue. We have been able to demonstrate that the gold NP assemblies could be detected from within both proteinaceous and high lipid containing animal tissue by employing a SORS technique with a backscattered geometry.

Polysaccharopeptide enhanced the anti-cancer effect of gamma-tocotrienol through activation of AMPK

Background Prostate cancer (PCa) frequently relapses after hormone ablation therapy. Unfortunately, once progressed to the castration resistant stage, the disease is regarded as incurable as prostate cancer cells are highly resistant to conventional chemotherapy. Method We recently reported that the two natural compounds polysaccharopeptide (PSP) and Gamma-tocotrienols (γ-T3) possessed potent anti-cancer activities through targeting of CSCs. In the present study, using both prostate cancer cell line and xenograft models, we seek to investigate the therapeutic potential of combining γ-T3 and PSP in the treatment of prostate cancer. Result We showed that in the presence of PSP, γ-T3 treatment induce a drastic activation of AMP-activated protein kinase (AMPK). This was accompanied with inactivation of acetyl-CoA carboxylase (ACC), as evidenced by the increased phosphorylation levels at Ser 79. In addition, PSP treatment also sensitized cancer cells toward γ-T3-induced cytotoxicity. Furthermore, we demonstrated for the first time that combination of PSP and γ-T3 treaments significantly reduced the growth of prostate tumor in vivo. Conclusion Our results indicate that PSP and γ-T3 treaments may have synergistic anti-cancer effect in vitro and in vivo, which warrants further investigation as a potential combination therapy for the treatment of cancer.

Randomised clinical trial of a family-based lifestyle intervention for childhood obesity involving parents as the exclusive agents of change

Parent-centred interventions for childhood obesity aim to improve parents' skills and confidence in managing children's dietary and activity patterns, and in promoting a healthy lifestyle in their family. However, few studies assess changes in parenting over the course of treatment. This study describes the evaluation of a lifestyle-specific parenting program (Group Lifestyle Triple P) on multiple child and parent outcomes. One-hundred-and-one families with overweight and obese 4- to 11-year-old children participated in an intervention or waitlist control condition. The 12-week intervention was associated with significant reductions in child BMI z score and weight-related problem behaviour. At the end of the intervention, parents reported increased confidence in managing children's weight-related behaviour, and less frequent use of inconsistent or coercive parenting practices. All short-term intervention effects were maintained at one-year follow-up assessment, with additional improvements in child body size. The results support the efficacy of Group Lifestyle Triple P and suggest that parenting influences treatment outcomes. Further research is needed to evaluate the long-term effectiveness of the intervention and to elucidate the mechanisms of change. © 2010 Elsevier Ltd.

William James, Sciences of Mind, and Anti-imperial Discourse

In the past few decades, the humanities and social sciences have developed new methods of reorienting their conceptual frameworks in a “world without frontiers.” In this book, Bernadette M. Baker offers an innovative approach to rethinking sciences of mind as they formed at the turn of the twentieth century, via the concerns that have emerged at the turn of the twenty-first. The less-visited texts of Harvard philosopher and psychologist William James provide a window into contemporary debates over principles of toleration, anti-imperial discourse, and the nature of ethics. Baker revisits Jamesian approaches to the formation of scientific objects including the child mind, exceptional mental states, and the ghost to explore the possibilities and limits of social scientific thought dedicated to mind development and discipline formation around the construct of the West.

DC-SIGN and alpha 2,6-sialylated IgG Fc interaction is dispensable for the anti-inflammatory activity of IVIg on human dendritic cells

Intravenous immunoglobulin (IVIg) is widely used to treat autoimmune diseases. Several mutually nonexclusive mechanisms are proposed to explain the beneficial effects of IVIg in patients (1, 2). Lately, Ravetch and colleagues (3) demonstrate that anti-inflammatory activity of IVIg is mediated mainly by antibodies that contain terminal _2,6-sialic acid linkages at the Asn297-linked glycan of Fc region.

