Community priorities for obesity prevention among low-income adults in Kuala Lumpur: a discrete choice experiment.

Non-communicable diseases and associated risk factors, such as obesity, are prevalent and increasing in Malaysia. To address this burden and the heightened vulnerability of low-income communities to these risk factors, the Better Health Programme Malaysia conducted a partial-profile discrete choice experiment (DCE) to inform the design of a community-based obesity-prevention programme. The DCE survey was conducted with community members (n = 1453) from three publicly supported low-cost, high-rise flat complexes in urban Kuala Lumpur. In the survey, community members were asked to choose between different sets of potential evidence-based interventions for obesity prevention. Their responses to these choice tasks were analysed to quantify preferences for these different health interventions using a random utility maximization model. Based on these results, we determined participants' relative prioritization of the different options. The most preferred interventions were those that reduced the price of fruit and vegetables; altered cooking practices at restaurants and food vendors to reduce salt, sugar and oil; and offered reward incentives for completing online educational activities. Community members did not prioritize several evidence-based interventions, including changes to product placement or product labelling, suggesting that these effective approaches may be less familiar or simply not preferred by respondents. The DCE enabled the clear articulation of these community priorities for evidence-based interventions that focus on the supply and promotion of affordable healthy foods within the local food environment, as well as community demand for healthier food options.

Non-communicable diseases (NCDs) and the factors that increase NCD risk, such as obesity, are widespread and increasing in Malaysia. Low-income communities are particularly vulnerable to these risk factors. The Better Health Programme (BHP) Malaysia conducted a discrete choice experiment (DCE) to elicit community member preferences for evidence-based health promotion interventions to prevent obesity and NCDs. DCE is a research method used to identify participant preferences between different pre-determined options. The DCE survey was conducted with community members (n = 1453) from three publicly supported low-cost, high-rise flat complexes in urban Kuala Lumpur. In the survey, community members were asked to choose between different potential sets of interventions to alter the environment to prevent obesity. Based on their responses, we determined which interventions were most preferred in each community. The most preferred interventions were those that reduced the price of fruit and vegetables; altered cooking practices at restaurants and food vendors to reduce salt, sugar and oil; and offered rewards for completing online educational activities. The survey enabled the clear articulation of these community priorities for evidence-based interventions. These priorities were used to design the BHP Malaysia intervention programme.

An Injectable Microparticle Formulation Provides Long-Term Inhibition of Hypothalamic ERK1/2 Activity and Sympathetic Excitation in Rats with Heart Failure.

Sympathetic excitation contributes to clinical deterioration in systolic heart failure (HF). Significant inhibition of hypothalamic paraventricular nucleus (PVN) ERK1/2 signaling and a subsequent reduction of plasma norepinephrine (NE) levels in HF rats were achieved 2 weeks after a single subcutaneous injection of PD98059-loaded polymeric microparticles, without apparent adverse events, while blank microparticles had no effect. Similar reductions in plasma NE, a general indicator of sympathetic excitation, were previously achieved in HF rats by intracerebroventricular infusion of PD98059 or genetic knockdown of PVN ERK1/2 expression. This study presents a clinically feasible therapeutic approach to the central abnormalities contributing to HF progression.

Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis.

We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human-like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital or N-acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA.

Synthetically lethal nanoparticles for treatment of endometrial cancer.

Uterine serous carcinoma, one of the most aggressive types of endometrial cancer, is characterized by poor outcomes and mutations in the tumour suppressor p53. Our objective was to engender synthetic lethality to paclitaxel (PTX), the frontline treatment for endometrial cancer, in tumours with mutant p53 and enhance the therapeutic efficacy using polymeric nanoparticles (NPs). First, we identified the optimal NP formulation through comprehensive analyses of release profiles and cellular-uptake and cell viability studies. Not only were PTX-loaded NPs superior to PTX in solution, but the combination of PTX-loaded NPs with the antiangiogenic molecular inhibitor BIBF 1120 (BIBF) promoted synthetic lethality specifically in cells with the loss-of-function (LOF) p53 mutation. In a xenograft model of endometrial cancer, this combinatorial therapy resulted in a marked inhibition of tumour progression and extended survival. Together, our data provide compelling evidence for future studies of BIBF- and PTX-loaded NPs as a therapeutic opportunity for LOF p53 cancers.

Cationic CaMKII Inhibiting Nanoparticles Prevent Allergic Asthma.

Asthma is a common lung disease affecting over 300 million people worldwide and is associated with increased reactive oxygen species, eosinophilic airway inflammation, bronchoconstriction, and mucus production. Targeting of novel therapeutic agents to the lungs of patients with asthma may improve efficacy of treatments and minimize side effects. We previously demonstrated that Ca2+/calmodulin-dependent protein kinase (CaMKII) is expressed and activated in the bronchial epithelium of asthmatic patients. CaMKII inhibition in murine models of allergic asthma reduces key disease phenotypes, providing the rationale for targeted CaMKII inhibition as a potential therapeutic approach for asthma. Herein we developed a novel cationic nanoparticle (NP)-based system for delivery of the potent and specific CaMKII inhibitor peptide, CaMKIIN, to airways.1 CaMKIIN-loaded NPs abrogated the severity of allergic asthma in a murine model. These findings provide the basis for development of innovative, site-specific drug delivery therapies, particularly for treatment of pulmonary diseases such as asthma.

