The flavonoids comprise a large class of low-molecular-weight plant metabolites ubiquitously distributed in food plants. These dietary antioxidants exert significant antitumor, antiallergic, and anti-inflammatory effects. The molecular mechanisms of their biological effects remain to be clearly understood. We investigated the anti-inflammatory potentials of a safe, common dietary flavonoid component, quercetin, for its ability to modulate the production and gene expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-␣) by human peripheral blood mononuclear cells (PBMC). Our results showed that quercetin significantly inhibited TNF-␣ production and gene expression in a dose-dependent manner. Our results provide direct evidence of the anti-inflammatory effects of quercetin by PBMC, which are mediated by the inhibition of the proinflammatory cytokine TNF-␣ via modulation of NF-␤1 and I␤.The natural antioxidant flavonoids constitute significant components of the diet and display a diverse array of biological effects (16,19,21,26). Polyphenolic compounds, including a large class of flavonoids, are enriched in certain vegetables, fruits, seeds, and beverages (e.g., tea and wine) and are regarded as a class of semiessential nutrients for humans. Dietary intake rich in these compounds has been suggested to improve the health of individuals and decrease the risk of cardiovascular disease. The beneficial effects of flavonoids have been attributed to their antioxidant and anti-inflammatory properties (18,19,31). The effects of flavonoids, including quercetin, on a variety of inflammatory processes and immune functions have been extensively reviewed (4,6,11,17,25,27,28,40). Tumor necrosis factor alpha (TNF-␣) is one of the major proinflammatory cytokines involved in the pathogenesis of chronic inflammatory diseases and is modulated by oxidative stress (5, 35). TNF-␣ is a multifunctional cytokine that regulates the growth, proliferation, differentiation, and viability of activated leukocytes. TNF-␣ also triggers the cellular release of other cytokines, chemokines, or inflammatory mediators and displays antiviral and antimicrobial effects (1, 2, 39).Numerous signaling cascades have been elucidated in promotion of proinflammatory conditions by proinflammatory cytokines, such as TNF-␣, which involves the activation of inducible transcriptional factors (1,12,13,14,29,39). NF-␤ is one of the principal inducible transcription factors whose modulation triggers a cascade of signaling events involving an integrated sequence of protein-regulated steps, some of which are potential key targets for intervention in treating inflammatory conditions (3,7,20,29,33,34). Previous studies have shown that quercetin inhibits lipopolysaccharide (LPS)-stimulated NF-␤ activation in RAW 264.7 macrophage (8, 37) and also inhibits LPS-induced I␤ phosphorylation in bone marrowderived macrophage (11). Although quercetin exhibits several biological effects, the molecular mechanisms of its anti-inflammatory effects by peripheral blood ...

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Although highly active anti-retroviral therapy has resulted in remarkable decline in the morbidity and mortality in AIDS patients, inadequately low delivery of anti-retroviral drugs across the blood-brain barrier results in virus persistence. The capability of high-efficacytargeted drug delivery and on-demand release remains a formidable task. Here we report an in vitro study to demonstrate the on-demand release of azidothymidine 5 0 -triphosphate, an anti-human immunodeficiency virus drug, from 30 nm CoFe 2 O 4 @BaTiO 3 magneto-electric nanoparticles by applying a low alternating current magnetic field. Magneto-electric nanoparticles as field-controlled drug carriers offer a unique capability of field-triggered release after crossing the blood-brain barrier. Owing to the intrinsic magnetoelectricity, these nanoparticles can couple external magnetic fields with the electric forces in drug-carrier bonds to enable remotely controlled delivery without exploiting heat. Functional and structural integrity of the drug after the release was confirmed in in vitro experiments with human immunodeficiency virus-infected cells and through atomic force microscopy, spectrophotometry, Fourier transform infrared and mass spectrometry studies.