Oxovanadium(IV)-based near-IR PDT agents: design to biological evaluation

An oxovanadium(IV) complex of dipyridophenazine, as a potent metal-based PDT agent, shows efficient DNA photocleavage activity at near-IR region and high photocytotoxicity in both UV-A and visible light in HeLa cells.

Structural basis for the function of anti-idiotypic antibody in immune memory

We had earlier proposed a hypothesis to explain the mechanism of perpetuation of immunological memory based on the operation of idiotypic network in the complete absence of antigen. Experimental evidences were provided for memory maintenance through anti-idiotypic antibody (Ab2) carrying the internal image of the antigen. In the present work, we describe a structural basis for such memory perpetuation by molecular modeling and structural analysis studies. A three-dimensional model of Ab2 was generated and the structure of the antigenic site on the hemagglutinin protein H of Rinderpest virus was modeled using the structural template of hemagglutinin protein of Measles virus. Our results show that a large portion of heavy chain containing the CDR regions of Ab2 resembles the domain of the hemagglutinin housing the epitope regions. The similarity demonstrates that an internal image of the H antigen is formed in Ab2, which provides a structural basis for functional mimicry demonstrated earlier. This work brings out the importance of the structural similarity between a domain of hemagglutinin protein to that of its corresponding Ab2. It provides evidence that Ab2 is indeed capable of functioning as surrogate antigen and provides support to earlier proposed relay hypothesis which has provided a mechanism for the maintenance of immunological memory.

Structural basis for the function of anti-idiotypic antibody in immune memory

We had earlier proposed a hypothesis to explain the mechanism of perpetuation of immunological memory based on the operation of idiotypic network in the complete absence of antigen. Experimental evidences were provided for memory maintenance through anti-idiotypic antibody (Ab(2)) carrying the internal image of the antigen. In the present work, we describe a structural basis for such memory perpetuation by molecular modeling and structural analysis studies. A three-dimensional model of Ab(2) was generated and the structure of the antigenic site on the hemagglutinin protein H of Rinderpest virus was modeled using the structural template of hemagglutinin protein of Measles virus. Our results show that a large portion of heavy chain containing the CDR regions of Ab(2) resembles the domain of the hemagglutinin housing the epitope regions. The similarity demonstrates that an internal image of the H antigen is formed in Ab(2), which provides a structural basis for functional mimicry demonstrated earlier. This work brings out the importance of the structural similarity between a domain of hemagglutinin protein to that of its corresponding Ab(2). It provides evidence that Ab(2) is indeed capable of functioning as surrogate antigen and provides support to earlier proposed relay hypothesis which has provided a mechanism for the maintenance of immunological memory.

Timing the Emergence of Resistance to Anti-HIV Drugs with Large Genetic Barriers

New antiretroviral drugs that offer large genetic barriers to resistance, such as the recently approved inhibitors of HIV-1 protease, tipranavir and darunavir, present promising weapons to avert the failure of current therapies for HIV infection. Optimal treatment strategies with the new drugs, however, are yet to be established. A key limitation is the poor understanding of the process by which HIV surmounts large genetic barriers to resistance. Extant models of HIV dynamics are predicated on the predominance of deterministic forces underlying the emergence of resistant genomes. In contrast, stochastic forces may dominate, especially when the genetic barrier is large, and delay the emergence of resistant genomes. We develop a mathematical model of HIV dynamics under the influence of an antiretroviral drug to predict the waiting time for the emergence of genomes that carry the requisite mutations to overcome the genetic barrier of the drug. We apply our model to describe the development of resistance to tipranavir in in vitro serial passage experiments. Model predictions of the times of emergence of different mutant genomes with increasing resistance to tipranavir are in quantitative agreement with experiments, indicating that our model captures the dynamics of the development of resistance to antiretroviral drugs accurately. Further, model predictions provide insights into the influence of underlying evolutionary processes such as recombination on the development of resistance, and suggest guidelines for drug design: drugs that offer large genetic barriers to resistance with resistance sites tightly localized on the viral genome and exhibiting positive epistatic interactions maximally inhibit the emergence of resistant genomes.