Surface-modified particles loaded with CaMKII inhibitor protect cardiac cells against mitochondrial injury.

An excess of calcium (Ca2+) influx into mitochondria during mitochondrial re-energization is one of the causes of myocardial cell death during ischemic/reperfusion injury. This overload of Ca2+ triggers the mitochondrial permeability transition pore (mPTP) opening which leads to programmed cell death. During the ischemic/reperfusion stage, the activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) enzyme is responsible for Ca2+ influx. To reduce CaMKII-related cell death, sub-micron particles composed of poly(lactic-co-glycolic acid) (PLGA), loaded with a CaMKII inhibitor peptide were fabricated. The CaMKII inhibitor peptide-loaded (CIP) particles were coated with a mitochondria targeting moiety, triphenylphosphonium cation (TPP), which allowed the particles to accumulate and release the peptide inside mitochondria to inhibit CaMKII activity. The fluorescently labeled TPP-CIP was taken up by mitochondria and successfully reduced reactive oxygen species (ROS) caused by Isoprenaline (ISO) in a differentiated rat cardiomyocyte-like cell line. When cells were treated with TPP-CIP prior to ISO exposure, they maintained mitochondrial membrane potential. The TPP-CIP protected cells from ISO-induced ROS production and decreased mitochondrial membrane potential. Thus, TPP-CIP has the potential to be used in protection against ischemia/reperfusion injury.

Size-dependent cytotoxicity of copper oxide nanoparticles in lung epithelial cells.

The increasing use of copper oxide (CuO) nanoparticles (NPs) in medicine and industry demands an understanding of their potential toxicities. In this study, we compared the in vitro cytotoxicity of CuO NPs of two distinct sizes (4 and 24 nm) using the A549 human lung cell line. Despite possessing similar surface and core oxide compositions, 24 nm CuO NPs were significantly more cytotoxic than 4 nm CuO NPs. The difference in size may have affected the rate of entry of NPs into the cell, potentially influencing the amount of intracellular dissolution of Cu2+ and causing a differential impact on cytotoxicity.

Silica Nanoparticle-Generated ROS as a Predictor of Cellular Toxicity: Mechanistic Insights and Safety by Design.

Evaluating toxicological responses of engineered nanomaterials such as silica nanoparticles is critical in assessing health risks and exposure limits. Biological assays can be used to evaluate cytotoxicity of individual materials, but specific nano-bio interactions-which govern its physiological response-cannot currently be predicted from materials characterization and physicochemical properties. Understanding the role of free radical generation from nanomaterial surfaces facilitates understanding of a potential toxicity mechanism and provides insight into how toxic effects can be assessed. Size-matched mesoporous and nonporous silica nanoparticles in aminopropyl-functionalized and native forms were investigated to analyze the effects of porosity and surface functionalization on the observed cytotoxicity. In vitro cell viability data in a murine macrophage cell line (RAW 264.7) provides a model for what might be observed in terms of cellular toxicity upon an environmental or industrial exposure to silica nanoparticles. Electron paramagnetic resonance spectroscopy was implemented to study free radical species generated from the surface of these nanomaterials and the signal intensity was correlated with cellular toxicity. In addition, in vitro assay of intracellular reactive oxygen species (ROS) matched well with both the EPR and cell viability data. Overall, spectroscopic and in vitro studies correlate well and implicate production of ROS from a surface-catalyzed reaction as a predictor of cellular toxicity. The data demonstrate that mesoporous materials are intrinsically less toxic than nonporous materials, and that surface functionalization can mitigate toxicity in nonporous materials by reducing free radical production. The broader implications are in terms of safety by design of nanomaterials, which can only be extracted by mechanistic studies such as the ones reported here.

Amine modification of nonporous silica nanoparticles reduces inflammatory response following intratracheal instillation in murine lungs.

Amorphous silica nanoparticles (NPs) possess unique material properties that make them ideal for many different applications. However, the impact of these materials on human and environmental health needs to be established. We investigated nonporous silica NPs both bare and modified with amine functional groups (3-aminopropyltriethoxysilane (APTES)) in order to evaluate the effect of surface chemistry on biocompatibility. In vitro data showed there to be little to no cytotoxicity in a human lung cancer epithelial cell line (A549) for bare silica NPs and amine-functionalized NPs using doses based on both mass concentration (below 200µg/mL) and exposed total surface area (below 14m(2)/L). To assess lung inflammation, C57BL/6 mice were administered bare or amine-functionalized silica NPs via intra-tracheal instillation. Two doses (0.1 and 0.5mg NPs/mouse) were tested using the in vivo model. At the higher dose used, bare silica NPs elicited a significantly higher inflammatory response, as evidence by increased neutrophils and total protein in bronchoalveolar lavage (BAL) fluid compared to amine-functionalized NPs. From this study, we conclude that functionalization of nonporous silica NPs with APTES molecules reduces murine lung inflammation and improves the overall biocompatibility of the nanomaterial.