Flavonoids are plant metabolites that are dietary antioxidants and exert significant anti-tumor, anti-allergic, anti-inflammatory and anti-viral effects. It is generally accepted that Th-1 derived cytokines such as IL-2, IFNgamma and IL-12 promote cellular immunity while Th-2 derived cytokines such as IL-4, IL-5, IL-6 exert negative immunoregulatory effects on cellular immunity while upregulating humoral immunity. The molecular mechanisms underlying the biological activities of flavonoids have not been elucidated. We hypothesize that the flavonoid, quercetin, exert significant anti-viral and anti-tumor effects possibly by modulating the production of Th-1 and Th-2 derived cytokines. Peripheral blood mononuclear cells (PBMC, 1 x 10(6) cells/ml) from normal subjects were cultured with different concentrations of quercetin (0.5-50 microM) for 24-72 h and supernates were quantitated for IFN-gamma and IL-4 by ELISA and antiviral activity of IFNgamma by bioassay. FACS analysis was done to determine the number of IFN-gamma and IL-4 positive cells and RT-PCR was done to quantitate gene expression. Quercetin significantly induces the gene expression as well as the production of Th-1 derived IFNgamma and the downregulates Th-2 derived IL-4 by normal PBMC. Further, quercetin treatment increased the phenotypic expression of IFNgamma cells and decreased IL-4 positive cells by FACS analysis, which corroborate with protein secretion and gene expression studies. These results suggest that the beneficial immuno-stimulatory effects of quercetin may be mediated through the induction of Th-1 derived cytokine, IFNgamma, and inhibition of Th-2 derived cytokine, IL-4.

ABSTRACT

In spite of significant advances in anti-retroviral (ARV) therapy, the elimination of human immunodeficiency virus (HIV) reservoirs from the periphery and the CNS remains a formidable task. The incapability of ARV to go across the blood-brain-barrier (BBB) after systemic administration makes the brain one of the dominant HIV reservoirs. Thus, screening, monitoring, and elimination of HIV reservoirs from the brain remain a clinically daunting and key task. The practice and investigation of nanomedicine possesses potentials for therapeutics against neuroAIDS. This review highlights the advancements in nanoscience and nanotechnology to design and develop specific sized therapeutic cargo for efficient navigation across BBB so as to recognize and eradicate HIV brain reservoirs. Different navigation and drug release strategies, their biocompatibility and efficacy with related challenges and future prospects are also discussed. This review would be an excellent platform to understand nano-enable multidisciplinary research to formulate efficient nanomedicine for the management of neuroAIDS.

The nanotechnology capable of high-specificity targeted delivery of anti-neoplastic drugs would be a significant breakthrough in Cancer in general and Ovarian Cancer in particular. We addressed this challenge through a new physical concept that exploited (i) the difference in the membrane electric properties between the tumor and healthy cells and (ii) the capability of magneto-electric nanoparticles (MENs) to serve as nanosized converters of remote magnetic field energy into the MENs' intrinsic electric field energy. This capability allows to remotely control the membrane electric fields and consequently trigger high-specificity drug uptake through creation of localized nano-electroporation sites. In in-vitro studies on human ovarian carcinoma cell (SKOV-3) and healthy cell (HOMEC) lines, we applied a 30-Oe d.c. field to trigger high-specificity uptake of paclitaxel loaded on 30-nm CoFe2O4@BaTiO3 MENs. The drug penetrated through the membrane and completely eradicated the tumor within 24 hours without affecting the normal cells.

Unconventional characteristics of magnetic toroidal multipoles have triggered researchers to study these unique resonant phenomena by using both 3D and planar resonators under intense radiation. Here, going beyond conventional planar unit cells, we report on the observation of magnetic toroidal modes using artificially engineered multimetallic planar plasmonic resonators. The proposed microstructures consist of iron (Fe) and titanium (Ti) components acting as magnetic resonators and torus, respectively. Our numerical studies and following experimental verifications show that the proposed structures allow for excitation of toroidal dipoles in the terahertz (THz) domain with the experimental Q-factor of ∼18. Taking the advantage of high-Q toroidal line shape and its dependence on the environmental perturbations, we demonstrate that room-temperature toroidal metasurface is a reliable platform for immunosensing applications. As a proof of concept, we utilized our plasmonic metasurface to detect Zika-virus (ZIKV) envelope protein (with diameter of 40 nm) using a specific ZIKV antibody. The sharp toroidal resonant modes of the surface functionalized structures shift as a function of the ZIKV envelope protein for small concentrations (∼pM). The results of sensing experiments reveal rapid, accurate, and quantitative detection of envelope proteins with the limit of detection of ∼24.2 pg/mL and sensitivity of 6.47 GHz/log(pg/mL). We envision that the proposed toroidal metasurface opens new avenues for developing low-cost, and efficient THz plasmonic sensors for infection and targeted bioagent detection.