Glucosinolate composition and anti-cancer potential of daikon and radish sprouts

Daikon and radish sprouts contain high levels of glucoraphenin, a glucosinolate which hydrolyses to form sulphoraphene. Sulphoraphene, like sulphoraphane from broccoli, is a potent inducer of phase 2 detoxification enzymes and consequently has potential anti-cancer action. Unlike broccoli however, daikon and radish do not possess epithiospecifier protein, a protein that inhibits conversion of glucosinolates to isothiocyanates, and consequently they may represent more suitable sources of phyto-chemicals with anti-cancer potential. Concentrations of glucoraphenin were highest in the seed, declining exponentially with sprout development. The rate of decline was observed to vary considerably between varieties of daikon and radish, with some varieties maintaining significantly high levels of glucoraphenin. Varieties maintaining a high level of glucoraphenin included 'Cherry Belle' and 'French Breakfast'.

GABAAα1 and GABAAρ1 subunits are expressed in cultured human RPE cells and GABAA receptor agents modify the intracellular calcium concentration.

Purpose: Gamma-aminobutyric acid A (GABAA) receptors (GABAARs), which are ionotropic receptors involving chloride channels, have been identified in various neural (e.g., mouse retinal ganglion cells) and nonneural cells (e.g., mouse lens epithelial cells) regulating the intracellular calcium concentration ([Ca(2+)]i). GABAAR β-subunit protein has been isolated in the cultured human and rat RPE, and GABAAα1 and GABAAρ1 mRNAs and proteins are present in the chick RPE. The purpose of this study was to investigate the expression of GABAAα1 and GABAAρ1, two important subunits in forming functional GABAARs, in the cultured human RPE, and further to explore whether altering receptor activation modifies [Ca(2+)]i. Methods: Human RPE cells were separately cultured from five donor eye cups. Real-time PCR, western blots, and immunofluorescence were used to test for GABAAα1 and GABAAρ1 mRNAs and proteins. The effects of the GABAAR agonist muscimol, antagonist picrotoxin, or the specific GABAAρ antagonist 1,2,5,6-tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA) on [Ca(2+)]i in cultured human RPE were demonstrated using Fluo3-AM. Results: Both GABAAα1 and GABAAρ1 mRNAs and proteins were identified in cultured human RPE cells; antibody staining was mainly localized to the cell membrane and was also present in the cytoplasm but not in the nucleus. Muscimol (100 μM) caused a transient increase of the [Ca(2+)]i in RPE cells regardless of whether Ca(2+) was added to the buffer. Muscimol-induced increases in the [Ca(2+)]i were inhibited by pretreatment with picrotoxin (300 μM) or TPMPA (500 μM). Conclusions: GABAAα1 and GABAAρ1 are expressed in cultured human RPE cells, and GABAA agents can modify [Ca(2+)]i.

Climatic-requirements models of cat's claw creeper Macfadyena unguis-cati (Bignoniaceae) to prioritise areas for exploration and release of biological control agents

Climate matching software (CLIMEX) was used to prioritise areas to explore for biological control agents in the native range of cat's claw creeper Macfadyena unguis-cati (Bignoniaceae), and to prioritise areas to release the agents in the introduced ranges of the plant. The native distribution of cat's claw creeper was used to predict the potential range of climatically suitable habitats for cat's claw creeper in its introduced ranges. A Composite Match Index (CMI) of cat's claw creeper was determined with the 'Match Climates' function in order to match the ranges in Australia and South Africa where the plant is introduced with its native range in South and Central America. This information was used to determine which areas might yield climatically-adapted agents. Locations in northern Argentina had CMI values which best matched sites with cat's claw creeper infestations in Australia and South Africa. None of the sites from where three currently prioritised biological control agents for cat's claw creeper were collected had CMI values higher than 0.8. The analysis showed that central and eastern Argentina, south Brazil, Uruguay and parts of Bolivia and Paraguay should be prioritised for exploration for new biological control agents for cat's claw creeper to be used in Australia and South Africa.